WO2013182636A1 - Synthesis of a viral protease inhibitor - Google Patents

Synthesis of a viral protease inhibitor Download PDF

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Publication number
WO2013182636A1
WO2013182636A1 PCT/EP2013/061681 EP2013061681W WO2013182636A1 WO 2013182636 A1 WO2013182636 A1 WO 2013182636A1 EP 2013061681 W EP2013061681 W EP 2013061681W WO 2013182636 A1 WO2013182636 A1 WO 2013182636A1
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supported
oxidising agent
process according
tempo
solvent
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PCT/EP2013/061681
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French (fr)
Inventor
Pietro Allegrini
Enrico BRUNOLDI
Emanuele Attolino
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Dipharma Francis S.R.L.
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Publication of WO2013182636A1 publication Critical patent/WO2013182636A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • the present invention relates to a process for the preparation of a viral protease inhibitor and intermediates useful for its preparation.
  • the compounds of formulas A and F are pyrazine-carboxylic acid and cyclopropylamine respectively.
  • the compounds of formulas B, C, D and E are four amino acids, all with the (S) configuration.
  • the compounds of formulas B and C are (S)-cyclohexylglycine and (S)-tert-leucine respectively, namely amino acids available on the market, while the compounds of formulas D and E are two synthetic amino acids with a more complex structure.
  • WO 2010/126881 describes the oxidation of the compound of formula
  • telaprevir (IV) The capacity of the diastereoisomer of telaprevir (IV) as a viral protease inhibitor is about thirty times less than that of telaprevir.
  • the compound of formula (IV) represents the main impurity present in telaprevir.
  • TEMPO tetramethyl piperidine N-oxide
  • APIs active pharmaceutical ingredients
  • Said novel method should in particular be more easily industrially scalable, and consequently include the use of a cheaper, safer, easier to handle oxidation system. Said method should also involve mild reaction conditions and at the same time provide high yields of the compound.
  • the invention relates to a process for the preparation of telaprevir comprising oxidation of a compound of formula (II) in a solvent, in the presence of a supported oxidising agent.
  • the subject of the present invention is a process for the preparation of telaprevir of
  • a supported oxidising agent namely an oxidising agent which is covalently bonded to an inert support and insoluble in the reaction medium, or soluble in the reaction mixture but that can be insolubilized at the end of the reaction, prevents the formation of the diastereoisomer of telaprevir of formula (IV). Moreover, said oxidant does not remain as an impurity in the finished product.
  • a salt of a compound of formula (I) or (II) is typically a pharmaceutically acceptable salt.
  • the starting compound of formula (II) is obtained, for example, according to the teaching of US 7820671.
  • a supported oxidising agent according to the invention is, for example, a supported organic or supported inorganic oxidising agent able to oxidise alcohols, which is covalently bonded to an inert support and preferably insoluble in the reaction medium.
  • a supported inorganic oxidising agent can be prepared starting from an oxidising agent typically selected among a chromate, dichromate, permanganate, bromate and a iodate anion of a tetralkylammonium salt.
  • one or more of the alkyl chains of the tetralkylammonium cation acts as a spacer to an inert support which can be an inorganic polymer support, such as silica, or an organic polymer support, such as a polystyrene-based polymer, typically polystyrene cross- linked with 1% divinylbenzene or PEG (polyethylene glycol).
  • an inert support can be an inorganic polymer support, such as silica, or an organic polymer support, such as a polystyrene-based polymer, typically polystyrene cross- linked with 1% divinylbenzene or PEG (polyethylene glycol).
  • a supported organic oxidising agent is for example, supported TEMPO or a supported reagent based on hypervalent iodine such as supported 2-iodoxybenzoic acid (IBX), supported bis(acetoxy)iodobenzene (BAIB) or supported Dess-Martin Periodinane reagent.
  • IBX 2-iodoxybenzoic acid
  • BAIB supported bis(acetoxy)iodobenzene
  • Dess-Martin Periodinane reagent is for example, supported TEMPO or a supported reagent based on hypervalent iodine such as supported 2-iodoxybenzoic acid (IBX), supported bis(acetoxy)iodobenzene (BAIB) or supported Dess-Martin Periodinane reagent.
