Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C247/00—Compounds containing azido groups
  • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
  • C07C247/12—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
  • C07C291/10—Isocyanides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
  • C07C309/63—Esters of sulfonic acids
  • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
  • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
  • C07C309/66—Methanesulfonates
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
• • 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
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

• the present invention relates to a multicomponent process for the preparation of N-acyl bicyclic prolinamides which can be easily converted into one of the HCV protease inhibitors, particularly Telaprevir or Boceprevir, or the salts and the intermediates useful in the synthesis thereof.
• Hepatitis C virus is a (+)-sense single-stranded RNA virus that has been implicated as the major causative agent in non-A, non-B hepatitis (NANBH), particularly in blood-associated NANBH.
• NANBH is to be distinguished from other types of viral-induced liver disease, such as hepatitis A virus (HAV), hepatitis B virus (HBV), delta hepatitis virus (HDV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV), as well as from other forms of liver diseases such as alcoholism and primary biliary cirrhosis.
• HAV hepatitis A virus
• HBV hepatitis B virus
• HDV delta hepatitis virus
• CMV cytomegalovirus
• EBV Epstein-Barr virus
• HCV protease necessary for polypeptide processing and viral replication has been identified, cloned and expressed.
• This approximately 3000 amino acid polyprotein contains, from the amino terminus to the carboxy terminus, a nucleocapsid protein C, envelope proteins (El and E2) and several non-structural proteins (NS 1, 2, 3, 4a, 5a and 5b).
• NS3 is an approximately 68 KDa protein, encoded by approximately 1893 nucleotides of the HCV genome and has two distinct domains: (a) a serine protease domain consisting of approximately 200 of the N-terminal amino acids; and (b) an RNA- dependent ATPase domain at the C-terminus of the protein.
• the HCV NS3 serine protease is responsible for proteolysis of the polypeptide (polyprotein) at the NS3/NS4a, NS4a/NS4b, NS4b/NS5a and NS5a/NS5b junctions and is thus responsible for generating four viral proteins during viral replications. This has made the HCV NS3 serine protease an attractive target for antiviral chemotherapy.
• Boceprevir and Telaprevir are two of the most interesting serine protease inhibitors, disclosed respectively in international patent applications WO 2003/062265 Al and WO 2002/018369 Al .
• Fragment A Fragment B
• Fragment C Fragment C
• Fragment B synthesis (according to WO 2002/018369 Al and WO 2007/022459 Al) entails preparing octahydrocyclopenta[c]pyrrole-l-carboxylic acid from the corresponding symmetrical (achiral) bicyclic amine by forming the N-Boc derivative, and reacting it with sec-butyllithium (a pyrophoric agent) in the presence of an excess of bulky chelating diamine (preparation described in WO 2007/022459 Al), followed by addition of C0 2 . All these operations are carried out below -70 °C to produce the racemic N-Boc amino acids as depicted below:
• Fragment C preparation in accordance with WO 2003/062265 A2, entails adding acetone cyanohydrin to an aldehyde derived from 2-((tert-butoxycarbonyl)amino)-3- cyclobutylpropanoic acid; the a-hydroxynitrile is subsequently hydrolyzed to yield tert- butyl (4-amino-l-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)carbamate and the Boc group is removed.
• Fragment B' (according to WO 2003/062265 A2) is prepared reacting (3R,7aS)-3- phenyl-l,7a-dihydropyrrolo[l,2-c]oxazol-5(3H)-one (prepared according to J. Org. Chem. (1999), 64(2), 547) with n-butyllithium and isopropyl triphenylposphonium iodide to yield the corresponding dimethyl cyclopropane, which is subsequently reduced and hydrogenated to obtain ((li?,25',55)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2- yl)methanol. Said amino alcohol is protected with benzyl chloroformate and oxidized to give the desired amino acid.
• the synthetic routes proposed are multistep, complex, expensive, inefficient and low yielding. Furthermore they include the use of cryogenic temperatures and employ dangerous reagents, such as cyanides or sec-butyllithium. Fragment B' can also be produced according to the method described in international patent application WO 2004/113295 Al .
• the synthetic route entails the asymmetric opening of caronic anhydride mediated by quinidine, a cinchona alkaloid, followed by a diasteromeric salt resolution via the formation of a salt with a single enatiomer of a chiral amine (probably due to low enantiomeric purity of the product).
• the proposed synthetic path is very long and complex, including several steps of protection and deprotection and in some cases the use of highly toxic reagents, such as trimethylsilyl cyanide or boron trifluoride etherate.
• a further method of producing fragment B' is disclosed in patent application WO 2007/075790 Al .
• This method involves the production of the methyl ester of the bicyclic proline analogue (li?,25',55)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid from the corresponding symmetrical (achiral) bicyclic amine (li?,5S)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane (prepared from caronic anhydride in 2 steps), beginning with its oxidation to the corresponding racemic imine, which is subsequently reacted with cyanide to provide the racemic aminonitrile; the aminonitrile is reacted with acid and methanol to give the racemic amino acid methyl ester of the following structural formula:
• the required isocyanide is prepared by reacting (5)-N-(l-oxopentan-2-yl)formamide with cyclopropylisocyanide in a Passerini reaction, followed by dehydration of the formamide.
