WO2013131978A1

WO2013131978A1 - Process for the preparation of intermediates useful in the preparation of a viral protease inhibitor

Info

Publication number: WO2013131978A1
Application number: PCT/EP2013/054537
Authority: WO
Inventors: Simone Mantegazza; Emanuele Attolino; Pietro Allegrini
Original assignee: Dipharma Francis S.R.L.
Priority date: 2012-03-07
Filing date: 2013-03-06
Publication date: 2013-09-12
Also published as: ITMI20120359A1

Abstract

Process for the preparation of intermediates useful in the synthesis of the viral protease inhibitor Telaprevir. The claimed process involves reacting formula (IV) with a formula (III) compound using DMMTM as coupling reagent to get a formula (II) compound.

Description

PROCESS FOR THE PREPARATION OF INTERMEDIATES USEFUL IN

THE PREPARATION OF A VIRAL PROTEASE INHIBITOR

FIELD OF INVENTION

The present invention relates to a novel process for the preparation of peptide synthesis intermediates useful in the preparation of a viral protease inhibitor.

STATE OF THE ART

(I S, 3a , 6aS)-2-[(2S)-2-[[(2S)-2-Cyclohexyl-2-[(2-pyrazinylcarbonyl) amino]acetyl]amino-3,3-dimethylbutanoyl]-N-[(l S)- l-[(cyclopropylamino) (oxo)acetyl]butyl]-3,3a,4,5,6,6a-hexahydro- lH-cyclopenta[c]pyrrole-3- carboxyamide of formula (I), also known as telaprevir, is a potent viral protease inhibitor used in the treatment of hepatitis C infections.

The preparation of telaprevir is reported in US 7,820,671 , and involves the assembly of 6 different structural units, with the creation of 5 amide bonds as re orted in the Scheme below

_A B c D E F

Scheme

and the subsequent oxidation of the alcoholic hydroxyl in the structural unit of formula E. The structural units of formula A and F are pyrazine-carboxylic acid and cyclopropylamine respectively.

The structural units of formula B, C, D and E are amino acids, all with the (S) configuration.

In particular, the compounds of formula B and C are the commercially available amino acids (S)-cyclohexylglycine and (S)-tert-leucine respectively. The compounds of formula D and E are synthetic amino acids with a more complex structure.

The preparation of the compounds of formula D and E is reported in US 7,820,671.

The preparation of the amino acid deriving from norvaline of formula E, which has long been reported in the literature, can be effected by known methods. The preparation of the key amino acid of formula D, which is rather complex, was described in US 7,820,671 and US7,776,887.

Once all the constituent structural units have been prepared, they can be assembled to obtain telaprevir by known methods, for example by reacting an amino-acid residue only bearing the free acid moiety with another residue bearing the free amine moiety in the presence of a condensing agent, as required by the classic peptide synthesis.

However, the assembly of structural units A-F is a key point for effective industrialisation of the process, because incorrect selection of the condensing agent or amino-acid assembly sequence or excessive, but unfortunately necessary use of protecting groups may prevent the preparation of the peptide from being applied on an industrial scale.

In US 7,820,671 , for example, the assembly of the amino acids is sequential; considering the scheme set out below, peptide ABC is therefore condensed first with D to give ABCD and subsequently with EF, whereas in US 7,776,887, C and D, which are selectively protected, are condensed first, followed sequentially by B, A and the EF residue.

_A B C D E F

Scheme

In any event, the synthesis process designed to obtain telaprevir involves the continuous use of protecting groups and toxic, expensive, complex condensing systems such as DCC (dicyclohexylcarbodiimide)/HOBt (1-hydroxybenzotriazole) or EDCI (N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride/HOAt (l -hydroxy-7-azabenzotriazole); or even worse, the very expensive Bop (benzotriazolyloxy)trisdimethylamino- phosphonium hexafluorophosphate and PyBop(benzotriazolyloxy)- trispyrrolidinophosphonium hexafluorophosphate.

In particular, the synthesis of peptide ABC described in US 7,820,671 involves the reaction of cyclohexylglycine (B) protected as Boc (t-butyloxycarbonyl) or Cbz (benzyloxycarbonyl) with tert-leucine methyl ester (C) followed, after the removal of the protecting group, by a second condensation with piperazine carboxylic acid (A), again using a condensing system employed for peptide synthesis.

