WO2019197274A1 - Process for the preparation of opioid modulators - Google Patents

Process for the preparation of opioid modulators Download PDF

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Publication number
WO2019197274A1
WO2019197274A1 PCT/EP2019/058554 EP2019058554W WO2019197274A1 WO 2019197274 A1 WO2019197274 A1 WO 2019197274A1 EP 2019058554 W EP2019058554 W EP 2019058554W WO 2019197274 A1 WO2019197274 A1 WO 2019197274A1
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formula
process according
salt
protected
alanine derivative
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PCT/EP2019/058554
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French (fr)
Inventor
Giuseppe Barreca
Giovanni Marras
Andrea Poggiali
Luca Carcone
Przemyslaw Jozef ZAWADZKI
Barbara Karonlina WOLEK
Martyna Urszula JATCZAK
Katarzyna Michalina CIEPIELA
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Quimica Sintetica, S. A.
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Publication of WO2019197274A1 publication Critical patent/WO2019197274A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00Carboxylic acid amides
    • C07C233/64Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/65Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals

Definitions

  • the present invention relates to an industrially viable and advantageous process for the preparation of mu/delta opioid modulators and of protected alanine derivatives useful as intermediates in the synthesis thereof.
  • the invention also relates to intermediates obtained in the process.
  • IBS Irritable Bowel Syndrome
  • This compound is approved for the treatment of irritable bowel syndrome (IBS) with diarrhoea (IBS-d).
  • Eluxadoline and other similar compounds were first described in international patent application WO 2005/090315 A1.
  • the process described therein entails, as key steps, triflation of a protected dimethyl-tyrosine; treatment of methyl (S)-2-((fe/f-butoxycarbonyl)amino)-3- (2,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate with gaseous carbon monoxide (CO); amidation of (S)-4-(2-((fe/f-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)- 3,5-dimethylbenzoic acid; and the coupling between (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4- carbamoyl-2,6-dimethylphenyl)propanoic acid and methyl (S)-2-methoxy-5-(((1-
  • the precursor of eluxadoline is prepared by coupling (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)propanoic acid and methyl (S)-2-methoxy-5-(((1-(4-phenyl-1 /-/-imidazol-2- yl)ethyl)amino)methyl)benzoate in the presence of EDC-HCI/HOBT at room temperature (normally 25 °C) and that said coupling proceeds with a molar yield of 50%, thus making its application on industrial scale hardly feasible to the extent that about 50% of the starting compounds do not react or degrade.
  • Aim of the present invention is to provide a chemical method to prepare protected mixed pOR agonist/50R antagonists, preferably eluxadoline, as well as intermediates in the synthesis thereof with improved yields and appropriate purity.
  • - n is 1 , 2, 3 or 4;
  • each R 1 is independently selected from (C1-C6)alkyl-, (C1-C6)alkoxy- and fluoro;
  • R 5 and R 10 are independently selected from hydrogen and (C1-C4)alkyl-; alternatively, R 5 and R 10 taken together with the nitrogen atom to which they are bound form a five to seven membered heterocyclic radical;
  • - Pg is a nitrogen protecting group
  • R 6 is selected from hydrogen, (C1-C6)alkyl-, (C3-C8)cycloalkyl-, aryl(C1-C6)alkyl- and heteroaryl(C1-C6)alkyl-, wherein the aryl and the heteroaryl group can be further substituted with at least one group selected from the group consisting of OH, CN, NO2, CO2H, halogen, (C1-C6)alkyl-, (C1-C6)alkoxy-, and (C1-C6)alkoxycarbonyl-;
  • R 7 is (C1-C4)alkyl
  • R 8 is selected from hydrogen and (C1-C4)alkyl
  • R 9 is selected from (C1-C6)alkyl, aryl, aryl(C1-C6)alkyl-, aryl(C2-C6)alkenyl-, aryl(C2- C6)alkynyl-, heteroaryl, heteroaryl(C1-C6)alkyl-, heteroaryl(C2-C6)alkenyl-, heteroaryl(C2- C6)alkynyl-, amino, (C1-C6)alkylamino-, (C1-C6) 2 -alkylamino-, arylamino-, heteroarylamino-, aryloxy-, heteroaryloxy-, trifluoromethyl and halogen.
  • Figure 1 depicts the X-Ray powder diffractogram of a protected carbamoyl phenyl propanoate of formula (5B) in which R 5 and R 10 are hydrogen, R 2 is methyl and Pg is tert- butyloxycarbonyl crystallized from acetone.
  • Figure 2 depicts the X-Ray powder diffractogram of a protected alanine derivative of formula (6B) in which R 5 and R 10 are hydrogen and Pg is tert- butyloxycarbonyl.
  • Figure 3 depicts the X-Ray powder diffractogram of the hemi-oxalate salt of the compound of formula (8B).
  • Figure 4 depicts the X-Ray powder diffractogram of a sodium salt of a protected amide of formula (7G) in which R 5 and R 10 are hydrogen and Pg is tert- butyloxycarbonyl.
  • Figure 5 depicts the X-Ray powder diffractogram of a hydrochloride salt of eluxadoline having a chloride content of 18.5% (w/w).
  • Figure 6 depicts the X-Ray powder diffractogram of a hydrochloride salt of eluxadoline having a chloride content of 15.3% (w/w).
  • Figure 7 depicts an X-Ray powder diffractogram of a protected carbamoyl phenyl propanoate of formula (5B) in which R 5 and R 10 are hydrogen, R 2 is methyl and Pg is tert- butyloxycarbonyl crystallized from 2-propanol.
  • Figure 8 depicts the X-Ray powder diffractogram of a diethylamine salt of a protected alanine derivative of formula (6B) in which R 5 and R 10 are hydrogen and Pg is tert- butyloxycarbonyl.
  • Figure 9 depicts the X-Ray powder diffractogram of a protected alanine derivative of formula (6B) in which R 5 and R 10 are hydrogen and Pg is tert- butyloxycarbonyl.
  • the compounds prepared by the processes of the present invention may have one or more stereogenic centers and may exist and may be used or isolated in enantiomerically pure forms, as enantiomeric enriched mixtures as well as in diastereomerically pure forms or as diastereomeric enriched mixtures. It is to be understood that the processes of the present invention can give rise to any of the previous forms or a combination thereof. It is to be further understood that the products of the processes described herein, can be isolated as enantiomerically and/or diastereomerically pure forms or as enantiomerically and/or diastereomerically enriched mixtures.
  • a mixture of ( R,S ) enantiomers can contain the two enantiomers in any ratio to each other.
  • the enantiomeric purity is generally expressed as“enantiomeric excess” or ee and is defined, for example for the (S) enantiomer, as [(S-R)I(R+S)]x 100, wherein S and R are respectively the amounts of the (S) and (R) enantiomers (as determined for example by GC or HPLC on a chiral stationary phase or polarimetry).
  • a/yf refers to any substituent derived from a monocyclic or a polycyclic aromatic hydrocarbon by removal of a hydrogen atom from a ring carbon atom (e.g., phenyl, tolyl, 1 -naphtyl or 2-napthyl).
  • seed refers to a crystalline substance that is added to a dispersion, preferably a solution, of the same substance to induce its crystallization. Seeding with a specific crystalline form has often the useful effect of promoting crystallization of the substance in the same crystalline form of the seed.
  • the use of the indefinite article “a” means “at least one” and should not be limited to “only one” unless explicitly indicated to the contrary.
  • the term“ racemic” refers to a sample of a chiral compound which contains both the (+) and (-) isomers in equal amount.
  • enantiomerically enriched means that one of the enantiomers of a compound is present in excess compared to the other enantiomer.
  • enantiomerically pure means that the enantiomeric purity is usually at least about 96%, preferably at least 99%, more preferably at least 99.5%.
  • diastereomerically enriched means that one of the diastereomers of a compound is present in excess compared to the other diastereomer.
  • diastereomerically pure means that the diastereomeric purity is usually at least about 96%, preferably at least 99%, more preferably at least 99.5%.
  • nitrogen protecting group refers to a group that may be attached to a nitrogen atom to protect it from participating in the reaction and that may be readily removed following the reaction.
  • the compounds obtained by the chemical transformations of the present invention can be used without further purification or can be separated and purified by employing conventional methods well known to those skilled in the art, such as recrystallization, column chromatography, or by transforming them into a salt or into a co-crystal with an appropriate co- former, or by washing with an organic solvent or with an aqueous solution, optionally adjusting pH.
  • the present invention relates to a process for the preparation of a mixed pOR agonist/60R antagonist (9) or a salt thereof:
  • the first operation of the process of the invention, a), consists in the provision of a protected alanine derivative of formula (6), preferably a protected alanine derivative of formula (6A), more preferably a protected phenyl propanoate of formula (6B) or a salt of any one of them:
  • the present invention is also directed to a process for the preparation of a protected alanine derivative of formula (6), (6A), (6B) or a salt of any one of them for using in step a) above.
  • Said protected alanine derivative of formula (6), (6A), (6B) can be conveniently prepared starting from a protected phenyl propanoate of formula (2), (2A) or (2B), as detailed below, according to the following steps:
  • R 4 is different from R 10 R 5 N, converting said phenyl propanoate of formula (4), (4A) or (4B) into a protected carbamoyl phenyl propanoate of formula (5), preferably a protected carbamoyl phenyl propanoate of formula (5A) or (5B), by treatment with an amine of formula R 10 -NH-R 5 :
  • R 2 is selected from (C1-C4)alkyl
  • R 3 is a leaving group able to undergo a nucleophilic aromatic substitution, such as for example, a mesylate, a tosylate, a halogen, a triflate, a nonaflate, a fluorosulfonate, or a nosylate; and
  • R 4 is halogen, (C1-C6)alkoxy-, hydroxy, amino, (C1-C4)alkylamino-, (C1-C4) 2 - alkylamino-.
  • Operation d) comprises the provision of a protected phenyl propanoate of formula (2), preferably a protected phenyl propanoate of formula (2A), more preferably a protected phenyl propanoate of formula (2B):
  • Protected phenyl propanoates of formulae (2), (2A) and (2B) are commercially available; alternatively, they can be prepared according to standard techniques in organic synthesis, for example, starting from the corresponding alcohols of formulae (1 ), (1A) or (1 B) (in which the substituents assume the meanings reported above) and following the procedure described in Org. Process Res. Dev. 2011 , 15, 1 124-1 129:
  • R 3 is a sulfonate (such as mesylate, trifluoromethanesulfonate (triflate) or tosylate)
  • its preparation can be performed with one of the methods generally known in the field, for example by treating the corresponding alcohols of formulae (1 ), (1A) or (1 B) with a sulfonyl halide (preferably a methanesulfonyl halide, such as methanesulfonyl chloride or trifluoromethanesulfonyl chloride) or a sulfonyl anhydride (preferably methanesulfonic anhydride or trifluoromethanesulfonic anhydride), normally in the presence of an organic base and of a suitable solvent.
  • a sulfonyl halide preferably a methanesulfonyl halide, such as methanesulfonyl chloride or trifluoromethanesulfonyl chloride
  • the base is a tertiary amine (cyclic or acyclic), such as triethylamine, N,N- diisopropylethylamine, /V,/V-diisopropylmethylamine, /V-methylpyrrolidine, 4- methylmorpholine, /V,/V-dicyclohexylmethylamine, L/,/V-diethylaniline, pyridine, 2- methylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine or 4-dimethylaminopyridine.
  • a tertiary amine such as triethylamine, N,N- diisopropylethylamine, /V,/V-diisopropylmethylamine, /V-methylpyrrolidine, 4- methylmorpholine, /V,/V-dicyclohexylmethylamine, L/,/V-diethylaniline, pyridine, 2- methylpyridine,
  • Solvents useful for the aim are, for example, chlorinated solvent (preferably dichloromethane), ethers, hydrocarbons (preferably aromatic, for example toluene), polar aprotic solvents, such as acetonitrile, and mixture thereof.
  • the quantity of sulfonyl halide or of sulfonyl anhydride used is normally from 1 .0 to 3.0 equivalents, preferably from 1 .01 to 2.50 equivalents, more preferably from 1 .02 to 2.10 equivalents, even more preferably from 1.05 to 2 equivalents compared to the molar quantity of the alcohols of formulae (1 ), (1A) or (1 B).
  • the amount of the organic base used is normally from 1 to 3 equivalents, preferably from 1 .25 to 2.5 equivalents, more preferably from 1 .5 to 2 equivalents compared to the molar quantity of the alcohols of formulae (1 ), (1A) or (1 B).