• An object of the invention is therefore to provide an alternative synthetic route for the industrial preparation of N-acyl bicyclic prolinamides which can be easily converted into one of the HCV protease inhibitors, particularly Telaprevir or Boceprevir, their salts, or the intermediates useful for the synthesis thereof, characterized by a lower number of steps, a high overall yield and an excellent diasteroisomeric and optical purity.
• a further object of the invention is to provide novel compounds that can be used in the processes. Summary of the invention
• R 5 is Ci-C 6 linear or branched alkyl optionally substituted with a Ci-C 6 cyclic alkyl (preferably n-propyl or cyclobutylmethyl);
• R 10 is cyclopropyl, or one of the removable groups of the convertible isocyanide as detailed hereinafter;
• - R is NH 2 ; NH-Pg; or NH-R ,
• - R 16 is OH; OPg;
• - 17 is hydrogen or cyclopropyl
• R 19 is OH; a Ci-C 6 linear or branched alkoxy optionally substituted with a C 6 -Cio aryl; NH-R 10 ; or NH-R 17 ;
• R 20 is hydrogen or a Ci-C 6 linear or branched alkyl, optionally substituted with a
• - Pg is a protecting group; in the group -OPg in R 16 , it is an alcohol protecting group, while in the group -NH-Pg in R 13 or in R 15 it is a nitrogen protecting group.
• Useful alcohol protecting groups are known in the field and comprise, e.g., esters (e.g. acetate, phenylacetate or benzoates optionally substituted, such as /?-nitrobenzoate), silyl ethers (for example trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert- butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS)), or ethers (such as benzyl, /?-methoxybenzyl, allyl, tetrahydropyranyl (THP), 1-ethoxyethyl, methoxymethyl, /?-methoxybenzyloxymethyl, or 2-trimethylsilylethyl).
• esters e.g. acetate, phenylacetate or benzoates optionally substituted, such as /?-nitrobenzoate
• silyl ethers for example trimethylsilyl
• Nitrogen protecting groups useful for the invention are, e.g., tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethyloxycarbonyl (Fmoc).
• the prolinamide of formula (IX) can be further transformed into one of the serine protease inhibitors, their salts, or one of the intermediates useful in the synthesis thereof.
• the compounds prepared by the processes of the present invention may have one or more stereogenic centers and may exist and may be used or isolated in optically active or racemic forms as well as in diastereomerically pure forms or as diastereomeric mixtures. It is to be understood that the processes of the present invention can give rise to any racemic- or optically-active forms, or mixture thereof. It is to be further understood that the products of the processes described herein, can be isolated as racemic, or optically active forms, or mixtures thereof. Purification and characterization procedures for such products are known to those of ordinary skill in the art, and include recrystallization techniques, chiral chromatographic separation procedures, as well as other methods.
• aryl refers to any substituent derived from a monocyclic or a polycyclic aromatic hydrocarbon by removal of an hydrogen atom from a ring carbon atom (i.e. phenyl, tolyl, 1-naphtyl or 2-napthyl).
• racemic refers to a sample of a chiral compound which contains both the (+) and (-) isomers in equal amount.
• enantiomerically enriched means that one of the enantiomers of a compound is present in excess compared to the other enantiomer.
• single (S)- or ( ?)-enantiomer means that the enantiomeric purity is usually at least about 96%, preferably at least 99%, more preferably at least 99.5%.
• the compounds obtained by the chemical transformations of the present invention can be used for the following steps without further purification or can be separated and purified by employing conventional methods well known to those skilled in the art, such as recrystallization, column chromatography, or by transforming them into a salt or in a co-crystal with an appropriate co-former, or by washing with an organic solvent or with an aqueous solution, optionally adjusting pH.
• the process of the invention comprises, as a first operation, the preparation of a ⁇ -acylamino-a-hydroxyamide of formula (VIII) given above.
• the desired compound of formula (VIII) can be prepared, in operation a) of the process of the invention, according to two alternative synthetic routes, a.i) and a.ii).
• reaction pathway a.i comprises the following steps:
• step a.i.l an azido aldehyde of formula (VI) is reacted with a carboxylic acid of general formula (R 2 C0 2 H) and an isocyanide of formula (R 3 NC), wherein the substituents R 2 and R 3 assume the meanings given above, according to Passerini reaction conditions in a chlorinated solvent, preferably dichloromethane, or in an aprotic polar solvent, such as, an ether (preferably tetrahydroiuran), an ester (preferably ethyl acetate), acetonitrile (ACN) or a mixture thereof, at a temperature comprised in the range between 0 and 60 °C (preferably at 20 °C), to yield a ⁇ -azido-a-acyloxyamide of formula (VII).
