HK1199449B - Processes and intermediates for preparing a macrocyclic protease inhibitor of hcv - Google Patents

Description

Processes and intermediates for preparing macrocyclic protease inhibitors of HCV

Technical Field

The present invention relates to synthetic methods and synthetic intermediates for macrocyclic protease inhibitors of Hepatitis C Virus (HCV).

Background

Hepatitis C Virus (HCV) is a cause of chronic hepatitis, which can progress to liver fibrosis, leading to cirrhosis, end-stage liver disease, and HCC (hepatocellular carcinoma), making it a cause of liver transplantation. Current anti-HCV therapy is based on the combination of (pegylated) interferon-alpha (IFN- α) with ribavirin, which suffers from limited efficacy, significant side effects, and is poorly tolerated in many patients. This has prompted the study of more effective, convenient and more tolerable treatments.

The genomic replication of HCV is mediated by several enzymes, among which HCV NS3 serine protease and its related cofactor NS 4A. Various agents have been described that inhibit this enzyme. WO 05/073195 discloses linear macrocyclic NS3 serine protease inhibitors with a central substituted proline moiety and WO 05/073216 describes inhibitors with a central cyclopentane moiety. Among these, macrocyclic derivatives are attractive due to their remarkable activity against HCV and attractive pharmacokinetic properties.

WO2007/014926 describes macrocyclic cyclopentane and proline derivatives having the structures shown below, including compounds of formula I. The compounds of formula I are very potent inhibitors of the HCV serine protease and are particularly attractive in terms of pharmacokinetics. Due to its advantageous properties, it has been selected as a potential candidate for anti-HCV drug development. Therefore, there is a need to produce larger amounts of such active ingredients based on processes that provide the product in high yield and high purity. WO2008/092955 describes processes and intermediates for the preparation of compounds of formula I.

According to WO2007/014926, the compound of formula I can be prepared starting from the bicyclic lactone carboxylic acid, which is referred to as compound 39 in example 4, or compound 17b in the general description of this reference, or compound II in the present description and claims. The carboxylic acid in the bicyclic lactone carboxylic acid is coupled with N-methylhexa-5-enylamine 38, and the lactone is subsequently opened to form the 4-hydroxycyclopentane derivative 41. The latter derivative 41 is then coupled with aminocyclopropyl carboxylate to cyclopentanedicarboxylic acid diamide 43, and cyclopentanedicarboxylic acid diamide 43 is coupled with quinoline 36 in a Mitsunobu ether-forming reaction involving inversion at the carbon bearing the hydroxyl group. The resulting intermediate 44 is cyclized by metathesis to a macrocyclic derivative in which the ester group is hydrolyzed and coupled with a cyclopropyl sulfonamide to yield the desired end product of formula I. These reactions are illustrated in the following schemes, wherein R represents C_1-4Alkyl, in example 4, R is ethyl.

Enantiomerically pure bicyclic lactone 39 was prepared starting from the enantiomer of 3, 4-bis (methoxycarbonyl) cyclopentanone, referred to as (17a) in WO 2007/014926. The latter was prepared as described by Rosenquist et al in Acta Chemica Scandinavica46(1992) 1127-1129. Synthesis of racemic methyl cyclohexenedicarboxylate by Diels-Alder reaction of 3-sulfolene and dimethyl fumarate, followed by oxidative cleavage of the double bond, cyclization and decarboxylation to give (+) 4-Ketocyclopentanedicarboxylic acid dimethyl ester. The latter is resolved by hydrolysis using pig liver esterase to give the corresponding (+) -monoacid and (-) diester, which are intermediates (17a) of WO 2007/014926.

After removal of the (+) -monoacid, trans (3R,4R) -3, 4-bis (methoxycarbonyl) cyclopentanone diester (17a) is converted to the bicyclolactone 17b (also referred to as compound II, supra) by first ketone to alcohol reduction followed by hydrolysis of the ester and the formation of the lactone.

The synthetic procedure described in WO2008/092955 for preparation I starts from intermediate D, in which the ester function is hydrolyzed and coupled with the cyclopropylamino acid ester C. The obtained intermediate B is cyclized into a macrocyclic ester A through olefin metathesis reaction, the macrocyclic ester A is hydrolyzed and coupled with cyclopropyl sulfonamide to form a final product I. These reactions are outlined in the reaction schemes below. In this and the following schemes, R is C_1-4Alkyl, in particular R is ethyl. R¹Is C_1-4Alkyl, in particular R¹Is methyl or ethyl.