If the protecting group is Boc, the two condensations reported above take place with yields of between 30 and 36% (the yield for the entire synthesis process being only 1 1%), whereas with the use of protecting group Cbz, the yields are between 52 and 69%. However, said yields are still inadequate for an efficient, industrially scalable process.

Chem. Commun. 2010, 46, 7918-7920 describes a process for optimisation of the synthesis of peptide ABC which involves condensation of acid (A) with cyclohexylglycine protected as methyl ester to obtain residue AB, which subsequently leads to the formation of peptide ABC, by condensation with tert-leucine methyl ester without the use of groups protecting the amino-acid amine moiety.

The yield reported for this latter process is good, but unfortunately the synthesis, which is entirely carried out in dimethylformamide due to the insolubility of the amino acids used, makes extensive use of the expensive condensing agents reported above.

There is consequently a need for an alternative, more advantageous method of preparing telaprevir and its synthesis intermediates, in particular peptide intermediate ABC, on an industrial scale. Said novel method should in particular be more industrially scalable, involve the use of cheaper, safer, easier to handle reagents and mild reaction conditions, and at the same time provide high yields of the desired compounds with high chemical purity.

BRIEF DESCRIPTION OF FIGURE AND ANALYSIS METHODS

(S)-2-((S)-2-Cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3- dimethylbutanoic acid in crystalline form, designated here as Form a, having formula (II), where the stereocentres indicated by asterisk * both have absolute configuration (S), has been characterised by X-ray powder diffraction (X PD). The X-ray diffraction spectrum (XRPD) was collected with the APD-2000 automatic powder diffractometer manufactured by Ital- Structures under the following operating conditions: CuKoc radiation (λ = 1 ,54 A), scanning with a 2Θ angle range of 3-40° and a step size of 0.03° for a time of 1 sec. The detector used is a scintillator.

Figure: XRPD spectrum of (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoic acid in crystalline form, designated here as Form a; where the main peaks (expressed in ° in 2Θ) fall at 5.37, 7.17, 10.38, 10.71 , 14.43, 16.38, 17.10, 17.70, 18.09, 18.81 , 20.04, 20.49, 20.88, 21.96 and 24.21 SUMMARY OF THE INVENTION

It has surprisingly been found that a compound of formula (II), or a salt thereof,

(II)

wherein is H, or a straight or branched, optionally substituted Ci-C₆ alkyl group; and the asterisk * indicates the presence of a stereocentre, can be advantageously prepared by a process comprising reacting a compound of formula (III), or a salt thereof,

(HI)

wherein R and asterisk * are as defined above, with a compound of formula (IV)

(IV)

wherein R and asterisk * are as defined above; in the presence of a base, a solvent, and DMTMM (i.e. 4-(4,6-dimethoxy(l ,3,5)triazin-2-yl)-4- methylmorpholinium chloride).

A compound of formula (IV) can also be advantageously prepared by condensing a compound of formula (V) or a salt thereof with a compound of formula (VI) or a salt thereof,

(V) (VI)

wherein X is as defined below.

The processes according to the invention involve the use of cheap reagents and mild reaction conditions, and at the same time enable all the desired compounds to be produced with higher yields and higher purity than known processes. Such advantages consequently positively affect the end product telaprevir.

DETAILED DESCRIPTION OF THE INVENTION

Object of the present invention is a process for the preparation of a compound of formula (II), or a salt thereof,

(II)

wherein R is H, or a straight or branched, optionally substituted Ci-C₆ alkyl group; and the asterisk * indicates the presence of a stereocentre with configuration (R) or (S) or a racemic mixture thereof; comprising condensing a compound of formula (III), or a salt thereof,

(HI)

wherein R and asterisk * are as defined above, with a compound of formula (IV) or a salt thereof

(IV)

wherein and asterisk * are as defined above; and, if the case, converting a compound of formula (II) into another compound of formula (II) and/or, if the case, converting an acid of formula (II) into a salt thereof and/or, if the case, converting a salt of an acid of formula (II) into the free acid; wherein the condensing reaction is carried out in the presence of a base, DMTMM (i.e. 4-(4,6-dimethoxy(l ,3,5)triazin-2-yl)-4-methylmorpholinium chloride), and a solvent.