  • R 3 is a halogen
  • said compound can be prepared by treating the protected phenyl propanoates of formulae (2), (2A) and (2B), in which R 3 is a sulfonate, with a halogenating agent such as a tetraalkylammonium halide (preferably tetrabutylammonium iodide, fluoride or bromide) or, preferably, with a halide of an alkali metal optionally in the presence of a catalytic system comprising at least one element selected from groups 8, 9 10 and 11 of the Periodic Table (preferably palladium, ruthenium, iridium, copper or rhodium) and, preferably, of at least one ligand, more preferably a phosphine.
  • a halogenating agent such as a tetraalkylammonium halide (preferably tetrabutylammonium iodide, fluoride or bromide) or,
  • Halides of alkali metals are more preferably selected from the group comprising, or even more preferably consisting of, LiF, NaF, KF, CsF, LiCI, NaCI, KCI, CsCI, LiBr, NaBr, KBr, CsBr, Lil, Nal, Kl, and Csl.
  • the quantity of halogenating agent is generally from 1.0 to 5.0 equivalents, preferably from 1.1 to 3.0 equivalents compared to the molar quantity of the protected phenyl propanoates of formulae (2), (2A) and (2B) in which R 3 is a sulfonate.
  • Operation e) of the process of the invention comprises the conversion of a protected phenyl propanoate of formula (2), (2A) or (2B), optionally isolated, into a phenyl propanoate of formula (4), preferably a phenyl propanoate of formula (4A), more preferably a phenyl propanoate of formula (4B):
  • This operation e) includes:
  • steps e.1 ) and e.2) being carried out subsequently or concurrently.
  • step e.1 the protected phenyl propanoate of formula (2), preferably a phenyl propanoate of formula (2A) or (2B), is subjected to a carbonylation by treatment with gaseous CO or at least one CO surrogate, in the presence of a transition metal-comprising catalytic system.
  • the carbonylation of the protected phenyl propanoate of formula (2) (2A) or (2B) is carried out using a catalytic system comprising, preferably based on, a transition metal such as, for example, ruthenium, rhodium, iridium, nickel, platinum or more preferably palladium.
  • a transition metal such as, for example, ruthenium, rhodium, iridium, nickel, platinum or more preferably palladium.
  • this step is conveniently carried out in the presence of at least one base, preferably a base capable to promote decarbonylation of the CO source.
  • said carbonylation step is carried out in the presence of a palladium- comprising catalytic system, more preferably a palladium-based catalytic system, optionally in an organic solvent, preferably a polar aprotic solvent (such as tetrahydrofuran, dioxane or preferably dimethylformamide, dimethylacetamide or acetonitrile), at a temperature normally from 40 to 160 °C, preferably from 50 °C to 100 °C, more preferably from 60 °C to 90 °C, even more preferably from 65 °C to 70 °C.
  • a palladium- comprising catalytic system more preferably a palladium-based catalytic system
  • an organic solvent preferably a polar aprotic solvent (such as tetrahydrofuran, dioxane or preferably dimethylformamide, dimethylacetamide or acetonitrile)
  • a polar aprotic solvent such as tetrahydrofuran
  • the transition metal-comprising catalytic system preferably has oxidation state 0 (zero) or II (two) and/or comprises, more preferably substantially consists of, even more preferably consists of, palladium, such as, palladium chloride (PdCI 2 ), palladium acetate (Pd(OAc) 2 ) or tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), optionally in the presence of mono- or bidentate ligands.
  • palladium chloride PdCI 2
  • Pd(OAc) 2 palladium acetate
  • Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium
  • Mono- or bidentate ligands useful for the aim are for example selected from the group comprising, preferably consisting of, triphenyl phosphine (PPfi3), tri(o- tolyl)phosphine (P(o-tol)3), 1 ,1 -bis(diphenylphosphino)methane (DPPM), 1 ,T- bis(diphenylphosphino)ferrocene (DPPF), 1 ,2-bis(diphenylphosphino)ethane (DPPE), 1 ,3- bis(diphenylphosphino)propane (DPPP), 1 ,4-bis(diphenylphosphino)butane (DPPB), 1 ,2- bis(diphenylphosphino)benzene (DPPBz), racemic-2,2'-bis(diphenylphosphino)-1 ,T- binaphthyl (rac-BINAP), tri-fe/f-butylphospho
  • the mono- or bidentate ligands are selected from the group comprising, or preferably consisting of, tri-fe/f-butylphosphonium tetrafluoroborate (P(f-Bu)3 * HBF4), (oxydi- 2,1 -phenylene)bis(diphenylphosphine) (DPEphos), 1 ,T-bis(diphenylphosphino)ferrocene (DPPF) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos).
  • P(f-Bu)3 * HBF4 tri-fe/f-butylphosphonium tetrafluoroborate
  • DPEphos di- 2,1 -phenylene)bis(diphenylphosphine)
  • DPPF 1 ,T-bis(diphenylphosphino)ferrocene
  • Xantphos 4,5-bis(diphenylphosphino)-9
  • the bidentate ligand is 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (Xantphos) or 1 ,T-bis(diphenylphosphino)ferrocene (DPPF).
  • the transition metal-comprising catalytic system (preferably the palladium-comprising or palladium-based catalytic system) is conveniently used in a stoichiometry from 0.001 to 20 mol%, preferably from 0.005 to 5 mol%, more preferably from 0.01 to 3 mol%, even more preferably from 0.015 to 1 mol%, compared to the molar quantity of the protected phenyl propanoate of formula (2), (2A) or (2B).
  • CO surrogates suitable to be used in step e) or e.1 ) are alkyl formates (for example methyl formate), formamides (for example /V,/V-dimethylformamide), dichlorocarbenes (generated, e.g., from chloroform and alkali under aqueous conditions), metal carbonyls (for example [Cr(CO)6], [MO(00)Q], and [W(CO)6]).
  • alkyl formates for example methyl formate
  • formamides for example /V,/V-dimethylformamide
  • dichlorocarbenes generated, e.g., from chloroform and alkali under aqueous conditions
  • metal carbonyls for example [Cr(CO)6], [MO(00)Q], and [W(CO)6]).
  • CO surrogates are selected from the group comprising, more preferably consisting of, phenyl formates, for example ortho- or para-substituted phenyl formates (e.g., 4-fluorophenyl formate, 4-chlorophenyl formate, 4- (trifluoromethyl)phenyl formate, 2,6-trifluorophenyl formate, and even more preferably 2,4,6- trichlorophenyl formate) and /V-formylsaccharin.
  • phenyl formates for example ortho- or para-substituted phenyl formates (e.g., 4-fluorophenyl formate, 4-chlorophenyl formate, 4- (trifluoromethyl)phenyl formate, 2,6-trifluorophenyl formate, and even more preferably 2,4,6- trichlorophenyl formate) and /V-formylsaccharin.
  • phenyl formates for example ortho-
  • CO surrogates are normally used in a stoichiometry from 100 to 250 mol%, preferably from 110 to 200 mol%, even more preferably from 1 15 to 150 mol% compared to the molar quantity of the protected phenyl propanoate of formula (2), (2A) or (2B).
  • Gaseous CO is normally used in step e) or e.1 ) such that the total pressure is in the range of 1 bar (100000 Pa) to 20 bar (2000000 Pa), preferably from 1.5 bar (150000 Pa) to 15 bar (1500000 Pa), more preferably from 2 bar (200000 Pa) to 10 bar (1000000 Pa), even more preferably at 4 ⁇ 2 bar (400000 ⁇ 200000 Pa).
  • Bases optionally added in step e) or e.1 ) are organic and inorganic bases, for example hydroxides, carbonates, or halides of alkali metals (such as KOH, NaOH, LiOH, K2CO 3 , Na 2 C0 3 , U2CO3, CS2CO 3 , LiF, NaF, KF, CsF, LiCI, NaCI, KCI, CsCI, LiBr, NaBr, KBr, CsBr, Lil,
  • alkali metals such as KOH, NaOH, LiOH, K2CO 3 , Na 2 C0 3 , U2CO3, CS2CO 3 , LiF, NaF, KF, CsF, LiCI, NaCI, KCI, CsCI, LiBr, NaBr, KBr, CsBr, Lil,
  • Nal, Kl, Csl) or tertiary amines such as triethylamine, N,N- diisopropylethylamine, /V,/V-diisopropylmethylamine, /V-methylpyrrolidine, N- methylmorpholine, /V,/V-dicyclohexylmethylamine, /V,/V-diethylaniline, pyridine, 2- methylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine or 4-dimethylaminopyridine.
  • tertiary amines such as triethylamine, N,N- diisopropylethylamine, /V,/V-diisopropylmethylamine, /V-methylpyrrolidine, N- methylmorpholine, /V,/V-dicyclohexylmethylamine, /V,/V-diethylaniline, pyridine, 2- methylpyridine
  • Said bases are preferably used in a stoichiometry from 100 to 500 mol%, more preferably from 1 10 to 400 mol%, more preferably from 115 to 350 mol% compared to the molar quantity of the protected phenyl propanoate of formula (2), (2A) or (2B).
  • step e.2) the oxidative insertion adduct prepared according to step e.1 ) is converted into a phenyl propanoate of formula (4) (preferably a phenyl propanoate of formula (4A) or (4B)) by treatment with at least one nucleophile.
  • step e.2) is carried out on an oxidative insertion adduct of formula (3A) or (3B):
  • - L is a neutral mono- or polydentate ligand.
  • Nucleophiles suitable to be used in step e.2) are, for example, selected from the group comprising, or preferably consisting of, halide ions (e.g., fluorides (F ), chlorides (Cl ), bromides (Br), iodides (l )), oxygen nucleophiles (e.g., hydroxide anions, alcohols, alkoxide anions), and nitrogen nucleophiles (e.g. ammonia, ammonium salts, amines or amides, preferably fc>/s-(trimethylsilyl)amine or more preferably an amine of formula R 10 -NH-R 5 , in which R 10 and R 5 assume the meanings reported above).
  • halide ions e.g., fluorides (F ), chlorides (Cl ), bromides (Br), iodides (l )
  • oxygen nucleophiles e.g., hydroxide anions, alcohols, alkoxide
  • Nucleophiles are preferably used in a stoichiometry from 100 to 500 mol%, more preferably from 120 to 300 mol%, even more preferably from 150 to 260 mol% compared to the molar quantity of the protected phenyl propanoate of formula (2), (2A) or (2B).
  • the base optionally used in step e.1 ) (more preferably a halide of an alkali metal) releases the nucleophile suitable for the purposes of step e.2) (preferably a halide), thus leading to the direct preparation of a phenyl propanoate of formula (4), (4A), or (4B).
  • operation e) is carried out one-pot by mixing the protected phenyl propanoate of formula (2) (preferably a protected phenyl propanoate of formula (2A) or (2B)) a palladium-comprising catalytic system (more preferably a catalytic system comprising palladium (II) acetate and Xantphos), at least one CO surrogate (preferably selected from the group consisting of /V-formylsaccharin and phenyl formates) and at least one base selected from the group consisting of tertiary amines (preferably triethylamine) and alkali metals (preferably a fluoride of an alkali metal).
  • a palladium-comprising catalytic system more preferably a catalytic system comprising palladium (II) acetate and Xantphos
  • at least one CO surrogate preferably selected from the group consisting of /V-formylsaccharin and phenyl formates
  • a palladium- comprising catalytic system preferably a catalytic system comprising palladium (II) acetate and Xantphos
  • at least one CO surrogate preferably selected from the group consisting of N- formylsaccharin and phenyl formates
  • at least one base preferably selected from the group consisting of tertiary amines and alkali metals
  • a solution of the protected phenyl propanoate of formula (2) preferably a protected phenyl propanoates of formula (2A) or (2B)
  • a polar aprotic solvent preferably dimethylformamide, dimethylacetamide, acetonitrile, tetrahydrofuran or dioxane
  • palladium (II) acetate, Xantphos, /V-formylsaccharin and potassium fluoride are mixed with a solution of a protected phenyl propanoate of formula (2), (2A) or (2B) in dimethylformamide.
  • operation e) is carried out by adding a palladium-comprising catalytic system (preferably a catalytic system comprising palladium (II) acetate and dppf), and gaseous CO to a dispersion of the protected phenyl propanoate of formula (2), (2A) or (2B), and at least one base (preferably selected from the group consisting of tertiary amines and alkali metals) in an organic solvent (preferably dimethylformamide).
  • a palladium-comprising catalytic system preferably a catalytic system comprising palladium (II) acetate and dppf
  • gaseous CO preferably a dispersion of the protected phenyl propanoate of formula (2), (2A) or (2B), and at least one base (preferably selected from the group consisting of tertiary amines and alkali metals) in an organic solvent (preferably dimethylformamide).
  • palladium (II) acetate, DPPF, and gaseous CO are added to a dispersion of the protected phenyl propanoate of formula (2), (2A) or (2B) and potassium carbonate in dimethylformamide.