• a chlorinated solvent preferably dichloromethane
• an aprotic polar solvent such as, an ether (preferably tetrahydroiuran), an ester (preferably
• the amount of the carboxylic acid of general formula (R 2 C0 2 H) and of the isocyanide of formula (R 3 NC) are comprised between 1 and 1.5 equivalents, preferably 1 equivalent, compared to the molar quantity of the azido aldehyde of formula (VI).
• step a.i.2) the ⁇ -azido-a-acyloxyamide of formula (VII) is reduced to the amine of formula (Vlld).
• the reduction reaction can be carried out using one of the methods generally known in the field for example using borane-dimethylsulfide, borane- tetrahydrofuran, tin dichloride, hydrogenation using as catalysts, for example, palladium on calcium carbonate (lead poisoned), palladium on carbon, palladium (II) hydroxide on carbon, platinum (IV) oxide, rhodium on alumina; the reaction takes place in a polar protic solvent, preferably ethanol, or in an aprotic polar solvent, as tetrahydroiuran, or a mixture thereof.
• a polar protic solvent preferably ethanol, or in an aprotic polar solvent, as tetrahydroiuran, or a mixture thereof.
• said reduction can be performed by treating the ⁇ -azido-a- acyloxyamide of formula (VII) with a trivalent phosphorus compound (according to Staudinger reaction conditions), such as a trialkyl- or triarylphosphine (e.g. tris(3- hydroxypropyl)phosphine or preferably triphenylphosphine) optionally supported, in a polar aprotic solvent, such as ethers (preferably tetrahydroiuran) in the presence of water to yield the corresponding amine, at a temperature comprised in the range between 40 and 80 °C, preferably 60 °C.
• a trivalent phosphorus compound accordinging to Staudinger reaction conditions
• a trialkyl- or triarylphosphine e.g. tris(3- hydroxypropyl)phosphine or preferably triphenylphosphine
• a polar aprotic solvent such as ethers (preferably tetrahydro
• step a.i.3) the amine of formula (Vlld) (optionally isolated) is subjected to an 0 ⁇ N acyl migration to yield the ⁇ -acylamino-a-hydroxyamide of formula (VIII) with one of the known methods, optionally by means of base catalysis; an organic base, such as a tertiary amine, is optionally added to increase the reaction rate of the 0 ⁇ N acyl migration.
• this step occurs in the same solvent used for the reduction, at a temperature comprised in the range between 20 and 80 °C (preferably 60 °C).
• the alternative reaction pathway a.ii) comprises the following steps:
• Step a.ii. l) entails the preparation of the ⁇ -azido-a-hydroxyamide of formula (Vllb) via a truncated Passerini reaction (i.e. a variation of the Passerini reaction where the final product is an a-hydroxyamide rather than an a-acyloxyamide, see for example Organic Reactions, Volume 65, Chapter 1 "The Passerini Reaction”) by treating the azido aldehyde of formula (VI) with an isocyanide of formula (R 3 NC) and an acid as detailed below, in a chlorinated solvent (preferably dichloromethane) or in an aprotic polar solvent, such as, ethers (preferably tetrahydroiuran), esters (alkylacetates, such as ethyl acetate), acetonitrile, amides (such as dimethylformamide (DMF), dimethylacetamide (DMA) or N-methyl pyrrolidone), or a mixture thereof, at
• Suitable acids for the aim are, for example, trifluoroacetic acid (TFA), pyridinium trifluoroacetate or, preferably, boric acid, used in an amount comprised between 1 and 2 equivalents, preferably 1 equivalent, compared to the molar quantity of the azido aldehyde of formula (VI).
• TFA trifluoroacetic acid
• pyridinium trifluoroacetate or, preferably, boric acid
• the amount of the isocyanide of formula (R 3 NC) is comprised between 1 and 1.5 equivalents, preferably 1.2 equivalent, compared to the molar quantity of the azido aldehyde of formula (VI).
• Step a.ii.2) is the reduction of the azido group, for example with one of the methods mentioned above in step a.i.2.
• Step a.ii.3) is the N-acylation of the amine of formula (Vile) obtained in step a.ii.2 with a carboxylic acid of formula (R 2 C0 2 H) as defined above, to yield said ⁇ -acylamino-a- hydroxy amide of formula (VIII).
• N-acylation is carried out using one of the peptide coupling reagents generally known in the field (e.g. see Valeur E. et ah : Chem. Soc. Rev., (2009), 38, 606-631), preferably 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), benzotriazol- 1 -yl- oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), O-(7-Azabenzotriazol-l- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or 6-chloro-l- ((dimethylamino)(morpho lino)-methylene)- 1 H-benzotriazo hum hexafluorophosphate 3 - oxide (6-HDMCB) and a tertiary amine (cyclic
• the second operation of the process of the invention, b), is the cyclization of a ⁇ - acylamino-a-hydroxyamide of formula (VIII) to yield the N-acyl bicyclic prolinamide of formula (IX).
• This operation comprises two reactions steps:
• step b.l a compound of formula (VIII) is converted into the corresponding a-activated-5-acylamino amide of formula (Vlllb).