Intermediate D can be prepared in turn starting from the hydroxycyclopentyldiphenyl diester of formula H1 by:

(a) reacting H1 with thiazolyl-substituted hydroxyquinoline E to quinolinyloxycyclopentyl diester of formula K, followed by cleavage of the benzyl ester group to form monocarboxylic acid J, which in turn is coupled with N-methylhexenamine to intermediate D; or

(b) Cleaving the benzyl ester in H1 to form a monocarboxylic acid G, coupling the latter with N-methylhexenylamine to form a hydroxycyclopentylamide F, which is then reacted with E to give D; as outlined in the reaction scheme below:

in this embodiment, each R¹As stated above, Bn represents a benzyl group.

In addition, WO2008/092955 describes a process for the preparation of intermediate H1 starting from 4-oxo-1, 2-cyclopentanedicarboxylic acid O by reduction from a ketone to an alcohol to give 4-hydroxy-1, 2-cyclopentanedicarboxylic acid N which is in turn cyclized to the bicyclic lactone M. Esterification of the carboxylic acid group in the latter to give the lactone benzyl ester L, where the lactone is at C_1-4Opened by transesterification in the presence of an alkanol to give intermediate H, which was resolved into its enantiomers H1 and H2 as outlined in the reaction scheme below:

one disadvantage of the above process is that it involves resolution of the enantiomers of H by chiral column chromatography, a cumbersome step that is difficult to perform in large scale production. Another disadvantage is that the resolution is carried out at a later stage of the synthesis, so half of the building blocks H have to be discarded. The presence of different chiral centers in the compounds of formula I and their precursors presents particular problems, since enantiomeric purity is essential to have a product that is acceptable for therapeutic use. Thus, the process for preparing D should result in a product of acceptable enantiomeric purity without the use of cumbersome purification steps with a significant amount of loss of the undesired stereoisomeric form.

Honda et al, Tetrahedron Letters, vol.22, No. 28, pp 2679-+) -brefeldin a:

the synthesis of Honda et al starts from dl-trans-4-oxocyclopentane-1, 2-dicarboxylic acid 2, 2 is esterified to the corresponding methyl ester 3 and reduced to alcohol 4 with Raney nickel. 4 to monocarboxylic acid and benzylated with benzyl bromide, predominantly diastereomer 5, i.e. the diastereomer in which the hydroxyl and benzyl ester groups are in the cis position. The latter ester 5 and compound H of Honda et al are both racemates, but are diastereoisomers of each other, more specifically the epimer on carbon number 4 bearing the hydroxyl group. Compound H1 is one of the two enantiomers obtained by separation from racemic compound H. The other enantiomer was compound H2.

Bicyclic lactone (17b) is a structural unit of interest in the synthesis of compounds of formula I. It was found that a synthetic route to such lactones with good yield and high enantiomeric purity is a desired goal to achieve. The present invention provides such a method.

WO 2010/072742 describes the preparation of Intermediate (IX) and hence also HCV inhibitor (I) using the aforementioned cinchonidine salt of the bicyclic lactone as an intermediate.

In WO 2010/072742, cinchonidine salt (IV) is prepared by resolution of diastereomeric salt mixtures (III) by selective crystallization. Salt (III) is obtained by formation of the cinchonidine salt of racemic bicyclic lactone carboxylic acid (II), as outlined in the reaction scheme below:

it would be desirable to provide a more convenient process for the preparation of cinchonidine salt (IV).

Summary of The Invention

In one aspect, the present invention provides a process for preparing a cinchonidine salt of formula (IV), said process comprising the steps of:

(a) subjecting 4-oxo-1, 2-cyclopentanedicarboxylic acid (V) to reduction in an aqueous environment to provide an aqueous solution of racemic 4-hydroxy-1, 2-cyclopentanedicarboxylic acid (VI);

(b) adding an organic solvent (e.g., a water-miscible organic solvent) to the aqueous solution obtained in (a);

(c) subjecting said racemic hydroxyacid (VI) to cyclization to obtain an aqueous-organic solvent solution of the corresponding racemic lactonic acid (II);

(d) adding cinchonidine to the aqueous-organic solvent solution obtained in (c) to obtain the cinchonidine salt of lactone acid (III);

(e) crystallizing said cinchonidine salt to obtain enantiomerically purified crystalline lactone acid cinchonidine salt (IV),

the chemical formulae numbered herein are as follows:

，

，

，

and。

for example, in one aspect of the invention, steps (a), (b) and (c) are carried out (without necessarily followed by steps (d) and (e)), but preferably all steps (a) to (e) are carried out continuously. On the other hand, if steps (d) and (e) are carried out, it is not necessary to carry out all steps (a), (b) and (c) first (but preferably first).

The compounds (e.g., compounds of formulae (V), (VI), and (II) and other compounds, e.g., involved in downstream chemistry in the synthesis of HCV inhibitor compounds of formula I or salts thereof) used in the methods described herein can be in non-salt form, or they can be in salt form. For example, when used in the processes described herein, the compounds of formula (VI) may be present in the form of a salt, e.g., may be present as a double salt, where the salt is, e.g., an inorganic metal salt, such as Na or K (or the like), or the salt is an amine (e.g., an organic amine, such as triethylamine or N-methylmorpholine, etc.). Examples of formula (VI) include dipotassium salt and triethylammonium salt. Of course, there may be dissociation (to some extent) when the salt of formula (VI) is in aqueous solution.