  • the phenyl propanoate of formula (4) preferably a phenyl propanoate of formula (4A), more preferably a phenyl propanoate of formula (4B), even more preferably a phenyl propanoate of formula (4), (4A) or (4B) in which R 4 is -CO2H, are crystallized from an organic solvent, preferably a nitrile, more preferably acetonitrile before proceeding with the next operation of the process.
  • the following optional operation f) includes, in the case when R 4 is different from R 10 R 5 N, converting the phenyl propanoate of formula (4), preferably a phenyl propanoate of formula (4A) or (4B), into a protected carbamoyl phenyl propanoate of formula (5), preferably a protected carbamoyl phenyl propanoate of formula (5A) or (5B) by treatment with an amine of formula R 10 -NH-R 5 (preferably ammonia, an aqueous solution thereof or an ammonium salt, e.g. a salt of ammonia with an organic or inorganic acid, more preferably ammonium acetate):
  • an amine of formula R 10 -NH-R 5 preferably ammonia, an aqueous solution thereof or an ammonium salt, e.g. a salt of ammonia with an organic or inorganic acid, more preferably ammonium acetate
  • This optional operation can be performed according to different alternative synthetic pathways depending upon the starting phenyl propanoates of formula (4), (4A) or (4B).
  • R 4 is (C1-C6)alkoxy-
  • the phenyl propanoate of formula (4), (4A) or (4B) can be reacted with an amine of formula R 10 -NH-R 5 normally in the presence of a solvent at a temperature normally from 25 °C to the reflux temperature of the solvent used.
  • a base such as sodium hydroxide, lithium hydroxide or potassium hydroxide
  • an acid e.g. hydrogen chloride (optionally dissolved in an organic solvent), hydrochloric acid or sulfuric acid.
  • Said carboxylic acids can be further reacted with an amine of formula R 10 -NH-R 5 in the presence of a coupling agent such as 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), benzotriazol-1 -yl- oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP), 1 ,T-carbonyldiimidazole (CDI), 1-propanephosphonic anhydride (T3P) preferably in the presence of an organic base such as triethylamine, /V,/V-diisopropylethylamine, pyridine or in the presence of an amount of the amine of formula R 10 -NH-R 5 sufficient to act as the base.
  • a coupling agent such as 1- ethyl-3-(3-dimethyl
  • This step is preferably carried out in an organic solvent such as tetrahydrofuran, dioxane, or /V,/V-dimethylformamide.
  • a source of chlorine such as thionyl chloride (SOCI2), phosphorus
  • the phenyl propanoates of formulae (4), (4A) or (4B) can be reacted with an amine of formula R 10 -NH-R 5 in a suitable solvent (preferably the same solvent used in operation e), at a temperature normally from -25 °C to 40 °C and optionally in the presence of at least one base, either inorganic or organic, preferably a tertiary amine (cyclic or acyclic), such as triethylamine, /V,/V-diisopropylethylamine, /V,/V-diisopropylmethylamine, N- methylpyrrolidine, /V-methylmorpholine, /V,/V-dicyclohexylmethylamine, L/,/V-diethylaniline, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine or 4- dimethylaminopyridine.
  • a suitable solvent preferably the same solvent used in operation
  • the base optionally used in step f) is conveniently selected so as to ensure that the pH of mixture formed in this step is at maximum 10, preferably from 7 to 9, more preferably from 7 to 8. Even more preferably said base is potassium phosphate (i.e. K 3 PO4) or potassium phosphate dibasic (i.e. K2HPO4).
  • step f) has the advantageous effect of avoiding any racemization process of the protected carbamoyl phenyl propanoate of formula (5), preferably a protected carbamoyl phenyl propanoate of formula (5A) or (5B).
  • the optional operation f) is carried out by mixing at least one organic base (preferably potassium phosphate, potassium phosphate dibasic or a tertiary amine selected from the group consisting of triethylamine, /V,/V-diisopropylethylamine, /V,/V-diisopropylmethylamine, /V-methylpyrrolidine, /V-methylmorpholine, /V,/V-dicyclohexylmethylamine, L/,/V-diethylaniline, pyridine, 2- methylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine or 4-dimethylaminopyridine) an amine of formula R 10 -NH-R 5 (preferably ammonia, ammonium hydroxide or an ammonium salt) to the mixture resulting from step e.2) or e) maintained at a temperature from -25 °C to 40 °C, thus leading
  • at least one organic base preferably potassium phosphat
  • the following operation g) comprises the deprotection of the carbamoyl phenyl propanoates of formulae (5), (5A) or (5B) obtained in step e), e.2) or f), so as to provide a protected alanine derivative of formula (6), preferably a protected alanine derivative of formula (6A) or (6B).
  • This operation can be carried out with one of the methods known to the skilled person, such as those reported in Theodora W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons (1999), on pages 384-386 or 406-407, which are herein incorporated by reference.
  • this step is carried out by means of a hydroxide or a carbonate of an alkali metal (such as K2CO3, Na2CC>3, U2CO3, CS2CO3, KOH, NaOH, LiOH) in a water miscible solvent (e.g. methanol, ethanol, tetrahydrofuran, dimethoxyethane, dioxane or a mixture thereof) optionally in mixture with water.
  • a water miscible solvent e.g. methanol, ethanol, tetrahydrofuran, dimethoxyethane, dioxane or a mixture thereof
  • the amount of hydroxide or carbonate of the alkali metal used is normally from 1 to 5 equivalents, preferably from 1 .2 to 2.5 equivalents, for example from 1.3 to 2.2 equivalents compared to the molar quantity of the carbamoyl phenyl propanoates of formulae
  • suitable hydrolysis conditions include for example the treatment with hydrochloric acid or with a solution of hydrogen chloride in a suitable organic solvent, such as an alcohol (e.g. methanol).
  • a suitable organic solvent such as an alcohol (e.g. methanol).
  • a variant of the process object of this aspect of the invention includes an additional and optional step g’), carried out after step g), comprising converting a protected alanine derivative of formula (6), preferably a protected alanine derivative of formula (6A) or (6B) into a salt thereof (preferably a salt thereof with sodium, potassium, benzylamine, tributylamine, triethylamine and diethylamine).
  • an additional and optional step g”) is carried out after step g’), comprising converting the salt of the protected alanine derivative of formula (6), (6A) or (6B) into the corresponding acid.
  • This step is normally carried out by treatment with an acid, preferably an organic acid, more preferably formic acid, in the presence of a solvent, preferably water.
  • step b) the protected alanine derivative of formula (6), preferably a protected alanine derivative of formula (6A) or (6B), more preferably a protected alanine derivative of formula
  • the combined use of T3P and of a temperature lower than 0 °C in step b) has the advantageous effect of ensuring (1 ) a high recovery yield (i.e. at least 75%, preferably at least 80%, more preferably at least 85%, even more preferably at least 86%) of the protected amide (7), preferably protected amide (7A) or (7B); (2) an increased purity profile of the reaction (i.e., a total impurities content lower than 10%, preferably lower than 7%, more preferably lower than 5%, based on the HPLC area percent); (3) avoiding, at the same time, any epimerization and racemization phenomena.
  • a high recovery yield i.e. at least 75%, preferably at least 80%, more preferably at least 85%, even more preferably at least 86%) of the protected amide (7), preferably protected amide (7A) or (7B
  • an increased purity profile of the reaction i.e., a total impurities content lower than 10%, preferably lower than 7%,
  • Step b) is conveniently carried out in an organic solvent, preferably a polar aprotic solvent (e.g. dimethylformamide, tetrahydrofuran) or, more preferably, an acetate (e.g., ethyl acetate)
  • a polar aprotic solvent e.g. dimethylformamide, tetrahydrofuran
  • an acetate e.g., ethyl acetate
  • step b) is performed at a temperature of or lower than -5 °C, more preferably at a temperature of or lower than -10 °C. More preferably step b) is carried out at a temperature lower than 0 °C and of at least -40 °C, preferably of or higher than -30 °C, more preferably of or higher than -25 °C, even more preferably of or higher than -20 °C.
  • step b) is carried out at a temperature of at least -25 °C and lower than 0 °C, preferably from -20 °C to -5 °C, more preferably from -15 °C to -10 °C.
  • Amines of formula (8) suitable to be used in step b), preferably amines of formulae (8’), (8”), (8’”), (8A’), (8A) and (8B), are commercially available; alternatively, they can be prepared according to standard techniques in organic synthesis, for example, following the procedure described in WO 2005/090315 A1 :
  • said amines of formulae (8), (8’), (8”), (8’”), (8A’), (8A) and (8B) can be prepared by treating the corresponding oxalate salts, more preferably the corresponding hemi- oxalate salts, with a base, either organic or inorganic.
  • Amines of formula (8), (8’), (8”), (8’”), (8A’), (8A) or (8B) are normally used in a stoichiometry from 100 to 200 mol%, preferably from 101 to 150 mol%, more preferably from 105 to 120 mol% compared to the molar quantity of the protected alanine derivative of formula (6), (6A) or (6B).
  • T3P 1 -propanephosphonic anhydride
  • T3P is normally used in a stoichiometry from 100 to 250 mol%, preferably from 120 to 200 mol%, more preferably from 150 to 180 mol% compared to the molar quantity of the protected alanine derivative of formula (6), (6A) or (6B).
  • the base optionally used in step b) is preferably a tertiary amine (cyclic or acyclic), such as triethylamine, /V,/V-diisopropylethylamine, /V,/V-diisopropylmethylamine, N- methylpyrrolidine, /V-methylmorpholine, /V,/V-dicyclohexylmethylamine, L/,/V-diethylaniline, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, 4- dimethylaminopyridine, 2,2,6,6-tetramethylpiperidine, /V-ethylmorpholine, or a mixture thereof.
  • a tertiary amine such as triethylamine, /V,/V-diisopropylethylamine, /V,/V-diisopropylmethylamine, N- methylpyrrolidine,
  • the base is an aliphatic tertiary amine (cyclic or acyclic), such as triethylamine, L/,/V-diisopropylethylamine, /V,/V-diisopropylmethylamine, /V-methylpyrrolidine, N- methylmorpholine, /V,/V-dicyclohexylmethylamine, L/,/V-diethylaniline, 2,2,6,6- tetramethylpiperidine, /V-ethylmorpholine or a mixture thereof.
  • aliphatic tertiary amine such as triethylamine, L/,/V-diisopropylethylamine, /V,/V-diisopropylmethylamine, /V-methylpyrrolidine, N- methylmorpholine, /V,/V-dicyclohexylmethylamine, L/,/V-diethylaniline, 2,2,6,6
  • said base is preferably added in a stoichiometry from 200 to 600 mol%, preferably from 250 to 500 mol%, more preferably from 300 to 450 mol%, even more preferably from 340 to 400 mol% compared to the molar quantity of the protected alanine derivative of formula (6), (6A) or (6B).
  • operation b) is carried out by mixing an amine of formula (8), (8’), (8”), (8’”), (8A’), (8A) or (8B), a protected alanine derivative of formula (6), (6A) or (6B) (preferably a protected alanine derivative of formula (6), (6A) or (6B) prepared according to operations d) to g), d) to g’) or d) to g”) reported above), 1 -propanephosphonic anhydride (T3P), and at least one base (preferably an aliphatic tertiary amine, more preferably triethylamine) with an acetate (preferably ethyl acetate) at a temperature lower than 0 °C.
  • a protected alanine derivative of formula (6) (6A) or (6B) (preferably a protected alanine derivative of formula (6), (6A) or (6B) prepared according to operations d) to g), d) to g’) or d) to g”)
  • this preferred embodiment is performed at a temperature of or lower than -5 °C, more preferably at a temperature of or lower than -10 °C. Even more preferably, this preferred embodiment is carried out at a temperature lower than 0 °C and of at least -40 °C, preferably of or higher than -30 °C, more preferably of or higher than -25 °C, even more preferably of or higher than -20 °C. More preferably this embodiment is performed at a temperature of at least -25 °C and lower than 0 °C, preferably from -20 °C to - 5 °C, more preferably from -15 °C to -10 °C.
  • a variant of the process object of this aspect of the invention includes an additional and optional step b’), carried out after step b), comprising converting a protected amide of formula (7C) or (7D) (as obtainable by reacting, according to step b), a protected alanine derivative of formula (6) and an amine of formula (8A) or (8B)) into a protected amide of formula (7E) or (7F) or a salt thereof (preferably a sodium salt thereof):
  • step c) entails the conversion of the protected amide of formulae (7), (7 A)
  • Operation c) can be performed using any one of the methods generally known in the field to remove an amino protecting group, for example one of those described in Theodora W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons (1999), pages 503-598, which are herein incorporated by reference.
