WO2015036522A1 - Process for the preparation and isolation of (s)-3-amino-n-cyclopropyl-2,2-dialkoxyhexanamide and (s)-tert-butyl(1-(cyclopropylamino)-2,2-dialkoxy-1-oxohexan-3-yl)carbamate and use thereof for the preparation of telaprevir - Google Patents

Abstract

The present invention refers to processes for preparing (1S,3aR,6aS)-2-[(2Sv)-2-[[(2S)-2- Cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino]-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c] pyrrol-1-carboxamid via novel cyclic anhydrides as intermediates. The cyclic anhydrides can easily be reacted with cyclopropylamine to provide the intermediates (S)-3-Amino-N-cyclopropyl-2,2-dialkoxyhexanamide and (S)-tert-Butyl (1-(cyclopropylamino)-2,2-dialkoxy-1-oxohexan-3-yl)carbamate. The present invention also refers to intermediates of the process for preparing telaprevir and processes for the synthesis of said intermediates.

Description

Process for the preparation and isolation of fS)-3-Amino-/V-cvcloprqpy[-_2.2-dialkoxyhexanamide and (S)-tert-Butyl (Hc¥oloprop¥laroino)~2 -diaikox¥-1^ and use thereof for the preparation of telaprevir

The present invention refers to processes for preparing telaprevir via novel cyclic anhydrides as intermediates. The cyclic anhydrides can easily be reacted with cyclopropylamine to provide the intermediates (S)-3-Amino-/V-cyclopropyl-2,2-dialkoxyhexanamide and (S)-tert-Butyl (1- (cyclopropylamino)-2,2-dialkoxy-1-oxohexan-3-yl)carbamate (see Formulas 7a and 6aa below). The present invention also refers to said isolated intermediates as well as processes for the synthesis thereof.

Background prior art

Telaprevir {(1 S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethylbutanoyl)-N-((S)-1-(cyclopropylamino)-1 ,2-dioxohexan-3-yl)octahydrocyclopenta

[c]pyrrole-1 -carboxamide as shown in Formula 1 below} is a protease inhibitor that can be used as antiviral drug. By way of example, telaprevir inhibits the hepatitis C virus NS3-4A serine protease. A building block for telaprevir is the compound of Formula 7a (see also Figure 1 herein):

7a

WO 200 e preparation of a compound having the following

formula:

by using optically active oxazolines as intermediates.

WO 2007/109023 A1 describes the preparation of the same compound via epoxidation of an α,β-unsaturated carboxyamide, azidation of the epoxide, reduction of the azide group to provide an amine and subsequent racemic resolution. WO 2009/1 14633 A1 also describes a synthesis for the above compound starting from norvaline. In order to elongate the chain of norvaline, a cyanide addition is performed.

WO2009/152474 A2 describes a process for the preparation of 3-amino-N-cyclopropyl-2- hydroxyalkane amide derivatives as key intermediates in the production of HCV inhibitors. The synthesis route comprises a step of reacting an aminoaldehyde with a cyclopropyl isocyanide to obtain an 3-amino-2-hydroxycarboxylic acid amide.

Pelotier et al. ( Eur. J. Org. Chem. 2005, 2599-2606) discloses the synthesis of β-lactams via [2+2] cycloadditions of silylketenes and imines. Reference is also made to Gizecki et al.

(Tetrahedron Letters, 2004, 45, 9589-9592).

Yin et al. (Synthesis, 2010, 21 , 3583-3595) discloses the use of a-amido sulfones as in situ imine precursors for asymmetric catalytic nucleophilic addition reactions.

WO 2007/022459 A2 discloses a synthesis of Telaprevir in which the final step is an alcohol to ketone oxidation

Yamamoto (Journal of the American Chemical Society 1993, 115, 1 151 and Tetrahedron 1994, 50, 9, 2785) describes a process for the synthesis of building blocks for the synthesis of taxol. The synthesis includes the use of an imine, a silyl enol ether, a Lewis acid (LA) and chiral boron reagents (see Figure 2 herein).

PCT/EP2013/062737 and EP 12 172 775.4 (EP application number of the international application PCT/EP2013/062737), respectively, describes a new process for the preparation of β-amino acid derivatives based on an asymmetric Mukaiyama aldol reaction. This route for the intermediate 7aa is shown in Figure 3. Herewith, PCT/EP2013/062737 and EP 12 172 775.4, respectively, i.e. the international application as published (WO-publication), is incorporated by reference in its entirety.

Therein, a β-amino acid derivative (Compound 4a) is obtained from a Mukaiyama Aldol reaction between a silyl enol ether and a chiral imine in good yields and good diastereoselectivity. The chiral auxiliary is exchanged for an electron-withdrawing group via hydrogenation and the resulting ester is hydrolyzed with a base. The free carboxylic acid is then activated by an activating reagent (here DIC = diisopropyl carbodiimide) and converted into the N-protected cyclopropyl amide. Finally, the protecting group is cleaved and Compound 7a is isolated as a free base in form of an oil.

N-Carboxyanhyd rides of a-Aminoacids are well known in the literature. The formation can either be done by phosgene or its analoga or from a N-carbamate protected precursor (see for example Blacklock, T. J.; Shuman, R. F.; Butcher, J. W.; Schearin, W. E.; Budavari, J.; Granda, V. J. J. Org. Chem. 1988, 53, 836; Declerck, V.; Nun, P.; Martinez, J.; Lamaty, F. Angew.

Chem. Int. Ed. 2009, 48, 9318; Katakai, R.; lizuka, Y. J. Org. Chem. 1985, 50, 715; Oya, M.; Katakai, R.; Nakai, H. Chem. Lett. 1973, 1 143; Wilder, R.; Mobashery, S. J. Org. Chem. 1992, 57, 2755; Daly, W. H.; Poche, D. Tetrahedron Lett. 1988, 29, 5859; Smeets, N. M. B.; van der Weide, P. L. J.; Meuldijk, J.; Vekemans, J. A. J. M.; Hulshof, L. A. Org. Proc. Res. Dev. 2005, 9, 757; EP1362864; WO06078809; W010103405; US2005/0171 165; EP1367061 ; W09633984 and J. Org. Chem. 2001 , 4413, J. Med. Chem 1987, 1543). The five-membered cyclic sulfur analogue and its formation as a five membered ring are also known. However, the formation of N-Carboxyanhydrides of β-Amino acids is much less common and substantial difficulties have been reported (see Kricheldorf as cited below). Only a few protocols are known for the synthesis of six-membered carbocycles, all of them either requiring a carbamate protection of the amino group or using the carbamate protecting group as a sacrificial carbonyl source for the cyclisation under Lewis acid mediated conditions (see more detailed discussion below). In some cases, a simple carbamate protection did not suffice, and two carbamate protecting groups group had to be employed, one of them serving as the carbonyl source and the other as a protecting group (see McKiernan cited below). In addition, the substrates reported in the literature examples exhibit simple substitution patterns; to the best of our knowledge, there is no example for the formation of a six-membered ring from an a.a-dialkoxy-p-amino acid. From the field of polymer chemistry US2600596 discloses the formation of a 6-membered N-carboxyanhydride starting from an α,α-dialkyl β-amino acid by using poisonous gaseous phosgene. However, the yield of the reaction is very low (<20%). Six-membered sulfur analoga are only known employing condensed substrates with aromatic rings (e.g. with aminobenzoic acid). One of the major drawbacks for the use of β-amino acids as substrates and particularly of those α,α-disubstituted in amidation reactions, is the formation of the corresponding β-lactams as a prominent side reaction.

Reference is also made to Zografos et al. (J. Org. Chem. 2001 , 4413) and Hermecz et al. (J. Med. Chem 1987, 1543).

US2600596 refers to the field of polymer chemistry and discloses the formation of C-rings starting from dialkyl substrates by using gaseous phosgene.

Cheng et al. (J. Org. Lett. 2000, 2, 1943) refers to the field of polymer chemistry and discloses a Lewis acid-mediated (PBr3) breakup of a carbamate for the formation of a cyclic intermediate which is used for preparing amino acid polymer chains. Bose et al. (Synthesis 2010, 4, 643) discloses the synthesis of cyclic intermediates by using phosgene analogues or via the breakup of a carbamate (scheme 4). It also involves the opening of the cycle with a nitrogen nucleophile (i.e. proline, scheme 4).

Huck et al. (J. Peptide Res. 2003, 62, 233-237) describes a Boc-protected cyclic intermediate. The opening of a cycle with an amine nucleophile (there Figure 1 , 1 -> 9) is described.

McKiernan et al. (J. Org. Chem. 2001 , 66, 6541 -6544) describes the preparation of cyclic anhydrides. The formation of a cyclic intermediate via a Lewis acid-mediated (PBr3) breakup of a carbamate failed (see scheme 1 and page 6541 , line 5 from botton: "several reactions failed to afford the desired six-membered ring NCA 4"). Instead, the Boc-protected substrate had to be prepared from the doubly Boc-protected amino acid (schemes 2 and 3). The document also describes the opening of the Boc-protected cyclic intermediate with an amine nucleophile (scheme 4, Nu = NHBn).

Kolb et al. (Tetrahedron Lett. 2002, 43, 6897) describes a Lewis acid-mediated (PBr3) breakup of a carbamate for the formation of a cyclic intermediate for the preparation of a thiazole moiety of a drug compound.

Akssira et al. (Tetrahedron 1993, 49, 1985) discloses a Lewis acid-mediated (SOCI₂) breakup of a Boc-carbamate for the formation of a cyclic intermediate.

Kricheldorf (Angew. Chem. Int. Ed. 2006, 45, 5752-5784) is a review article which deals primarily with the formation of five-membered rings from a-amino acids and their application in the field of polymer chemistry. However, a statement on page 5776, left column, first paragraph, illustrates the difficulty of preparing six-membered intermediates: "In contrast to a-amino acids, β-amino acids do not readily form (six-membered) NCAs but rather undergo a polycondensation process yielding oligoamides when activated at the C0₂H group with 1 -ethyl 3-(3- dimethylaminopropyl) carbodiimide.".

Although the above-described processes are known, there is still a need for new processes for the preparation of telaprevir and its intermediates, in particular processes which may have a reduced number of process steps, are easy to perform and provide for a high yield and purity while avoiding the use of expensive and toxic reagents.

Although some processes for the synthesis of telaprevir and its pharmaceutically acceptable salts are available, it is an object of the present invention to provide new processes and new intermediates, in particular enhanced processes that overcome at least one of the problems of the prior art processes. Summary of the invention

Some of the known processes for the preparation of telaprevir are based on the use of 3-amino- N-cyclopropyl-2-hydroxyhexanamide as intermediate. The processes described herein (see e.g. Figure 18b and c) refer to the preparation of 3-amino-N-cyclopropyl-2,2-dialkoxyhexanamide intermediates. In particular, the invention relates to the preparation of (S)-3-Amino-/V- cyc!opropyl-2,2-dialkoxyhexanamide 7a

7a

and (S)-tert-Butyl (1-(cyclopropylamino)-2,2-dialkoxy-1 -oxohexan-3-yl)carbamate 6aa

Boc_s

6aa

Intermediates 7a and 6aa (6aa after removal of the Boc-group) can be reacted with an acid moiety such as

in order to provide dialkoxy ketal intermediates of Formula 9a

of telaprevir which can be easily converted into telaprevir. The Mukaiyama aldo! addition with silyl enol ethers described in PCT/EP2013/062737 and EP 12 172 775.4, respectively can be used for a stereoselective preparation of the starting materials of the present invention (see preparation of Compound 4aa in Figure 3 and use of Compound 4aa according to the present invention as e.g. shown in Figures 4 and 18a-c). The stereo information required for the telaprevir synthesis can thus be provided by (S)- phenylethylamine which is readily available and cheap. The combination of imine 2a and silyl enol ethers 3 in the presence of a Lewis acid has a high reactivity and allows achieving high selectivities even without using chiral Lewis acids.

Furthermore, the oxidation state in the a-position of the enol component used in the Mukaiyama aldol addition can freely be chosen independent of the imine. For example, after coupling 3- amino-N-cyclopropyl-2,2-dialkoxyhexanamides with the acid component 8a, the obtained telaprevir acetal intermediate already has the oxidation state of telaprevir and the acetal can thus easily be converted to telaprevir. This may provide a synthetic route with a reduced number of process steps.

Thus, the final chemical transformation of dialkoxy-telaprevir toward telaprevir is an acid deprotection of an acetal, as opposed to the prior art routes in which the last step is an oxidation of an alcohol to a ketone. Oxidative transformations on substrates containing oxidation-sensitive functional groups such as heteroaromatic systems, ketones and a-ketoamides are well known to give rise to byproducts: all these moieties are present in telaprevir and therefore the formation of oxidative byproducts is very likely and has been proven in our laboratory experimentally. By using the route described herein with no oxidation as final step, the formation of these byproducts is avoided. Thus, the route of the present invention using dialkoxy (such as diethoxy or dimethoxy)-telaprevir as final intermediate secures the absence of these oxidative byproducts. Given the fact that telaprevir prepared according to the prior art route (in which the last step is an oxidation of an alcohol to a ketone) contains these byproducts, an improvement of the product's quality can be achieved by using the oxidation free route described herein, without additional purification measures being necessary. Also one of this impurities (IMP1 ) can be removed via additional basic extraction at pH>11 (which can cause epimerization) (see Example 21 ), the other one is found in commercially available products.

Furthermore, the usage of cyclic anhydrides as activated intermediates according to the present invention provides a shorter route (with respect to the number of steps) towards Compound 7a in comparison with the process described in PCT/EP2013/062737 and EP 12 172 775.4. The protecting group interconversion and the usage of additional reagents can be avoided. Moreover, all intermediates crystallize and allow an isolation and purification during the process. In particular, the prior art amidation steps often require problematic reagents (costs, atom economy, waste) which can be avoided when using the process of the present invention. For example, anhydrous HOBt is a hazardous, potentially explosive chemical that cannot be transported by air, and DIC can potentially cause contact allergies.

The new route thus comprises: i) a small number of chemical steps (improving efficiency/yield and reducing costs), ii) solid intermediates suitable for isolation and purification, iii) solid 7aa in the form of a salt, if it is desired to not prepare the free base form of 7aa in the form of an oil, and iv) requires less reagents and solvents. The overall process utilizes simple and cheap reagents and standard techniques that are well-suited for pilot plant development and upscaling procedures.