• R 11 is a sulphonate, such as mesylate, trifluoromethanesulfonate (triflate) or tosylate
• its preparation can be performed with one of the methods generally known in the field, for example by treating the substrate with the corresponding sulfonyl halide or sulfonyl anhydride, in presence of an organic base in a suitable solvent.
• the base is a tertiary amine (cyclic or acyclic), such as triethylamine, N,N-diisopropylethylamine, N,N-diisopropylmethylamine, N- methylpyrrolidine, N-methylmorpholine, N,N-dicyclohexylmethylamine, N,N- diethylaniline, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine or 4-dimethylaminopyridine.
• Solvents useful for the aim are, for example, chlorinated solvent, e.g. dichloromethane, or a polar aprotic solvent, such as an ether, or a mixture thereof.
• the quantity of sulfonyl halide or of sulfonyl anhydride used is comprised between 1 and 1.5 equivalents, preferably 1.2 equivalents, compared to the molar quantity of the ⁇ -acylamino-a-hydroxyamide of formula (VIII).
• the amount of the organic base used is comprised between 1 and 3 equivalents, preferably 2 equivalents, compared to the molar quantity of the ⁇ -acylamino-a-hydroxyamide of formula (VIII).
• said compound when in the a-activated-5-acylamino amide of formula (Vlllb) R 11 is a halogen, said compound can be prepared by treating the ⁇ -acylamino-a-hydroxyamide of formula (VIII) with a halogenating agent such as CX 4 (preferably CBr 4 , CC ), in presence of a stoichiometric amount of a phosphine (preferably triphenylphosphine) in a chlorinated solvent, for example dichloromethane, or in an aprotic polar solvent, such as an ether (preferably tetrahydrofuran) or a mixture thereof, at a temperature in the range comprised between -10 °C and 10 °C, preferably 0 °C.
• a halogenating agent such as CX 4 (preferably CBr 4 , CC )
• a stoichiometric amount of a phosphine preferably triphenylphosphine
• the quantity of the halogenating agent is comprised between 1 and 2 equivalents, preferably 1.5 equivalents, compared to the molar quantity of the ⁇ -acylamino-a-hydroxyamide of formula (VIII).
• the quantity of the phosphine is comprised between 1 and 2 equivalents, preferably 1.5 equivalents, compared to the molar quantity of the ⁇ -acylamino-a-hydroxyamide of formula (VIII).
• said activated compound of formula (Vlllb) can be prepared by treating the ⁇ -acylamino-a-hydroxyamide of formula (VIII) with thionyl chloride, thionyl bromide, phosphoryl chloride, or phosphorus tribromide in a chlorinated solvent, such as dichloromethane, in a polar aprotic solvent, as acetates (preferably alkylacetates, such as ethyl acetate), ethers (preferably tetrahydrofuran or 1,4-dioxane), in a hydrocarbon, as toluene, or a mixture thereof, optionally in presence of an organic base (preferably pyridine).
• a chlorinated solvent such as dichloromethane
• a polar aprotic solvent as acetates (preferably alkylacetates, such as ethyl acetate), ethers (preferably tetrahydrofuran or 1,4-dioxane), in a hydro
• step b.2) said a-activated-5-acylamino amide of formula (Vlllb) is cyclized by treatment in a dipolar aprotic solvent, such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone or a mixture thereof, at a temperature between -30 °C and 40 °C (preferably at 0 °C), with an organic or inorganic base capable to promote said cyclization step, optionally in the presence of a halide salt such as a tetraalkylammonium halide (preferably tetrabutylammonium iodide or bromide) or an alkali metal halide (preferably Nal, NaBr, KI or KBr).
• a dipolar aprotic solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone or a mixture thereof
• an organic or inorganic base capable to promote said cyclization step, optionally in the presence of a halide
• Bases useful for the aim are strong bases, for example hydrides (preferably sodium, lithium or potassium hydrides), alkaline amides (preferably lithium bis(trimethylsilyl)amide (LiHMDS)) or alkaline tert-butoxides (such as sodium or potassium tert-butoxide).
• the amount of the base used is comprised between 1 and 2 equivalents, preferably 1.2 equivalents, compared to the molar quantity of the a-activated-5-acylamino amide of formula (Vlllb).
• the starting material for either operation a.i. l) or a.ii. l) described above is an enantiomerically enriched azido aldehyde having the following structure (VI'):
• N-acyl bicyclic prolinamide having one of the following formulae (A) and (B), in which the substituents assume the meanings given above:
• the starting compound for the synthetic routes of the invention is an azido aldehyde of formula (VI):
• the azido aldehyde (VI) can be prepared according to the following synthetic scheme:
• Path 2 consists in an enzymatic desymmetrization of a meso-diol of formula (I), by treating it with a vinyl alkanoate or a linear isopropenyl alkanoate of formula (XV), preferably vinyl acetate, to yield a monoalkanoate of formula (II), as detailed below:
• R 4 is a C1 -C5 linear alkyl
• R 12 is methyl or hydrogen
• the amount of the vinyl alkanoate or of the linear isopropenyl alkanoate (XV) is comprised between 1 and 1.5 equivalents, preferably 1.2 equivalents, compared to the molar quantity of the diol of formula (I).