  • said de-protection step may be operated according to the procedures detailed on pages 504-540 of the text referred to above.
  • step c) in the case when Pg is a benzyloxy carbonyl, can be carried out by treatment with hydrogen in the presence of a catalyst (e.g.
  • Pg is a tert- butoxy carbonyl
  • this step is performed by treating a protected amide of formulae (7), (7A), (7B), (7C), (7D), (7E) or (7F) with a solution of hydrogen chloride in water or in an organic solvent.
  • an additional and optional step c’) is carried out after step c), comprising converting a mixed pOR agonist/60R antagonist (9A) or (9B) (as obtainable by subjecting a protected amide of formula (7C) or (7D) to step c) above) into a mixed pOR agonist/60R antagonist (9E) or (9F) or a salt thereof, preferably eluxadoline, more preferably a hydrochloride salt of eluxadoline.
  • Said additional and optional steps b’) to c’) can be performed using any one of the methods generally known to the skilled person, e.g. one of those described above to carry out operation g).
  • step c) comprises converting a protected amide of formula (7E) or (7F) or a salt thereof (preferably a sodium salt thereof) into a mixed pOR agonist/60R antagonist (9E) or (9F) or a salt thereof, preferably eluxadoline, more preferably a hydrochloride salt of eluxadoline.
  • the protected alanine derivative (6) or the mixed pOR agonist/60R antagonist (9) obtained by the processes object of the present invention can be converted in a salt or a co- crystal thereof in a further optional step.
  • n is preferably 2.
  • said protected carbamoyl phenyl propanoate of formula (5B), in which R 5 and R 10 are hydrogen, R 2 is methyl and Pg is tert- butyloxycarbonyl, shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l 1.5406 A), is characterized by at least 5 peaks ( ⁇ 0.2° 20) selected from Table 1A or 1 B:
  • this aspect of the invention provides a process for the preparation of said crystalline form of a protected carbamoyl phenyl propanoate of formula (5B), in which R 5 and R 10 are hydrogen, R 2 is methyl and Pg is tert- butyloxycarbonyl, said process comprising the step of crystallizing the protected carbamoyl phenyl propanoate of formula (5B) in a medium comprising or, preferably consisting of, a ketone. More preferably said medium is an organic solvent selected from the group comprising or consisting of, acetone, 2-butanone, 3-pentanone, methyl isobutyl ketone and mixtures thereof.
  • Said crystallization is generally performed by heating a solution of the protected carbamoyl phenyl propanoate of formula (5B) in a medium comprising a ketone to a temperature next to the boiling point of the medium used, followed by cooling to a temperature between 0 and 30 °C optionally after having added a seed of the desired crystalline form (i., ii., Table 1 A, 1 B, Figure 1 ).
  • said protected alanine derivative of formula (6B), in which R 5 and R 10 are hydrogen and Pg is tert- butyloxycarbonyl, shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l 1.5406 A), is characterized by at least 5 peaks ( ⁇ 0.2° 20) selected from Table 2A or 2B:
  • this aspect of the invention provides a process for the preparation of said crystalline form of a protected alanine derivative of formula (6B), in which R 5 and R 10 are hydrogen and Pg is tert- butyloxycarbonyl, said process comprising the step of crystallizing the protected alanine derivative of formula (6B) from a medium comprising or, preferably consisting of, a polar aprotic solvent or a mixture thereof with water.
  • said polar aprotic solvent is selected from the group comprising, even more preferably consisting of, dimethylformamide, dimethylacetamide, /V-methyl-2-pyrrolidone and mixtures thereof.
  • this further embodiment is carried in a medium comprising or, preferably consisting of, water and dimethylformamide, for example a solvent mixture comprising water and dimethylformamide in a 1 :2 ratio on a volume basis.
  • Said crystallization is generally performed by heating a solution of the protected alanine derivative of formula (6B) to a temperature next to the boiling point of the used medium, followed by cooling to a temperature between 0 and 30 °C optionally after having added a seed of the desired crystalline form (iii., iv., Table 2A, 2B, Figure 2).
  • this aspect of the invention provides a process for the preparation of said crystalline hydrochloride salt of eluxadoline, said process comprising the steps of treating a sodium salt of formula (7G):
  • eluxadoline eluxadoline
  • said further crystalline salt of eluxadoline contains an amount of chloride
  • this aspect of the invention provides a process for the preparation of this further crystalline hydrochloride salt of eluxadoline, said process comprising the steps of dispersing a crystalline form of eluxadoline containing an amount of chloride from 18 to 19% w/w (v., vi., Table 3A, 3B, Figure 5) in at least one organic solvent, preferably an alcohol (more preferably methanol, ethanol, 1 -propanol, 2-propanol, tert- butanol and mixtures thereof) or a mixture thereof with water; and maintaining the resulting dispersion under stirring so as to cause precipitation of the crystalline hydrochloride salt of eluxadoline (vii., viii., Table 4A, 4B, Figure 6), preferably for at least 1 hour, more preferably for a period from 2 to 20 hours, more preferably from 3 to 15 hours.
  • an organic solvent preferably an alcohol (more preferably methanol, ethanol, 1 -propanol,
  • said sodium salt of formula (7G), in which in which R 5 and R 10 are hydrogen and Pg is tert- butyloxycarbonyl, shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l 1.5406 A), is characterized by at least 4 peaks ( ⁇ 0.2° 20) selected from Table 5A or 5B:
  • this aspect of the invention provides a process for the preparation of a crystalline form of said sodium salt of formula (7G), in which R 5 and R 10 are hydrogen and Pg is tert- butyloxycarbonyl, said process comprising the steps of dispersing a sodium salt of 5-(((S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6- dimethylphenyl)-/V-((S)-1-(4-phenyl-1 /-/-imidazol-2-yl)ethyl)propanamido)methyl)-2- methoxybenzoate in at least one organic solvent, preferably an alcohol (more preferably methanol, ethanol, 1 -propanol, 2-propanol, tert- butanol and mixtures thereof) or a mixture thereof with water; and maintaining the resulting dispersion under stirring so as to cause precipitation of the crystalline sodium salt of formula (7G), in which R 5 and
  • xii. 1 1.48°, 18.12°, 19.40°, 20.76°, 22.28°, and 22.84° ⁇ 0.2° 20.
  • said protected carbamoyl phenyl propanoate of formula (5B), in which R 5 and R 10 are hydrogen, R 2 is methyl and Pg is tert- butyloxycarbonyl, shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l 1.5406 A), is characterized by at least 4 peaks ( ⁇ 0.2° 20) selected from Table 6A or 6B:
  • this aspect of the invention provides a process for the preparation of this crystalline form of the protected carbamoyl phenyl propanoate of formula (5B), in which R 5 and R 10 are hydrogen, R 2 is methyl and Pg is tert- butyloxycarbonyl, said process comprising the step of the crystallizing the protected carbamoyl phenyl propanoate of formula (5B) in a medium comprising, or preferably consisting of, an alcohol. More preferably said medium is an alcohol selected from the group comprising, even more preferably consisting of, methanol, ethanol, 1 -propanol, 2-propanol, tert- butanol and mixtures thereof.
  • Said crystallization is generally performed by heating a solution of the protected carbamoyl phenyl propanoate of formula (5B) to a temperature next to the boiling point of the used medium, followed by cooling to a temperature between 0 and 30 °C optionally after having added a seed of the desired crystalline form (xi., xii., Table 6A, 6B, Figure 7).
  • said diethylamine salt of a protected alanine derivative of formula (6B), in which R 5 and R 10 are hydrogen and Pg is tert- butyloxycarbonyl, shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l 1.5406 A), is characterized by at least 3 peaks ( ⁇ 0.2° 20) selected from Table 7 A or 7B:
  • this aspect of the invention provides a process for the preparation of diethylamine salt of a protected alanine derivative of formula (6B), in which R 5 and R 10 are hydrogen and Pg is tert- butyloxycarbonyl, said process comprising the steps of dispersing a said protected alanine derivative of formula (6B), preferably (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)propanoate in a medium (preferably comprising a ketone, more preferably comprising acetone); mixing the resulting dispersion with diethylamine; and maintaining under stirring at a temperature normally from 0 to 50 °C (preferably from 20 to 35 °C), preferably for at least 10 minutes, more preferably for a period from 30 minutes to 20 hours, even more preferably from 1 to 15 hours so as to cause precipitation of the crystalline diethylamine salt of compound of formula (6B), in which R 5
  • said protected alanine derivative of formula (6B), in which R 5 and R 10 are hydrogen and Pg is tert- butyloxycarbonyl, shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l 1.5406 A), is characterized by at least 3 peaks ( ⁇ 0.2° 20) selected from Table 8A or 8B:
  • this aspect of the invention provides a process for the preparation of protected alanine derivative of formula (6B), in which R 5 and R 10 are hydrogen and Pg is tert- butyloxycarbonyl, said process comprising the steps of dispersing a diethylamine salt of said protected alanine derivative of formula (6B), preferably a diethylamine salt of (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6- dimethylphenyl)propanoate, more preferably the diethylamine salt of xiii., xiv., Table 7 A, 7B, Figure 8) in a medium (preferably water); treating the resulting dispersion with an acid (preferably an organic acid, more preferably formic acid); and maintaining under stirring at a temperature normally from 0 to 50 °C (preferably from 20 to 35 °C), preferably for at least 10 minutes, more preferably for a period from
  • the processes object of the present invention entails a further step of purification, for example by means of chromatography or crystallization, optionally after formation of an addition compound, such as for example a salt (preferably a hydrochloride salt) or a co-crystal, or by washing with an organic solvent or an aqueous solution, optionally adjusting the pH.
  • an addition compound such as for example a salt (preferably a hydrochloride salt) or a co-crystal
  • Chloride content was determined using a Series DL67 titrator (Mettler Toledo) equipped with Glass electrode DM141 -SC (KNO3 in water 1 M). To a solution of an accurately weighed amount of the sample to be tested (40 ⁇ 2 mg) dissolved in MeOH (20 ml.) and water (40 ml_), 1 ml. of nitric acid 70% was added. Then titrate with 0.1 N silver nitrate. Before each analysis, perform a blank determination.
  • This example is representative of operation d) of the process of the invention.
  • Glacial acetic acid (0.18 g, 3.0 mmol) was added thereto up to obtain a pH lower than 6.0 (determined by means of a pH strips).
  • the mixture was concentrated under reduced pressure to residue, which was dispersed in toluene (5 ml.) and water (2.5 ml_).
  • the resulting phases were separated and the organic layer was concentrated under reduced pressure up to obtaining an oily residue (2.85 g, quantitative yield).
  • This example is representative of operations e.1 ) and e.2) of the process of the invention.
  • This example is representative of operation g) of the process of the invention.
  • the attained product was analysed by XRPD, obtaining the diffractogram shown in
  • the aqueous layer was extracted with isopropyl acetate and the combined organic phases were concentrated under reduced pressure (monitoring that internal temperature did not exceed 45 °C) up to achieve a residual volume of 30 ml_.
  • Isopropyl acetate 40 ml. was added thereto and the resulting mixture maintained under stirring at 45 °C for 15 minutes.
  • the phases were separated, the organic phase was washed with water and concentrated under reduced pressure up to achieve a residual volume of 15 ml_.
  • This example is representative of operation b) of the process of the invention.
  • the resulting mixture was cooled to -15 °C and a 50% w/w solution of T3P in ethyl acetate (22.07 g, 34.68 mmol) added thereto monitoring that the internal temperature did not exceed -10 °C.
  • the mixture was maintained under stirring at -15/- 10 °C until complete conversion was achieved (about 1 hour) then water (34 ml.) was added thereto monitoring that internal temperature did not exceed 0 °C.
  • the resulting phases were heated to 25 °C, maintained under stirring at this temperature for 1 hour then separated.
  • the organic layer was washed with water and the combined organic phases concentrated under reduced pressure up to achieve a residual volume of 20 ml_.
  • the resulting residue was co- evaporated with isopropanol in order to remove residual ethyl acetate, then isopropanol (34 ml.) was added thus leading to 41 g of a solution suitable to be used in example 8.
  • This example is representative of optional operation b’) of the process of the invention.
  • the resulting solution was heated under stirring to 70 °C, then a 10 % w/w solution of sodium hydroxide in water (12.50 g, 34.68 mmol) was added.
  • the reaction mixture was maintained under stirring at the same temperature until complete conversion was achieved (about 3 hours) then it was cooled to 25 °C and maintained at this temperature for additional 3 hours.
  • the resulting solid was filtered, washed with isopropanol and dried under reduced pressure at 40 °C so as to obtain 12.40 g of the desired compound.