Accordingly, there is provided a process for the preparation of a racemic lactone of formula (II), said process comprising intramolecular cyclisation of a compound of formula (VI) (also as a racemic mixture), characterised in that the reaction is carried out in the presence of water (see step (c) described herein). As described herein, the compounds of formula (VI) may be used in the form of a salt (e.g., a double salt). This reaction may conveniently be preceded by a reaction carried out in the presence of water, e.g. the reduction of racemic compound (V) to racemic compound (VI) (see step (a) described herein). As described herein, step (a) may be carried out in the presence of a base, and thus, the compound of formula (VI) may form a salt with the base used (e.g., Na, K, triethylamine, N-methylmorpholine, or diisopropylethylamine). However, given that this step is carried out in the presence of water, any association between (VI) and the counter ion (i.e., "salt") can be minimized in water. Any salt of (VI) formed (or any non-salt form of (VI)) conveniently need not be isolated or purified in a later step, provided that the aforementioned process characteristic of the preparation of lactone (II) is carried out in the presence of water. Optionally, an organic solvent (e.g., a water-miscible organic solvent) is added (see step (b) above) as described herein after the reduction reaction to form (VI), i.e., in a step just prior to the lactone-forming step to produce (II). It is advantageous to perform the lactone formation step in water, particularly because water is removed as a by-product of the reaction, and thus the reaction proceeds surprisingly as described herein. The water utilized in the reaction step advantageously does not have to be removed for the subsequent reaction step (e.g., between steps (V) to (VI) and steps (VI) to (II), or between steps (VI) to (II) and steps (II) to (III) to (IV)).

In another aspect, there is provided a process for the preparation of a cinchonidine salt (i.e. a racemic or, preferably, enantiomerically pure salt) of formula (III) or (IV), said process comprising contacting cinchonidine with racemic lactone acid (III), characterised in that the reaction is carried out in the presence of water. The reaction may also be carried out in the presence of water in admixture with an organic solvent, and this reaction may therefore conveniently be carried out directly in the process described herein for the preparation of the lactone acid (II).

In another aspect, the present invention provides a process for the preparation of Intermediate (IX) useful in the preparation of HCV inhibitor compounds of formula I, said process comprising the steps of: preparation of enantiomerically purified crystals in a process comprising the foregoing (e.g., steps (a) to (e) as identified above or other processes described herein for the preparation of (IV))Cinchonidine esterate (IV) and reacting the cinchonidine lactone (IV) with N-methyl-hexenamine (NMHA) (VII) in an amide formation reaction to give bicyclic lactone amide (VIII) with the lactone group opened to give the desired product (IX), as shown in the scheme below, wherein R is¹Is C_1-4Alkyl groups:

in another aspect, the present invention provides a process for the preparation of compound (I), said process comprising the preparation of a cinchonidine salt as described above, followed by the preparation of compound IX as described above, and the synthesis of compound (I) using compound (IX) as an intermediate.

Description of the invention

An overview of the structures described in the present specification and claims.

The process of the present invention begins with providing 4-oxo-1, 2-cyclopentanedicarboxylic acid (V). The racemic 4-oxo-1, 2-cyclopentanedicarboxylic acid V starting material can be prepared as described in the background section of the invention above.

Subjecting the keto acid (V) to reduction in an aqueous environment to provide an aqueous solution of racemic 4-hydroxy-1, 2-cyclopentanedicarboxylic acid (VI). The reduction of the keto group to the hydroxyl group, which converts V to VI, can be carried out with suitable reducing agents, in particular by hydrogen in the presence of metal catalysts, for example rhodium on carbon or rhodium on alumina or Raney nickel, in reaction-inert solvents, for example in an aqueous medium, for example water, in the presence of bases, for example NaOH, KOH or organic bases, for example triethylamine, N-methylmorpholine or else Nichibase (Hunig's base, diisopropylethylamine). Thus, the reaction is carried out in the presence of water and the product (VI) is obtained in the presence of water (wherein (VI) is optionally in the form of a salt).