• vinyl alkanoate or the linear isopropenyl alkanoate of formula (XV) are vinyl acetate or isopropenyl acetate, they can also perform the function of solvent for the reaction.
• Hydrolases useful for the aim are, for example, lipases, such as a pig pancreatic lipase (PPL), a lipase SAM-2, a lipase from Candida Antarctica, or preferably the lipase PS "Amano” SD or the lipase A "Amano”, optionally adsorbed on celite , at a temperature comprised in the range between -20 and 20 °C, preferably at 0 °C.
• PPL pig pancreatic lipase
• SAM-2 lipase from Candida Antarctica
• lipase PS "Amano" SD or the lipase A "Amano” optionally adsorbed on celite , at a temperature comprised in the range between -20 and 20 °C, preferably at 0 °C.
• Such desymmetrization step can be performed in a polar aprotic solvent, preferably ethers, such as isopropyl ether, tetrahydrofuran or methyl tert-butyl ether, or a mixture thereof, optionally in presence of molecular sieves.
• a polar aprotic solvent preferably ethers, such as isopropyl ether, tetrahydrofuran or methyl tert-butyl ether, or a mixture thereof, optionally in presence of molecular sieves.
• path 3 entails the preparation of the monoalkanoate of formula (II) through the preparation of a dialkanoate formula (Ha) (step A), followed by an enzymatic hydrolysis (step B).
• Step A can be carried out with one of the methods generally known in the field (see e.g. Theodora W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons (1999)), for example by treating diol (I) with an anhydride or an acyl halide in presence of a tertiary amine.
• Hydrolases useful in step B for the aim are, for example, lipases, such as a pig pancreatic lipase (PPL), a lipase SAM-2, a lipase from Candida Antarctica, or preferably the lipase PS "Amano” SD or the lipase AK “Amano", in presence of a pH buffer and a variable amount (comprised between 0 and 20%) of an organic co-solvent, such as a protic polar solvent, preferably an alcohol, or an aprotic polar solvent, such as an ether, dimethylformamide, dimethylsulfoxide, or an apolar solvent, such as a hydrocarbon at a temperature comprised in the range between 5 and 30 °C.
• PPL pig pancreatic lipase
• SAM-2 lipase from Candida Antarctica
• a variable amount such as a protic polar solvent, preferably an alcohol, or an aprotic polar solvent, such as an ether, dimethylform
• Path 1 step A foresees the preparation of an activated monoalkanoate of formula (III), wherein the substituents have the meanings given above and R 1 represents one of the leaving groups, known to the person skilled in the art, able to undergo a nucleophilic substitution, such as for example, a mesylate, a tosylate, a halogen, a triflate, a nonaflate, a fluorosulfonate, or a nosylate.
• a nucleophilic substitution such as for example, a mesylate, a tosylate, a halogen, a triflate, a nonaflate, a fluorosulfonate, or a nosylate.
• Such step can be performed using one of the methods known to the ordinary skilled person, as for example those described in operation b. l to prepare an a-activated- ⁇ - acylamino amide of formula (VHIb).
• Path 1 step B entails the preparation of the azido alkanoate of formula (IV) by a displacement of the leaving group (namely R 1 ) by treating with an azide, preferably lithium, sodium, or potassium azide, in an aprotic polar solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran or a mixture thereof.
• an azide preferably lithium, sodium, or potassium azide
• an aprotic polar solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran or a mixture thereof.
• the quantity of the azide used is comprised between 1 and 1.5 equivalents, preferably 1.2 equivalents, compared to the molar quantity of the activated monoalkanoate of formula (III).
• the azido alkanoate of formula (IV) can be prepared by treating the activated monoalkanoate of formula (III) with an azide and a catalytic amount of an alkaline halide (Finkelstein reaction), such as sodium iodide or bromide, in an aliphatic ketone (e.g. methylethylketone or acetone), dimethylformamide, dimethylacetamide, N- methylpyrrolidone, tetrahydrofuran or a mixture thereof.
• an alkaline halide Fekelstein reaction
• an alkaline halide such as sodium iodide or bromide
• an aliphatic ketone e.g. methylethylketone or acetone
• dimethylformamide dimethylacetamide
• N- methylpyrrolidone tetrahydrofuran or a mixture thereof.
• the following step is the preparation of an azido alcohol of formula (V) through hydrolysis of the ester with one of the suitable methods known to a skilled person.
• the hydrolysis is carried out by contacting the azido alkanoate of formula (IV) with a hydroxide or a carbonate of an alkaline metal (such as K 2 CO 3 , Na 2 C0 3 , L1 2 CO 3 , CS 2 CO 3 , KOH, NaOH, LiOH) in a water miscible solvent, such as methanol, ethanol, tetrahydrofuran, dioxane or a mixture thereof) in the presence of water.