  • the supported oxidizing agent is a supported organic oxidising agent, more preferably supported TEMPO.
  • a supported TEMPO is represented in scheme 3 here below,
  • X ! is for example a hydroxy group, an amino group, a carboxylic group or a group which is able to be linked to the spacer, such as for example a 2-iodoacetamido group.
  • the spacer can be an organic alkyl or alkyl-aryl or aryl organic residue, typically a C3-C 12 alkyl chain, bearing a reactive moiety which is able to react with the Xi moiety of the compound of formula (III) or with the carbonyl group of compound of formula (Ilia) so as to obtain X.
  • a reactive moiety of the spacer can be for example a halide, an amino, an aldehyde or a carboxylic group.
  • the support to which the TEMPO oxidising agent is covalently bonded can be an inorganic polymer support, such as silica or an organically modified silica matrix (mixed organic-inorganic) or a completely organic polymer support, such as a polystyrene-based polymer, for example the commercially available Merrifield resin, largely employed for peptide synthesis, typically polystyrene cross-linked with 1% divinylbenzene or PEG (polyethylene glycol).
  • an inorganic polymer support such as silica or an organically modified silica matrix (mixed organic-inorganic)
  • a completely organic polymer support such as a polystyrene-based polymer, for example the commercially available Merrifield resin, largely employed for peptide synthesis, typically polystyrene cross-linked with 1% divinylbenzene or PEG (polyethylene glycol).
  • a functionalized derivative of TEMPO is commercially available or can be obtained starting for example from commercially available TEMPO derivatives, such as 4-hydroxy-TEMPO benzoate, 4-acetamido-TEMPO, 4-cyano-TEMPO.
  • 4-amino-TEMPO can be obtained from 4-acetamido- TEMPO
  • 4-hydroxy-TEMPO can be obtained from 4-oxo-TEMPO of formula (Ilia)
  • 4-carboxy-TEMPO can be obtained from 4-cyano-TEMPO, according to methods known to the man skilled in the art.
  • a functionalized derivative of TEMPO, as defined above, can be covalently linked to the spacer using common reactions in organic chemistry.
  • 4-hydroxy-TEMPO can be easily alkylated with alkyl chains via etherification reactions.
  • 4-amino-TEMPO can be linked to the spacer bearing at least an aldehyde moiety by classical reductive amination.
  • the supported oxidising agent can be soluble or insoluble in the reaction medium and normally inorganic support makes the corresponding supported reagent insoluble.
  • organic polymeric supported oxidising reagent can be used both as soluble and insoluble reagent depending on the experimental condition of the oxidation reaction and in particular depending on the solvent.
  • supported oxidising agent soluble in the reaction mixture, they are easily insolubilized at the end of the reaction by addition of an appropriate solvent in which the polymer employed as support is insoluble, typically methanol.
  • Supported silica TEMPO and supported polymer TEMPO are both commercially available supported reagents.
  • TEMPO supported on an organically modified silica is commercially available under the trade name SiliaCat ® TEMPO and a highly insoluble and easily recyclable polymer supported TEMPO under the trade name FibreCat ® TEMPO.
  • a supported reagent based on hypervalent iodine, according to the present invention can be prepared according to methods known to the skilled man.
  • the oxidising agent is TEMPO supported on an organically modified silica, more preferably SiliaCat ® TEMPO.
  • the supported oxidising agent can be used in catalytic or stoichiometric quantities, preferably in catalytic quantities.
  • the supported oxidising agent When used in catalytic quantities, it is preferably used in the presence of a co-oxidising agent.
  • a co-oxidising agent is an oxidising agent which is unable to oxidise alcohols itself, but is able to reoxidise the reduced form of the supported oxidising agent.
  • co- oxidants are hypochlorite or hypobromite of an alkali metal, preferably sodium, or an oxidising agent containing peroxymonosulphate, such as oxone ® .