The process of the present invention brings the advantage that a sequence of process steps can be carried out without the need for water removal, salt formation, precipitation or other separation techniques in between. Therefore, an organic co-solvent (e.g., a water-soluble organic co-solvent) is added to the aqueous solution resulting from the reduction of the ketone group to the hydroxyl group as described above. The skilled artisan will appreciate that the organic co-solvent should be inert to the reaction being carried out and should be sufficiently water-miscible (e.g., in the case of a water-miscible organic co-solvent) to form a single-phase solvent system. However, the solvent system need not be a single phase solvent system (e.g., a homogeneous mixture), but can be a biphasic (e.g., heterogeneous) solvent system. Suitable water-miscible organic co-solvents include ketones such as acetone or Methyl Ethyl Ketone (MEK); ethers, such as Tetrahydrofuran (THF) or 2-methyltetrahydrofuran (MeTHF) or acetonitrile. The preferred solvent in this step is acetone. Other solvents which may be mentioned are not necessarily water-miscible, for example they may be water-immiscible, or at least only moderately water-miscible, for example aromatic solvents such as toluene or benzene.

The racemic hydroxyacid (VI) thus produced, present in solution in an aqueous-organic solvent mixture, is subjected to cyclization to give an aqueous-organic solvent solution of the corresponding racemic lactonic acid (II). The cyclization can be carried out using known lactone formers (or those mentioned herein, e.g., triazines), e.g., chloroformates, e.g., ethyl or methyl chloroformates. A base, for example, a tertiary amine, such as triethylamine or N-methylmorpholine (NMM), may be added. In a preferred embodiment, the lactone generator is a triazine, more preferably 2,4, 6-trichloro-1, 3, 5-triazine (TCT) or a derivative thereof.

As an advantage of the process according to the invention, the cyclization is preferably carried out in a one-step process with the triazine derivative without isolation of the intermediate product. Triazine derivatives useful for this reaction include reagents such as 2,4, 6-trichloro-1, 3, 5-triazine (T)CT), chloro-dimethoxytriazine (CDMT), N- (3, 5-dimethoxytriazinyl) -N-methylchloromorpholine(DMTMM) or dichloro-methoxytriazine (DCMT). This reaction sequence provides a simple, short and economical process for the preparation of racemic lactonic acid II in high yield. The water used as solvent in the reduction step does not have to be removed and the intermediate 4-hydroxy-1, 2-cyclopentanedicarboxylic acid VI does not have to be isolated.

To obtain enantiomeric purity, cinchonidine was added. In the process of the present invention, this is advantageously carried out without isolation of the intermediate lactone acid (II). Thus, cinchonidine is added to an aqueous-organic solvent solution of lactone acid (II) to give its cinchonidine salt (III). According to WO 2010/072742, the enantiomerically pure cinchonidine salt (IV) can be isolated by crystallization, which provides a smart way of resolving the stereochemistry of the bicyclic lactone acid (II) such that the desired lactone acid is obtained in high enantiomeric purity. Recrystallization or reslurry allows further purification of this salt.

The present invention further provides a process for the preparation of Intermediate (IX) useful in the preparation of HCV inhibitor compounds of formula I. This process first comprises the step of preparing enantiomerically purified crystalline lactone acid cinchonidine salt (IV) as described above. Subsequently, the lactone acid cinchonidine salt (IV) is further reacted as described in WO 2010/072742.

This preferably requires reacting the cinchonidine lactone salt (IV) with N-methyl-hexenamine (NMHA) (VII) in an amide formation reaction to give the bicyclic lactone amide (VIII). The lactone group is opened here to give the desired product (IX), as shown in the scheme below, in which R¹Is C_1-4Alkyl, preferably methyl:

the reaction of cinchonidine salt (IV) with NMHA (VII) is amidogenA reaction comprising reacting the starting material with an amide coupling agent in a reaction inert solvent, optionally in the presence of a base. Solvents that may be used include halogenated hydrocarbons, for example, Dichloromethane (DCM) or chloroform; ethers, such as Tetrahydrofuran (THF) or 2-methyltetrahydrofuran (MeTHF); alcohols, such as methanol or ethanol; hydrocarbon solvents such as toluene or xylene; dipolar aprotic solvents such as DMF, DMA, acetonitrile or mixtures thereof. Dichloromethane, MeTHF, methanol, ethanol, toluene or mixtures thereof are preferred. Amide coupling agents include, for example, N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ), N-isopropoxycarbonyl-2-isopropoxy-1, 2-dihydroquinoline (in particular its hydrochloride salt) (IIDQ), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) ureaHexafluorophosphate (HATU), benzotriazol-1-yl-oxy-tris (pyrrolidinyl) phosphoniumHexafluorophosphate (as PyBOP)^®Commercially available), 1' -Carbonyldiimidazole (CDI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDI or EDCI) and its hydrochloride, dicyclohexyl-carbodiimide (DCC) or 1, 3-diisopropylcarbodiimide, O-benzotriazole-N, N, N ', N ' -tetramethylureaHexafluorophosphate (HBTU), and the like. A catalyst, such as 1-hydroxybenzotriazole (HOBt) or 4-Dimethylaminopyridine (DMAP), may be added. The reaction is usually carried out in the presence of a base, in particular an amine base, for example a tertiary amine, such as triethylamine, N-methylmorpholine, N-diisopropylethylamine (the latter also being known as schnixin, DIPEA or DIEA). Preferably, no base is used. In one embodiment, the reaction is carried out in DCM or MeTHF using EEDQ at the reflux temperature of the reaction mixture, optionally with addition of methanol at the end of the reaction.