Furthermore, as described above, one of the major drawbacks for the use of β-amino acids as substrates and particularly of that α,α-disubstituted in amidation reactions, is the formation of the corresponding β-lactams as a prominent side reaction. For example, attempts to synthesize 7a via amidation or amidation/hydrogenation from 2a' and 6a' using reaction conditions known in the art (i.e. (a): EDCI, HOBt (b): (COCI)2) resulted in the formation of the corresponding β- lactam byproducts (see Comparative Example 22). Furthermore, even the reaction of 6a' with phosgene or phosgene derivatives yielded the β-lactam product. However, it was unexpectedly found that the use of the specific combination of reagents such as phosgene analogues, SOCI₂/imidazol and specific reaction conditions of the present invention allow the synthesis of the cyclic intermediates and amide products for use in telaprevir synthesis as described herein.

Description of the Figures

Figure 1 : Shows (S)-3-Amino-A/-cyclopropyl-2,2-diethoxyhexanamide (7aa) which is a suitable building block of the NCV NS3 protease inhibitor telaprevir (1 ).

Figure 2: Shows a process developed by Yamamoto et al. (see above citation) for the synthesis of building blocks for the synthesis of taxol. The synthesis includes the use of an imine, a silyl enol ether, a lewis acid (LA) and chiral boron reagents. TBAF = tetra-n- butylammonium fluoride, (R)-BINOL = (R)-(+)-1 , 1 -Bi(2-naphthol).

Figure 3: Shows a process for the preparation of β-amino acid derivatives based on an asymmetric Mukaiyama aldol reaction as described in PCT/EP2013/062737 and EP 12 172 775.4, respectively. Figures 4 and 5: Show examples of the process of the invention for preparing intermediate 7aa.0.5 DTTA/LTTA and 3aa\ respectively.

Figure 6: Shows the deprotection of Compound 6aaa to provide Compound 7aa.

Figure 7. Shows prior art oxidation process including oxidative by-products

Figures 8-17. Show reaction schemes from the experimental examples.

Figure 18a-c. Show reaction schemes according to the present invention.

Figure 19. Shows a reaction scheme for the synthesis of 7a via amidation or amidation/hydrogenation (comparative example).

Detailed Description

The invention generally relates to processes and intermediates for the preparation of telaprevir according to Formula 1

or a pharmaceutically acceptable salt or solvate as well as intermediates thereof.

Herein, the expressions "compound of Formula X", "compound according to Formula X", "Compound X" and "Formula X" are interchangeably used for the compound depicted as Formula "X".

Pharmaceutically acceptable salts include, but are not limited to the group consisting of hydrochloride, hydrobromide, sulphates or phosphates as well as organic salts such as acetate, citrate, maleate, succinate, lactate, and benzoate. Pharmaceutically acceptable salts can be obtained according to standard methods, for example by addition of the respective acid to telaprevir as free base.

The invention thus relates to a process for the preparation of telaprevir of Formula 1

or a pharmaceutically acceptable salt or solvate thereof, comprising a step (i). Step (i) comprises or consists of providing a compound of Formula 2'

2'

wherein R₄ is methyl or ethyl, preferably a compound of Formula 2a'

The compound according to Formula 272a' can be prepared as described below. It can be used in enantiomerically pure form. Preferably, the compound of Formula 2', such as Compound 2a', has an enantiomeric excess of at least 70%, preferably 80%, further preferred 90%, even further preferred 95% and most preferably more than 97% based on the total amount of both isomers of Formula 272a'. The enantiomeric purity, referred to in the context of the present invention, can for example be determined by appropriate nuclear magnetic resonance (NMR) experiments as known in the art or by chiral high performance liquid chromatography (HPLC) as known in the art.

Subsequent to, preferably directly after, step (i), step (ii) is performed. Step (ii) comprises/consists of subjecting the compound of Formula 2', such as Formula 2a', to one of the steps/sequences (iia)-(iid):

Step/sequence (iia) comprises or consists of reacting the compound of Formula 2' or 2a' with phosgene or a phosgene analogue/derivative to obtain the compound of Formula 3a' or 3aa'

3a' wherein R₄ is as defined above

3aa' via cyclization reaction.

Steps (iia) (see above), (iib), (iicb), and (iidc) (see below) represent the key steps of this new process and refer to an in-situ formation of a six-membered anhydride of general Formula 3', which is activated for the subsequent cyclopropylamidation, with a suitable ring forming agent reagent such as phosgene, thionyl chloride (SOCI₂)/imidazole or imidazole derivatives and phosgene derivatives/analogues (see for example Figures 4 and 5). The cyclic anhydride is readily formed from the compound of Formula 2'. The anhydride of Formula 3' does not need to be isolated and can be directly converted, for example into 7a or 6aa by addition of cyclopropylamine. The term "cyclic anhydride" as used herein refers to all compounds of Formula 3'

in this context (regardless of the nature of X). In Formula 3', R can generally be H, any alkyl or aryl group or any nitrogen protecting group, preferably a carbamate protecting group, more preferably Boc, X is a non-metallic element of group 3, 4, 5 and 6 of the periodic table, preferably C or S, and R₄ is alkyl such as methyl or ethyl.

Reaction step (iia) can for example be performed an aprotic solvent, preferably in tetrahydrofuran (THF) or methylene chloride. For performing this reaction, for example, a solution of phosgene or phosgene derivative/analogue in an aprotic solvent or mixture of solvents is added to a solution/suspension of the compound of Formula 2' or 2a' in a solvent or mixture of solvents under stirring. The addition of the phosgene or phosgene derivative/analogue can for example be performed at a temperature of less than 5°C, such as in the range of from -20X to less than 5°C. The reaction mixture can then be stirred, e.g. at a temperature in the range of from 10°C to 30°C, for completion of the reaction, e.g. can be stirred for 1-6 hours.

For example, phosgene readily cyclizes Compound 2' into the cyclic anhydride of Formula 3a' at room temperature in THF. In order to avoid the potentially problematic reagent phosgene a phosgene-substitute/derivative/analogue such as for example "diphosgene" (trichlormethyl chloroformate) can be used. The formation of the cyclic anhydride can be monitored via HPLC.

Phosgene derivatives/substitutes/analogues are compounds capable of providing COX₂, wherein X is a halogen, in situ under suitable reaction conditions. Examples include, but are not limited to CF₃C(0)F, (CI₃CO)COCI, and (CI₃CO)₂CO. Preferably, phosgene or trichloromethylchloroformate is used in the context of the present invention. Depending on the reagent used, for example 0.3 to 1.1 equivalents of phosgene or of the phosgene derivative/substitute/analogue per amount of Compound 2' can be used.

Step/sequence (iib) comprises or consists of reacting the compound of Formula 2', such as Compound 2a', with a mixture of SOCI₂ and imidazole or imidazole derivatives to obtain the compound of Formula 3b' or 3ba'

3b' wherein R₄ is as defined above,

3ba' via cyclization reaction. In the context of the present invention, imidazole derivatives are defined as imidazole compounds in which one or more of the positions 2, 4 or 5 of the imidazole ring are substituted with a group other than hydrogen. Such compounds include, but are not limited to, 1 H-benzimidazole, 1 H-5-methyl-imidazole, 1 H-5-bromoimidazole, 1 H-2-ethyl-5-methyl- imidazole and 1 H-5-nitroimidazole.

In step (iib), thionyl chloride and imidazole are pre-mixed in an aprotic solvent or mixture of aprotic solvents, preferably dichloromethane, preferably at low temperatures such as below 0°C, e.g. -10°C. Depending on the molar ratio of SOCI₂:imidazole used, 1 H-imidazole-1 -sulfinyl chloride (1 :2) or 1 , 1 '-sulfinylbis(1 H-imidazole) (1 :4) is formed. Either one of these in situ generated reagents readily reacts with Compound 2' to give the cyclic anhydride 3b'. Suitable ratios SOCI₂:imidazole are for example 1 :1 ,5 to 1 :5, preferably 1 :2 or 1 :4.

Intermediate 3b' is then converted into 7a, preferably without isolating Compound 3', upon treatment with cyclopropylamine in step (iii). Ideally, in order to achieve the maximum yield and to minimize side-reactions, the whole process can be performed at low temperature such as about 0°C, or in a range of from -20°C to 5°C. The synthesis of the reagents 1 H-imidazole-1 - sulfinyl chloride and 1 , 1 '-sulfinylbis(1 H-imidazole) is fast and may be complete within one hour (see examples 14 and 15 below), and the cyclization to the cyclic anhydride 3b" may take less than an hour. The reaction with cyclopropylamine is almost instantaneous.

Reaction step (iib) can for example be performed in dichloromethane as the solvent or in other aprotic solvents. For performing this reaction, for example, the compound of Formula 2' or 2a' is added to a filtered solution of SOCI₂:imidazole in dichloromethane under stirring for example -10°C. The reaction mixture can then be stirred at a temperature in the range of from 10°C to 30°C for completion of the reaction, e.g. can be stirred for 1 -6 hours. The product can then be isolated. Sequence (iic) is described in the following. It comprises or consists of steps (iica) and (iicb). Step (iica) comprises or consists of protecting the compound of Formula 2', such as Compound 2a', to provide a compound of Formula 4' or 4a'

4'

wherein R₄ is as defined above,

4a'

The enantiomeric excess of the compounds of Formula 4', and 4a', described herein, corresponds to that of its precursors, i.e. Compounds 2' and 2a', respectively. Compounds of Formula 2' can be (te rt-b utoxyca rbo ny I )-protected by applying standard conditions known to a skilled person, such as those described in T. W. Greene & P.G.M Wuts, "Protective Groups in Organic Synthesis," 4th Edition, John Wiley & Sons, Inc. (2007), pages 706-776, especially pages 725-735. Step (iicb) comprises or consists of reacting the compound of Formula 4' or 4a' with a Lewis acid, such as SOCI₂ or methanesulfonyl chloride, to obtain the compound of Formula 3a' or 3aa'

3a'

wherein R₄ is as defined above,

3aa' via cyclization reaction.

Cyclization of the compounds of Formula 4', such as 4a', can be performed with thionyl chloride or methanesulfonyl chloride (MsCI) or other Lewis acids. Such cyclization reactions are oftentimes problematic; for example, doubly Boc-protected substrates had to be prepared according to prior art processes in order to synthesize the corresponding cyclic anhydrides because the unprotected cycle arising from single-Boc-protected substrates were too unstable to be isolated (McKieman et al., "Urethane N-Carboxyanhydrides from β-Amino Acids", The Journal of Organic Chemistry 2001 , 66, 6541-6544). The reaction can be performed by adding the Lewis acid to a solution of Compound 4', e.g. in dimethylformamide for example at room temperature, i.e.15°C to 25°C, using e.g. 1.2 equivalents of Lewis acid.

Sequence (iid) comprises or consists of steps (iida), (iidb) and (iidc). Step (iida) comprises or consists of protecting the compound of Formula 2', such as Compound 2a', to provide a compound of Formula 4' or 4a'

wherein R₄ is as defined above,

4a' The process for providing a Boc-protection group to Compound 2' is described above.

Step (iidb) comprises or consists of protecting the compound of Formula 4' or 4a' to provide a compound of Formula 5', preferably 5a'

5' wherein R₄ is as defined above,

5a'

The stereochemical purity of the compounds of Formula 5' and 5a' corresponds to that of its precursors, i.e. Compounds 2' and 2a', respectively. Compounds of the formula 4' can be Boc- protected by applying standard conditions, such as Boc₂0 in DMAP. A suitable amount of Boc₂0 is show in Example 17. The reaction can be performed for example at room temperature, i.e. in a range of from 15°C to 25°C, for example, the mixture can be stirred for 2-3 days at room temperature. The resulting product can then be isolated by applying standard techniques such as extraction from the aqueous mixture and subsequent solvent evaporation.

Step (iidc) comprises or consists of reacting the compound of Formula 5' or 5a' with a Lewis acid, such as SOCI₂ or methanesu!fonyl chloride, to obtain the compound of Formula 3c' or 3ca'

wherein R₄ is as defined above,

3ca' via cyclization reaction.

Step (iidc) proceeds via a cyclic anhydride 3c' in which the amine is Boc-protected. Cyclization of 5', such as 5a', can be performed with thionyl chloride or methanesulfonyl chloride or other Lewis acids in a manner similar to that described for step (iicb).

The enantiomeric excess of the compounds of Formula 3', 3a', 3aa\ 3b', 3ba\ 3c' and 3ca' described herein, corresponds to that of its precursors. The compounds according to Formula 3", 3a', 3aa\ 3b', 3ba\ 3c' and 3ca' can be provided in stereochemically pure form. Preferably, these compounds have an enantiomeric/stereochemical purity of at least 70%, preferably 80%, further preferred 90%, even further preferred 95% and most preferably more than 97% based on the total amount of all isomers of said compounds.

The process of the invention further comprises step (iii). Step (iii) comprises or consists of performing an amide coupling reaction of the compound of Formula 3', 3a'/3aa', 3b73ba' or 3c'/3ca' with cyclopropylamine in order to provide a compound of Formula 7a/7aa or 6aa/6aaa

Boc

NH₂ O NH₂ O NH O

R₄0 OR₄H EtO OEtH R₄0 OR₄H

7a 7aa 6aa

6aaa optionally isolating the compound of Formula 7a/7aa, or 6aa/6aaa.

Cyclopropylamine can be added after complete conversion into the cyclic anhydride in step (ii) either directly or as a solution, preferably in THF, ideally at a temperature < 15 °C, or in a range of from -80°C to -5°C. The conversion can then be completed e.g. by stirring the reaction mixture at room temperature, for example 8-24 hours. An excess of the amine is preferably used in order to neutralize the excess of HCI formed during the reaction. Preferably 5 equivalents of the amine are used. The usage of a second, cheaper amine for that purpose may possibly also be an option. The addition of cyclopropylamine converts the intermediately formed cyclic anhydride directly into the amide. The compounds according to Formula 7a, such as 7aa, and 6aa, such as 6aaa can be isolated as the free base.