A salt of a compound of formula (II), (III) or (IV) is typically a pharmaceutically acceptable salt thereof, such as a sodium, potassium or calcium salt.

A Ci-C₆ alkyl group is preferably a Ci-C₄ alkyl group, preferably methyl, ethyl, isopropyl or tert-butyl, optionally substituted by one or more substituents, typically 1 to 3, selected independently from phenyl and halogen, such as fluorine, chlorine and iodine, preferably fluorine.

The condensation proceeds with complete retention of the absolute configuration. The absolute configurations of the stereocentres of a final compound of formula (II) will therefore be the same as present on the intermediates of formula (III) and (IV) used in the reaction.

A base can be organic or inorganic. An organic base can be selected, for example, from a cyclic or acyclic tertiary amine, such as N-methylmorpholine, DBU (diazabicycloundecene) or imidazole. An inorganic base can be selected, for example, from an alkali or alkaline-earth metal carbonate; an alkali or alkaline-earth metal hydroxide; or an alkali or alkaline-earth metal hydride, such as sodium, potassium or calcium, preferably sodium or potassium.

A base according to the present invention is preferably N-methylmorpholine and sodium hydroxide.

A solvent according to the present invention can be, for example, an aprotic polar solvent, typically an amide, such as dimethylformamide, dimethylacetamide or N-methylpyrrolidone, preferably dimethylacetamide; acetonitrile or dimethyl sulphoxide; an acyclic or cyclic ether, such as methyl tert-butyl ether, tetrahydrofuran or dioxane; a chlorinated solvent, such as dichloromethane, dichloroethane, chloroform or chlorobenzene; an ester, such as ethyl or methyl acetate; an apolar aprotic solvent, typically toluene; a polar pro tic solvent, typically a straight or branched Ci-C₈ alkanol, such as a Ci-C₅ alkanol; water or a mixture of two or more, and preferably two or three, of said solvents.

A preferred solvent is ethyl acetate or methanol.

DMTMM is used in at least a stoichiometric ratio compared with the compound of formula (IV), or a salt thereof.

The condensation can be carried out at a temperature of between about 0°C and the reflux temperature of the solvent, preferably between about 10°C and 70°C, and more preferably between about 15°C and about 50°C.

In accordance with a particularly preferred aspect of the invention, the condensation can be carried out in the presence of N-methylmorpholine and ethyl acetate or sodium hydroxide and methanol.

A compound of formula (II) can be converted to another compound of formula (II) according to known methods. For example, a compound of formula (II), where is Ci-C₆ alkyl, can be converted to a compound of formula (II) where R is H, by hydrolysis of the ester moiety according to known methods. Similarly, the carboxylic acid of formula (II), where R is H, can be esterified by known methods. A compound of formula (II) can be converted to a salt thereof, or a salt thereof can be converted to the free acid, according to known methods.

The present invention also provides a process for the preparation of telaprevir of formula (I), comprising the use as intermediate of a compound of formula (II), or a salt thereof, obtained according to the present invention. Said process can be performed as reported in US 7,820,671.

Alternatively, a compound of formula (I) can be prepared by a process comprising coupling of a compound of formula (II), or a salt thereof, to the tripeptide DEF, in the presence of DMTMM (i.e. 4-(4,6-dimethoxy (1 ,3,5) triazin-2-yl)-4-methylmorpholinium chloride).

As reported in US 7,820,671 the compound of formula (II), wherein R is H, and wherein both the stereocentres indicated by asterisk * have both an absolute (S) configuration, is obtained by freeze-drying a solution of said compound in acetonitrile and water.

According to the process of the invention, said (S)-2-((S)-2-cyclohexyl- 2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoic acid, of formula (II), is obtained in a solid crystalline state, in particular in the form herein designated as Form a, which presents an XRPD spectrum where the main peaks (expressed in ° in 2Θ) fall at 5.37, 7.17, 10.38, 10.71 , 14.43, 16.38, 17.10, 17.70, 18.09, 18.81 , 20.04, 20.49, 20.88, 21.96 and 24.21 , as shown in the Figure.

A further object of the present invention is therefore (S)-2-((S)-2- cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoic acid of formula (II) in crystalline form, in particular in the crystalline form herein designated as Form a.