  • the oxidation reaction is preferably conducted in the presence of a catalytic quantity of a supported oxidising agent, preferably TEMPO, and a co-oxidising agent, preferably sodium hypochlorite.
  • a supported oxidising agent preferably TEMPO
  • a co-oxidising agent preferably sodium hypochlorite
  • the oxidation reaction can be carried out in a solvent, under homogenous or heterogeneous conditions.
  • a solvent can, for example, be selected from the group comprising a polar aprotic solvent, such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, acetonitrile or dimethyl sulphoxide; a chlorinated solvent, such as dichloromethane, chloroform or chlorobenzene; an apolar aprotic solvent, such as hexane or toluene; an ether, preferably methyl tert- butyl ether, tetrahydrofuran or dioxane; an ester, such as ethyl or methyl acetate; a ketone, such as acetone or methyl isobutyl ketone; a polar protic solvent, such as acetic acid or water and acid, neutral or mildly basic solutions thereof, so that the pH does not exceed 10; and a mixture, preferably a biphasic mixture, of two or more, preferably two or three, of said solvents.
  • the oxidation reaction of a compound of formula (II) is conducted in the presence of TEMPO supported on silica, preferably TEMPO supported on an organically modified silica and sodium hypochlorite, in the presence of a biphasic mixture water/dichloromethane.
  • the oxidation reaction can be conducted at a temperature between about -10°C and the reflux temperature of the solvent, preferably between about -10°C and 40°C, more preferably between 0°C and 25°C.
  • the insoluble supported oxidising agent at the end of the reaction it can be recovered by simply filtering the reaction mixture.
  • the soluble supported reagent In the case of the soluble supported reagent it can be recovered at the end of the reaction, by a procedure comprising a first insolubilization of the supported reagent, by addition of an appropriate solvent, and then filtering the reaction mixture. In both cases the recovered supported reagent can be recycled in a subsequent oxidation reaction without further purification or activation.
  • the product of formula (I) thus obtained, after separation by filtration of the supported oxidising agent, can be recovered from the end-of-reaction mixture by carrying out common aqueous washes and by crystallisation.
  • the telaprevir thus prepared is obtained with a purity equal to or greater than 99.5%, typically equal to or greater than 99.9%.
  • the mixture is cooled to 0°C and water (1.0 mL), NaHCO 3 (46.25 mg; 0.55 mmols; 1.5 eq) and NaBr (20 mg, 0.183 mmols, 0.5 eq) are added.
  • the mixture is vigorously stirred and treated with a solution of NaCIO (12.4% w/w; 0.202 mL; 0.404 mmols; 1.1 eq) added by slow dripping, to maintain the temperature below 5°C.
  • reaction mixture is maintained under stirring at 0°C for a further 30 minutes, and then treated with further aliquots of NaCIO (12.4% w/w; 0.02 mL; 0.04 mmols, 0.1 eq) until complete conversion of the starting product.
  • NaCIO 12.4% w/w; 0.02 mL; 0.04 mmols, 0.1 eq
  • the solids are filtered, washed with dichloromethane and dried under airflow, thus obtaining quantitatively the starting TEMPO supported on silica gel (55 mg).
  • the filtrate is diluted with water and the phases are separated.
  • the organic phase is treated with a 10% w/w solution of Na 2 SO 3 , and the phases are separated.

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  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
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Abstract

Disclosed is a process for the preparation of telaprevir of formula (I) or a salt thereof, comprising the oxidation reaction of a compound of formula (II) or a salt thereof, (II) wherein said oxidation is conducted in a solvent in the presence of a supported oxidising agent.

Description

SYNTHESIS OF A VIRAL PROTEASE INHIBITOR
The present invention relates to a process for the preparation of a viral protease inhibitor and intermediates useful for its preparation.