  • eluxadoline hydrochloride salt i.e. the hydrochloride salt of a compound of formula (9) wherein n is 2, R 1 and R 7 are methyl, R 5 and R 10 are H, R 6 is methyl 2-methoxy- 5-(A 3 -methyl)benzoate and D is 2-(A 3 -ethyl)-4-phenyl-1 /-/-imidazole.
  • the attained product was analysed by XRPD, obtaining the diffractogram shown in Figure 6.
  • This example is representative of operations e.1 ) and e.2) of the process of the invention.
  • the reaction was cooled to 20-25 °C and subjected to 3 cycles of vacuum/nitrogen (in order to remove the formed carbon monoxide) then it was further cooled to 0-5 °C and potassium phosphate (2.80 g, 13.2 mmol) and ammonium acetate (0.70 g, 9.0 mmol) were added thereto.
  • potassium phosphate (2.80 g, 13.2 mmol) and ammonium acetate (0.70 g, 9.0 mmol) were added thereto.
  • water 168 ml.
  • isopropyl acetate 8.5 ml.
  • the mixture was heated to 25 °C, then filtered on a pad of celite and charcoal. A 15% (w/w) aqueous solution of sodium chloride (25 g) was added to the filtrate then the phases were separated.
  • the aqueous phase was extracted with isopropyl acetate, then a 0.2% (w/w) aqueous solution of potassium hydrogen carbonate was added to the collected organic phases previously heated to 45 °C. After having separated the resulting layers, the organic phase is concentrated under reduced pressure so as to obtain an oily residue (2.85 g, quantitative yield).
  • This example is representative of operation g’) of the process of the invention.
  • This example is representative of operation g’) of the process of the invention.
  • This example is representative of operation g”) of the process of the invention.

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Abstract

It is described an industrially viable and advantageous process for the preparation of mixed µOR agonist/δOR antagonists (9). The invention also discloses the intermediates obtained in the process.

Description

PROCESS FOR THE PREPARATION OF OPIOID MODULATORS
Field of the invention
The present invention relates to an industrially viable and advantageous process for the preparation of mu/delta opioid modulators and of protected alanine derivatives useful as intermediates in the synthesis thereof.
The invention also relates to intermediates obtained in the process.
State of the art
Irritable Bowel Syndrome (IBS) is a chronic, relapsing gastrointestinal problem characterised primarily by intestinal pain and/or discomfort and associated alterations of defecation and/or bowel habit. Associations with other symptoms are regularly present, such as abdominal distension, bloating, constipation, and/or diarrhoea.
5-({[(2S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)propanoyl][(1 S)-1 -(4-phenyl-1 H- imidazol-2-yl)ethyl]amino}methyl)-2-methoxybenzoic acid, generally known as eluxadoline, is a locally acting, mixed mu opioid receptor (pOR) agonist/delta opioid receptor (50R) antagonist with low oral bioavailability:
Figure imgf000002_0001
This compound is approved for the treatment of irritable bowel syndrome (IBS) with diarrhoea (IBS-d).
Eluxadoline and other similar compounds were first described in international patent application WO 2005/090315 A1. The process described therein entails, as key steps, triflation of a protected dimethyl-tyrosine; treatment of methyl (S)-2-((fe/f-butoxycarbonyl)amino)-3- (2,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate with gaseous carbon monoxide (CO); amidation of (S)-4-(2-((fe/f-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)- 3,5-dimethylbenzoic acid; and the coupling between (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4- carbamoyl-2,6-dimethylphenyl)propanoic acid and methyl (S)-2-methoxy-5-(((1-(4-phenyl-1 /-/- imidazol-2-yl)ethyl)amino)methyl)benzoate, according to the following scheme:
Figure imgf000003_0001
Despite its applicability, it is noted that the precursor of eluxadoline is prepared by coupling (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)propanoic acid and methyl (S)-2-methoxy-5-(((1-(4-phenyl-1 /-/-imidazol-2- yl)ethyl)amino)methyl)benzoate in the presence of EDC-HCI/HOBT at room temperature (normally 25 °C) and that said coupling proceeds with a molar yield of 50%, thus making its application on industrial scale hardly feasible to the extent that about 50% of the starting compounds do not react or degrade.
The equivalent procedure described in Bioorganic & Medicinal Chemistry Letters 2012, vol. 22, no. 14, pages 4869-4872, is affected by the same drawbacks discussed above in respect of WO 2005/090315 A1 to the extent that the coupling between ( S)-2-((tert - butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)propanoic acid and methyl (S)-2- methoxy-5-(((1-(4-phenyl-1 /-/-imidazol-2-yl)ethyl)amino)methyl)benzoate leads to the desired product with a yield of only 56%.
A further procedure for the preparation of protected L-alanine derivatives was described in international patent application WO 2010/062590 and entails the use of 4-bromo-3,5- dimethylphenyl trifluoromethanesulfonate (A) as the starting material. ( S)-2-((tert - butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)propanoic acid was prepared via cyanation of (A) followed by Negishi coupling and hydrolysis:
Figure imgf000004_0001
Although being an interesting approach, it is not practical for multikilogram synthesis, because of the use of zinc cyanide, which requires specialized reactors and implementation of precautionary measures.
A subsequent procedure for the coupling between (S)-2-((fe/f-butoxycarbonyl)amino)-3-
(4-carbamoyl-2,6-dimethylphenyl)propanoic acid and methyl (S)-2-methoxy-5-(((1 -(4-phenyl- 1 /-/-imidazol-2-yl)ethyl)amino)methyl)benzoate involving the use of 2-chloro-4,6-dimethoxy- 1 ,3,5-triazine at 15-20 °C has been described in WO 2017/153471 A1 .
A further procedure for the coupling between (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4- carbamoyl-2,6-dimethylphenyl)propanoic acid and methyl (S)-2-methoxy-5-(((1 -(4-phenyl-1 /-/- imidazol-2-yl)ethyl)amino)methyl)benzoate in the presence of EDC-HCI/HOBT and N,N- diisopropylethylamine at a temperature from 10 to 30 °C has been described in WO 2017/191650 A1 .
Although potentially advantageous, these procedures are affected by a transformation yield of (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)propanoic acid into eluxadoline or an intermediate structurally close thereto still not acceptable (i.e. respectively 66.6%, examples 3 to 6 and 63.4%, examples 1 to 3).
Organic Letters 201 1 , vol. 13, no. 19, pages 5048-5051 , describes the use of a combination of 1 -propanephosphonic anhydride and pyridine at 0 °C as an effective procedure for preventing epimerization of the amide bond in the coupling of racemization-prone acid substrates and amines.
Aim of the present invention is to provide a chemical method to prepare protected mixed pOR agonist/50R antagonists, preferably eluxadoline, as well as intermediates in the synthesis thereof with improved yields and appropriate purity.
Summary of the invention
These objectives were achieved with the present invention, which, in a first aspect thereof, relates to a process for the preparation of a mixed pOR agonist/50R antagonist (9) or a salt thereof:
Figure imgf000005_0001
said process comprising the following operations:
a) providing a protected alanine derivative of formula (6) or a salt thereof:
Figure imgf000005_0002
b) reacting the protected alanine derivative of formula (6) or the salt thereof with an amine of formula (8) or a salt thereof in the presence of 1-propanephosphonic anhydride (T3P) at a temperature lower than 0 °C so as to provide a protected amide (7) or a salt thereof:
Figure imgf000005_0003
c) converting the protected amide (7) or the salt thereof into a mixed pOR agonist/60R antagonist (9) or a salt thereof:
Figure imgf000005_0004
wherein:
- n is 1 , 2, 3 or 4;
- each R1 is independently selected from (C1-C6)alkyl-, (C1-C6)alkoxy- and fluoro;
- R5 and R10 are independently selected from hydrogen and (C1-C4)alkyl-; alternatively, R5 and R10 taken together with the nitrogen atom to which they are bound form a five to seven membered heterocyclic radical;
- Pg is a nitrogen protecting group;
- R6 is selected from hydrogen, (C1-C6)alkyl-, (C3-C8)cycloalkyl-, aryl(C1-C6)alkyl- and heteroaryl(C1-C6)alkyl-, wherein the aryl and the heteroaryl group can be further substituted with at least one group selected from the group consisting of OH, CN, NO2, CO2H, halogen, (C1-C6)alkyl-, (C1-C6)alkoxy-, and (C1-C6)alkoxycarbonyl-;
- R7 is (C1-C4)alkyl;
Figure imgf000006_0001
- p is 0, 1 or 2;
- R8 is selected from hydrogen and (C1-C4)alkyl; and
- R9 is selected from (C1-C6)alkyl, aryl, aryl(C1-C6)alkyl-, aryl(C2-C6)alkenyl-, aryl(C2- C6)alkynyl-, heteroaryl, heteroaryl(C1-C6)alkyl-, heteroaryl(C2-C6)alkenyl-, heteroaryl(C2- C6)alkynyl-, amino, (C1-C6)alkylamino-, (C1-C6)2-alkylamino-, arylamino-, heteroarylamino-, aryloxy-, heteroaryloxy-, trifluoromethyl and halogen.
Brief description of the drawings
Figure 1 depicts the X-Ray powder diffractogram of a protected carbamoyl phenyl propanoate of formula (5B) in which R5 and R10 are hydrogen, R2 is methyl and Pg is tert- butyloxycarbonyl crystallized from acetone.
Figure 2 depicts the X-Ray powder diffractogram of a protected alanine derivative of formula (6B) in which R5 and R10 are hydrogen and Pg is tert- butyloxycarbonyl.
Figure 3 depicts the X-Ray powder diffractogram of the hemi-oxalate salt of the compound of formula (8B).
Figure 4 depicts the X-Ray powder diffractogram of a sodium salt of a protected amide of formula (7G) in which R5 and R10 are hydrogen and Pg is tert- butyloxycarbonyl.
Figure 5 depicts the X-Ray powder diffractogram of a hydrochloride salt of eluxadoline having a chloride content of 18.5% (w/w).
Figure 6 depicts the X-Ray powder diffractogram of a hydrochloride salt of eluxadoline having a chloride content of 15.3% (w/w).
Figure 7 depicts an X-Ray powder diffractogram of a protected carbamoyl phenyl propanoate of formula (5B) in which R5 and R10 are hydrogen, R2 is methyl and Pg is tert- butyloxycarbonyl crystallized from 2-propanol.
Figure 8 depicts the X-Ray powder diffractogram of a diethylamine salt of a protected alanine derivative of formula (6B) in which R5 and R10 are hydrogen and Pg is tert- butyloxycarbonyl.
Figure 9 depicts the X-Ray powder diffractogram of a protected alanine derivative of formula (6B) in which R5 and R10 are hydrogen and Pg is tert- butyloxycarbonyl.
Detailed description of the invention
All terms used in the present application, unless otherwise indicated, must be interpreted in their ordinary meaning as known in the technical field. Other more specific definitions for some terms used in the present application are given below and are intended to be applied uniformly to the entire description and claims, unless otherwise indicated.
In general, the nomenclature used in this Application is based on AUTONOM™ v.4.0, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. If there is a discrepancy between a depicted structure and a name given to that structure, the depicted structure should be considered correct. Furthermore, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure has to be interpreted as encompassing all existing stereoisomers of it.
The compounds prepared by the processes of the present invention may have one or more stereogenic centers and may exist and may be used or isolated in enantiomerically pure forms, as enantiomeric enriched mixtures as well as in diastereomerically pure forms or as diastereomeric enriched mixtures. It is to be understood that the processes of the present invention can give rise to any of the previous forms or a combination thereof. It is to be further understood that the products of the processes described herein, can be isolated as enantiomerically and/or diastereomerically pure forms or as enantiomerically and/or diastereomerically enriched mixtures.
The sign“*” (asterisk) present in some formulae of the description indicates stereogenic (asymmetric) center, although the absence of asterisks does not necessarily imply that the compound lacks a stereocenter. Such formulae may refer to the racemate or to individual enantiomers or diastereomers, which may or may not be substantially pure.
A mixture of ( R,S ) enantiomers can contain the two enantiomers in any ratio to each other. The enantiomeric purity is generally expressed as“enantiomeric excess” or ee and is defined, for example for the (S) enantiomer, as [(S-R)I(R+S)]x 100, wherein S and R are respectively the amounts of the (S) and (R) enantiomers (as determined for example by GC or HPLC on a chiral stationary phase or polarimetry).
The term “a/yf refers to any substituent derived from a monocyclic or a polycyclic aromatic hydrocarbon by removal of a hydrogen atom from a ring carbon atom (e.g., phenyl, tolyl, 1 -naphtyl or 2-napthyl).
The term“seed” refers to a crystalline substance that is added to a dispersion, preferably a solution, of the same substance to induce its crystallization. Seeding with a specific crystalline form has often the useful effect of promoting crystallization of the substance in the same crystalline form of the seed.