In an alternative embodiment, salt (IV) may be decomposed into cinchonidine and the bicyclic lactone, which may be reacted with NMHA in an amide formation reaction as described above. According to WO 2010/072742, it is advantageous to react the cinchonidine salt (IV) itself in an amide formation reaction and subsequently remove the cinchonidine. This removal can be easily achieved in a work-up of the reaction mixture, for example by treating the latter with an acid (e.g. HCl) and washing off the by-products with an aqueous phase.

The lactone function of the bicyclic lactone amide (VIII) obtained is opened by transesterification with an alcohol which can also be used as solvent, in particular C_1-4Alkanols, for example methanol or ethanol. Acids which may be used are strong organic acids, such as sulfonic acids, in particular methanesulfonic acid. Solvents may be added, for example ethers, in particular THF or MeTHF; or a hydrocarbon solvent such as toluene or xylene. The transesterification reaction gives an ester of the alcohol used, for example, in methanol, to give a methyl ester.

The resulting compound (VIII), wherein R¹Preferably methyl, for the procedure for the preparation of the compounds of formula (I).

The compound of formula VIII is further processed to the final product of formula I as outlined in the reaction scheme above, in particular as described in WO 2008/092955.

The synthetic procedure of the present invention offers the advantage of obtaining the correct stereochemistry of the cyclopentane moiety without using chiral chromatography and employing a method that avoids the isolation of intermediates.

As used above and below, the following definitions apply unless otherwise indicated. The term "C_1-4Alkyl "defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms, such as, for example, methylethyl, and 1-propyl, 2-propyl, methyl, ethyl, propyl, butyl,1-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl.

The generally accepted convention for representing stereochemical compounds (also attached hereto) is as follows:

the compounds not represented by a stereobond are racemic or do not define the configuration of the stereocenter.

-the compound represented by a steric bond and one of the descriptors "(±)," rel "or" rac "is racemic and the stereochemistry is relative.

Compounds represented by a steric bond but without descriptors "(±)," rel "or" rac "are non-racemic compounds (non-racemic (scalemic) substances), i.e. enantiomerically enriched.

For example, in the Honda et al reference, the use of the "(+ -.)" designation at the title of the article is meant to describe racemic syntheses utilizing racemic intermediates. However, the above specification may not necessarily be followed in all publications.

The enantiomeric purity is given as the enantiomeric ratio (e.r.). For salts, the e.r. value refers to the ratio of the two enantiomers of the acid in a mixture of diastereomeric salts.

Examples

The following examples are intended to illustrate the invention and should not be construed as limiting the scope of the invention.

Example 1: to a suspension of 32.7g (0.19mol) of racemic 4-oxo-1, 2-cyclopentanedicarboxylic acid (intermediate V) in 237.5ml of water under nitrogen was added 1.0ml (0.019mol) of 50% by weight aqueous NaOH. The mixture was warmed to 60 ℃ and 2.5g Rh/C (5% by weight) were added. The reaction flask was then purged with hydrogen and maintained under a hydrogen atmosphere while stirring until complete conversion was achieved. The warm reaction mixture was filtered through Celite and the filter cake was washed twice with 10ml of water. Adding threeEthylamine (55.61ml, 0.40mol) and 80% of the solvent volume was distilled off at a pressure of 30 mbar. The reaction flask was fitted with a Dean-Stark trap (Dean-Stark trap) filled with 2-methyltetrahydrofuran. 2-Methyltetrahydrofuran (100ml) was added to the reaction mixture. The mixture was refluxed for 4 hours to remove the remaining water. Then 80% of the solvent volume was distilled off at ambient pressure. The mixture was cooled to 50 ℃ and acetone (380ml) was added. The mixture was further cooled to 22 ℃ and additional acetone (760ml) was added. The resulting suspension was cooled to-5 ℃ under nitrogen and triethylamine (27.8ml, 20.24g, 0.2mol) was added. Subsequently, ethyl chloroformate (22.68g, 0.21mol) was added dropwise, and the mixture was stirred at 0 ℃ for 3 hours, and then at 22 ℃ for another 12 hours. The reaction mixture was filtered through Dicalite and the solid was washed with acetone (100 ml). The result was a solution of II in acetone.

However, it is preferred to collect the aqueous solution of VI (optionally in the form of a salt) prior to removal of water (via dean-stark trap) (after reduction of intermediate V) and subsequent cyclization/lactone formation as described below.