• a hydroxide or a carbonate of an alkaline metal such as K 2 CO 3 , Na 2 C0 3 , L1 2 CO 3 , CS 2 CO 3 , KOH, NaOH, LiOH
• a water miscible solvent such as methanol, ethanol, tetrahydrofuran, dioxane or a mixture thereof
• the amount of the alkaline base used is comprised between 1 and 5 equivalents, preferably 3 equivalents, compared to the molar quantity of the azido alkanoate of formula (IV).
• the monoalkanoate of formula (II) is obtained as the undesired enantiomer according to formula (lib), as detailed below, it can be converted into the azido alcohol of formula (V) with one of the methods generally known in the field, such as, for example the one depicted in the following scheme:
• Pg is one of the protecting groups of the alcohols orthogonal to the acyl (namely Pv 4 CO) derived from the enzymatic desymmetrization.
• Said azido alcohol of formula (V) is subsequently oxidized to an azido aldehyde of formula (VI), with one of the methods known in the field such as, for example, those reported in Burke-Danheiser, Handbook of Reagents for Organic Synthesis: Oxydizing and Reducing Agents, John Wiley & Sons (1999), or alternatively using one of the following methods:
• Swern oxidation by treating with oxalyl chloride (COCl) 2 or trifluoroacetic anhydride (TFAA), dimethylsulfoxide (DMSO) and a tertiary amine) or one of its variation, such as the Corey- Kim oxidation (by treating with
• N-chlorosuccinimide, dimethyl sulfide and a tertiary amine) or the Pfitzner- Moffat oxidation (by treating with dicyclohexyl carbodiimide (DCC), DMSO and a catalytic amount of phosphoric acid);
• hypervalent iodine based oxidizing agents such as 2-iodoxybenzoic acid (IBX) or Dess-Martin periodinane (DMP);
• TPAP tetrapropylammonium perruthenate
• NMO N-methylmorpholine-N-oxide
• DMSO dimethyl sulfoxide
• prolinamides according to formulae (IX), (IX') > (A) or (B) above are further reacted to produce intermediates in the synthesis of the serine protease inhibitors described in the introduction of this description, their salts or their co- crystals.
• Another preferred embodiment of the invention is directed to the preparation of an aldehyde of formula (XIa):
• Steps a') and b') correspond to steps a) and b) of the most general embodiment of the invention, carried out using, as the isocyanide of formula R 3 NC, the isocyanide of formula (XII):
• the isocyanide of formula (XII) has one of the following formulae:
• the optional step c) consists in deprotecting the N-acyl bicyclic proline amide of formula (IXa) obtained in step b') to provide the N-acyl bicyclic proline (hydroxyalkyl)amide of formula (Xa) with one of the suitable methods known to a skilled person, such as those reported in Theodora W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons (1999), preferably, in the case when the protecting group is an ester, for instance benzoate, /?-nitrobenzoate or acetate, by means of an alkaline hydroxide (e.g. LiOH, KOH, NaOH) in water optionally using a water miscible co-solvent.
• an alkaline hydroxide e.g. LiOH, KOH, NaOH
• step d) compound (Xa) is oxidized to provide an aldehyde of formula (XIa).
• Said oxidation step can be performed using one of the oxidizing methods known in the field, such as, for example, those reported hereinbefore for the preparation of an azido aldehyde of formula (VI) starting from an azido alcohol of formula (V).
• this step can be performed under biocatalyzed conditions using one of the alcohol dehydrogenase enzymes generally known in the field.
• Preferred conditions entails the use of TEMPO and sodium hypochlorite (optionally in the presence of sodium or potassium bromide) or the use of dimethyl sulfoxide (DMSO) activated by the sulfur trioxide pyridine complex in the presence of a tertiary amine.
• TEMPO and sodium hypochlorite optionally in the presence of sodium or potassium bromide
• DMSO dimethyl sulfoxide
• steps a') to d) is preferably carried out on the enantiomerically enriched azido aldehyde of formula (VI'), leading to an enantiomerically enriched aldehyde of formula (XIa'):
• the aldehydes (XIa) or (XIa') may be further reacted to produce one of the serine protease inhibitors described in the introduction of this description, the salts, the co-crystals, or one of the intermediates useful in the synthesis thereof; this more preferred embodiment will be described hereinbelow with reference to aldehyde (XIa) as starting compound, but will be apparent that the same sequence of steps described below may be applied starting from an aldheyde (XIa'). According to this more preferred embodiment, starting from an aldehyde of formula (XIa), it is produced an a-ketoamide of formula (XVIIIa):
• the a-ketoamide of formula (XVIIIa) can represent both Telaprevir and Boceprevir.
• An a-ketoamide of formula (XVIIIa) can be prepared from an aldehyde of formula (XIa) according to two alternative routes, the first one comprising operations e) and f), the second one comprising steps g) to j).
• aldehyde (XIa) is transformed into an a-ketoamide (XVIIIa) via the following two operations:
• Operation e) can be carried out according to two alternative routes of synthesis, e.i) and e.ii).