As known, the freeze-drying technique requires the use of specific equipment, which is expensive and not available at all facilities where pharmaceutical active constituents are manufactured. Moreover, the freeze- drying technique is characterised by low energy efficiency, because the solvent (water) is removed under vacuum at low temperature. This method is generally used when the normal techniques for isolating the chemical intermediates are not applicable, especially due to the low thermal- stability of the products.

Moreover, compounds obtained by a freeze-drying process are generally in amorphous form and very often highly hygroscopic (see, for example, "Polymorphism in Pharmaceutical Solids", p. 538, published by Informa Healthcare USA, Inc, Harry G. Brittain - second edition (New York, 2009). The absorption of water during condensations is known to have an adverse effect on both the yield and the quality of the product obtained.

The use of said acid of formula (II), wherein is H and both the stereocentres indicated by asterisk * have an absolute (S) configuration, in solid crystalline form, and in particular in its Form a, in the condensation with tripeptide DEF described above, therefore favourably influences its kinetics by eliminating the problems associated with the use of the amorphous form.

A compound of formula (II), where both the stereocentres indicated by asterisk * have an absolute (S) configuration, in particular in the crystalline form, preferably in the novel crystalline form a obtained by the process according to the invention, can be advantageously used in a process for the preparation of telaprevir of formula (I).

It has surprisingly been found that a compound of formula (IV), or a salt thereof, as defined above, can be advantageously prepared in a relatively simple way, with a high yield and purity, by a process comprising condensation between piperazine carboxylic acid or a salt thereof and cyclohexylglycine or a salt thereof.

According to a further aspect thereof, the invention consequently provides a process for the preparation of a compound of formula (IV), or a salt thereof,

(IV)

wherein R is as defined above, and asterisk * is as defined above; comprising condensing a compound of formula (V) or a salt thereof,

(V)

wherein X is OH, or preferably the reactive residue of a carboxylic acid; with a compound of formula (VI), or a salt thereof

(VI)

and, if the case, converting a compound of formula (IV) wherein R is H, thus obtained, into another compound of formula (IV), wherein R is a straight or branched, optionally substituted Ci-C₆ alkyl group, or a salt thereof.

A salt of a compound of formula (IV), (V) or (VI) is typically a pharmaceutically acceptable salt thereof.

The stereocentre in a compound of formula (IV) or a compound of formula (VI) can be (R) or (S) or a racemic mixture thereof. The condensation proceeds with complete retention of the absolute configuration; the absolute configuration of the stereocentre of a compound of formula (IV) will consequently be the same as the compound of formula (VI) used in the reaction.

The reactive residue of a carboxylic acid of formula (V) is a known good leaving group. Examples of reactive residues X are, in particular, halogen, preferably chlorine; imidazole; or an -OCORa or -OCOORa group, where Ra is a straight or branched Ci-C₆ alkyl, optionally substituted, for example, by phenyl or halogen, such as chlorine or fluorine.

According to a preferred aspect, the condensation of a compound of formula (V) with a compound of formula (VI) can be carried out by activating the carboxylic acid of formula (V), by its reaction with an activating agent in a solvent, and optionally in the presence of a base, and subsequently reacting it with cyclohexylglycine (VI), or a salt thereof, for example in the same reaction mixture, without the use of protections on either the acid moiety or the amine moiety of cyclohexylglycine.

The activation of a carboxylic acid of formula (V) to obtain a reactive derivative thereof can be carried out by reaction with a suitable activating agent according to known methods.

For example, an activating agent able to convert a compound of formula (V), where X is OH, to another compound of formula (V), where X is chlorine, is, for example, thionyl chloride.

An activating agent able to convert a compound of formula (V) where X is OH, to a compound of formula (V) where X is -OCORa, is for example an acyl chloride, such as acetyl chloride or pivaloyl chloride.

An activating agent able to convert a compound of formula (V), wherein X is OH, to a compound of formula (V), where X is -OCOORa, for example, is an alkyl chloro formate, such as ethyl or isopropyl chloroformate.

A common activating agent able to convert a compound of formula (V), where X is OH, to a compound of formula (V), where X is imidazole is for example carbonyl diimidazole (CDI).