PRIOR ART
(I S, 3a , 6aS)-2-[(2S)-2-[[(2S)-2-cyclohexyl-2-[(2-pyrazinylcarbonyl) amino]acetyl]amino-3,3-dimethylbutanoyl]-N-[(l S)- l-[(cyclopropylamino) (oxo)acetyl]butyl]-3,3a,4,5,6,6a-hexahydro- lH-cyclopenta[c]pyrrole-3- carboxy amide of formula I), also known as telaprevir, is a potent viral protease inh
Figure imgf000002_0001
The reparation of telaprevir, reported in US 7820671 , involves the
Figure imgf000002_0002
A B c
Scheme 1
to obtain a compound of formula (II)
Figure imgf000002_0003
and subsequent oxidation of the alcoholic hydroxyl in the structural unit of formula E.
The compounds of formulas A and F are pyrazine-carboxylic acid and cyclopropylamine respectively.
The compounds of formulas B, C, D and E are four amino acids, all with the (S) configuration.
The compounds of formulas B and C are (S)-cyclohexylglycine and (S)-tert-leucine respectively, namely amino acids available on the market, while the compounds of formulas D and E are two synthetic amino acids with a more complex structure.
The preparation of the compounds of formulas D and E is reported in US 7,820,671.
The same patent describes the oxidation of the compound of formula (II) to telaprevir by means of Dess-Martin Periodinane (DMP) reagent.
WO 2010/126881 describes the oxidation of the compound of formula
(II) with the TEMPO system (2,2,6,6-tetramethylpiperidine N-oxyl)/NaClO.
Said two oxidising systems, DMP and TEMPO/NaCIO, guarantee that the ketoamide functionality thus generated does not cause partial epimerisation of the stereocentre in position a, through the enol intermediate of formula (III), with the formation of the diastereoisomer of telaprevir of formula (IV), Scheme 2, as known from J. Med. Chem. , 2009, 52, 7993.
Figure imgf000004_0001
Scheme 2
The capacity of the diastereoisomer of telaprevir (IV) as a viral protease inhibitor is about thirty times less than that of telaprevir.
Moreover, in analytical terms, the compound of formula (IV) represents the main impurity present in telaprevir.
The problem associated with the use of TEMPO (tetramethyl piperidine N-oxide) is that said compound can remain in the finished product, albeit in small quantities. As TEMPO is a genotoxic compound, its presence in the medicament is highly undesirable. Moreover, although Dess-Martin Periodinane reagent is a safer reagent than TEMPO, it is still a compound with a high molecular weight and is extremely expensive, which prejudices its use on an industrial scale.
Moreover, the regulatory authorities require manufacturers of active pharmaceutical ingredients (APIs) to isolate, identify and characterise the impurities present in their products. API manufacturers are therefore required to check the level of impurities in the API at the end of the synthesis process and ensure that it is as low as possible, and preferably absent if they are genotoxic.
There is consequently a need for a more advantageous alternative method of preparing telaprevir from the intermediate of formula (II). Said novel method should in particular be more easily industrially scalable, and consequently include the use of a cheaper, safer, easier to handle oxidation system. Said method should also involve mild reaction conditions and at the same time provide high yields of the compound.
SUMMARY OF THE INVENTION
The invention relates to a process for the preparation of telaprevir comprising oxidation of a compound of formula (II) in a solvent, in the presence of a supported oxidising agent.
DETAILED DESCRIPTION OF THE INVENTION
The subject of the present invention is a process for the preparation of telaprevir of
Figure imgf000005_0001
comprising oxidation of a compound of formula (II) or a salt thereof, wherein said oxidation is conducted in a solvent in the presence of a supported oxidising agent.
It has been found that the use of a supported oxidising agent, namely an oxidising agent which is covalently bonded to an inert support and insoluble in the reaction medium, or soluble in the reaction mixture but that can be insolubilized at the end of the reaction, prevents the formation of the diastereoisomer of telaprevir of formula (IV). Moreover, said oxidant does not remain as an impurity in the finished product.
A salt of a compound of formula (I) or (II) is typically a pharmaceutically acceptable salt.
The starting compound of formula (II) is obtained, for example, according to the teaching of US 7820671.