According to the present invention, the use of the indefinite article "a" means "at least one" and should not be limited to "only one" unless explicitly indicated to the contrary. The term“ racemic” refers to a sample of a chiral compound which contains both the (+) and (-) isomers in equal amount.
The term“enantiomerically enriched” as used herein means that one of the enantiomers of a compound is present in excess compared to the other enantiomer.
The term“enantiomerically pure” as used herein means that the enantiomeric purity is usually at least about 96%, preferably at least 99%, more preferably at least 99.5%.
The term “diastereomerically enriched’ as used herein means that one of the diastereomers of a compound is present in excess compared to the other diastereomer.
The term“diastereomerically pure” as used herein means that the diastereomeric purity is usually at least about 96%, preferably at least 99%, more preferably at least 99.5%.
The symbol . (dashed bond) present in some of the formulae of the description and the claims indicates that the substituent is directed below the plane of the sheet.
The symbol — (wedge bond) present in some of the formulae of the description and the claims indicates that the substituent is directed above the plane of the sheet.
As used herein, the term “nitrogen protecting group” refers to a group that may be attached to a nitrogen atom to protect it from participating in the reaction and that may be readily removed following the reaction. Suitable nitrogen protecting groups include carbamates (in which the nitrogen atom is linked to a group of formula -C(0)0R wherein R is, e.g., (C1 - C6)alkyl- (preferably methyl, ethyl, tert- butyl), aryl(C1 -C6)alkyl- (preferably benzyl, phenylethyl), CH2=CH-CH2-, wherein the aryl and the alkyl group can be further substituted with at least one group selected from the group consisting of OH, CN, NO2, CO2H, halogen, (C1 -C6)alkyl, (C1 -C6)alkoxy-, and (C1 -C6)alkoxycarbonyl-); amides (in which the nitrogen atom is linked to a group of formula -C(0)-R’, wherein R’ is for example (C1 -C6)alkyl (preferably methyl), aryl (preferably phenyl), wherein the aryl and the alkyl group can be further substituted with at least one group selected from the group consisting of OH, CN, NO2, CO2H, halogen, (C1 -C6)alkyl, (C1 -C6)alkoxy-, and (C1 -C6)alkoxycarbonyl-; preferably R’ is trifluoromethyl); /V-sulfonyl derivatives (in which the nitrogen atom is linked to a group of formula -SO2-R”, wherein R” is, e.g., (C1 -C6)alkyl or aryl, wherein the aryl and the alkyl group can be further substituted with at least one group selected from the group consisting of OH, CN, NO2, CO2H, halogen, (C1 -C6)alkyl, (C1 -C6)alkoxy-, and (C1 -C6)alkoxycarbonyl-; preferably R” is tolyl, phenyl, trifluoromethyl, 2,3,6-trimethyl-4-methoxybenzene, or 2, 2, 5,7,8- pentamethylchroman-6-yl).
The compounds obtained by the chemical transformations of the present invention can be used without further purification or can be separated and purified by employing conventional methods well known to those skilled in the art, such as recrystallization, column chromatography, or by transforming them into a salt or into a co-crystal with an appropriate co- former, or by washing with an organic solvent or with an aqueous solution, optionally adjusting pH.
It will be understood that any one of the compounds described herein also refer to salts or co-crystals thereof.
According to its most general aspect, the present invention relates to a process for the preparation of a mixed pOR agonist/60R antagonist (9) or a salt thereof:
Figure imgf000009_0001
said process comprising the operations a) to c) described above.
The first operation of the process of the invention, a), consists in the provision of a protected alanine derivative of formula (6), preferably a protected alanine derivative of formula (6A), more preferably a protected phenyl propanoate of formula (6B) or a salt of any one of them:
Figure imgf000009_0002
wherein the substituents assume the meanings reported above.
The present invention is also directed to a process for the preparation of a protected alanine derivative of formula (6), (6A), (6B) or a salt of any one of them for using in step a) above. Said protected alanine derivative of formula (6), (6A), (6B) can be conveniently prepared starting from a protected phenyl propanoate of formula (2), (2A) or (2B), as detailed below, according to the following steps:
d) providing a protected phenyl propanoate of formula (2), preferably a protected phenyl propanoate of formula (2A) or (2B):
Figure imgf000009_0003
e) subjecting the protected phenyl propanoate of formula (2), (2A) or (2B) to a metal- catalysed carbonylation by treatment with gaseous CO or at least one CO surrogate in the presence of a transition metal-comprising catalytic system and, subsequently or concurrently, with at least one nucleophile so as to provide a phenyl propanoate of formula (4), preferably a phenyl propanoate of formula (4A) or (4B):
Figure imgf000010_0001
Figure imgf000010_0004
f) optionally, when in the phenyl propanoate of formula (4), (4A) or (4B) R4 is different from R10R5N, converting said phenyl propanoate of formula (4), (4A) or (4B) into a protected carbamoyl phenyl propanoate of formula (5), preferably a protected carbamoyl phenyl propanoate of formula (5A) or (5B), by treatment with an amine of formula R10-NH-R5:
Figure imgf000010_0002
g) converting the protected carbamoyl phenyl propanoate of formula (5), preferably a protected carbamoyl phenyl propanoate of formula (5A) or (5B), into a protected alanine derivative of formula (6), preferably a protected alanine derivative of formula (6A) or (6B), or a salt thereof:
Figure imgf000010_0003
wherein the substituents assume the meanings reported above and
- R2 is selected from (C1-C4)alkyl;
- R3 is a leaving group able to undergo a nucleophilic aromatic substitution, such as for example, a mesylate, a tosylate, a halogen, a triflate, a nonaflate, a fluorosulfonate, or a nosylate; and
- R4 is halogen, (C1-C6)alkoxy-, hydroxy, amino, (C1-C4)alkylamino-, (C1-C4)2- alkylamino-.
Operation d) comprises the provision of a protected phenyl propanoate of formula (2), preferably a protected phenyl propanoate of formula (2A), more preferably a protected phenyl propanoate of formula (2B):
Figure imgf000011_0002
wherein the substituents assume the meanings reported above.
Protected phenyl propanoates of formulae (2), (2A) and (2B) are commercially available; alternatively, they can be prepared according to standard techniques in organic synthesis, for example, starting from the corresponding alcohols of formulae (1 ), (1A) or (1 B) (in which the substituents assume the meanings reported above) and following the procedure described in Org. Process Res. Dev. 2011 , 15, 1 124-1 129:
Figure imgf000011_0001
When in the protected phenyl propanoates of formulae (2), (2A) and (2B) R3 is a sulfonate (such as mesylate, trifluoromethanesulfonate (triflate) or tosylate), its preparation can be performed with one of the methods generally known in the field, for example by treating the corresponding alcohols of formulae (1 ), (1A) or (1 B) with a sulfonyl halide (preferably a methanesulfonyl halide, such as methanesulfonyl chloride or trifluoromethanesulfonyl chloride) or a sulfonyl anhydride (preferably methanesulfonic anhydride or trifluoromethanesulfonic anhydride), normally in the presence of an organic base and of a suitable solvent. Preferably the base is a tertiary amine (cyclic or acyclic), such as triethylamine, N,N- diisopropylethylamine, /V,/V-diisopropylmethylamine, /V-methylpyrrolidine, 4- methylmorpholine, /V,/V-dicyclohexylmethylamine, L/,/V-diethylaniline, pyridine, 2- methylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine or 4-dimethylaminopyridine. Solvents useful for the aim are, for example, chlorinated solvent (preferably dichloromethane), ethers, hydrocarbons (preferably aromatic, for example toluene), polar aprotic solvents, such as acetonitrile, and mixture thereof. The quantity of sulfonyl halide or of sulfonyl anhydride used is normally from 1 .0 to 3.0 equivalents, preferably from 1 .01 to 2.50 equivalents, more preferably from 1 .02 to 2.10 equivalents, even more preferably from 1.05 to 2 equivalents compared to the molar quantity of the alcohols of formulae (1 ), (1A) or (1 B). The amount of the organic base used is normally from 1 to 3 equivalents, preferably from 1 .25 to 2.5 equivalents, more preferably from 1 .5 to 2 equivalents compared to the molar quantity of the alcohols of formulae (1 ), (1A) or (1 B).
Alternatively, when in protected phenyl propanoates of formulae (2), (2A) and (2B) R3 is a halogen, said compound can be prepared by treating the protected phenyl propanoates of formulae (2), (2A) and (2B), in which R3 is a sulfonate, with a halogenating agent such as a tetraalkylammonium halide (preferably tetrabutylammonium iodide, fluoride or bromide) or, preferably, with a halide of an alkali metal optionally in the presence of a catalytic system comprising at least one element selected from groups 8, 9 10 and 11 of the Periodic Table (preferably palladium, ruthenium, iridium, copper or rhodium) and, preferably, of at least one ligand, more preferably a phosphine. Halides of alkali metals are more preferably selected from the group comprising, or even more preferably consisting of, LiF, NaF, KF, CsF, LiCI, NaCI, KCI, CsCI, LiBr, NaBr, KBr, CsBr, Lil, Nal, Kl, and Csl. The quantity of halogenating agent is generally from 1.0 to 5.0 equivalents, preferably from 1.1 to 3.0 equivalents compared to the molar quantity of the protected phenyl propanoates of formulae (2), (2A) and (2B) in which R3 is a sulfonate.
Operation e) of the process of the invention comprises the conversion of a protected phenyl propanoate of formula (2), (2A) or (2B), optionally isolated, into a phenyl propanoate of formula (4), preferably a phenyl propanoate of formula (4A), more preferably a phenyl propanoate of formula (4B):
Figure imgf000012_0001
wherein the substituents assume the meanings reported above.
This operation e) includes:
e.1 ) subjecting the protected phenyl propanoate of formula (2), preferably a protected phenyl propanoate of formula (2A) or (2B), to a metal-catalysed carbonylation by treatment with gaseous CO or at least one CO surrogate in the presence of a transition metal-comprising catalytic system and optionally of a base; and e.2) converting the resulting oxidative insertion adduct into a phenyl propanoate of formula (4) by treatment with at least one nucleophile;
said steps e.1 ) and e.2) being carried out subsequently or concurrently.
In step e.1 ) the protected phenyl propanoate of formula (2), preferably a phenyl propanoate of formula (2A) or (2B), is subjected to a carbonylation by treatment with gaseous CO or at least one CO surrogate, in the presence of a transition metal-comprising catalytic system.
The carbonylation of the protected phenyl propanoate of formula (2) (2A) or (2B) is carried out using a catalytic system comprising, preferably based on, a transition metal such as, for example, ruthenium, rhodium, iridium, nickel, platinum or more preferably palladium. In the case when a CO surrogate is used in step e.1 ), this step is conveniently carried out in the presence of at least one base, preferably a base capable to promote decarbonylation of the CO source.
Preferably, said carbonylation step is carried out in the presence of a palladium- comprising catalytic system, more preferably a palladium-based catalytic system, optionally in an organic solvent, preferably a polar aprotic solvent (such as tetrahydrofuran, dioxane or preferably dimethylformamide, dimethylacetamide or acetonitrile), at a temperature normally from 40 to 160 °C, preferably from 50 °C to 100 °C, more preferably from 60 °C to 90 °C, even more preferably from 65 °C to 70 °C.
The transition metal-comprising catalytic system preferably has oxidation state 0 (zero) or II (two) and/or comprises, more preferably substantially consists of, even more preferably consists of, palladium, such as, palladium chloride (PdCI2), palladium acetate (Pd(OAc)2) or tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), optionally in the presence of mono- or bidentate ligands. Mono- or bidentate ligands useful for the aim are for example selected from the group comprising, preferably consisting of, triphenyl phosphine (PPfi3), tri(o- tolyl)phosphine (P(o-tol)3), 1 ,1 -bis(diphenylphosphino)methane (DPPM), 1 ,T- bis(diphenylphosphino)ferrocene (DPPF), 1 ,2-bis(diphenylphosphino)ethane (DPPE), 1 ,3- bis(diphenylphosphino)propane (DPPP), 1 ,4-bis(diphenylphosphino)butane (DPPB), 1 ,2- bis(diphenylphosphino)benzene (DPPBz), racemic-2,2'-bis(diphenylphosphino)-1 ,T- binaphthyl (rac-BINAP), tri-fe/f-butylphosphonium tetrafluoroborate (P(f-Bu)3*HBF4), (oxydi- 2,1 -phenylene)bis(diphenylphosphine) (DPEphos), and 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (Xantphos).