The reaction of a compound of formula (V), a salt thereof or a reactive derivative thereof, with a compound of formula (VI) or a salt thereof can be carried out in the presence of a base and in a solvent selected, for example, from those mentioned above in relation to the reaction between a compound of formula (III) and a compound of formula (IV).

The condensation is preferably carried out in tetrahydrofuran using a compound of formula (V), wherein X is imidazole.

The condensation can be carried out at a temperature of between about 0°C and the reflux temperature of the solvent, preferably between about 40°C and about 70°C.

A compound of formula (IV), wherein is H, can be converted to another compound of formula (IV), wherein R is as defined above, according to known methods.

A compound of formula (IV), (V) or (VI) can be converted to a salt thereof, and similarly, a salt thereof can be converted to the free compound, according to known methods.

A compound of formula (IV), wherein the stereocentre indicated by asterisk * has an absolute (S) configuration, obtained by the process according to the present invention, can be advantageously used in a process for the preparation of telaprevir of formula (I).

The present invention thus also provides a process for the preparation of telaprevir of formula (I), comprising the use as intermediate of a compound of formula (IV), or a salt thereof, obtained according to the present invention.

A compound of formula (IV), as defined above, wherein the stereocentre indicated by asterisk * has an absolute ( ) configuration or is an (R,S) mixture, obtained by the process according to the present invention, and similarly a compound of formula (II), as defined above, wherein at least one of the stereocentres indicated by asterisk * has an absolute configuration (R) or is an (R,S) mixture, can be advantageously used in a process for the preparation of diastereoisomers of telaprevir of formula (I). Said compounds can be usefully employed in analytical chemistry to determine the chemical and stereochemical purity of telaprevir.

The following examples illustrate the invention.

Example 1 - Synthesis of (S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)-acetic acid (IV)

Carbonyldiimidazole (10.8 g, 66.8 mmol) is added to a suspension of pyrazine-carboxylic acid (7.90 g, 63.6 mmol) in tetrahydrofuran (40 ml) maintained under inert atmosphere at ambient temperature, and heated at the temperature of 55-60°C for 1.5-2 hours. The resulting solution is cooled to ambient temperature and added slowly, dripping in about 2 hours, to an L-cyclohexyl-glycine potassium salt solution (12.4 g, 63.6 mmol) in tert-butyl alcohol (120 ml) maintained under inert atmosphere with vigorous stirring. When the addition has been completed, the solution is left to react at ambient temperature for 16-18 hours. The reaction mixture is diluted with water (100 ml) and concentrated at 45-50°C under low pressure to remove the organic solvent, and 5-10% hydrochloric acid is added to the aqueous solution until a pH of about 1 -2 is reached. The solid in suspension is filtered and stove-dried at 50°C under low pressure for 24 hours; 15.2 g of the crude product is obtained, which is used "as is" for the subsequent reactions, with a yield of 91%.

Ή-NMR 300 MHz, δ (DMSO-d₆): 9.18 (d, 1H); 8.88 (d, 1H); 8.76 (dd, 1H); 8.46 (bd, 1H); 4.38 (dd, 1H); 1.90 (m, 1H); 1.74-1.50 (m, 5H); 1.30-0.98 (m, 5H).

Example 2 - Synthesis of methyl (S)-2-((S)-2-cyclohexyl-2-(pyrazine- 2-carboxamido)-3,3-dimethylbutanoate (II)

4-(4,6-dimethoxy-l ,3,5-triazin-2-yl)-4-methylmorpholine hydrochloride (23.1 g, 83.6 mmol) is added at ambient temperature to the solution obtained by mixing (S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)-acetic acid (20.0 g, 76.0 mmol), L-tert-leucine methyl ester (1 1.0 g, 76.0 mmol) and N-methylmorpholine (23.1 g, 228 mmol) in ethyl acetate (400 ml) and maintaining it under an inert atmosphere, and left to react for 2-3 hours. The reaction mixture is quenched by adding a 1M aqueous solution of hydrochloric acid (300 ml), the phases are separated and the organic phase is washed with a 1 M solution of hydrochloric acid (200 ml), then with a saturated solution of sodium bicarbonate (2x200 ml), and finally with a saturated solution of sodium chloride (100 ml). The organic phase, dried with sodium sulphate, is concentrated to residue, and a crude product with an HPLC purity of 98% is obtained, namely 28.7g of white solid, with a yield of 96%.