The compounds according to Formula 7a, such as 7aa, and 6aa, such as 6aaa can be provided in stereochemically pure form. The enantiomeric excess of the compounds of Formula 7a, such as 7aa, and 6aa, such as 6aaa described herein, corresponds to that of its precursors. Preferably, these compounds have an enantiomeric/stereochemical purity of at least 70%, preferably 80%, further preferred 90%, even further preferred 95% and most preferably more than 97% based on the total amount of all isomers of said compounds.

The process of the invention further comprises an optional step (iv). Step (iv) comprises converting the compound of Formula 7a/7aa, into a salt and isolating said salt.

The salts of the compounds according to Formula 7a/7aa can be provided in stereochemically pure form. Preferably, these compounds have an enantiomeric/stereochemical purity of at least 70%, preferably 80%, further preferred 90%, even further preferred 95% and most preferably more than 97% based on the total amount of all isomers of said compounds.

The compounds according to Formula 7a, such as 7aa, and 6aa, such as 6aaa, can be isolated as the free base as described above. Compounds of the Formula 7a, such as 7aa, can also be isolated as a solid in the form of a salt, preferably in the form of a tartrate such as e.g. Ο,Ο'-di- p-toluoyl-D-tartaric acid or O.O'-di-p-toluoyl-L-tartaric acid salts 7a.0.5DTTA or 7a.0.5LTTA by crystallization. Compounds 2a', 6a' and the salts of 7aa described herein are solids.

Other salts include the HCI, di-O.O'-benzoyl-D-tartrate (DBTA), di-O.O'-anisoyl-D-tartrate (DATA) and p-phenylbenzoic acid salts. The use of the aforementioned acids is disadvantageous due to low yields (HCI), tendency to resin formation (DBTA, DATA) and cumbersome removal of excess free acid (DATA, DBTA, p-phenylbenzoic acid). Thus, the use of DTTA or LTTA is preferred.

The process of the invention further comprises an optional step (v). If the compound of Formula 6aa/6aaa is prepared in steps (iii)/(iv), step (v) comprises or consists of converting the compound of Formula 6aa/6aaa into a compound of Formula 7a/7aa, and optionally isolating the compound of Formula 7a/7aa. The Boc-protection group in Compound 6aa/6aaa (see Figure 6) can be removed by applying standard techniques as described in T. W. Greene & P.G.M Wuts, "Protective Groups in Organic Synthesis," 4th Edition, John Wiley & Sons, Inc. (2007), pages 727-732 (see also acidic removal as described in PCT/EP2013/062737 and EP 12 172 775.4, respectively).

The process of the invention further comprises a step (vi). Step (vi) comprises or consists of bringing the compound of Formula 7a/7aa or its salt into contact with a compound of Formula 8a or its salt

8a in the presence of one or more coupling agents, thereby obtaining a compound of Formula 9a or 9aa

optionally isolating the compound of Formula 9a/9aa.

The amine coupling reactions can for example be carried out as described in described in PCT/EP2013/062737 and EP 12 172 775.4, to which reference is made.

The amine coupling reactions can for example be carried out in the presence of a base and one or more coupling agents selected from the group consisting of dicyclohexylcarbodiimide (DCC), diispropylcarbodiimide (DIG), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), 1 -hydroxy-benzotriazole (HOBt) or 1 -hydroxy-7-aza-benzotriazole (HOAt), O- Benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate (HBTU), 0-(7-

Azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 0-(6- Chiorobenzotriazol-l-ylJ-N.N.N'.N'-tetramethyiuronium hexafluorophosphate (HCTU), O- (Benzotriazol-1 -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (TBTU), (benzotriazol-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate) (PyBOP), substituted 1 ,3,5,2,4,6- trioxatriphosphorinane-2,4,6-trioxide and via the formation of a mixed anhydride using a chloroformate ester, pivaloyl chloride, mesyl chloride or similar reagents known to persons skilled in the art. Preferred coupling reagents for amidation of beta-amino acids are DIC/HOBt and TBTU; for the amide coupling reaction the preferred reagents are T3P, EDC/HOBt, DIC/HOBt and isobutyl chloroformate.

A preferred substituted 1 ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide is a compound of Formula 22

wherein R₃ is a saturated or unsaturated, branched, cyclic or linear, substituted or unsubstituted Ci-io hydrocarbon compound, preferably, R₃ is n-propyl or phenyl. Examples of compounds of are 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P) and 2,4,6-triphenyl- 1 ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide. It is preferred to use it as the only coupling agent.

However, it is also possible to use other coupling agents known in the art such as uranium coupling agents. For an overview of possible coupling reagents, reference is made to Han, S.- Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447-2467.

The amount of coupling agent(s) can be from 0.8 to 6 equivalents, preferably from 0.9 to 4 equivalents, further preferred from 1 to 2 equivalents, based on the total amount of the acid compound that is to be coupled. If more than one coupling agent is used, the different types of coupling agents can be used in the same or different amounts. Preferably, they are all used in an amount of more than 1 equivalent based on the amount of the acid compound. Further preferred, each coupling agent is used in an amount of 1 to 2 equivalents based on the total amount of the acid compound. The process of the invention further comprises step (vii). Step (vii) comprises or consists of deprotecting/cleaving the acetal in the compound of Formula 9a/9aa in the presence of an acid thereby obtaining telaprevir of Formula 1 , or a pharmaceutically acceptable salt or solvate thereof. During the deprotection step, the presence of a ketone such as acetone is preferred. According to the invention, an oxidation reaction in the last step of the preparation of telaprevir can be avoided by performing an acetal deprotection step as the last synthesis step as described above. The thus obtained telaprevir is preferably essentially free of oxidative side- products and preferably contains oxidative side products in amounts of less than 0.10 area% as determined by HPLC or LC-MS analysis (see Example 20).

In the process of the invention, step (i) of providing a compound of Formula 2' can include one of the sequences (ia)-(ic).

Sequence (ia) comprises or consists of steps (iaa), (iab) and (iac).

Step (iaa) comprises or consists of providing a compound of Formula 4a

4a

wherein R₄ is methyl or ethyl, and R₅ is selected from the group consisting of linear, branched, or cyclic aliphatic groups, aromatic groups, and heteroaromatic groups as well as combinations thereof preferably in all aforementioned definitions R₅ has 1-12 carbon atoms or 1-6 carbon atoms, in particular R₅ is a linear, branched, or cyclic aliphatic C1-C12 or d-C₆ group, in addition in all aforementioned definitions R₅ is preferably a saturated and unsubstituted hydrocarbon group; R₅ preferably only comprises hydrogen and carbon atoms; preferably R₅ is methyl or ethyl; preferably a compound of Formula 4aa

4aa

Step (iaa) starts from Compound 4a which can be obtained by a Mukaiyama aldol reaction as described herein and in PCT/EP2013/062737 and EP 12 172 775.4, to which reference is made.

Step (iab) comprises or consists of hydrolyzing the compound of Formula 4a/4aa to provide the compound of Formula 6' or 6a'

6' 6a'

The compound of formula 6', such as 6a', is easily obtained by standard hydrolysis with various bases. For example, hydrolysis can be performed with KOH in water/ethanol at increased temperatures, e.g. above 60°C or above 80°C. Purification is simply done by extraction and/or by crystallization and a considerable increase in quality is observed. For example, the ethyl ester of Formula 4a can be hydrolyzed with a strong base such as a metal hydroxide such as KOH and the corresponding carboxylic acid 6', for example 6a', can be isolated by crystallization.

The compounds according to Formula 6' and 6a' can be provided in stereochemically pure form. Preferably, these compounds have an enantiomeric/stereochemical purity of at least 70%, preferably 80%, further preferred 90%, even further preferred 95% and most preferably more than 97% based on the total amount of all isomers of said compounds.

Step (iac) comprises or consists of deprotecting the compound of Formula 6a' or 6aa' to provide the compound of Formula 2'. In this step, the chiral auxiliary 6', such as 6a', is cleaved by hydrogenation to give the free amino acid of Formula 2', which can also be isolated after crystallization. The hydrogenation of the compound of Formula 6a', such as 6aa', can be performed under various conditions (neat H₂-atmosphere or forming gas, various metal catalysts, and various solvents). For example, hydrogenation is performed with H₂, Pd/C, for example in ethyl acetate. The compound of Formula 2' crystallizes from several solvents, such as EtOH, and the process delivers a product with a high purity.

Sequence (ib) comprises or consists of steps (iba), (ibb) and (ibc).

Step (iba) comprises or consists of providing a compound of Formula 4a as in step (iaa), to which reference is made.

Step (ibb) comprises or consists of deprotecting the compound of Formula 4a/4aa to provide the compound of Formula 7', such as 7a'

7a'

The compounds according to Formula 7', and 7a' can be provided in stereochemically pure form. Preferably, these compounds have an enantiomeric/stereochemical purity of at least 70%, preferably 80%, further preferred 90%, even further preferred 95% and most preferably more than 97% based on the total amount of all isomers of said compounds. The deprotection step can be performed as in step (iac).

Step (ibc) comprises or consists of hydrolyzing the compound of Formula 777a' to provide the compound of Formula 2'. The hydrolysis step can be performed as in step (iab).

Sequence (ic) comprises or consists of steps (ica) and (icb). Step (ica) comprises or consists of providing a compound of Formula 4' or 4a'

wherein R₄ is as defined above,

4a'

Compound 4a' can be prepared as described herein (see above and Example 1 1 ) or as described in PCT/EP2013/062737 and EP 12 172 775.4.

Step (icb) comprises or consists of deprotecting the compound of Formula 4' or 4a' to provide the compound of Formula 2'. The deprotection step can be performed as in step (v).

In the process of the invention, providing a compound of Formula 4a/4aa in steps (iaa) and (iba) can include steps/stages (i) and (ii). Step (i) comprises or consists of providing a compound of Formula 2a

2a The compound according to Formula 2a can be prepared by applying standard synthesis methods (see e.g. Eur. J. Org. Chem. 2005, 2599-2606 and "March's advanced organic chemistry" Ed.5. p.1 185-1 187).

The compound according to Formula 2a can be used in stereochemically pure form, based on synthesis from enantiomerically-enriched building blocks. Preferably, the compound of Formula 2a has an enantiomeric/stereochemical purity of at least 70%, preferably 80%, further preferred 90%, even further preferred 95% and most preferably more than 97% based on the total amount of all isomers of Formula 2a. The stereochemical purity/enantiomeric purity, referred to in the context of the present invention, can for example be determined by appropriate nuclear magnetic resonance (NMR) experiments as known in the art or by chiral high performance liquid chromatography (HPLC) as known in the art.

Step (ii) comprises or consists of bringing the compound of Formula 2a into contact with a compound of Formula 3

3 , wherein

R₄ is selected from the group consisting of linear, branched, or cyclic aliphatic groups, aromatic groups, and heteroaromatic groups as well as combinations thereof, preferably in all aforementioned definitions R₄ has 1 -12 carbon atoms or 1 -6 carbon atoms, in particular R₄ is a linear, branched, or cyclic aliphatic C C₁₂ or CTC₆ group, in addition in all aforementioned definitions R₄ is preferably a saturated and unsubstituted hydrocarbon group; R₄ preferably only comprises hydrogen and carbon atoms; preferably R is methyl or ethyl;

R₅ is selected from the group consisting of linear, branched, or cyclic aliphatic groups, aromatic groups, and heteroaromatic groups as well as combinations thereof preferably in all aforementioned definitions R₅ has 1-12 carbon atoms or 1 -6 carbon atoms, in particular R₅ is a linear, branched, or cyclic aliphatic C C ₂ or C C₆ group, in addition in all aforementioned definitions R₅ is preferably a saturated and unsubstituted hydrocarbon group; R₅ preferably only comprises hydrogen and carbon atoms; R₅ is methyl or ethyl; and

Re is selected from the group consisting of linear, branched, or cyclic aliphatic groups, and aromatic groups as well as combinations thereof, preferably in all aforementioned definitions R₆ has 1 -12 carbon atoms or 1-6 carbon atoms, in particular R₆ is a linear, branched, or cyclic aliphatic C C ₂ or Ci-C₆ group, in addition in all aforementioned definitions R_e is preferably a saturated and unsubstituted hydrocarbon group; R₆ is methyl or ethyl.

Preferred is a compound of Formula 3a

3a

The reaction is performed in the presence of an acid, preferably Lewis acid, thereby obtaining a compound of Formula 4a/4aa, wherein optionally the stereochemical purity of the compound of Formula 4a/4aa is improved by extraction of said compound from the reaction mixture.

Suitable acids such as Lewis acids and solvents are described in the general part below. Preferably, no chiral Lewis acid is used.

In order to provide a compound of Formula 4'

4'

the following steps can be conducted: (a) deprotecting the compound of Formula 4a in order to provide an NH₂-group. This step can be performed as in reaction step (iac) described above or as described in PCT/EP2013/062737 and EP 12 172 775.4. Step (b) comprises protecting the obtained NH₂-group in order to provide a compound of Formula 5a

5a

This step can be performed as in reaction step (iida)/(iica) described above.

In the next step, the compound of Formula 5a can be hydrolyzed in order to substitute the OR₅- group with an OH-group and to provide Compound 4'.

The present invention also relates to a process for the preparation of a compound of Formula 7a, preferably 7aa, or 6aa, preferably 6aaa

6aaa

wherein R₄ is methyl or ethyl, by performing steps (i) to (iii) described in detail above.

The present invention also relates to a process for the preparation of a compound of Formulas 7a/7aa' or 6aa, preferably 6aaa, wherein R₄ is methyl or ethyl, comprising the step of: (ia) providing a compound of Formula 4', preferably 4a'

wherein R₄ is as defined above,

4a' ; or

(ib) providing a compound of Formula 5a

5a

wherein R₄ is as defined above, and R₅ is selected from the group consisting of linear, branched, or cyclic aliphatic groups, aromatic groups, and heteroaromatic groups as well as combinations thereof,

and hydrolyzing the compound of Formula 5a in order to substitute the OR₅-group with an OH- group and to provide Compound 4'; and

(ii) using Compound 4' and performing steps (iicb), or (iidb) and (iidc); and then (iii) as described above.