• reaction pathway e.i comprises the following steps:
• Step e.i. l) entails the preparation of an acyloxyamide of formula (Xlla) according to the Passerini reaction conditions as described above with reference to step a.i. l) of the process, replacing the carboxylic acid of formula (R 2 C0 2 H) and the isocyanide of formula (R 3 NC) respectively with a carboxylic acid of formula (R 7 C0 2 H) and an isocyanide of formula (R 10 NC), wherein R 10 has the meaning given above and R 7 is a Ci-C 6 linear or branched alkyl optionally substituted with a C 6 -Cio aryl (such as, e.g. methyl or benzyl), or an optionally substituted C 6 -Cio aryl (such as phenyl).
• R 7 is a Ci-C 6 linear or branched alkyl optionally substituted with a C 6 -Cio aryl (such as, e.g. methyl or benzyl),
• Step e.i.2) consists in the conversion of acyloxyamide (Xlla) into the hydroxyamide of formula (XHIa). Said step is carried out using one of the conditions generally known in the field, such as, for example, those described hereinbefore for the preparation of the azido alcohol of formula (V).
• Reaction pathway e.ii) is a single-step reaction, and involves the preparation of the hydroxyamide of formula (XHIa) through a truncated Passerini reaction by treating the aldehyde of formula (XIa) with an isocyanide of formula (R 10 NC) in presence of an acid, for instance pyridinium trifluoroacetate or, preferably, boric acid.
• an acid for instance pyridinium trifluoroacetate or, preferably, boric acid.
• the isocyanide of formula (R 10 NC) useful for the reaction is one of the convertible isocyanides (i.e. an isocyanide wherein R 10 is a group that can be easily transformed into H after the multicomponent reaction, such as Passerini or Ugi reaction) known to the skilled person such as, for example, tert- butylisocyanide (as described in Organic & Biomolecular Chemistry, 2010, 8(16), 3631- 3634), the l-(acyloxy)-2-isocyanobenzenes (as detailed in Journal of American Chemical Society, 2006, 128(36), 1 1772-1 1773), l-(silyloxymethyl)-2-isocyanobenzene (as detailed in Journal of Organic Chemistry, 1999, 64(2), 336-337) or one of the convertible isocyanides as described in Topics Heterocyclic Chemistry, 2010, 23, 1-39.
• the convertible isocyanides i.e. an isocyanide wherein R 10 is a group that can be easily transformed
• hydroxyamide (XHIa) is then converted, in operation f) of the method, into the a-ketoamide of formula (XVIIIa), according to three possible synthesis routes f.i), f.ii) and f.iii).
• step f.i. 2 deprotection of the ⁇ -ketoamide of formula (XlVa) to yield an ⁇ -ketoamide of formula (XVIIIa).
• the oxidation of step f.i. l) may be achieved with a variety of known oxidizing reagents, such as, for example, Dess-Martin periodinane ( 1,1 -dihydro- 1,1,1 -triacetoxy- 1,2- benzoiodooxol-3(lH)-one), TEMPO and sodium hypochlorite (optionally in the presence of sodium or potassium bromide) or the use of dimethyl sulfoxide (DMSO) activated by the sulfur trioxide pyridine complex in the presence of a tertiary amine.
• DMSO dimethyl sulfoxide
• Step f.i.2) entails the deprotection of a-ketoamide of formula (XlVa) to yield the a- ketoamide (XVIIIa), by removing the substituent derived by the convertible isocyanides used, with one of the methods known in the field, such as those described in the documents cited above.
• step g) the preparation of the cyanohydrin of formula (XVa) is achieved by reacting the aldehyde of formula (XIa) with a cyanide, such as sodium or potassium cyanide and optionally in the presence of an acid, organic or inorganic, such as hydrochloric acid or acetic acid.
• a cyanide such as sodium or potassium cyanide
• an acid, organic or inorganic such as hydrochloric acid or acetic acid.
• the cyanohydrin of formula (XVa) can be prepared reacting the aldehyde of formula (XIa) with a trialkylsilyl cyanide, optionally generated in situ, such as trimethylsilyl cyanide, or by treatment with a cyanohydrin, such as, for example, acetone cyanohydrin, in the presence of a base.
• step h) the cyanohydrin of formula (XVa) is converted into the a-hydroxyacid of formula (XVIa) using one of the generally known methods, for example, in the presence of HC1 in a suitable solvent, such as dioxane, at a temperature comprised in the range between 50 and 110 °C.
• a suitable solvent such as dioxane
• said step can be carried out using a biocatalyst, such as a nitrilase (i.e. an enzyme that transforms directly a nitrile into the corresponding carboxylic acid).
• a biocatalyst such as a nitrilase (i.e. an enzyme that transforms directly a nitrile into the corresponding carboxylic acid).
• step i) the a-hydroxyacid (XVIa) is coupled with an amine of general formula (R 17 NH 2 ) to yield the hydroxy amide of formula (XVIIa) using one of the conditions generally known in the field, such as, e.g. those reported to perform operation a.ii.3) to prepare a ⁇ -acylamino-a-hydroxyamide of formula (VIII).
• step j the hydroxyamide of formula (XVIIa) is oxidized with one of the methods described hereinbefore to provide the a-ketoamide of formula (XVIIIa).