More preferably the mono- or bidentate ligands are selected from the group comprising, or preferably consisting of, tri-fe/f-butylphosphonium tetrafluoroborate (P(f-Bu)3*HBF4), (oxydi- 2,1 -phenylene)bis(diphenylphosphine) (DPEphos), 1 ,T-bis(diphenylphosphino)ferrocene (DPPF) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos).
Even more preferably the bidentate ligand is 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (Xantphos) or 1 ,T-bis(diphenylphosphino)ferrocene (DPPF).
The transition metal-comprising catalytic system (preferably the palladium-comprising or palladium-based catalytic system) is conveniently used in a stoichiometry from 0.001 to 20 mol%, preferably from 0.005 to 5 mol%, more preferably from 0.01 to 3 mol%, even more preferably from 0.015 to 1 mol%, compared to the molar quantity of the protected phenyl propanoate of formula (2), (2A) or (2B).
CO surrogates suitable to be used in step e) or e.1 ) are alkyl formates (for example methyl formate), formamides (for example /V,/V-dimethylformamide), dichlorocarbenes (generated, e.g., from chloroform and alkali under aqueous conditions), metal carbonyls (for example [Cr(CO)6], [MO(00)Q], and [W(CO)6]). Preferably said CO surrogates are selected from the group comprising, more preferably consisting of, phenyl formates, for example ortho- or para-substituted phenyl formates (e.g., 4-fluorophenyl formate, 4-chlorophenyl formate, 4- (trifluoromethyl)phenyl formate, 2,6-trifluorophenyl formate, and even more preferably 2,4,6- trichlorophenyl formate) and /V-formylsaccharin.
CO surrogates are normally used in a stoichiometry from 100 to 250 mol%, preferably from 110 to 200 mol%, even more preferably from 1 15 to 150 mol% compared to the molar quantity of the protected phenyl propanoate of formula (2), (2A) or (2B).
Gaseous CO is normally used in step e) or e.1 ) such that the total pressure is in the range of 1 bar (100000 Pa) to 20 bar (2000000 Pa), preferably from 1.5 bar (150000 Pa) to 15 bar (1500000 Pa), more preferably from 2 bar (200000 Pa) to 10 bar (1000000 Pa), even more preferably at 4±2 bar (400000±200000 Pa).
Bases optionally added in step e) or e.1 ) are organic and inorganic bases, for example hydroxides, carbonates, or halides of alkali metals (such as KOH, NaOH, LiOH, K2CO3, Na2C03, U2CO3, CS2CO3, LiF, NaF, KF, CsF, LiCI, NaCI, KCI, CsCI, LiBr, NaBr, KBr, CsBr, Lil,
Nal, Kl, Csl) or tertiary amines (cyclic or acyclic), such as triethylamine, N,N- diisopropylethylamine, /V,/V-diisopropylmethylamine, /V-methylpyrrolidine, N- methylmorpholine, /V,/V-dicyclohexylmethylamine, /V,/V-diethylaniline, pyridine, 2- methylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine or 4-dimethylaminopyridine.
Said bases are preferably used in a stoichiometry from 100 to 500 mol%, more preferably from 1 10 to 400 mol%, more preferably from 115 to 350 mol% compared to the molar quantity of the protected phenyl propanoate of formula (2), (2A) or (2B).
In step e.2) the oxidative insertion adduct prepared according to step e.1 ) is converted into a phenyl propanoate of formula (4) (preferably a phenyl propanoate of formula (4A) or (4B)) by treatment with at least one nucleophile. Preferably, when a palladium-based catalytic system is used in step e.1 ), step e.2) is carried out on an oxidative insertion adduct of formula (3A) or (3B):
Figure imgf000014_0001
wherein the substituents assume the meanings reported above and
- L is a neutral mono- or polydentate ligand.
Nucleophiles suitable to be used in step e.2) are, for example, selected from the group comprising, or preferably consisting of, halide ions (e.g., fluorides (F ), chlorides (Cl ), bromides (Br), iodides (l )), oxygen nucleophiles (e.g., hydroxide anions, alcohols, alkoxide anions), and nitrogen nucleophiles (e.g. ammonia, ammonium salts, amines or amides, preferably fc>/s-(trimethylsilyl)amine or more preferably an amine of formula R10-NH-R5, in which R10 and R5 assume the meanings reported above).
Nucleophiles are preferably used in a stoichiometry from 100 to 500 mol%, more preferably from 120 to 300 mol%, even more preferably from 150 to 260 mol% compared to the molar quantity of the protected phenyl propanoate of formula (2), (2A) or (2B).
According to a preferred embodiment of this aspect of the invention, the base optionally used in step e.1 ) (more preferably a halide of an alkali metal) releases the nucleophile suitable for the purposes of step e.2) (preferably a halide), thus leading to the direct preparation of a phenyl propanoate of formula (4), (4A), or (4B).
According to a further preferred embodiment of this aspect of the invention, operation e) is carried out one-pot by mixing the protected phenyl propanoate of formula (2) (preferably a protected phenyl propanoate of formula (2A) or (2B)) a palladium-comprising catalytic system (more preferably a catalytic system comprising palladium (II) acetate and Xantphos), at least one CO surrogate (preferably selected from the group consisting of /V-formylsaccharin and phenyl formates) and at least one base selected from the group consisting of tertiary amines (preferably triethylamine) and alkali metals (preferably a fluoride of an alkali metal). According to a more preferred embodiment of this aspect of the invention, in operation e) a palladium- comprising catalytic system (preferably a catalytic system comprising palladium (II) acetate and Xantphos), at least one CO surrogate (preferably selected from the group consisting of N- formylsaccharin and phenyl formates) and at least one base (preferably selected from the group consisting of tertiary amines and alkali metals) are mixed with a solution of the protected phenyl propanoate of formula (2) (preferably a protected phenyl propanoates of formula (2A) or (2B)) in a polar aprotic solvent (preferably dimethylformamide, dimethylacetamide, acetonitrile, tetrahydrofuran or dioxane). According to an even more preferred embodiment of this aspect of the invention, palladium (II) acetate, Xantphos, /V-formylsaccharin and potassium fluoride are mixed with a solution of a protected phenyl propanoate of formula (2), (2A) or (2B) in dimethylformamide.
According to an alternative embodiment of this aspect of the invention, operation e) is carried out by adding a palladium-comprising catalytic system (preferably a catalytic system comprising palladium (II) acetate and dppf), and gaseous CO to a dispersion of the protected phenyl propanoate of formula (2), (2A) or (2B), and at least one base (preferably selected from the group consisting of tertiary amines and alkali metals) in an organic solvent (preferably dimethylformamide).
According to a more preferred embodiment of this aspect of the invention, palladium (II) acetate, DPPF, and gaseous CO are added to a dispersion of the protected phenyl propanoate of formula (2), (2A) or (2B) and potassium carbonate in dimethylformamide.
According to an even more preferred embodiment of this aspect of the invention, the phenyl propanoate of formula (4), preferably a phenyl propanoate of formula (4A), more preferably a phenyl propanoate of formula (4B), even more preferably a phenyl propanoate of formula (4), (4A) or (4B) in which R4 is -CO2H, are crystallized from an organic solvent, preferably a nitrile, more preferably acetonitrile before proceeding with the next operation of the process.
The following optional operation f) includes, in the case when R4 is different from R10R5N, converting the phenyl propanoate of formula (4), preferably a phenyl propanoate of formula (4A) or (4B), into a protected carbamoyl phenyl propanoate of formula (5), preferably a protected carbamoyl phenyl propanoate of formula (5A) or (5B) by treatment with an amine of formula R10-NH-R5 (preferably ammonia, an aqueous solution thereof or an ammonium salt, e.g. a salt of ammonia with an organic or inorganic acid, more preferably ammonium acetate):
Figure imgf000016_0001
wherein the substituents assume the meanings reported above.
This optional operation can be performed according to different alternative synthetic pathways depending upon the starting phenyl propanoates of formula (4), (4A) or (4B).
For example, when R4 is (C1-C6)alkoxy-, the phenyl propanoate of formula (4), (4A) or (4B) can be reacted with an amine of formula R10-NH-R5 normally in the presence of a solvent at a temperature normally from 25 °C to the reflux temperature of the solvent used.
Alternatively, when R4 is (C1-C6)alkoxy-, the phenyl propanoate of formula (4), (4A) or (4B) can be hydrolyzed to the corresponding carboxylic acids (R4 = CO2H) according to known methods, for example by reaction with a base such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or by reaction with an acid, e.g. hydrogen chloride (optionally dissolved in an organic solvent), hydrochloric acid or sulfuric acid. Said carboxylic acids can be further reacted with an amine of formula R10-NH-R5 in the presence of a coupling agent such as 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), benzotriazol-1 -yl- oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP), 1 ,T-carbonyldiimidazole (CDI), 1-propanephosphonic anhydride (T3P) preferably in the presence of an organic base such as triethylamine, /V,/V-diisopropylethylamine, pyridine or in the presence of an amount of the amine of formula R10-NH-R5 sufficient to act as the base. This step is preferably carried out in an organic solvent such as tetrahydrofuran, dioxane, or /V,/V-dimethylformamide. Said carboxylic acids can be, alternatively, reacted with a source of chlorine, such as thionyl chloride (SOCI2), phosphorus trichloride (PCI3), phosphorus pentachloride (PCI5), oxalyl chloride ((COCI)2), in an organic solvent such as dichloromethane, /V,/V-dimethylformamide preferably at a temperature from 20 °C to 60 °C to yield the corresponding acyl chloride (R4 = Cl), which is further reacted with the amine of formula R10-NH-R5 so as to provide a protected carbamoyl phenyl propanoate of formula (5), (5A) or (5B).
Alternatively, when R4 is a halogen, the phenyl propanoates of formulae (4), (4A) or (4B) can be reacted with an amine of formula R10-NH-R5 in a suitable solvent (preferably the same solvent used in operation e), at a temperature normally from -25 °C to 40 °C and optionally in the presence of at least one base, either inorganic or organic, preferably a tertiary amine (cyclic or acyclic), such as triethylamine, /V,/V-diisopropylethylamine, /V,/V-diisopropylmethylamine, N- methylpyrrolidine, /V-methylmorpholine, /V,/V-dicyclohexylmethylamine, L/,/V-diethylaniline, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine or 4- dimethylaminopyridine.
The base optionally used in step f) is conveniently selected so as to ensure that the pH of mixture formed in this step is at maximum 10, preferably from 7 to 9, more preferably from 7 to 8. Even more preferably said base is potassium phosphate (i.e. K3PO4) or potassium phosphate dibasic (i.e. K2HPO4).
The use of a base giving rise to a pH of at maximum 10 in step f) has the advantageous effect of avoiding any racemization process of the protected carbamoyl phenyl propanoate of formula (5), preferably a protected carbamoyl phenyl propanoate of formula (5A) or (5B).
According to a preferred embodiment of this aspect of the invention, the optional operation f) is carried out by mixing at least one organic base (preferably potassium phosphate, potassium phosphate dibasic or a tertiary amine selected from the group consisting of triethylamine, /V,/V-diisopropylethylamine, /V,/V-diisopropylmethylamine, /V-methylpyrrolidine, /V-methylmorpholine, /V,/V-dicyclohexylmethylamine, L/,/V-diethylaniline, pyridine, 2- methylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine or 4-dimethylaminopyridine) an amine of formula R10-NH-R5 (preferably ammonia, ammonium hydroxide or an ammonium salt) to the mixture resulting from step e.2) or e) maintained at a temperature from -25 °C to 40 °C, thus leading to the conversion of the protected phenyl propanoate of formula (2) (preferably a protected phenyl propanoate of formula (2A) or (2B)) into the carbamoyl phenyl propanoates of formulae (5), (5A) or (5B) avoiding any isolation steps.
The following operation g) comprises the deprotection of the carbamoyl phenyl propanoates of formulae (5), (5A) or (5B) obtained in step e), e.2) or f), so as to provide a protected alanine derivative of formula (6), preferably a protected alanine derivative of formula (6A) or (6B). This operation can be carried out with one of the methods known to the skilled person, such as those reported in Theodora W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons (1999), on pages 384-386 or 406-407, which are herein incorporated by reference.
Preferably, in the case when R2 is methyl, ethyl, n-propyl, /'so-propyl, n-butyl, iso- butyl, this step is carried out by means of a hydroxide or a carbonate of an alkali metal (such as K2CO3, Na2CC>3, U2CO3, CS2CO3, KOH, NaOH, LiOH) in a water miscible solvent (e.g. methanol, ethanol, tetrahydrofuran, dimethoxyethane, dioxane or a mixture thereof) optionally in mixture with water. The amount of hydroxide or carbonate of the alkali metal used is normally from 1 to 5 equivalents, preferably from 1 .2 to 2.5 equivalents, for example from 1.3 to 2.2 equivalents compared to the molar quantity of the carbamoyl phenyl propanoates of formulae
(5), (5A) or (5B).