The present invention also relates to a process for the preparation of a salt of the compounds of Formula 7a, preferably 7aa

7a 7aa comprising the steps of

(i) reacting the free base form of the compound of Formula 7a/7aa', wherein R₄ is methyl or ethyl, preferably obtained by the processes described herein, with an acid, preferably an organic carboxylic acid, more preferably a tartaric acid derivative, more preferably Ο,Ο'- ditoluoyl-D-tartaric acid or 0,0'-ditoluoyl-L-tartaric acid; and

(ii) crystallizing the salt of the compound of Formula 7a/7aa, into a salt with 0,0'-di-p-toluoyl- D-tartaric acid (DTTA) or Ο,Ο'-di-p-toluoyl-L-tartaric acid (LTTA) and isolating said salt.

Preferably, the salt is one of: compound of Formula 7a/7aa'. 0.5 0,0'-di-p-toluoyl-D-tartaric acid, compound of Formula 7a/7aa'. 0.5 Ο,Ο'-di-p-toluoyl-L-tartaric acid.

The resulting crystals can be isolated by using standard techniques, such as filtration and washing steps.

The present invention also relates to a process for the preparation of a compound of Formula 3'

3'

wherein X is a non-metallic element of group 3, 4, 5 and 6 of the periodic table, preferably X is C or S; wherein R is H or Boc, and wherein R₄ is methyl or ethyl, preferably a compound of Formula 3a', 3b' or 3c'

3a' , 3b' , 3c" , further preferred a compound of Formula 3aa\ 3ba' or 3ca'

3aa' 3ba' 3ca" comprising steps (i) and (ii) as defined herein.

The present invention also relates to a compound of Formula 7a/7aa' as described above in the form of a salt, preferably a salt with an organic carboxylic acid, more preferably a salt with a tartaric acid derivative, more preferably a salt with 0,0'-ditolyl-D-tartaric acid or 0,0'-ditolyl-L- tartaric acid. These compounds can be prepared as described herein.

The present invention also relates to a compound of Formula 3'

3"

wherein X is a non-metallic element of group 3, 4, 5 and 6 of the periodic table preferably X is C or S; wherein R is H or Boc, and wherein R₄ is methyl or ethyl, preferably a compound of Formula 3a', 3b' or 3c"

3a' 3b" 3c' further preferred a compound of Formula 3aa', 3ba' or 3ca'

3aa' 3ba' 3ca'

These compounds can be prepared as described herein.

The present invention also relates to a compound of Formula 2'

2'

wherein R₄ is methyl or ethyl, preferably a compound of Formula 2a'

2a'

These compounds can be prepared as described herein.

The present invention also relates to a compound of Formula 5'

5"

wherein R₄ is methyl or ethyl, preferably a compound of Formula 5a'

5a'

These compounds can be prepared as described herein.

The present invention also relates to a compound of Formula 6'

6^*

wherein R₄ is methyl or ethyl, preferably a compound of Formula 6a'

6a'

These compounds can be prepared as described herein.

The present invention also relates to a compound of Formula 7"

r

wherein R₄ is methyl or ethyl, preferably a compound of Formula 7a'

7a'

These compounds can be prepared as described herein.

In the following, general protocols/definitions are given:

A stage/step of bringing a compound into contact with a further compound can for example be carried out by dissolving said compounds either separately or as a mixture of compounds or by dissolving one of the compounds and adding to this solution the respective other compound. The order of combining the compounds can be chosen by a person skilled in the art.

Preferably, the stage/step of providing a compound includes dissolving said compound in a solvent or mixture of solvents. However, it is also possible to add said compound in pure form to the respective other compound(s) in the next stage/step.

Suitable solvents can be chosen by a person skilled in the art of common practice. Preferably, inert solvents are used. The term "inert solvent" refers to any solvent that does not react with the chemical system at hand. Inert solvents suitable in this respect are commonly known. Solvents can be selected from the group consisting of ethylacetate, isopropyl acetate, dichloromethane, Ν,Ν-dimethylacetamide, dimethyl sulfoxide (DMSO), N-methylpyrrolidone, Ν,Ν-dimethylformamide, acetonitrile, methyl tert-butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, aromatic hydrocarbons such as toluene and, hydrocarbon solvents, for example hexane and heptane, alcohols, for example methanol and ethanol, and water.

THF or 2-methyltetrahydrofuran (2-MeTHF) are preferably used for the formation of silyl enol ether 3, and as mixture with water for amine protection; dichloromethane, 2- m ethy Itetra hyd rof u ra n and toluene are preferably used for the aldol addition; EtOAc and ethanol are preferably used for hydrogenation; MeOH or EtOH and water mixtures were preferably used for saponification; dichloromethane and dimethylformamide were preferably used for amidation. The addition of the imine and the silyl enol ether can be performed in the presence of an acid, such as a Lewis acid for example at a temperature of about 0°C. Particular suitable acids are Lewis acids like MgBr₂Et₂0, BF₃Et₂0 and HBF₄. It has been found in the context of the present invention that it is not required to use chiral boron reagents and the use of chiral boron reagents or chiral Lewis acids in general is not preferred according to the invention since it may only provide a slight increase in selectivity but purification may be significantly harder to achieve.

The acid, such as Lewis acid, can for example be used in an amount of 1 to 2 equivalents based on the silyl enol ether compound. The imine and silyl enol ether can be used in equal amounts.

The addition of the imine and the silyl enol ether can for example be performed in

dichloromethane, toluene or 2-methy Itetra hyd rof u ran .

Suitable reaction temperatures for the reactions described herein can be chosen by a person skilled in the art. For example, the step of combining the coupling agent(s) with the other compounds can be carried out at 0°C to room temperature (for example for a time of 1 minute to 1 hour) and the reaction can then be completed at 0°C to 50°C (for example for a time of 1 hour to 30 hours). Room temperature is defined herein as a temperature range of 20-25°C. Furthermore, reactions with strong bases such as lithiumdiisopropylamide or other types of reactions that include the use of reactive compounds are conducted at low temperatures of e.g. below -20°C, below -50°C or at about -78°C.

The amounts of the compounds as used herein can be chosen by a person skilled in the art. If two compounds are reacted with each other to provide a product compound based on a stochiometric 1 :1 ratio of the starting materials, the starting compounds (including all potentially present isomers) can for example each be used in an amount from 0.8 to 3 equivalents, preferably from 0.9 to 2.0 equivalents, preferably from 1.0 to 1.6 equivalents.

Suitable amount(s) of solvent(s) can be chosen by a person skilled in the art. The use of lower amounts of solvents leads to higher concentrations and may provide for a faster reaction rate.

Generally, all stages/steps can include the isolation of the respective product compounds. Suitable methods for isolating said compounds are known in the art and comprise for example the washing of the organic layer with an aqueous salt solution (e.g. brine), separation of the organic layer, drying of said organic layer and removal of the organic solvent in vacuo. Dependent on the specific conditions, the work-up may further include acid and/or base washes. Furthermore, the compounds may be purified by using flash chromatographic techniques. However, if a compound is subjected to subsequent stages/steps it is possible to continue directly with the next stage/step without isolation of said intermediate product compounds.

Stages/steps for providing pharmaceutically acceptable salts of telaprevir (1 ) can additionally comprise adding compounds such as acids to the reaction mixture which includes telaprevir. Telaprevir or a pharmaceutically acceptable salt or solvate thereof can be isolated by precipitation and for example filtration, washing with solvent and drying. Prior to isolating the product, flash chromatographic techniques may be applied for purification. It is also preferred to isolate telaprevir, or a pharmaceutically acceptable salt or solvate thereof by crystallization.

Separation of racemic mixtures in the context of the present invention can for example be performed as follows: chiral HPLC, resolution of diastereomeric ammonium salts.

Separation of diastereomeric mixtures in the context of the present invention can for example be performed as follows: column chromatography or extraction of diastereoisomers showing different solubilities.

Strong bases that can be used in the context of the present invention are lithium diisopropylamide, LiT P, LiHMDS.

Cleaving the dialkoxy ketal group in the compound of Formula 9a in order to provide telaprevir can be performed by the addition of acid to an acetone/water mixture. Suitable examples include - but are not limited to - HCI, TFA or H₂S0₄.

Agents for deprotecting nitrogen-protecting groups are known to those skilled in the art; they can for example be selected from hydrogen on Pd/C (palladium on charcoal) and strong acids like TFA or HCI.

Hydrolyzing compounds such as esters can be performed according to methods known in the art.

In the context of this invention, the term "Lewis acid" has the meaning which is well-known in the art and can be defined as a molecular entity that is an electron-pair acceptor and therefore able to react with a Lewis base to form a Lewis adduct by sharing the electron pair furnished by the Lewis base. Thus, examples of Lewis acids include, but are not limited to, proton (H+), boron trifluoride and its diethyl ether adduct, tetrafluoroboric acid and its diethyl ether adduct, magnesium dibromide and its diethyl ether adduct, aluminium trichloride or anhydrous iron trichloride.

Another aspect is the preparation of a pharmaceutical composition or pharmaceutical dosage form comprising telaprevir according to Formula 1 , or a pharmaceutically acceptable salt or solvate thereof. The preparation comprises the process steps as described above and further comprises formulating the obtained telaprevir or a pharmaceutically acceptable salt or solvate thereof (the aforementioned compound may also be referred to as active pharmaceutically compound, API) into a pharmaceutical composition or pharmaceutical dosage form. The expression "a pharmaceutically acceptable salt or solvate thereof as used herein always refers to telaprevir. The step of formulating the API into a dosage form may be carried out by applying techniques known in the art. For example, the API can be formulated into tablets by using direct compression, dry or wet granulation processes, spray-coating processes or the like. The API may be formulated as an acid solution or as a solid.

The aldol addition reaction with silyl enol ethers can for example generally be carried out as follows: To the imine in a solvent, e.g. in CH₂CI₂ (e.g. 0.2M), at low temperatures (e.g. below 10°C or at 0°C or below), is added an acid, such as a Lewis acid (e.g. 1-2 eq.) such as MgBr₂Et₂0 or HBF₄OEt₂ and the mixture is stirred for e.g. 1-100 min, e.g. for 15 min. The silyl enol ether in a solvent (e.g. 1 eq.), e.g. in CH₂CI₂ (1 M), is added and the reaction is stirred at low temperatures (e.g. below 10°C or at OX or below), for e.g. 1-8 h. Brine can be added, layers can be separated and the aqueous layer can be extracted with CH₂CI₂. The combined organic layers can be dried and the solvent can be removed under reduced pressure. Purification can be performed by column chromatography (e.g. with silicagel, cyclohexane: EtOAc) to give the aldol adduct.

According to a preferred aspect, the invention provides telaprevir which is essentially free of 16a and 16aa

According to a preferred aspect, the invention provides telaprevir containing compound 7a and 9a in an amount of less than 0.15 area%.

The invention also refers to telaprevir obtainable or obtained by the process described herein, preferably

(i) containing oxidative side products of telaprevir in less than 0.10 area % as determined by HPLC analysis,

(ii) being basically free of, preferably less than 0.10 area % as determined by HPLC analysis, 15a

15a wherein Rn is a protecting group

and 16a

wherein Rn is a protecting group or H (Compound 16aa)

and/or

(iii) containing 7a

7a wherein Rn is a protecting group or H, or a group as defined for Compound 7a above, and 9a

wherein R-π is a protecting group or H, or a group as defined for Compound 9a/7a/7aa above, in less than 0.15 area% as determined by HPLC analysis.

Telaprevir obtainable or obtained by the method described herein has a high purity which may not be achieved when preparing telaprevir on a large scale by using prior art processes, since it may not be possible to purify said large amounts of telaprevir, e.g. 1 kg of telaprevir, by using common purification methods, as believed by the present inventors.

Examples

The following examples describe the present invention in detail, but are not to be construed to be in any way limiting for the present invention. In the examples below, the following abbreviations have the following meanings. Any abbreviations not defined have their generally accepted meaning. Unless otherwise stated, all temperatures are in degrees Celsius (°C).

DMF: dimethylformamide; EtOAc: ethyl acetate; DCM/CH₂CI₂/MED: dichloromethane; TEMPO: (2,2,6,6-Tetramethylpiperidin-1-yl)-oxyl; Eq.: equivalents; rt: room temperature; Room temperature is defined herein as a temperature range of 20-25°C; DIPEA: diisopropylethylamine; DIPET: diisopropyl ether; DMAP: p-dimethylaminopyridine; TBTU: O- (Benzotriazol-1-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate; Boc₂0: Di-tert-butyl dicarbonate; MS: molecular sieve; THF: tetrahydrofuran; MTBE: methyl tert-butyl ether; TBSCI: tert-butyldimethylsilyl chloride; LDA: lithium diisopropylamide; tol: toluene; TFA trifluoroacetic acid; Cbz: benzyloxycarbonyl; DIC: diispropylcarbodiimide; EDC: (1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride); HOBt: 1 -hydroxy-benzotriazole, Et₂0: diethyl ether, CbzCI: benzyl chloroformate.

Example 1 - (S,E)-N-butylidene-1-phenylethanamine (compound of Formula 2a)

To a suspension of 10g 3A MS in CH₂CI₂ (150 mL) under N₂ at rt was added butyraldehyde (4.96 mL, 55 mmol) followed by (S)-(-)-1 -phenylethylamine (6.45 mL, 50 mmol). The mixture was stirred at rt for 1.5 h, filtered over celite and the solvent removed under reduced pressure to give 9g of the crude imine, which was used in the next step without further purification.

1H NMR (500MHz, CDCI₃): δ = 7.67 (t, J = 5.05Hz, 1 H), 7.28-7.23 (m, 4H), 4.21 (q, J = 6.74Hz, 1 H), 2.18 (dt, J = 7.48, 5.17Hz, 2H), 1.53-1.49 (m, 2H), 1.42 (d, J = 6.60Hz, 3H), 0.87 (t, J = 7.40Hz, 3H).

¹³C NMR (125MHz, CDCI₃): δ = 163.79, 145.09, 128.36, 126.72, 126.51 , 69.70, 37.74, 24.59, 19.51 , 13.72.