Dipotassium salt of examples 1(a) to (VI)

344mg (2mmol) (V) and 224mg (4mmol) of potassium hydroxide are dissolved in 5ml of water. The solution was stirred overnight at room temperature under a hydrogen atmosphere in the presence of 82mg of wet 5% rhodium on carbon as catalyst. The catalyst is filtered off to give a filtrate comprising the dipotassium salt of (VI), which can be used (e.g. directly) to prepare (II).

Bis (triethylamine) salts of examples 1(b) - (VI)

The hydrogenation autoclave was charged with 2.5kg (14.5mol) (V), 1kg Raney nickel, 4.04L (29mol) triethylamine and 4.16L water. The solution was stirred and heated to 120 ℃ under 20 bar hydrogen pressure for 23 hours. The mixture was cooled, the catalyst was filtered off, and used as is (i.e. directly, without isolation/removal of water) for filtrate preparation (II).

Lactonization procedure to give bicyclic lactones (II)

Example 1(c)

87.7g (0.499mol) of 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT) and 860.3ml of acetone are introduced into the reaction vessel under nitrogen. The mixture was cooled to 15 ℃ and 192.8g of a portion of the solution prepared as in example 1(b) (i.e. the bis (triethylamine) salt of (VI) mixed with water, i.e. an aqueous mixture or solution) containing 0.227mol of (VI) as its bis (triethylamine) salt was added. 52.8g (0.522mol) of N-methylmorpholine (NMM) are added to the reactor over a period of 3 hours (the temperature is raised from 15 ℃ to 25 ℃). The reaction mixture was then stirred at 15 ℃ for 2 hours. The precipitate (mainly consisting of triazine by-product) was filtered, the reactor was rinsed with 57.8ml acetone and poured onto the filter.

Racemic cinchonidine salt (III) is formed and subsequently converted into the single enantiomer (IV) of the cinchonidine salt

Example 1(d)

The main filtrate and washings were combined and added to the reactor. To this solution was added 66.8g (0.227mol) of cinchonidine at room temperature. The mixture was heated and stirred at 30 ℃ for 40 minutes, then cooled to 20 ℃ and seeded with 1.02g of cinchonidine salt (IV) (i.e. the enantiomerically pure salt). The mixture was stirred at 20-25 ℃ for 20 hours, filtered and the precipitate washed with a mixture of 11.4ml water and 11.4ml acetone. The crude wet product (33.6g) was charged to a reactor, 140.2mL ethanol and 5.5mL water were added, the mixture was heated, and stirred at 77 ℃ for 3 hours. The mixture was cooled to 23 ℃ over 2 hours with stirring and then stirred at 22 ℃ for 12.5 hours. The solid was filtered, washed with 11.4mL of ethanol and dried under vacuum at 50 ℃ for 4 hours to give 26.2g of (iv) having the following analytical characteristics: chemical purity-acid titration 99.4% by weight, base titration 100% by weight; chiral purity-e.r.96.5/3.5

Lactonization procedure to give bicyclic lactones (II)

Example 2: 735mg of a 23.7% by weight aqueous solution of VI dipotassium salt (1mmol) was diluted in 4ml of water and mixed with 728 μ L NMM (6.6 mmol). 406mg (2.2mmol) of TCT were added and the reaction mixture was stirred at room temperature overnight, after which it was diluted to a final volume of 10ml to give II in 78mM water (yield: 78%).

Example 3: 728. mu.L NMM (6.6mmol) were mixed with 4ml water and 406mg (2.2mmol) TCT were added. The mixture was stirred for a few minutes, after which 735mg of a 23.7% by weight aqueous solution of VI dipotassium salt (1mmol) were added. The resulting reaction mixture was further stirred at room temperature overnight, after which it was diluted to a final volume of 10ml to give a 57mM aqueous solution of II (yield: 57%).

Example 4: 735mg of a 23.7% by weight aqueous solution of VI dipotassium salt (1mmol) was diluted in 4ml of water and mixed with 221 μ L NMM (2 mmol). 648mg (2.2mmol) of DMTMM.H were added₂O, and the reaction mixture was stirred at room temperature overnight, after which it was diluted to a final volume of 10ml to give II in 54mM aqueous solution (yield: 54%).

Example 5: 386mg (2.2mmol) CDMT was dissolved in 4ml acetone and 463. mu.L (4.2mmol) NMM was added. The mixture was stirred for several minutes, then 735mg of a 23.7% by weight aqueous solution of the VI dipotassium salt was added. The resulting mixture was further stirred at room temperature overnight, after which it was diluted to 10ml of final volume to give a 69mM solution of II (yield: 69%).

Example 6: 386mg (2.2mmol) CDMT was dissolved in 4ml MeTHF and 463. mu.L (4.2mmol) NMM was added. The mixture was stirred for several minutes, then 735mg of a 23.7% by weight aqueous solution of VI dipotassium salt was addedAnd (4) liquid. The resulting mixture was further stirred at room temperature overnight, after which it was diluted to a final volume of 10ml to give a 54mM solution of II (yield: 54%).