Ή-NMR 300 MHz, δ (CDC1₃): 9,40 (d, 1H); 8,69 (d, 1H); 8,49 (dd, 1H); 8,30 (bd, J=9Hz, 1H); 6,96 (bd, J=9Hz, 1H); 4,63 (dd, 1H); 4,41 (d, J=9Hz, 1H); 3,68 (s, 3H); 1 ,85-1 ,55 (m, 6H); 1 , 18-1 ,02 (m, 5H); 0,87 (s, 9H).

1³C-NM 100 MHz, δ (CDC1₃): 171 ,22; 170,23; 162,55; 146,98;

144, 10; 143,70; 142,29; 54,74; 57,58; 54,85; 51 ,35; 40,26; 34, 17; 29, 1 1 ; 28,33; 26,09; 25,60; 25,41.

MS(ES⁺): m/z 413 [M+Na]⁺.

Example 3 - Synthesis of (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)acetamido)-3,3-dimethylbutanoic acid (II)

A 1M aqueous solution of sodium hydroxide (440 ml, 440 mmol) is added to a solution of methyl (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- carboxamido)-3,3-dimethylbutanoate (28.7 g, 73.5 mmol) in methanol (150 ml) maintained under inert atmosphere, and the mixture is heated to 40-45 °C and maintained under stirring for 24 hours. The mixture is acidified with 37% hydrochloric acid to a pH of 1 -2 and extracted with ethyl acetate (3x200 ml); the combined organic phases are washed with a saturated solution of sodium chloride (200 ml), dried with sodium sulphate, and concentrated to residue. The crude product obtained is taken up with ethyl acetate, heated at reflux temperature for about an hour and cooled in 4-5 hours to 0-5°C, and the solid is filtered by washing with ethyl acetate (3x50 ml). The solid is dried at 45-50°C at low pressure and 26.5 g of crystalline product is obtained, with an HPLC purity of 99.7% and a yield of 95%.

Ή-NMR 300 MHz, δ (CD₃OD): 9,23 (s, 1H); 8,77 (s, 1H); 8,66 (s, 1H); 8,30 (bd, J=9Hz, 1H); 4,65 (d, J=7Hz, 1H); 4,32-4,30 (m, 1H); 1 ,88-1 ,59 (m, 6H); 1 ,24-1 ,07 (m, 5H); 0,99 (s, 9H).

¹³C-NM 100 MHz, δ (CD₃OD): 172,05; 171 ,45; 162,95; 147,06; 143,95; 143,08; 142,93; 60,38; 57,77; 39,91 ; 33,09; 28,07; 26,26; 25,91 ; 25,56; 25,21 ; 24,84.

MS(ES⁺): m/z 399 [M+Na]⁺.

XRPD analysis of (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)- acetamido)-3,3-dimethylbutanoic acid, as shown in the Figure, detects main peaks (expressed in ° in 2Θ) at 5.37, 7.17, 10.38, 10.71 , 14.43, 16.38, 17.10, 17.70, 18.09, 18.81 , 20.04, 20.49, 20.88, 21.96 and 24.21.

Claims

1. Process for preparing a compound of formula (II), or a salt thereof,

(II)

wherein R is H, or a straight or branched Ci-C₆, optionally substituted alkyl group; and the asterisk * indicates the presence of a stereocentre with configuration (R) or (S) or a racemic mixture thereof; comprising condensing a compound of formula (III), or a salt thereof,

(HI)

wherein R and the asterisk * are as defined above; with a compound of formula (IV), or a salt thereof,

(IV)

wherein R and the asterisk * are as defined above; and, if the case, the conversion of a compound of formula (II) into another compound of formula (II), and/or, if the case, converting an acid of formula (II) into a salt thereof, and/or, if the case, converting a salt of an acid of formula (II) into the free acid; wherein said condensing reaction is carried out in the presence of a base, DMTMM (i.e. 4-(4,6-dimethoxy(l ,3,5)triazin-2-yl)-4-methylmorpholinium chloride), and a solvent.