General procedure to generate TMS silyl enol ethers:

To a solution of diisopropylamine (1.5 eq.) in THF (1.5M) at 0°C under N₂ was added nBuLi (1.4eq., 1.6M in hexane) and the mixture was stirred for 20 min. The LDA was cooled to -80°C and TMSCI (1.4 eq.) was added followed by the ester (1 eq.). The reaction was allowed to reach 0°C over 3 h, brought to rt and stirred for 30 min. Pentane was added and the white precipitate filtered off over celite. The solvent was removed under reduced pressure. Purification if necessary was performed by bulb-to-bulb distillation.

Example 2 - trimethyl((1,2,2-trimethoxyvinyl)oxy)silane (compound of Formula 3)

The synthesis was conducted using the general procedure of Example 6.

H NMR (500MHz, C₆D₆): δ = 3.45 (s, 3H), 3.44 (s, 3H), 3.37 (s, 3H), 0.25 (s, 9H).

Example 3 - trimethyl((1,2,2-triethoxyvinyl)oxy)silane (compound of Formula 3)

The synthesis was conducted using the general procedure of Example 6

¹H NMR (500MHz, C₆D₆): δ = 3.85 (q, J = 7.04Hz, 2H), 3.80 (q, J = 7.02Hz, 2H), 3.78 (q, J = 7.05Hz, 2H), 1.18 (t, J = 7.10Hz, 3H), 1.17 (t, J = 7.08Hz, 3H), 1.16 (t, J = 7.08Hz, 3H), 0.29 (s, 9H).

Example 4 - General procedure for the aldol addition with MgBr₂Et₂0:

To imine of Example 1 (1eq.) in CH₂CI₂ (0.2M) at 0°C was added MgBr₂Et₂0 (1.5 eq.) and the mixture was stirred for 15 min. The silyl enol ether of Example 6 (1 eq.) in CH₂CI₂ (1 M) was added and the reaction was stirred at 0°C for 4 h. Brine was added, the layers were separated and the aqueous layer was extracted with CH₂CI₂. The combined organic layers were dried and the solvent was removed under reduced pressure.

Example 4a - (S)-methyl 2,2-dimethoxy-3-(((S)-1-phenylethyl)amino)hexanoate (compound of Formula 4a)

To imine of Example 1 (4g, 22.8 mmol) in CH₂CI₂ (90mL) at 0°C was added MgBr₂Et₂0 (8.84g, 34.2 mmol) and the mixture was stirred for 15 min. The silyl enol ether of Example 9 (5g, 24.2 mmol) in CH₂CI₂ (15 mL) was added and the reaction was stirred at 0°C for 4 h. Brine was added, layers were separated and the aqueous layer was extracted with CH₂CI₂. The combined organic layers were dried and the solvent was removed under reduced pressure. Purification by column chromatography (silicagel, cyclohexane: EtOAc 10:1→ 3:1 ) gave the aldol adduct.

¹H NMR (500MHz, CDCI₃): δ = 7.33-7.28 (m, 4H), 7.21 (m, 1 H), 4.23 (q, J = 6.62Hz, 1 H), 3.82 (s, 3H), 3.27 (s, 3H), 3.19 (s, 3H), 2.73 (dd, J = 10.08, 2.52Hz, 1 H), 1.49 (m, 1 H), 1.37 (m, 1 H), 1.27 (d, J = 6.65Hz, 3H), 1.09-0.97 (m, 2H), 0.67 (t, J = 8.23Hz, 3H).

1³C NMR (125MHz, CDCI₃): δ = 169.25, 146.29, 128.09, 127.33, 126.68, 106.08, 56.22, 55.96, 52.15, 50.61 , 49.75, 33.36, 24.86, 19.66, 13.84. Example 4b - (S)-ethyl 2,2-diethoxy-3-(((S)-1-phenylethyl)amino)hexanoate (compound of Formula 4aa)

With BF₃OEt₂: (S,E)-N-butylidene-1 -phenylethanamine (Example 1 , 10.0 g, 57.0 mmol) was dissolved in 250 mL 2-methyltetrahydrofuran and cooled to 0°C. BF₃OEt₂ (7.0 mL, 57.0 mmol) was added to the mixture followed by a solution of trimethyl((1 ,2,2-triethoxyvinyl)oxy)silane (Example 10, 1 1 .34 g, 45.6 mmol) in 80 mL 2-methyltetrahydrofuran, and the mixture was stirred at 0°C. After four hours, further imine (1 .8 g, 10.2 mmol) and BF₃OEt₂ (1 .2 mL, 9.7 mmol) were added and the mixture was stirred at 0°C for further three hours. The volume of the mixture was halved by evaporation, water was added, the mixture was neutralized (pH = 7.2) with 2N NaOH, and the phases were separated. Removal of the solvent in vacuo yielded 19.1 g crude (S)-ethyl 2,2-diethoxy-3-(((S)-1 -phenylethyl)amino)hexanoate as a 85, 15 (syn:anti) diastereomeric mixture.

With HBF₄OEt₂: (S,E)-N-butylidene-1 -phenylethanamine (Example 1 , 10.0 g, 57.0 mmol) was dissolved in 250 mL 2-methyltetrahydrofuran and cooled to 0°C. HBF₄OEt₂ (9.24 g, 57.0 mmol) was added to the mixture followed by a solution of trimethyl((1 ,2,2-triethoxyvinyl)oxy)silane (Example 10, 1 1 .34 g, 45.6 mmol) in 80 mL 2-methyltetrahydrofuran, and the mixture was stirred at 0°C for three hours and fifteen minutes. Water (400 mL) was added to quench the reaction, the mixture was neutralized (pH = 7.6) with 10N NaOH, the phases were separated and the organic phase was extracted once more with further 400 mL water. Water (300 mL) and 2-methyltetrahydrofuran (50 mL) were added to the mixture, the pH was acidified (pH = 5.6) with 2N HCI and the phases were separated. The organic phase was extracted with further 300 mL water and 50 mL 2-methyltetrahydrofuran and the solvent of the organic phase was removed in vacuo to yield 17.1 g crude (S)-ethyl 2,2-diethoxy-3-(((S)-1 -phenylethyl)amino)hexanoate as a 86, 14 (syn:anti) diastereomeric mixture.

Diastereomer separation in (S)-ethyl 2,2-diethoxy-3-(((S)-1 -phenylethyl)amino)hexanoate by extraction (representative procedure):

A diastereomeric mixture of (S)-ethyl 2,2-diethoxy-3-(((S)-1 -phenylethyl)amino)hexanoate (6.4 g, d.r.: 85:15) was dissolved in 100mL iPr₂0 and 2mL water were added. The mixture was acidified to pH = 2.21 with 50% H₂S0₄ and the resulting organic phase was concentrated to half its volume (50ml_). 1 mL water was added, and the mixture was acidified again to pH = 2.22 with 50% H₂S0₄. The aqueous phase was combined with the aqueous phase from the previous extraction (V = 1 .5 mL) and extracted with 1 1 mL DIPET (diisopropyl ether) after adjusting the pH to 2.17 with 5M NaOH. The combined organic phases were concentrated (V = 40mL), 1 mL water was added and the mixture was acidified to pH = 2.18 with 50% H₂S0₄. The organic phase was separated and the solvent was removed in vacuo to yield a 98:2 (syn:anti) mixture of diastereomers (37.5 mL solution, assay: 28 %, 76 % yield).

Ή NMR (δ, CDCI₃, 300MHz): 7.34-7.14 (m, 5H, H_Ar), 4.39-4.16 (m, 3H, COOCH₂ and CH(CH₃)), 3.58-3.31 (m, 5H, OCH₂CH₃ and CHNH), 2.69 (dd, J = 7.80 Hz, J = 2.37 Hz, 1 H, NH), 1.47-1.12 (m, 19H, CH₃, CH₂, COCH₂CH₃ and OCH₂CH₃), 0.63 (t, J = 7.00 Hz, CH₃). ¹³C NMR (δ, CDCI₃, 75MHz): 169.0, 146.4, 128.0, 127.5, 126.6, 105.4, 61.0, 59.0, 57.0, 56.8, 56.3, 33.6, 24.8, 19.6, 15.3, 15.2, 14.3, 13.8.

Example 5 - (S)-methyl 3-amino-2,2-dimethoxyhexanoate

To benzylamine of Example 4a (500 mg, 1.62 mmol) in EtOAc (16 mL) was added Pd/C (170 mg, 0.16 mmol, 10%w/w) and the suspension was stirred under an H₂ atmosphere for 2.5h. The catalyst was filtered off over celite and the solvent removed under reduced pressure to give 200 mg amine, which was used without further purification.

¹H NMR (500MHz, CDCI₃): δ = 3.80 (s, 3H), 3.31 (s, 6H), 3.06 (dd, J = 10.70, 2.20Hz, 1 H), 1.65 (m, 1 H), 1.57 (m, 1 H), 1.40-1.30 (m, 1 H), 1.01 (m, 1 H), 0.92 (t, J = 7.25Hz, 3H).

¹³C NMR (125MHz, CDCI₃): δ = 168.44, 104.37, 53.76, 52.26, 50.34, 50.22, 33.46, 20.14, 14.01. Example 6 - (S)-methy! 3-((tert-butoxycarbonyl)amino)-2,2-dimethoxyhexanoate

(compound of Formula 5a)

To ((S)-methyl 3-amino-2,2-dimethoxyhexanoate) of Example 15 (170 mg, 0.83 mmol) in THF (3ml_) was added Boc₂0 (271 mg, 1.24 mmol) and DIPEA (432 μΙ_, 2.48 mmol) and the mixture was stirred for 16h. Then EtOAc was added, washed with a saturated NaHC0₃ solution, dried and concentrated.

¹H NMR (500MHz, CDCI₃): δ = 4.93 (d, J = 10.05Hz, 1 H), 4.05 (dt, J = 11.05, 2.20Hz, 1 H), 3.38 (s, 3H), 3.30 (s, 3H), 1.64 (m, 1 H), 1.53 (s, 9H), 1.44 (m, 1 H), 1.33 (m, 1 H), 1.06 (m, 1 H), 0.91 (t, J = 7.55Hz, 3H).

Example 7 - (S)-3-((tert-butoxycarbonyl)amino)-2,2-dimethoxyhexanoic acid

To ((S)-methyl 3-((tert-butoxycarbonyl)amino)-2,2-dimethoxyhexanoate) of Example 16 (0.8 mmol) in methanol (8mL) was added an aqueous KOH solution (0.13mL, 2.4 mmol, 50w/w%) and the reaction was stirred for 20h. pH was adjusted to pH = 3 with 1 N HCI and extraction with CH₂CI₂ provided 260 mg of the crude acid.

¹H NMR (500MHz, CDCI₃): δ = 4.89 (d, J = 9.80Hz, 1 H), 4.07 (t, J = 9.30Hz, 1 H), 3.38 (s, 3H), 3.35 (s, 3H), 1.63 (m, 1H), 1.45 (s, 9H), 1.44 (m, 1 H), 1.33 (m, 1 H), 1.25 (m, 1 H), 0.92 (t, J = 7.33Hz, 3H).

Example 8 - Deprotection of (S)-tert-butyl 1-(cyclopropylamino)-2,2-diethoxy-1-oxohexan- 3-ylcarbamate (see Figure 6)

TFA (2.45 mL, 32.1 mmol) was added to a solution of (S)-tert-butyl 1 -(cyclopropylamino)-2,2- diethoxy-1 -oxohexan-3-ylcarbamate (2.3 g, 6.41 mmol) in 45 mL CH₂CI₂ and the mixture was stirred at room temperature for 18 hours. A saturated NaHC0₃ solution was carefully added to the mixture, the aqueous phase was extracted with CH₂CI₂ (2x30 mL) and the combined organic phases were dried over Na₂S0₄. Removal of the solvent in vacuo yielded 1.44 g (3S)-3-Amino- N-cyclopropyl-2,2-diethoxyhexanamide as a pale yellow oil.

1H NMR (δ, CDCIg, 300MHz): 7.01 (bs, 1 H, CONH), 3.61-3.39 (m, 4H, OCH₂CH₃), 3.08 (dd, J = 10.56 Hz, J = 2.64 Hz, 1 H, CHNH₂), 2.79-2.70 (m, 3H, CH(CH₂)₂ and NH₂(pH-dependent)),1.64- 1.31 (m, 4H, CH₂), 1.22 (t, J = 7.04 Hz, 6H, OCH₂CH₃), 0.92 (t, J = 7.14 Hz, 3H, CH₃), 0.85-0.78 (m, 2H, CH₂), 0.55-0.52 (m, 2H, CH₂). ³C NMR (δ, CDCI₃, 75MHz): 170.0 (CONH), 101.5 (C(OEt)₂), 58.7 (OCH₂CH₃), 57.0 (OCH₂CH₃), 54.4 (CHNH₂), 32.7 ((CH₂)₂CH₃), 22.0 (CH(CH₂)₂), 19.9 ((CH₂)₂CH₃), 15.4 (OCH₂CH₃), 15.1 (OCH₂CH₃), 14.0 ((CH₂)₂CH₃), 6.5 (CH(CH₂)₂), 6.5 (CH(CH₂)₂).

Example 9 - Preparation of 6a' from 4aa by hydrolysis

Figure 8 shows the reaction scheme for this example.

KOH (30.5 g, assay ~ 85%, 462 mmol, 6.5 equivalents) was added to a solution of 4aa (31.2 g, prepared according to example 4b, assay ~ 77%, 70.5 mmol) in EtOH (137 mL) and H₂0 (137 mL). The reaction mixture was stirred at 80°C for 18.5 hours before being cooled to room temperature and diluted with CH₂CI₂ (100 mL). The pH-value was adjusted to pH = 6.5 by the addition of HCI (5.0 M). The resulting two phases were separated and the aqueous layer was extracted with CH₂CI₂ (100 mL) at pH = 6.5. The combined organic layers were dried over

Na₂S0₄, filtered and the solvent was removed by distillation under reduced pressure to give a glassy solid (35.7 g). 2-MeTHF (60 mL) was added to the residue and the solution was stirred overnight at room temperature. PEADEA crystallized during that period. The solid was filtered off (12.1 g) and the mother liquor was concentrated under reduced pressure (17.7 g residue). After the addition of 2-MeTHF (20 mL) a second crystallization took place and the solid was isolated by filtration (5.3 g). The two crystalline fractions were combined to give 12.1 g + 5.3 g = 17.4 g 6a' as colorless fine crystals in 76% yield (assay > 95%).