A supported oxidising agent according to the invention is, for example, a supported organic or supported inorganic oxidising agent able to oxidise alcohols, which is covalently bonded to an inert support and preferably insoluble in the reaction medium.
A supported inorganic oxidising agent, according to the present invention, can be prepared starting from an oxidising agent typically selected among a chromate, dichromate, permanganate, bromate and a iodate anion of a tetralkylammonium salt.
In a supported inorganic oxidising agent one or more of the alkyl chains of the tetralkylammonium cation acts as a spacer to an inert support which can be an inorganic polymer support, such as silica, or an organic polymer support, such as a polystyrene-based polymer, typically polystyrene cross- linked with 1% divinylbenzene or PEG (polyethylene glycol).
A supported organic oxidising agent, according to the present invention, is for example, supported TEMPO or a supported reagent based on hypervalent iodine such as supported 2-iodoxybenzoic acid (IBX), supported bis(acetoxy)iodobenzene (BAIB) or supported Dess-Martin Periodinane reagent.
According to a preferred embodiment of the present invention the supported oxidizing agent is a supported organic oxidising agent, more preferably supported TEMPO.
A supported TEMPO, according to the present invention, is represented in scheme 3 here below,
Figure imgf000007_0001
Scheme 3
wherein X is O or a group based on N or C, for example NH or C=O or
CH
It can be prepared by covalently linking the Xi moiety of a functionalized derivative of TEMPO of formula (III) or (Ilia) to a support through a spacer
Figure imgf000007_0002
wherein X! is for example a hydroxy group, an amino group, a carboxylic group or a group which is able to be linked to the spacer, such as for example a 2-iodoacetamido group.
The spacer can be an organic alkyl or alkyl-aryl or aryl organic residue, typically a C3-C12 alkyl chain, bearing a reactive moiety which is able to react with the Xi moiety of the compound of formula (III) or with the carbonyl group of compound of formula (Ilia) so as to obtain X. Such reactive moiety of the spacer can be for example a halide, an amino, an aldehyde or a carboxylic group.
The support to which the TEMPO oxidising agent is covalently bonded can be an inorganic polymer support, such as silica or an organically modified silica matrix (mixed organic-inorganic) or a completely organic polymer support, such as a polystyrene-based polymer, for example the commercially available Merrifield resin, largely employed for peptide synthesis, typically polystyrene cross-linked with 1% divinylbenzene or PEG (polyethylene glycol).
A functionalized derivative of TEMPO is commercially available or can be obtained starting for example from commercially available TEMPO derivatives, such as 4-hydroxy-TEMPO benzoate, 4-acetamido-TEMPO, 4-cyano-TEMPO.
For example, 4-amino-TEMPO can be obtained from 4-acetamido- TEMPO, 4-hydroxy-TEMPO can be obtained from 4-oxo-TEMPO of formula (Ilia), 4-carboxy-TEMPO can be obtained from 4-cyano-TEMPO, according to methods known to the man skilled in the art.
A functionalized derivative of TEMPO, as defined above, can be covalently linked to the spacer using common reactions in organic chemistry.
For example 4-hydroxy-TEMPO can be easily alkylated with alkyl chains via etherification reactions.
4-amino-TEMPO can be linked to the spacer bearing at least an aldehyde moiety by classical reductive amination.
The supported oxidising agent can be soluble or insoluble in the reaction medium and normally inorganic support makes the corresponding supported reagent insoluble. Interestingly organic polymeric supported oxidising reagent can be used both as soluble and insoluble reagent depending on the experimental condition of the oxidation reaction and in particular depending on the solvent.
In the case of supported oxidising agent, soluble in the reaction mixture, they are easily insolubilized at the end of the reaction by addition of an appropriate solvent in which the polymer employed as support is insoluble, typically methanol.
Supported silica TEMPO and supported polymer TEMPO are both commercially available supported reagents.
In particular, TEMPO supported on an organically modified silica is commercially available under the trade name SiliaCat®TEMPO and a highly insoluble and easily recyclable polymer supported TEMPO under the trade name FibreCat® TEMPO.