• the synthetic pathway of the invention includes a purification step, for example by chromatographic purification or by crystallization, optionally after formation of an addition compound, such as a salt or a co-crystal.
• Another embodiment of the present invention is the preparation of the isocyanide of formula (R 10 NC) suitable for steps e.i. l) and e.ii) described above.
• R 10 cyclopropyl
• the isocyanide can be prepared via dehydration of N-cyclopropylformamide, reacting it with methyl N-(methoxycarbonyl)-N- [(triethylammonium)sulfonyl]azanide (commonly referred to as the Burgess reagent) or one of the Burgess-type reagents of general formula (XIX):
• R 21 is a Ci-C 6 linear or branched alkyl optionally halogen substituted (preferably methyl ethyl, isopropyl, tert-butyl and 2,2,2-trifluoroethyl); and R 22 is a cyclic or acyclic tertiary amine such as tributylamine, triethylamine, 1 ,4- diazabicyclo[2.2.2]octane (DABCO), N,N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine.
• DABCO diazabicyclo[2.2.2]octane
• the Burgess or Burgess-type reagents can be prepared using, for instance, the procedure described in the Journal of the American Chemical Society (2004), 126(20), 6234.
• Such reagents can be used in the subsequent dehydration (i.e. the reaction with N- cyclopropylformamide leading to cyclopropyl isocyanide) in isolated and purified form; or, alternatively, in mixture with the hydrochloride of the tertiary amine used for their preparation or without isolation in a one-pot operation.
• Such dehydration is normally carried out in an aprotic solvent, such as a chlorinated solvent (preferably dichloromethane), an ester, such as ethyl acetate or isopropyl acetate, or a nitrile (preferably acetonitrile) at a temperature comprised in the range between 0 °C and the reflux temperature of the solvent, preferably at room temperature.
• aprotic solvent such as a chlorinated solvent (preferably dichloromethane)
• an ester such as ethyl acetate or isopropyl acetate
• a nitrile preferably acetonitrile
• reaction mixture resulting from the dehydration step can be conveniently used as such in the Passerini reaction as described in the steps e.i. l) and e.ii) without the isolation of the cyclopropyl isocyanide.
• FIG. 1 Further embodiments of the present invention are the compound (VII), (Vila), (Vllb), (Vlld), (Vile), (VIII), (Villa), (Vlllb), (IXa), (Xa), (XIa) and (XII), as defined above and the enantiomerically enriched isomers thereof.
• the e.e. (97%) is determined by 1H-NMR by Mosher ester analysis.
• the organic layer is washed with a saturated aqueous solution of NaHC0 3 , followed by water and brine, dried over anhydrous sodium sulfate and co-evaporated with CH 2 C1 2 to have a final solution of (6) (3.22 mmol) in ca. 1.1 mL of CH 2 C1 2 .
• Phase A H 2 0-ACN-TFA Phase B: H 2 0-ACN-TFA 10:90:0.1
• Wavelength channel A 210 nm
• Wavelength channel B 232 nm
• Phase B H20-ACN-NH 4 OH 10:90:0.1
• Wavelength channels A 210 nm & 232 nm
• Phase B H 2 0-ACN-TFA 10:90:0.1
• the reaction mixture is stirred at room temperature for 3.5 h, then treated with a saturated aqueous NH 4 CI and extracted with AcOEt, washed with a saturated aqueous NaHC0 3 and brine dried over anhydrous sodium sulfate, filtered and concentrated.
• the crude product is purified by flash chromatography eluting with hexanes- AcOEt (2: 1 ⁇ 3 :2) to give the coupling product (101 mg, 90%) as an amorphous solid.
• R f 0.62 (hexanes: AcOEt 1 : 1).
• To a cooled (0 °C) solution of the coupling product in CH 2 C1 2 (2 mL) is added dropwise CF 3 C0 2 H (1 mL).
• the solution is allowed to reach room temperature in 1 h, then concentrated.
• the solution of the crude trifluoroacetate salt in dry CH 2 C1 2 (2 mL) is treated with NMM (139 ⁇ , 1.24 mmol), pyrazinecarboxylic acid (24 mg, 190 ⁇ ) and PyBOP (112 mg, 220 ⁇ ).
• the reaction mixture is stirred at room temperature for 2 h, then treated with a saturated aqueous solution of NH 4 C1 and extracted with AcOEt, washed with a saturated aqueous solution of NaHC0 3 and brine, dried over anhydrous sodium sulfate, filtered and concentrated.
• reaction mixture is warmed to 20 °C and stirred for 30 minutes at the same temperature, then concentrated under vacuum to give the sulfamoyl chloride intermediate as a colorless solid which is taken up in toluene (305 mL) warming at 40 °C.
• This solution is added dropwise, in about 1 hour, to a solution of Et 3 N (48.6 mL, 348.6 mmol) in toluene (105 mL) keeping the temperature between 25 -
• the reaction is monitored by GC and complete conversion is achieved in about 2 hours.
• the DCM solution containing cyclopropyl isocyanide is used as such in the Passerini reaction with aldehyde (18).

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