¹H NMR (300 MHz, CDCI₃): δ = 10.00 (br s, 2H, NH, C0₂H), 7.76 (m, 2H, H_arom.), 7.40 (m, 3H, H_arom ), 4.53 (q, J = 6.8 Hz, 1 H, PhCHN), 3.58 - 3.77 (m, 3H, CH₂0+CH_aO), 3.31 (m, 1 H,

CH_bO), 2.97 (dd, J = 1 1.0, 1.5 Hz, 1 H, CH₂CH H), 1.77 (d, J = 7.0 Hz, 3H, CH₃CH), 1.63 (m, 1 H, CHgCHN), 1.43 (m, 1 H, CH„CHN), 1.27 (t, J = 7.3 Hz, 3H, CH₃CH₂0), 1.25 (t, J = 7.0 Hz, 3H, CH₃CH₂0), 1.19 (m, 1 H, CH₃CH_e), 0.58 (m, 1 H, C ₃CH_b), 0.49 (t, J = 6.7 Hz, 3H, CH₃CH₂); ¹³C (75 MHz, CDCI₃): δ = 170.6, 137.3, 129.2, 128.2, 100.5, 60.1 , 59.9, 58.3, 56.1 , 29.5, 20.9, 18.3, 15.5, 15.3, 13.1.

Example 10 - Preparation of 2a' from 6a' by hydrogenation

Figure 9 shows the reaction scheme for this example.

Pd/C (41.8 g, 10w% Pd, ~ 50% H₂0, - 20mol% Pd) was added to a solution of 6a' (63.4 g, calculated as approximately 98 mmol) in EtOH (600 mL). The hydrogenation was started at 2.5 bar in a shaken reaction vessel and the pressure was gradually raised to 4 bar. The reaction mixture was shaken overnight and an HPLC analysis indicated complete conversion. The solids were filtered off over a K150 filter, washed with EtOH and the solution was concentrated under reduced pressure (46 g residue). EtOAc (50 mL) was added and the crystallization of 2a' started immediately. The solid was filtered off and dried in vacuo to give 2a' (19.8 g, - 92% yield, as is) as a white crystalline solid.

¹H NMR (300 MHz, saturated solution in CDCI₃): δ = 8.33 (very br s, 3H), 3.63 (m, 2H), 3.46 (m, 3H), 1.38 - 1.75 (series of m, 4H), 1.24 (t, J = 6.9 Hz, 3H), 1.16 (t, J = 6.9 Hz, 3H), 0.88 (t, J = 6.4 Hz, 3H); ¹H NMR (300 MHz, D₂0): δ = 3.45 - 3.56 ( m, 4H), 3.32 (m, 1 H), 1.63 (m, 1 H), 1.41 (m, 3H), 1.18 (t, J = 6.9 Hz, 3H), 1.16 (t, J = 6.9 Hz, 3H), 0.90 (t, J = 7.0 Hz, 3H); H NMR (300 MHz, sample prepared from 2a' and methanolic HCI (1.25 M in MeOH) after solvent removal, DMSO-D₆): δ = 8.08 (br s, 3H), 5.10 (very br s, 1 H), 3.40 - 3.61 (m, 4H), 3.33 (br s, 1 H), 1.31 - 1.56 (m, 4H), 1.20 (t, J = 7.5 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 6.4 Hz, 3H); ¹³C (75 MHz, saturated solution in CDCI₃): δ = 171.2, 100.1 , 77.2, 57.0, 53.1 , 30.4, 19.4, 15.7, 15.0, 14.1 ; ¹³C NMR (75 MHz, D₂0): δ = 173.0, 99.5, 59.7, 57.1 , 52.7, 29.3, 18.4, 14.3, 14.1 , 12.9; ¹³C NMR (75 MHz, sample prepared from 2a' and methanolic HCI (1.25 M in MeOH) after solvent removal, DMSO-D₆): δ = 167.7, 99.1 , 58.9, 57.9, 52.4, 30.1 , 18.7, 15.2, 14.9, 13.8.

Example 11 - Preparation of 4a' by Boc-protection of 2a' with Boc₂0

Figure 10 shows the reaction scheme for this example.

H₂0 (200 mL) was added to a stirred solution of 2a' (freshly prepared from 6a' by

hydrogenation, 20.3 g 6a', 62.8 mmol) in EtOH (~ 200 mL) followed by the addition of Boc₂0

(16.4 g, 75.4 mmol). The pH value was adjusted to pH = 9.0 - 9.5 by the addition of NaOH (10

M). The internal temperature rose to ~ 30°C and the reaction was stirred overnight. The reaction progress was monitored by thin layer chromatography (and the reaction could have been judged complete after approximately 1 hour). The reaction mixture was concentrated under reduced pressure to a total volume of ~ 150 mL and ethyl acetate (150 mL) was added. The pH value was adjusted to pH = 2.5 with HCI (18%) and the resulting two phases were separated. The aqueous phase was extracted with ethyl acetate (50 mL) and the combined organic layers were dried over Na₂S0₄, filtered and concentrated under reduced pressure to give 17.2 g 4a' (86% yield) as a colorless oil.

Example 12 - Preparation of 7aa.0.5DTTA from 2a' by cyclic anhydride formation with diphosgene

Figure 1 1 shows the reaction scheme for this example.

A suspension of 2a' (2.19 g, 10 mmol, as is) in THF (50 mL) was cooled to 0 - 2°C. A solution of trichloromethylchloroformate (0.9 mL, 7.5 mmol) in THF (5 mL) was added at a rate to keep the internal temperature < 5 °C which resulted in the formation of a solution. The reaction mixture was stirred at room temperature for 4 hours. The solution was re-cooled to 0 - 2°C and cyclopropylamine (3.5 mL, 50.5 mmol) was added at a rate to keep the internal temperature <15°C. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in MED (25 mL) and H₂0 (25 mL). The pH value was adjusted with NaOH (10.0 M) to pH = 12.0 and the two phases were separated. The organic layer was dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue (2.0 g) was dissolved in ;Pr₂0 (35 mL) and the solution was filtered. A solution of DTTA (= Ο,Ο'-ditoluoyl- D-tartic acid, 3.0 g, 7.7 mmol) in /Pr₂0 (20 mL) was added and the mixture was stirred for one hour at room temperature. The precipitate was filtered, washed with MTBE and dried under reduced pressure to give 7aa.0.5DTTA (2.9 g, 64% as is) as a colorless solid.

¹H NMR (300 MHz, CDCI₃): δ = 7.92 (d, J = 8.1 Hz, 2H_DTTA), 7.13 (d, J = 8.1 Hz, 2H_DTrA), 7.09 (d, J = 3.6 Hz, 1 H)*, 7.03 (br, s, 2Η + 1 H_DTTA)*, 5.72 (s, 1 H_DTTA), 3.53 - 3.68 (m, 2Η), 3.39 - 3.50 (m, 2H), 3.33 (m, 1 H), 2.72 (m, 1 H), 2.34 (s, 3Η), 1.34 - 1.64 (series of m, 4Η), 1.17 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 6.9 Hz, 3H), 0.81 (t, J = 6.5 Hz, 3H), 0.78 (m, 2H), 0.52 (m, 2H), 'flexible chemical shift depending on pH, H₂0, concentration; ¹³C (75 MHz, CDCI₃): δ = 171.1 , 169.7, 165.8, 143.4, 130.0, 128.4, 127.2, 98.3, 77.2, 73.6, 59.6, 57.5, 53.3, 30.2, 22.9, 22.3, 21.6, 18.9, 15.2, 14.7, 13.9, 6.5, 6.5. Example 13 - Preparation of 7a' by hydrogenation of 4aa

Figure 12 shows the reaction scheme for this example.

Under nitrogen, 4aa Prepared according to example 4b, 3.67g, 10.4 mmol) was dissolved in 50ml_ ethyl acetate and palladium on charcoal (1.1 1g, 10% w/w, 10mol%, 1.0 mmol) was carefully added. The nitrogen was exchanged for a hydrogen atmosphere and the mixture was stirred at room temperature for 3.5 hours. The catalyst was filtered off with the help of Celite and the solvent from the filtrate was removed in vacuo to yield 2.8g 7a' (quant., as is).

¹H NMR (300 MHz, CDCI₃): δ = 4.27 (q, J = 7.1 Hz, 2H, COOCH₂CH₃), 3.70 - 3.45 (m, 4H, OCH₂CH₃), 3.03 (dd, J = 10.8 Hz, J = 2.4 Hz, 1 H, CHNH₂), 1.72 - 1.59 (bs and m, 4H, NH₂ and CH₂), 1.33 (t, J = 7.1 Hz, 3H, COOCH₂CH₃), 1.27 - 1.22 (m, 8H, OCH₂CH₃ and CH₂), 0.93 (t, J = 7.2 Hz, 3H, CH₃).

Example 14 - Preparation of 7aa.0.5DTTA from 2a' by cyclic anhydride formation with 1 H- imidazole-1-sulfinyl chloride

Figure 13 shows the reaction scheme for this example.

Thionyl chloride (2.65mL, 36.5 mmol) and imidazole (4.96g, 72.8 mmol) were added to 80ml_ dichloromethane cooled at 0°C and the mixture was stirred at this temperature for one hour. 2a' (prepared according to example 10, 4.0g, 18.2 mmol) was added and the mixture was stirred for 20 minutes at 0°C, after which cyclopropylamine (12.8ml_, 0.2mol) was added and the mixture was stirred for 30 minutes at 0°C. The reaction mixture was quenched with water (120mL), the organic phase was further extracted with water (2x120ml_) and the organic phase was dried under vacuum to yield 7aa as a yellow oil (3.16g, 67.2% yield as is). The residue was dissolved in iPr₂0 (64mL) and a solution of DTTA (2.6g, 6.7 mmol) in iPr₂0 (26mL) was added. The resulting suspension was stirred at room temperature for four hours, filtered, and the remaining solid was washed twice with 10mL cold iPr₂0 and dried in vacuo to give 4.76g 7aa.0.5DTTA (58% yield as is).

¹H NMR (300 MHz, CDCI₃): δ = 7.93 (d, J = 8.0Hz, 2H), 7.49 (bs, 1 H), 7.15-7.08 (m, 3H), 5.73 (s, 1 H), 3.65-3.56 (m, 2H), 3.51-3.39 (m, 2H), 3.37-3.31 (m, 1 H), 2.72 (m, 1 H), 2.35 (s, 3H), 1.59-1.34 (m, 4H), 1.21-1.13 (m, 6H), 0.84-0.80 (m, 5H), 0.54-0.53 (m, 2H). ¹³C (75 MHz, CDCI₃): δ = 171.2, 169.7, 165.8, 143.4, 130.0, 128.9, 127.2, 98.4, 73.5, 59.6, 57.5, 53.4, 30.3, 22.9, 22.3, 21.6, 18.9, 15.2, 14.7, 13.9, 6.5.

Example 15 - Preparation of 7aa from 2a' by cyclic anhydride formation with 1,1'- sulfinylbis(1 H-imidazole)

Figure 14 shows the reaction scheme for this example.

Imidazole (0.94g, 13.8 mmol) was dissolved in 25mL dichloromethane and cooled to -10°C. Thionyl chloride (0.25ml_, 3.4 mmol) was carefully added and the mixture was stirred at -10°C for 20 minutes. The resulting imidazole hydrochloride was filtered off, washed with

dichloromethane (3x5mL) and 2a' (489.9mg, 2.2 mmol) was added to the filtrate. After stirring at room temperature for two hours, cyclopropylamine (1.6mL, 23.1 mmol) was added to the reaction mixture and stirred for 2.5 hours. The mixture was stirred with water (3x25mL) and the solvent was removed in vacuo to yield 300 mg of 7aa (52% yield, as is).

¹H NMR (300 MHz, CDCI₃): δ = 7.01 (bs, 1 H, CONH), 3.49-3.38 (m, 4H, OCH₂CH₃), 2.96 (dd, J = 2.2Hz, J = 0.9 Hz, 1 H, CHNH₂), 2.71 (m, J = 3.7 Hz, 1 H, CH(CH₂)₂), 2.15 (bs, 2H, NH₂), 1.61 -1.41 (m, 2H, CH₂), 1.37-1.30 (m, 1 H, CH₂), 1.18 (t, J = 7.0 Hz, 7H, OCH₂CH₃ and CH₂), 0.88 (t, J = 7.1 Hz, 3H, CH₃), 0.81-0.75 (m, 2H, CH₂), 0.51-0.46 (m, 2H, CH₂). ¹³C (75 MHz, CDCI₃): δ = 170.1 , 101.9, 58.5, 56.8, 54.4, 33.0, 22.0, 20.0, 15.4, 15.1 , 14.1 , 6.5, 6.5.

Example 16 - Preparation of 7aa from 4a" by cyclic anhydride formation with thionyl chloride or methanesulfonyl chloride

Figure 15 shows the reaction scheme for this example.

(a) With thionyl chloride: Thionyl chloride (136μΙ_, 1.88 mmol) was added to a solution of 4a' (prepared according to example 1 1 , 500mg, 1.57 mmol) in 10mL DMF and the mixture was stirred for 3.5 hours at room temperature, after which cyclopropylamine (1.08mL, 15.7 mmol) was added. After stirring for 2.5 hours at room temperature, the reaction was quenched with water (10ml_) and dichloromethane (10ml_) and the organic phase was extracted with 10ml_ water. The organic phase was dried in vacuo to yield 230mg 7aa as a pale yellow oil (56.9% yield as is). (b) With methanesulfonyl chloride: Methanesulfonyl chloride (121 pL, 1.88 mmol) was added to a solution of 4a' (prepared according to example 1 1 , 500mg, 1.57 mmol) in 10ml_ DMF and the mixture was stirred for 4.5 hours at room temperature, after which cyclopropylamine (1.08mL, 15.7 mmol) was added. After stirring for 2.5 hours at room temperature, the reaction was quenched with water (10ml_) and dichloromethane (10ml_) and the organic phase was extracted with 10ml_ water. The organic phase was dried in vacuo to yield 210mg 7aa as a pale yellow oil (51.9% yield as is).