Example 7: 5.66g (32.2mmol) CDMT were dissolved in 59ml MeTHF. 3.7ml (33.7mmol) NMM were added and the mixture was stirred at 25 ℃ for 1 hour. 10.0g of a 25.5% by weight aqueous solution of VI.2NMM (14.6mmol) are added and the resulting mixture is stirred further at 25 ℃ for several hours. 15ml of water and 3ml of concentrated HCl are added. The mixture was stirred for several minutes, the insoluble material was filtered off, the filtrate was decanted off, and the aqueous layer was extracted with 15ml of MeTHF. The organic layers were combined and washed with 7ml of brine to give 53.1g of a 2.59% by weight solution of II in MeTHF which also contained 0.23% by weight of VI (yield: 60%).

Example 8: 5.66g (32.2mmol) CDMT were dissolved in 59ml isopropyl acetate. 3.7ml (33.7mmol) NMM were added and the mixture was stirred at 25 ℃ for 1 hour. 10.0g of a 25.5% by weight solution of VI in water of the bis (N-methylmorpholine) salt (14.6mmol) were added and the resulting mixture was stirred for a further several hours at 25 ℃. 15ml of water and 3ml of concentrated HCl are added. The mixture was stirred for several minutes, the insoluble material was filtered off, the filtrate was decanted, and the aqueous layer was extracted with 15ml of isopropyl acetate. The organic layers were combined and washed with 7ml of brine to give 56.6g of a 1.3% by weight solution of II in isopropyl acetate which also contained 0.18% by weight VI (yield: 32%).

Example 9: 5.66g (32.2mmol) CDMT was dissolved in 59ml acetone. 3.7ml (33.7mmol) NMM were added and the mixture was stirred at 25 ℃ for 1 hour. 10.0g of a 25.5% by weight solution of VI in water of the bis (N-methylmorpholine) salt (14.6mmol) were added and the resulting mixture was stirred for a further several hours at 25 ℃. The insoluble material was filtered off, 1ml of concentrated HCl was added to the filtrate, and the filtrate was decanted off. The organic layer was washed with 7ml of brine, yielding 44.4g of a 1.44% by weight solution of II in MeTHF, which also contained 0.04% by weight VI (yield: 28%).

Example 10: 19.80g (113mmol) of CDMT were dissolved in 205ml of MeTHF. 13ml (118mmol) NMM were added and the mixture was stirred at 25 ℃ for 2 h. 35g of a 25.5% by weight solution of VI in water of the bis (N-methylmorpholine) salt (51.3mmol) were added and the reaction mixture was stirred at 25 ℃ overnight. 51ml of water and 10.6ml of concentrated HCl were added and the mixture was stirred at 25 ℃ for several minutes. The resulting solid was filtered off and the filtrate was decanted off. The organic layer was washed with 51ml of water and 26ml of brine to give 181.7g of a 2.13% by weight solution of II in MeTHF (yield: 48%).

Example 11: 19.80g (113mmol) of CDMT were dissolved in 205ml of MeTHF. 13ml (118mmol) NMM were added and the mixture was stirred at 25 ℃ for 2 h. 35g of a 25.5% by weight solution of VI in water of the bis (N-methylmorpholine) salt (51.3mmol) were mixed with 14.3ml (102.5mmol) of triethylamine, then a mixture of CDMT and VI in bis (N-methylmorpholine) salt (NMM) was added and the reaction mixture was stirred at 25 ℃ overnight. 51ml of water and 19.9 ml of concentrated HCl were added and the mixture was stirred at 25 ℃ for several minutes. The resulting solid was filtered off and the filtrate was decanted off. The organic layer was washed with 51ml of water and 26ml of brine to give 163.6g of a 2.56% by weight II solution in MeTHF (yield: 52%).

Racemic cinchonidine salt (III) is formed and subsequently converted into the single enantiomer (IV) of the cinchonidine salt

Example 12：

To 192.8g of an aqueous solution of lactonic acid (II) was added 66.8g of cinchonidine with stirring, and the mixture was stirred at a temperature of 20 ℃ to 25 ℃ for 10 minutes. The mixture was allowed to warm to 30 ℃ over 5 minutes and then stirred at this temperature during 30-40 minutes. The reaction mixture was cooled to 20 ℃ over 5 minutes and stirred for 10 minutes. The reaction mixture was seeded and allowed to crystallize at 20 ℃ to 25 ℃ for 20 hours with slow stirring, followed by obtaining a suspension. The precipitate was filtered off and washed with a mixture of 11.4ml water and 11.4ml acetone. The result is the octenidine salt (III) in enantiomeric purity e.r. 91/9. Then, 33.6g of the resulting wet crude product was reslurried under an inert atmosphere by adding 140.2ml of ethanol with 2% MEK (methyl ethyl ketone). Stirring was then started and 5.5.ml water was added. The reaction mixture was heated to 77 ℃ under reflux and stirred at reflux for 3 hours. The reaction mixture was cooled to 23 ℃ over 2 hours and stirred at 22 ℃ for 12.5 hours. The resulting precipitated product was filtered off and washed with 11.4ml ethanol with 2% MEK. The solid was dried under vacuum at 50 ℃ over a period of 4 hours to give 22.8g of cinchonidine salt (III) in enantiomeric purity e.r. 97/3 (i.e. (IV) as previously defined).