A supported reagent based on hypervalent iodine, according to the present invention, can be prepared according to methods known to the skilled man.
In a preferred embodiment of the present invention the oxidising agent is TEMPO supported on an organically modified silica, more preferably SiliaCat®TEMPO.
The supported oxidising agent can be used in catalytic or stoichiometric quantities, preferably in catalytic quantities.
When the supported oxidising agent is used in catalytic quantities, it is preferably used in the presence of a co-oxidising agent. A co-oxidising agent is an oxidising agent which is unable to oxidise alcohols itself, but is able to reoxidise the reduced form of the supported oxidising agent. Examples of co- oxidants are hypochlorite or hypobromite of an alkali metal, preferably sodium, or an oxidising agent containing peroxymonosulphate, such as oxone ® .
The oxidation reaction is preferably conducted in the presence of a catalytic quantity of a supported oxidising agent, preferably TEMPO, and a co-oxidising agent, preferably sodium hypochlorite.
The oxidation reaction can be carried out in a solvent, under homogenous or heterogeneous conditions.
A solvent can, for example, be selected from the group comprising a polar aprotic solvent, such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, acetonitrile or dimethyl sulphoxide; a chlorinated solvent, such as dichloromethane, chloroform or chlorobenzene; an apolar aprotic solvent, such as hexane or toluene; an ether, preferably methyl tert- butyl ether, tetrahydrofuran or dioxane; an ester, such as ethyl or methyl acetate; a ketone, such as acetone or methyl isobutyl ketone; a polar protic solvent, such as acetic acid or water and acid, neutral or mildly basic solutions thereof, so that the pH does not exceed 10; and a mixture, preferably a biphasic mixture, of two or more, preferably two or three, of said solvents.
More preferably the oxidation reaction of a compound of formula (II) is conducted in the presence of TEMPO supported on silica, preferably TEMPO supported on an organically modified silica and sodium hypochlorite, in the presence of a biphasic mixture water/dichloromethane.
The oxidation reaction can be conducted at a temperature between about -10°C and the reflux temperature of the solvent, preferably between about -10°C and 40°C, more preferably between 0°C and 25°C.
In the case of the insoluble supported oxidising agent, at the end of the reaction it can be recovered by simply filtering the reaction mixture.
In the case of the soluble supported reagent it can be recovered at the end of the reaction, by a procedure comprising a first insolubilization of the supported reagent, by addition of an appropriate solvent, and then filtering the reaction mixture. In both cases the recovered supported reagent can be recycled in a subsequent oxidation reaction without further purification or activation. The product of formula (I) thus obtained, after separation by filtration of the supported oxidising agent, can be recovered from the end-of-reaction mixture by carrying out common aqueous washes and by crystallisation.
The telaprevir thus prepared is obtained with a purity equal to or greater than 99.5%, typically equal to or greater than 99.9%.
The following example illustrates the invention:
Example: Preparation of telaprevir (I)
TEMPO supported on silica gel (SiliaCat®, 55 mg) is added to a solution of ((I S, 3a , 6aS)-2-[(2S)-2-[[(2S)-2-cyclohexyl-2-[(2- pyrazinylcarbonyl)amino] acetyl]amino]-3,3-dimethylbutanoyl]-N-[(l S)-l - [(cyclopropylamino)(hydroxy) acetyl]butyl]-3,3a,4,5,6,6a-hexahydro-lH- cyclopenta [c]pyrrole-3-carboxamide II (250 mg; 0.367 mmols; 1.0 eq) in dichloromethane (1.25 mL). The mixture is cooled to 0°C and water (1.0 mL), NaHCO3 (46.25 mg; 0.55 mmols; 1.5 eq) and NaBr (20 mg, 0.183 mmols, 0.5 eq) are added. The mixture is vigorously stirred and treated with a solution of NaCIO (12.4% w/w; 0.202 mL; 0.404 mmols; 1.1 eq) added by slow dripping, to maintain the temperature below 5°C. At the end of the addition, the reaction mixture is maintained under stirring at 0°C for a further 30 minutes, and then treated with further aliquots of NaCIO (12.4% w/w; 0.02 mL; 0.04 mmols, 0.1 eq) until complete conversion of the starting product. When the reaction is complete the solids are filtered, washed with dichloromethane and dried under airflow, thus obtaining quantitatively the starting TEMPO supported on silica gel (55 mg). The filtrate is diluted with water and the phases are separated. The organic phase is treated with a 10% w/w solution of Na2SO3, and the phases are separated. The organic phase is dried on Na2SO4, filtered and concentrated at low pressure to give the compound of formula (I) which, after crystallisation from dichloromethane/ethyl acetate, provides telaprevir of formula (I) with a yield of 90%, a chemical purity exceeding 99%, and a telaprevir diastereoisomer content of formula (IV) lower than 0.10% as evaluated by HPLC.