Example 17 - Preparation of 5a'

Figure 16 shows the reaction scheme for this example.

DMAP (200.8mg, 1.6 mmol) and Boc₂0 (3.43g, 15.7 mmol) were added to a cooled solution of 4a' (2.47g, 7.7 mmol) at 0°C and the mixture was stirred at room temperature. After two hours, further DMAP (208.3mg, 1.70 mmol) and Boc₂0 (3.42g, 15.7 mmol) were added and the mixture was stirred at room temperature for one hour and then let stand for 60 hours. The solvent was removed under vacuum and the residue was partitioned between water and ethyl acetate (30mL each). The pH of the mixture was adjusted to 2.7 with HCI, the phases were separated and the aqueous phase was extracted three times with 5mL ethyl acetate. The combined organic phases were dried over Mg₂S0₄ and the solvent was removed in vacuo. Column chromatography over silica gel (ethyl acetate: methanol 4:1 ) yielded 2.24g 5a', which was used without further purification.

¹H NMR (300 MHz, CDCI₃): δ = 3.95 - 3.74 (m, 2H), 3.66 - 3.48 (m, 2H), 3.46 - 3.35 (m, 1 H), 1.85 - 1.53 (m, 2H, CH2), 1.45 - 1.36 (m, 18H, Boc-CH3), 1.22 - 1.09 (m, 8H), 0.91 - 0.81 (m, 4H). ³C (75 MHz, CDCI₃): δ = 167.9, 163.1 , 156.1 , 148.6, 106.4, 101.6, 83.5, 82.7, 78.8, 64.6, 60.9, 59.5, 58.8, 58.5, 33.3, 30.2, 28.4, 28.0, 19.5, 19.2, 15.4, 15.1 , 14.2, 14.0.

Example 18 - Preparation of 6aaa from 5a' by cyclic anhydride formation with thionyl chloride or methanesulfonyl chloride

Figure 17 shows the reaction scheme for this example.

(a) With thionyl chloride: Thionyl chloride (92μΙ_, 1.27 mmol) was added to a solution of 5a' (prepared according to example 17, 426.9mg, 1.0 mmol) in 15ml_ DMF and the mixture was stirred for 4 hours and 50 minutes at room temperature, after which cyclopropylamine (700μΙ_, 10 mmol) was added. After stirring for 16 hours at room temperature, the reaction was quenched with water (10mL) and dichloromethane (10mL). The organic phase was extracted with 10ml_ water, adjusting the pH to 7 with 10% HCI and the solvent was removed in vacuo.

(b) With methanesulfonyl chloride: Methanesulfonyl chloride (94μ1_, 1.2 mmol) was added to a solution of 5a' (prepared according to example 17, 435.0mg, 1.03 mmol) in 15mL DMF and the mixture was stirred for 4 hours and 50 minutes at room temperature, after which

cyclopropylamine (700μΙ_, 10 mmol) was added. After stirring for 16 hours at room temperature, the reaction was quenched with water (10mL) and dichloromethane (10ml_). The organic phase was extracted with 10ml_ water, adjusting the pH to 7 with 10% HCI and the solvent was removed in vacuo.

¹H NMR (δ, CDCI₃, 300MHz): 6.96 (bs, 1 H, CONH), 5.70 (d, J = 9.78 Hz, 1 H, NH), 3.91 (t, J = 10.55 Hz, CHNH), 3.63-3.26 (m, 4H, OCH₂CH₃), 2.68 (m, 1 H, CH(CH₂)₂), 1.41 (s, 11 H, Boc-CH₃ and CH₂), 1.21-1.12 (m, 8H, OCH₂CH₃ and CH₂), 0.88 (t, J = 7.06 Hz, 3H, CH₃), 0.81-0.78 (m, 2H, CH₂), 0.53-0.48 (m, 2H, CH₂₎. ¹³C NMR (δ, CDCI₃, 75MHz): 170.8, 157.0, 100.5, 78.5, 58.6, 56.8, 52.6, 32.5, 28.4, 22.0, 19.3, 15.4, 15.0, 14.0, 6.5, 6.4.

Example 19 - diethoxy-telaprevir (compound of Formula 9a)

DCM as solvent

To a solution of the compound of Formula 8a (362 mg, 0.704 mmol), EDC.HCI (162 mg, 0.844 mmol) and HOBt (119 mg, 0.844 mmol) in DCM (10 ml.) was added amine of Example 24 (200 mg, 0.774 mmol) and the mixture was stirred at ambient temperature for 15h. Water was added and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with an aqueous, saturated NaHC0₃ solution and brine, dried over Na₂S0₄ and the organic solvent was removed under reduced pressure to give 570 mg diethoxy- telaprevir. DMF as solvent

2.9 g of amine of example 24 (10.74 mmol, 1.2 eq) were dissolved in 30 ml DMF. To the mixture 4.6 g of compound 8a (8.95 mmol, 1.0 eq), 3.43 g EDC.HCI (17.9 mmol, 2.0 eq) and 2.5 ml triethylamine (17.9 mmol, 2 eq) and 1.7 g HOBt^*H₂0 (10.74 mmol, 1.2 eq) was added. The mixture was stirred for 3.5 until no starting material was detected. To the reaction mixture 90ml ethyl acetate and 50ml water was added. pH was adjusted to 1.5 by addition of 2M HCI. The organic phase was separated and the aqueous phase was washed with 50 ml ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonat and the aqueous phase was washed with 30ml ethyl acetate. The combined organic phases were washed with 50 ml water and the solvent was removed to dryness. The yellow residue was dissolved in methylene chloride and the solvent was again removed to dryness. 6.5g of a white solid was isolated (96% yield).

¹H NMR (500MHz, CDCI₃): δ = 9.38 (d, J = 1.26Hz, 1 H), 8.74 (d, J = 2.52Hz, 1 H), 8.55 (dd, J = 2.30, 1.48Hz, 1 H), 8.36 (d, J = 9.46Hz, 1 H), 7.11 (d, J = 9.46Hz, 1 H), 6.99 (d, J = 2.83Hz, 1 H), 6.47 (d, J = 9.46Hz, 1 H), 4.70 (d, J = 9.77Hz, 1 H), 4.46 (dd, J = 8.88, 6.55Hz, 1 H), 4.33 (d, J = 10.25Hz, 1 H), 4.21 (d, J = 4.10Hz, 1 H), 3.88 (dd, J = 10.40, 7.25Hz, 1 H), 3.72 (dd, J = 10.25, 2.68Hz, 1 H), 3.60 (m, 1 H), 3.53 (m, 1 H), 3.41 (m, 1 H), 3.30 (m, 1 H), 2.85 (m, 1 H), 2.76 (m, 1 H), 2.72 (m, 1 H), 1.96-1.82 (m, 3H), 1.76-1.60 (m, 7H), 1.57 (bs, 6H), 1.45-1.35 (m, 3H), 1.33-1.22 (m, 2H), 1.20 (t, J = 6.93Hz, 3H), 1.12 (t, J = 7.09Hz, 3H), 1.08 (m, 2H), 1.01 (s, 9H), 0.86 (t, J = 7.25Hz, 3H), 0.83 (m, 2H), 0.53 (m, 2H).

1 H-NMR (500MHz):d6-DMSO

δ = 9.18 (1 H, d, J = 1.5Hz); 8.89 (1 H, d, J = 2.5Hz); 8.75 (1 H, dd, J₂ = 2.5Hz, J = 1.6Hz); 8.50 (1 H, d, J = 9.2Hz); 8.22 (1 H, d, J = 9.2Hz); 7.61 (1 H, d, J = 4.1 Hz); 7.34 (1 H, d, J = 9.6Hz); 4.67 (1 H, dd, J = 9.1 Hz, J₇ = 6.4Hz); 4.54 (1 H, d, J = 9.3Hz); 4.17 (1 H, d, J = 3.8Hz); 4.12 (m, 1 H); 3.73-3.63 (2H, m); 3.51-3.19 (4H, m); 2.63 (2H, m); 2.57 (1 H, m); 1.81-0.99 (21 H, m); 1.13 (3H, t, J = 7.0Hz); 1.06 (3H, t, J = 7.1 Hz); 0.93 (9H, s); 0.79 (3H, t, J = 7.2Hz); 0.63-0.47 (4H, m).

13C-NMR (125MHz): d6-DMSO

δ = 171.2, 170.3, 169.2, 169.0, 161.9,147.8,144.0, 143.4, 143.3,.100.3, 65.4, 57.4, 57.0, 56.4, 56.3, 54.1 , 50.3, 46.9, 42.5, 41.3, 34.4, 31.9, 31.7, 29.1 , 27.9, 25.7, 25.6, 25.5, 25.0,24.7, 26.3, 22.2, 15.1 , 15.0,, 13.6, 5.7, 5.6. Example 20 - telaprevir (compound of Formula 1)

TFA deprotection:

To a compound of formula 9a of Example 25 (20 mg, 0.026 mmol) was added TFA (900 μΙ_), acetone (100 μΙ_) and water (10 μΙ_). After 22h, full conversion to telaprevir occurred.

HCI-deprotection:

To a solution of 5.0 g (6.63 mmol) diethoxy-telaprevir (compound of formula 9a) in 10 ml acetone 45 ml cone, aqueous HCI was added and stirred for 5.5 h until complete conversion was observed. No oxidative byproduct (IMP 1 ) at rt=3.0min was detected. Afterwards 150ml water and 75ml methylene chloride was added. pH 5 2.5 was adjusted by slow addition of 5M aqueous NaOH. The organic phase was removed and the aqueous phase was extracted with 75ml methylene chloride. The organic phases were combined and the organic solvent was removed to dryness. 4.3g of yellow foam was isolated. IPC HPLC shows no oxidative byproduct (IMP 1 ) at rt = 3.0 min. After crystallization from 15 ml isopropanol 3.4 g telaprevir was isolated.

IPC HPLC:

Column: Water X-Bridge, Phenyl, 4.6 x 50 mm, 2.5 pm

Temp: 60°C Flow: 1 ml/min

Detection: 270 nm

Eluent A: 0.77 g Ammonium acetate/100 ml MeOH/900 ml H₂0

Eluent B: 0.77 mg Ammonium acetat/900ml MeOH/100 ml H₂0

Gradient: 0 min: 50 %B, 15 min: 95 %B, 17 min: 95 %B, 18 min: 50 %B H₂S0₄-deprotection:

100 mg diethoxy-telaprevir was dissolved in 100 μΙ acetone, 0.5 ml water and 0.5 ml cone. H₂S0₄ at 0 °C. The mixture was stirred at room temperature for 17 h until complete conversion was observed. Water and methylene chloride was added, the organic phase was separated and solvent was reduced to dryness.

Comparative Example 21 - telaprevir (compound of Formula 1) obtained via oxidation

As demonstrated below, the preparation of telaprevir via oxidation of hydroxyl-telaprevir as last step results in the formation of impurities (see Figure 7 for the reaction scheme):

To a solution of 28.1 g hydroxyl-telaprevir in 230 ml methylene chloride 3.5 ml 15 % aqueous KOH, 13 ml 7.5% aqueous NaHC0₃ was added and 170.3 mg (2.7 mol%) TEMPO was added. To the stirred mixture 43 ml 6-14 % NaOCI solution was added. After 19.5 h, 86 % conversion was observed. Additional 7 ml NaOCI was added and after an additional hour complete conversion was observed. IPC HPLC shows 2-3 area % of oxidative byproduct with rt = 3min. 150 ml water was added, the organic phase was separated and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with 150 ml 1 % Na₂S₂0₃ and the aqueous phase was extracted with 75 ml methylene chloride. The combined organic phases were extracted with 100 ml water and the aqueous phase was extracted with 75 ml methylene chloride. The organic phases were combined and solvent was removed to dryness leading to 27.0 g of yellow foam containing about 1.5 area% of oxidative byproduct (IMP1 ) with rt =3.0 min. After crystallization from 100 ml isopropanol, 20.3 g telaprevir was isolated containing 0.98 area% of oxidative byproduct (IMP1 ) with rt= 3.0 min and 0.11 area% of a second oxidative byproduct (IMP2).

HPLC analysis

Column: XBridge C18; 4.6*150 mm, 3.5 μιτι;

Stock solution 1 : Dissolve 0.9 g of K₂HP0₄ in 1000 mL of water

Stock solution 2: Mix 500 mL of MeOH, 150 mL of EtOH and 350 mL of ISO

Eluent A: Mix 400 mL of stock solution 1 with 100 mL of stock solution 2

Eluent B: Mix 100 mL of stock solution 2 with 400 mL of ACNL

Solvent: Mix 400 mL of EtOH, 100 mL of water and 100 pL of H₃P0₄

Flow rate: 1.1 mL/min Oven temperature: 38 °C

Stop time: 35 min (Post-time 6

Injection volume: 6.0 μΙ_

Detection: 210 nm

Gradient

Structure of I P2 (LC-MS: 582.4):

Isolation of oxidative byproduct (I P1 ) with rt= 3.0 min:

From a mother liquor of crystallization of telaprevir according example above containing IMP1 the solvent was removed to dryness leading to 9.0 g of yellow foam. The foam was dissolved in 10 ml methylene chloride and 100 ml water was added. pH was adjusted to 12.5. IMP1 was then found in the aqueous phase. The phases were separated and to the aqueous phase 100 ml methylene chloride was added. Afterwards pH was adjusted to 2.5 and the organic phase was separated. The organic solvent was removed to dryness and 0.8 g of yellow foam was isolated.

1H NMR (300MHz, CDCI₃): δ = 9.44 (m, 1 H), 8.75 (m, 1 H), 8.56 (s, 1 H), 8.37 (m, 1 H), 7.53 (d, 1 H), 4.84 (d, 1 H), 4.72 (m, 1 H), 4.59 (m, 2H), 3.81 (m, 3 ), 2.78-3.00 (m, 2H), 0.86-2.00 (m,

33H).