2. Process according to claim 1 , wherein the base is selected between an organic base, such as a cyclic or acyclic tertiary amine, DBU (diazabicycloundecene) or imidazole, and an inorganic base, such as an alkali or alkaline earth metal carbonate, an alkali or alkaline earth metal hydroxide; or an alkali or alkaline earth metal hydride, for instance sodium, potassium or calcium, preferably sodium or potassium.

3. Process according to claim 1 or 2, wherein the base is selected between N- methyl-morpholine and sodium hydroxide.

4. Process according to claim 1 , wherein the solvent is selected among a polar aprotic solvent, for instance an amide, or a cyclic or acyclic ether, a chlorinated solvent, an ester, an apolar aprotic solvent, a polar protic solvent, water and a mixture of two or more, preferably two or three, of said solvents.

5. Process according to claim 1 or 4, wherein the solvent is selected between ethyl acetate and methanol.

6. Process according to claims 1 to 5, wherein DMTMM is used in at least a stoichiometric ratio compared with the compound of formula (IV), or a salt thereof.

7. Process according to anyone of claims 1 to 6, wherein the condensation is carried out in the presence of N-methyl morpholine and in ethyl acetate or in the presence of sodium hydroxide and methanol.

8. Process according to anyone of claims 1 to 7, further comprising the preparation of a compound of formula (IV)

wherein is as defined in claim 1 , or a salt thereof, and the asterisk * is as defined above; comprising condensing a compound of formula (V), or a salt thereof,

(V)

wherein X is OH, or preferably the reactive residue of a carboxylic acid; with a compound of formula (VI), or a salt thereof,

(VI)

and, if the case, converting a compound of formula (IV) wherein R is H, into another compound of formula (IV), wherein R is a straight or branched, optionally substituted Ci-C₆ alkyl group; or a salt thereof.

9. Process according to claim 8, wherein the condensation of a compound of formula (V) with a compound of formula (VI), or a salt thereof, is carried out by activating first the carboxylic acid of formula (V) by reaction with an activating agent, optionally in the presence of a base, to yield a reactive derivative thereof, and then reacting said activated carboxylic acid, for instance in the same reaction mixture, with cyclohexylglycine of formula (VI), or a salt thereof, without protecting either the acid or the amine moiety of cyclohexylglycine.

10. Process according to claim 9, wherein the condensation is carried out in tetrahydrofuran using a compound of formula (V), wherein X is imidazole.

1 1. Process according to claims 8 to 10, wherein the condensation is carried out at a temperature of between about 0°C and the reflux temperature of the solvent, preferably between about 40°C and about 70°C.

12. (S)-2-((S)-2-Cyclohexyl-2-(pyrazin-2-carboxamido)acetamido)-3,3- dimethylbutanoic acid, having formula (II), in crystalline form, in particular in the crystalline form designated as Form a, wherein the most important peaks (in ° in 2Θ) fall at 5.37, 7.17, 10.38, 10.71 , 14.43, 16.38, 17.10, 17.70, 18.09, 18.81 , 20.04, 20.49, 20.88, 21.96 and 24.21.

13. Process according to claim 1 or 8, further comprising the preparation of telaprevir, having formula (I),

(I)

utilizing, as starting material, a compound of formula (II), or a salt thereof,

(Π)

wherein is as defined in claim 1 , and the stereocentres indicated by the asterisk * both have absolute configuration (S), preferably in crystalline form, in particular in the crystalline form a as defined in claim 12, obtained by the process of claim 1 ; or utilizing, as starting material, a compound of formula (IV)

(IV) wherein R is H, or a salt thereof, and the asterisk * is as defined in claim 1 , obtained by the process of claim 8.

14. Process for preparing a diastereoisomer of telaprevir of formula (I),

(I)

comprising utilising, as starting material, a compound of formula (IV), as defined in claim 1 , wherein the stereocentre indicated by the asterisk * is in absolute configuration (R), or an (R,S) mixture thereof; or utilising, as starting material, a compound of formula (II), as defined in claim 1 , wherein at least one of the stereocentres indicated by the asterisk * is in absolute configuration (R), or an (R,S) mixture thereof.

15. Process for preparing a compound of formula (I)

(I)

comprising coupling of a compound of formula (II), or a salt thereof, to the tripeptide DEF,

in the presence of DMTMM (i.e. 4-(4,6-dimethoxy (1 ,3,5) triazin-2-yl)--methylmorpholinium chloride).