Claims

1. Process for reparing telaprevir of formula (I) or a salt thereof,
Figure imgf000013_0001
comprising the oxidation of a compound of formula (II), or a salt thereof,
Figure imgf000013_0002
wherein said oxidation is carried out in a solvent in the presence of a supported oxidising agent.
2. Process according to claim 1 , wherein the supported oxidising agent is an organic or inorganic supported oxidising agent, able to oxidise alcohols, covalently bound to an inert support.
3. Process according to claim 2 wherein the supported oxidising agent is insoluble in the reaction medium.
4. Process according to claim 2, wherein the supported organic oxidising agent is selected from the group comprising supported TEMPO and a supported hypervalent iodine-based reagent.
5. Process according to claim 4, wherein the supported organic oxidising agent is supported TEMPO.
6. Process according to claims 2 or 5, wherein the supported oxidising agent is covalently bound to an inorganic polymer support or to an organically modified silica matrix (mixed organic-inorganic) or to a completely organic polymer support.
7. Process according to claim 6 wherein the inorganic polymer support is silica.
8. Process according to claims 6 wherein the supported oxidising agent is TEMPO supported on an organically modified silica matrix, preferably SiliaCat®TEMPO.
9. Process according to claim 1 wherein the supported oxidising agent is used in catalytic or stoichiometric amounts.
10. Process according to claim 9 wherein the supported oxidising agent is used in catalytic amounts.
1 1. Process according to claim 10 wherein the supported oxidising agent is used in catalytic amounts and, preferably, in the presence of a co-oxidising agent.
12. Process according to claim 1 1 wherein the co-oxidising agent is selected from the hypochlorite or hypobromite of an alkali metal, in particular sodium hypochlorite or hypobromite.
13. Process according to claim 1 , 1 1 or 12 wherein the oxidation is carried out in the presence of a catalytic amount of a supported oxidising agent, preferably supported TEMPO, and of a co-oxidising agent, preferably sodium hypochlorite, in a solvent under homogeneous or heterogeneous conditions.
14. Process according to claim 1 wherein the solvent is selected from the group comprising a polar aprotic solvent; a chlorinated solvent; an apolar aprotic solvent; an ether; an ester; a ketone; a polar protic solvent; and a mixture of two or more of said solvents.
15. Process according to claim 14 wherein the mixture of solvents is a biphasic mixture of solvents, preferably a water/dichloromethane mixture.
PCT/EP2013/061681 2012-06-07 2013-06-06 Synthesis of a viral protease inhibitor WO2013182636A1 (en)

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Citations (2)

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WO2007022459A2 (en) * 2005-08-19 2007-02-22 Vertex Pharmaceuticals Incorporated Processes and intermediates
WO2010126881A1 (en) * 2009-04-27 2010-11-04 Vertex Pharmaceuticals Incorporated Processes and intermediates

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WO2007022459A2 (en) * 2005-08-19 2007-02-22 Vertex Pharmaceuticals Incorporated Processes and intermediates
WO2010126881A1 (en) * 2009-04-27 2010-11-04 Vertex Pharmaceuticals Incorporated Processes and intermediates

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