LC-MS: 612.3u

Structure of IMP 1 :

Comparative Example 22 - synthesis of 7a via amidatlon

Figure 19 shows the reaction schemes for these examples

Synthesis of Compound 7a via amidation or amidation/hydrogenation from 2a' and 6a' using reaction conditions known in the art (i.e. (a): EDCI, HOBt (b): (COCI)2) resulted in the formation of the corresponding β-Sactam byproducts. Furthermore, even the reaction of 6a' with phosgene or phosgene derivatives yielded the β-lactam product

1. Formation of the β-lactam from 6a' (Method A)

6a' (323 mg, 1.0 mmol) was dissolved in MED (5 mL) and cyclopropylamine (139 μΙ_, 2.0 mmol), anhydrous HOBt (270 mg, 2.0 mmol), EDCI.HCI (384 mg, 2.0 mmol) and diisoprolylethylamine (0.73 mL, 4.0 mmol) were added at room temperature. The formation of the β-lactam was monitored by HPLC.

2. Formation of the β-lactam from 6a' (Method B)

A solution of oxalyl chloride (42 pL, 0.5 mmol) in MED (2.0 mL) was added dropwise to a solution of 6a' (81 mg, 0.25 mmol) in MED (2.5 mL) at 0 °C. The formation of the β-lactam was monitored by HPLC.

3. Formation of the β-lactam from 2a' (Method A)

2a' (219 mg, 1.0 mmol) was dissolved in MED (10 mL) and cyclopropylamine (139 pL, 2.0 mmol), anhydrous HOBt (270 mg, 2.0 mmol), EDCI.HCI (384 mg, 2.0 mmol) and

diisopropylethylamine (0.73 mL, 4.0 mmol) were added at room temperature and the reaction mixture was stirred overnight. The formation of the β-lactam was monitored by HPLC. 4. Formation of the β-lactam from 2a' (Method B)

A solution of oxalyl chloride (168 μΙ_, 2.0 mmol) in MED (5 mL) was added dropwise to a solution of 2a' (219 mg, 1.0 mmol) in MED (10 mL) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C. A solution of cyclopropylamine (278 pL, 4.0 mmol) and pyridine (323 μί, 4.0 mmol) in MED (5 mL) was added dropwise and the reaction progress was monitored by TLC. The reaction was quenched with H₂0 (20 mL) after 30 minutes and the pH was adjusted to pH = 10 by the addition of NaOH (2.0 M). The organic layer was separated and the aqueous layer was extracted with MED (10 mL). The combined organic phases were dried over Na₂S0₄, filtered and concentrated under reduced pressure to give a complex mixture of products. The corresponding β-lactam forms the main component of the mixture.

5. Formation of the β-lactam from 6a' with triphosgene

To a suspension of 6a' (323 mg, 1.0 mmol) in THF (5 mL) was added activated charcoal (3 mg, type CECA ENO) followed by trichlormethyl chloroformate (90 L) and the reaction mixture was stirred at room temperature. The formation of the β-lactam was monitored by HPLC.

Cited literature

EP1362864;

EP1367061 ;

US 2600596;

US 2005/0171 165;

WO 96/33984;

WO 2006/078809;

WO 2007/022459 A2;

WO 2007/109023 A1 ;

WO 2007/138928 A1 ;

WO 2009/1 14633 A1 ;

WO 2009/152474 A2;

WO 2010/103405;

PCT/EP2013/062737 / EP 12 172 775.4;

Akssira et al. "A convenient synthesis of bridged azatricyclic anhydrides", Tetrahedron 1993, 49, 1985-1992;

Blacklock, T. J.; Shuman, R. F.; Butcher, J. W.; Schearin, W. E.; Budavari, J.; Granda, V. J. J. Org. Chem. 1988, 53, 836-844;

Bose et al. "First Total Synthesis of (-)-Circumdatin H, a Novel Mitochondrial NADH Oxidase Inhibitor", Synthesis 2010, 4, 643-650;

Cheng et al. "Synthesis of Optically Active β-Amino Acid N-Carboxyanhyd rides" T. J. Org. Lett. 2000, 2, 1943;

Daly, W. H.; Poche, D. Tetrahedron Lett. 1988, 29, 5859-5862;

Declerck, V.; Nun, P.; Martinez, J.; Lamaty, F. Angew. Chem. Int. Ed. 2009, 48, 9318;

Gizecki et al. "Diastereoselective preparation of novel tetrahydrooxazinones via

heterocycloaddition of N-Boc, O-Me-acetals", Tetrahedron Letters, 2004, 45, 9589-9592;

Greene, T. W., & Wuts, P.G.M , "Protective Groups in Organic Synthesis," 4th Edition, John Wiley & Sons, Inc. (2007), particularly relevant pages: p189-196 (synthesis of ROTBS); p102- 120 (synthesis of ROBn); p553-561 (synthesis of RC02Me); p814-818 (synthesis of NH-Bn); p748-756 (synthesis of NHCbz); p725-735 (synthesis of NHBoc).

Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447-2467;

Huck et al. "From β-Ν-tert-buty!oxycarbonyl N-arobxyanhydrides to β-aminoacid derivatives", J. Peptide Res. 2003, 62, 233-237;

Katakai, R.; lizuka, Y. J. Org. Chem. 1985, 50, 715-716;

Kolb et al. "Simultaneous assembly of the β-!actam and thiazole moiety by a new

multicomponent reaction", Tetrahedron Lett. 2002, 43, 6897;

Kricheldorf "Polypeptides and 100 Years of Chemistry of a-Amino Acid N-Carboxyanhyd rides" , Angew. Chem. Int. Ed. 2006, 45, 5752-5784;

"March's advanced organic chemistry" Ed.5. p.1 185-1 187;

McKiernan et al. "Urethane N-Carboxyanhyd rides from β-Amino Acids", J. Org. Chem. 2001 , 66, 6541-6544;

Oya, M.; Katakai, R.; Nakai, H. Chem. Lett. 1973, 1 143-1 144;

Smeets, N. M. B.; van der Weide, P. L. J.; Meuldijk, J.; Vekemans, J. A. J. M.; Hulshof, L. A. Org. Proc. Res. Dev. 2005, 9, 757-763;

Pelotier et al. "The Formation of Silylated β- Lactams from Silylketenes through Lewis Acid Promoted [2+2] Cycloaddition: A Combined Theoretical and Experimental Study" Eur. J. Org. Chem. 2005, 2599-2606;

Wilder, R.; Mobashery, S. J. Org. Chem. 1992, 57, 2755-2756;

Yamamoto "Highly Selective and Operationally Simple Synthesis of Enantiomerically Pure β- Amino Esters via Double Stereodifferentiation" Journal of the American Chemical Society 1993, 115, 1151 ;

Yamamoto "Practical Preparation of a-Hydroxy-B-Amino Ester Units; Stereoselective Synthesis of Taxol Side Chain and Norstatine" Tetrahedron 1994, 50, 9, 2785.

Yin et al. "Recent Applications of a-Amido Su If ones as in situ Equivalents of Activated Imines for Asymmetric Catalytic Nucleophilic Addition Reactions" Synthesis, 2010, 21 , 3583-3595.

Zografos et al. "Chemoselective Cyclization of Aminonicotinic Acid Derivatives to 1 ,8- Naphthyridin-2-ones via a Potential Intramolecular Azadiene-Ketene Electrocyclization

Reaction" J. Org. Chem. 2001 , 4413. Hermecz et al. "Nitrogen Bridgehead Compounds. 66. Bronchodilator Nitrogen Bridgehead Compounds with a Pyrimidinone Moiety " J. Med. Chem 1987, 1543.

Claims

Claims

1. Process for the preparation of te!aprevir of Formula 1

or a pharmaceutically acceptable salt or solvate thereof, comprising the steps of:

(i) providing a compound of Formula 2'

2^s wherein R₄ is methyl or ethyl;

(ii) subjecting the compound of Formula 2' to one of the sequences (iia)-(iid):

(iia) reacting the compound of Formula 2' with phosgene or a phosgene analogue to obtain the compound of Formula 3a'

3a' wherein R₄ is as defined above, via cyclization reaction; or

(i«b) reacting the compound of Formula 2' with a mixture of SOCI₂ and imidazole or imidazole derivatives to obtain the compound of Formula 3b'

3b' wherein R₄ is as defined above, via cyclization reaction; or

performing steps (iica) and (iicb):

) protecting the compound of Formula 2' to provide a compound of Formula 4'

4' wherein R₄ is as defined above; and

(iicb) reacting the compound of Formula 4' with a Lewis acid to obtain the compound of Formula 3a'

3a' wherein R₄ is as defined above, via cyclization reaction; or

(iid) performing steps (iida), (iidb) and (iidc):

(iida) protecting the compound of Formula 2' to provide a compound of Formula 4'

wherein R₄ is as defined above;

(iidb) protecting the compound of Formula 4' to provide a compound of Formula 5'

5' wherein R₄ is as defined above; and

(iidc) reacting the compound of Formula 5' with a Lewis acid to obtain the compound of Formula 3c'

3c" wherein R₄ is as defined above, via cyclization reaction;

performing an amide coupling reaction of the compound of Formula 3a', 3b' with cyclopropylamine in order to provide a compound of Formula 7a or 6aa

Boc_s

7a 6aa optionally isolating the compound of Formula 7a, or 6aa;

optionally converting the compound of Formula 7a into a salt and isolating said salt; if the compound of Formula 6aa is prepared in steps (iii)/(iv), converting the compound of Formula 6aa into a compound of Formula 7a, optionally isolating the compound of Formula 7a, further optionally converting the compound of Formula 7a into a salt and isolating said salt;

bringing the compound of Formula 7a or a salt thereof into contact with a compound of Formula 8a or a salt thereof

8a in the presence of one or more coupling agents, thereby obtaining a compound of Formula 9a

optionally isolating the compound of Formula 9a; and

(vii) deprotecting/cleaving the acetal in the compound of Formula 9a in the presence of an acid thereby obtaining telaprevir of Formula 1 , or a pharmaceutically acceptable salt or solvate thereof.

The process of claim 1 , wherein step (i) of providing a compound of Formula 2' includes one of the sequences (ia)-(ic):

(ia) performing steps (iaa), (iab) and (iac):

(iaa) providing a compound of Formula 4a

4a

wherein R₄ and R₅ are independently methyl or ethyl;

(iab) hydrolyzing the compound of Formula 4a to provide the compound of Formula 6'

6'

(iac) hydrogenating the compound of Formula 6a' to provide the compound of Formula 2"; (ib) performing steps (iba), (ibb) and (ibc):

(iba) providing a compound of Formula 4a

4a

wherein R₄ is methyl or ethyl, and R₅ is selected from the group consisting of linear, branched, or cyclic aliphatic groups, aromatic groups, and heteroaromatic groups as well as combinations thereof; preferably R₅ is methyl or ethyl;

(ibb) hydrogenating the compound of Formula 4a to provide the compound of Formula 7'

T

(ibc) hydrofyzing the compound of Formula 7' to provide the compound of Formula 2'; (ic) performing steps (ica) and (icb):

(ica) providing a compound of Formula 4'

wherein R₄ is as defined above;

(icb) deprotecting the compound of Formula 4' to provide the compound of Formula 2'.

The process of claim 2, wherein providing a compound of Formula 4a in steps (iaa) and (iba) includes the steps of:

(i) providing a compound of Formula 2a

2a bringing the compound of Formula 2a into contact with a compound of Formula 3

3 wherein R₄ and R₅ are independently methyl or ethyl; and

R₆ is methyl or ethyl,

in the presence of an acid, preferably Lewis acid, thereby obtaining a compound of Formula 4a, wherein optionally the stereochemical purity of the compound of Formula 4a is improved by extraction of said compound from the reaction mixture.

Process for the preparation of a compound of Formula 7a or 6aa

7a 6aa wherein R₄ is methyl or ethyl, by performing steps (i) to (iii) according to any of claims 1-3.

Process for the preparation of a compound of Formula 7a or 6aa

7a 6aa wherein R₄ is methyl or ethyl, comprising the step of:

(ia) providing a compound of Formula 4'

4' wherein R₄ is as defined above: or (ib) providing a compound of Formula 5a

5a

wherein R₄ is as defined above, and R₅ is selected from the group consisting of linear, branched, or cyclic aliphatic groups, aromatic groups, and heteroaromatic groups as well as combinations thereof,

and hydrolyzing the compound of Formula 5a in order to substitute the OR₅-group with an OH-group and to provide Compound 4'; and

(ii) using Compound 4' and performing step (iicb) according to claim 1 to provide a compound of Formula 3a', or steps (iidb) and (iidc) according to claim 1 to provide a compound of Formula 5'; and then step (iii) according to claim 1 to provide a compound of Formula 7a or 6aa.

Process for the preparation of a salt of the compound of Formula 7a

7a wherein R₄ is methyl or ethyl and Boc is tert-butoxycarbonyl, comprising the steps of:

(i) reacting the free base form of the compound of Formula 7a with an acid, preferably an organic carboxylic acid; and

(ii) crystallizing the salt of the compound of Formula 7a and isolating said salt. Process for the preparation of a compound of Formula 3'

3' wherein X is C or S, wherein R is H or Boc, wherein Boc Is tert-butoxycarbonyl, and wherein R₄ is methyl or ethyl, comprising steps (i) and (ii) according to any of claims 1-3.

Compound of Formula 7a

7a wherein R4 is methyl or ethyl in the form of a salt, preferably a salt with an organic carboxylic acid.

Compound of Formula 3'

3'

wherein X is C or S; wherein R is H or Boc, wherein Boc is tert-butoxycarbonyl, and wherein R₄ is methyl or ethyl.

10. Compound of Formula 1

wherein R₄ is methyl or ethyl.

Compound of Formula 5'

wherein R₄ is methyl or ethyl, and wherein Boc is tert-butoxycarbonyl.

Compound of Formula 6'

wherein R4 is methyl or ethyl. Compound of Formula 7'

T wherein R₄ is methyl or ethyl.

14. Telaprevir obtainable or obtained by the process of any of claims 1-3.

15. Telaprevir of claim 14

(i) containing oxidative side products of telaprevir in less than 0.10 area % as determined by HPLC analysis; and/or

(ii) being free of, determined by HPLC analysis, the compounds of Formulae 15a

15a wherein Rn is a protecting group or H

and 16a

wherein Rn is a protecting group or H;

and/or

(iii) containing 7a

7a

wherein R₄ is a protecting group or H,

and 9a

wherein R₄ is a protecting group or H,

in an amount of from 0 to less than 0.15 area% as determined by HPLC analysis.