Claims (16)

1. A process for preparing a cinchonidine salt of formula (IV), said process comprising the steps of:

(a) subjecting 4-oxo-1, 2-cyclopentanedicarboxylic acid (V) to reduction in an aqueous environment to provide an aqueous solution of racemic 4-hydroxy-1, 2-cyclopentanedicarboxylic acid (VI);

(b) adding a water-miscible organic solvent to the aqueous solution obtained in (a);

(c) subjecting the racemic hydroxyacid (VI) to cyclization to give an aqueous-water miscible organic solvent solution of the corresponding racemic lactonic acid (II);

(d) adding cinchonidine to the aqueous-water miscible organic solvent solution obtained in (c) to obtain the cinchonidine salt of lactone acid (III);

(e) crystallizing said cinchonidine salt to obtain enantiomerically purified crystalline lactone acid cinchonidine salt (IV),

the chemical formulae numbered herein are as follows:

，

，

，

and。

2. a process according to claim 1, wherein the racemic lactone of formula (II) is prepared by intramolecular cyclization of a compound of formula (VI), characterized in that the reaction is carried out in the presence of water.

3. A process according to claim 2, which first reduces racemic compound (V) as defined in claim 1 to racemic compound (VI) as defined in claim 1, said reduction being carried out in the presence of water, and the reduction optionally being carried out by addition of an organic solvent.

4. The process according to claim 1, wherein the cinchonidine salt of formula (III) or (IV) is prepared by a process comprising contacting cinchonidine with racemic lactone acid (II), characterized in that the reaction is carried out in the presence of water.

5. The process of claim 2 or 3, which is carried out by the process of claim 4 for preparing (III) or (IV).

6. The process of claim 1 or 3, wherein the water-miscible organic solvent is selected from the group consisting of acetone, Methyl Ethyl Ketone (MEK), Tetrahydrofuran (THF), MeTHF, CPME (cyclopentyl methyl ether), acetic acid C_1-4Alkyl esters, propionic acid C_1-4Alkyl esters, butyric acid C_1-4Alkyl esters or toluene.

7. The process of any one of claims 1,2, 3, wherein the cyclization is carried out with a triazine derivative.

8. The process of claim 7, wherein the triazine derivative is selected from the group consisting of 2,4, 6-trichloro-1, 3, 5-triazine (TCT), chloro-dimethoxytriazine (CDMT), N- (3, 5-dimethoxytriazinyl) -N-methylchloromorpholine(DMTMM) and dichloro-methoxytriazine (DCMT).

9. The process of any of claims 1-3 or 8, wherein the cyclization is carried out in the presence of a tertiary amine.

10. The process of claim 9, wherein the tertiary amine is triethylamine or N-methylmorpholine (NMM).

11. A process for preparing an Intermediate (IX) useful in the preparation of an HCV inhibitor compound of formula I, said process comprising the steps of: preparing enantiomerically purified crystalline cinchonidine lactone salt (IV) in the process of any of claims 1 or 4 to 10 and reacting said cinchonidine lactone salt (IV) with N-methyl-hexenamine (NMHA) (VII) in an amide formation reaction according to the following scheme to give bicyclic lactone amide (VIII) with lactone group opened to give the desired product (IX):

，

wherein R is¹Is C_1-4An alkyl group.

12. The method of claim 11, wherein R¹Is methyl.

13. A process for the preparation of compound (I), which comprises preparing cinchonidine salt (IV) as claimed in any one of claims 1 or 4 to 8, followed by the preparation of compound (IX), and the synthesis of (I) using compound (IX) as an intermediate

，。

14. A process according to claim 13, wherein compound (IX) is prepared according to the process as described in claim 11 or 12.

15. A process for the preparation of compound (I) as defined in claim 13, which comprises preparing the lactone acid (II) as defined in claim 2 or 3, followed by the preparation of compound (IV), followed by the preparation of compound (IX), and the synthesis of (I) using compound (IX) as an intermediate

，。

16. A process according to claim 15, wherein compound (IV) is prepared according to the process of claim 4, and/or compound (IX) is prepared according to the process of claim 11 or 12.