Alternatively, when R2 is tert- butyl, suitable hydrolysis conditions include for example the treatment with hydrochloric acid or with a solution of hydrogen chloride in a suitable organic solvent, such as an alcohol (e.g. methanol).
A variant of the process object of this aspect of the invention includes an additional and optional step g’), carried out after step g), comprising converting a protected alanine derivative of formula (6), preferably a protected alanine derivative of formula (6A) or (6B) into a salt thereof (preferably a salt thereof with sodium, potassium, benzylamine, tributylamine, triethylamine and diethylamine).
In a further variant of this embodiment of the invention, an additional and optional step g”) is carried out after step g’), comprising converting the salt of the protected alanine derivative of formula (6), (6A) or (6B) into the corresponding acid. This step is normally carried out by treatment with an acid, preferably an organic acid, more preferably formic acid, in the presence of a solvent, preferably water.
In step b) the protected alanine derivative of formula (6), preferably a protected alanine derivative of formula (6A) or (6B), more preferably a protected alanine derivative of formula
(6), (6A) or (6B) prepared according to operations d) to g), d) to g’) or d) to g”) reported above, is converted into a protected amide (7), preferably a protected amide of formula (7 A) or (7B), by treatment with an amine of formula (8) or a salt thereof in the presence of 1 - propanephosphonic anhydride (T3P) and optionally of a base at a temperature lower than 0 °C.
Figure imgf000018_0001
The combined use of T3P and of a temperature lower than 0 °C in step b) has the advantageous effect of ensuring (1 ) a high recovery yield (i.e. at least 75%, preferably at least 80%, more preferably at least 85%, even more preferably at least 86%) of the protected amide (7), preferably protected amide (7A) or (7B); (2) an increased purity profile of the reaction (i.e., a total impurities content lower than 10%, preferably lower than 7%, more preferably lower than 5%, based on the HPLC area percent); (3) avoiding, at the same time, any epimerization and racemization phenomena.
Step b) is conveniently carried out in an organic solvent, preferably a polar aprotic solvent (e.g. dimethylformamide, tetrahydrofuran) or, more preferably, an acetate (e.g., ethyl acetate) Preferably step b) is performed at a temperature of or lower than -5 °C, more preferably at a temperature of or lower than -10 °C. More preferably step b) is carried out at a temperature lower than 0 °C and of at least -40 °C, preferably of or higher than -30 °C, more preferably of or higher than -25 °C, even more preferably of or higher than -20 °C. According to an even more preferred embodiment of this aspect of the invention step b) is carried out at a temperature of at least -25 °C and lower than 0 °C, preferably from -20 °C to -5 °C, more preferably from -15 °C to -10 °C.
Amines of formula (8) suitable to be used in step b), preferably amines of formulae (8’), (8”), (8’”), (8A’), (8A) and (8B), are commercially available; alternatively, they can be prepared according to standard techniques in organic synthesis, for example, following the procedure described in WO 2005/090315 A1 :
Figure imgf000019_0001
Preferably said amines of formulae (8), (8’), (8”), (8’”), (8A’), (8A) and (8B) can be prepared by treating the corresponding oxalate salts, more preferably the corresponding hemi- oxalate salts, with a base, either organic or inorganic.
According to an even more preferred embodiment of this aspect of the invention the hemi-oxalate salt used as starting materials for preparing the amine of formula (8B) shows an X-ray powder diffraction pattern as substantially depicted in Figure 3 and/or a diffractogram that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by a halo between 12° and 30° 2Q. Amines of formula (8), (8’), (8”), (8’”), (8A’), (8A) or (8B) are normally used in a stoichiometry from 100 to 200 mol%, preferably from 101 to 150 mol%, more preferably from 105 to 120 mol% compared to the molar quantity of the protected alanine derivative of formula (6), (6A) or (6B).
1 -propanephosphonic anhydride (T3P) is normally used in a stoichiometry from 100 to 250 mol%, preferably from 120 to 200 mol%, more preferably from 150 to 180 mol% compared to the molar quantity of the protected alanine derivative of formula (6), (6A) or (6B).
The base optionally used in step b) is preferably a tertiary amine (cyclic or acyclic), such as triethylamine, /V,/V-diisopropylethylamine, /V,/V-diisopropylmethylamine, N- methylpyrrolidine, /V-methylmorpholine, /V,/V-dicyclohexylmethylamine, L/,/V-diethylaniline, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, 4- dimethylaminopyridine, 2,2,6,6-tetramethylpiperidine, /V-ethylmorpholine, or a mixture thereof.
Preferably the base is an aliphatic tertiary amine (cyclic or acyclic), such as triethylamine, L/,/V-diisopropylethylamine, /V,/V-diisopropylmethylamine, /V-methylpyrrolidine, N- methylmorpholine, /V,/V-dicyclohexylmethylamine, L/,/V-diethylaniline, 2,2,6,6- tetramethylpiperidine, /V-ethylmorpholine or a mixture thereof.
When used, said base is preferably added in a stoichiometry from 200 to 600 mol%, preferably from 250 to 500 mol%, more preferably from 300 to 450 mol%, even more preferably from 340 to 400 mol% compared to the molar quantity of the protected alanine derivative of formula (6), (6A) or (6B).
According to a preferred embodiment of this aspect of the invention, operation b) is carried out by mixing an amine of formula (8), (8’), (8”), (8’”), (8A’), (8A) or (8B), a protected alanine derivative of formula (6), (6A) or (6B) (preferably a protected alanine derivative of formula (6), (6A) or (6B) prepared according to operations d) to g), d) to g’) or d) to g”) reported above), 1 -propanephosphonic anhydride (T3P), and at least one base (preferably an aliphatic tertiary amine, more preferably triethylamine) with an acetate (preferably ethyl acetate) at a temperature lower than 0 °C. More preferably this preferred embodiment is performed at a temperature of or lower than -5 °C, more preferably at a temperature of or lower than -10 °C. Even more preferably, this preferred embodiment is carried out at a temperature lower than 0 °C and of at least -40 °C, preferably of or higher than -30 °C, more preferably of or higher than -25 °C, even more preferably of or higher than -20 °C. More preferably this embodiment is performed at a temperature of at least -25 °C and lower than 0 °C, preferably from -20 °C to - 5 °C, more preferably from -15 °C to -10 °C.
A variant of the process object of this aspect of the invention includes an additional and optional step b’), carried out after step b), comprising converting a protected amide of formula (7C) or (7D) (as obtainable by reacting, according to step b), a protected alanine derivative of formula (6) and an amine of formula (8A) or (8B)) into a protected amide of formula (7E) or (7F) or a salt thereof (preferably a sodium salt thereof):
Figure imgf000021_0001
wherein the substituents assume the meanings reported above.
The following step c), entails the conversion of the protected amide of formulae (7), (7 A)
(7B), (7C), (7D), (7E) or (7F), optionally isolated, into a mixed pOR agonist/50R antagonist (9) or a salt thereof, preferably eluxadoline, more preferably a hydrochloride salt of eluxadoline.
Operation c) can be performed using any one of the methods generally known in the field to remove an amino protecting group, for example one of those described in Theodora W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons (1999), pages 503-598, which are herein incorporated by reference. Preferably, in the case when Pg forms together with the nitrogen atom a carbamate group, said de-protection step may be operated according to the procedures detailed on pages 504-540 of the text referred to above. According to an even more preferred embodiment of this aspect of the invention, in the case when Pg is a benzyloxy carbonyl, step c) can be carried out by treatment with hydrogen in the presence of a catalyst (e.g. palladium, platinum or nickel) optionally supported on an appropriate carrier (such as carbon or barium carbonate) in an alcohol (preferably methanol or ethanol) or an aqueous mixture thereof. Conversely, when Pg is a tert- butoxy carbonyl, it can be carried out according to one of the procedures described in Theodora W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons (1999), pages 520-522. Preferably this step is performed by treating a protected amide of formulae (7), (7A), (7B), (7C), (7D), (7E) or (7F) with a solution of hydrogen chloride in water or in an organic solvent.
In a variant of this embodiment of the invention, an additional and optional step c’) is carried out after step c), comprising converting a mixed pOR agonist/60R antagonist (9A) or (9B) (as obtainable by subjecting a protected amide of formula (7C) or (7D) to step c) above) into a mixed pOR agonist/60R antagonist (9E) or (9F) or a salt thereof, preferably eluxadoline, more preferably a hydrochloride salt of eluxadoline.
Figure imgf000022_0001
Said additional and optional steps b’) to c’) can be performed using any one of the methods generally known to the skilled person, e.g. one of those described above to carry out operation g).
According to a preferred embodiment of this aspect of the invention, step c) comprises converting a protected amide of formula (7E) or (7F) or a salt thereof (preferably a sodium salt thereof) into a mixed pOR agonist/60R antagonist (9E) or (9F) or a salt thereof, preferably eluxadoline, more preferably a hydrochloride salt of eluxadoline.
The protected alanine derivative (6) or the mixed pOR agonist/60R antagonist (9) obtained by the processes object of the present invention can be converted in a salt or a co- crystal thereof in a further optional step.
In the compound of formula (1 ), (2), (4), (5), (6), (7) or (9) n is preferably 2.
A further object of the present invention relates to a crystalline form of a protected carbamoyl phenyl propanoate of formula (5B), in which R5 and R10 are hydrogen, R2 is methyl and Pg is tert- butyloxycarbonyl, which shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by main peaks at: i. 5.92°, 1 1.80°, 21.08°, 21.48° and 23.76° ± 0.2° 2Q; or
ii. 5.92°, 1 1.80°, 19.52°, 21.08°, 21.48° and 23.76° ± 0.2° 20.
More preferably said protected carbamoyl phenyl propanoate of formula (5B), in which R5 and R10 are hydrogen, R2 is methyl and Pg is tert- butyloxycarbonyl, shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by at least 5 peaks (± 0.2° 20) selected from Table 1A or 1 B:
Figure imgf000023_0001
Figure imgf000023_0002
According to a further embodiment thereof, this aspect of the invention provides a process for the preparation of said crystalline form of a protected carbamoyl phenyl propanoate of formula (5B), in which R5 and R10 are hydrogen, R2 is methyl and Pg is tert- butyloxycarbonyl, said process comprising the step of crystallizing the protected carbamoyl phenyl propanoate of formula (5B) in a medium comprising or, preferably consisting of, a ketone. More preferably said medium is an organic solvent selected from the group comprising or consisting of, acetone, 2-butanone, 3-pentanone, methyl isobutyl ketone and mixtures thereof.
Said crystallization is generally performed by heating a solution of the protected carbamoyl phenyl propanoate of formula (5B) in a medium comprising a ketone to a temperature next to the boiling point of the medium used, followed by cooling to a temperature between 0 and 30 °C optionally after having added a seed of the desired crystalline form (i., ii., Table 1 A, 1 B, Figure 1 ).
A further object of the present invention relates to a protected alanine derivative of formula (6B), in which R5 and R10 are hydrogen and Pg is tert- butyloxycarbonyl, which shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by main peaks at: iii. 14.60°, 15.92°, 18.20°, 20.56° and 25.48° ± 0.2° 20; or
iv. 10.80°, 14.60°, 15.92°, 18.20°, 20.56° and 25.48° ± 0.2° 20.
More preferably said protected alanine derivative of formula (6B), in which R5 and R10 are hydrogen and Pg is tert- butyloxycarbonyl, shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by at least 5 peaks (± 0.2° 20) selected from Table 2A or 2B:
Figure imgf000024_0001
Figure imgf000024_0002
According to a further embodiment thereof, this aspect of the invention provides a process for the preparation of said crystalline form of a protected alanine derivative of formula (6B), in which R5 and R10 are hydrogen and Pg is tert- butyloxycarbonyl, said process comprising the step of crystallizing the protected alanine derivative of formula (6B) from a medium comprising or, preferably consisting of, a polar aprotic solvent or a mixture thereof with water.
More preferably said polar aprotic solvent is selected from the group comprising, even more preferably consisting of, dimethylformamide, dimethylacetamide, /V-methyl-2-pyrrolidone and mixtures thereof.
Even more preferably this further embodiment is carried in a medium comprising or, preferably consisting of, water and dimethylformamide, for example a solvent mixture comprising water and dimethylformamide in a 1 :2 ratio on a volume basis.
Said crystallization is generally performed by heating a solution of the protected alanine derivative of formula (6B) to a temperature next to the boiling point of the used medium, followed by cooling to a temperature between 0 and 30 °C optionally after having added a seed of the desired crystalline form (iii., iv., Table 2A, 2B, Figure 2).
A further object of the present invention relates to a crystalline hydrochloride salt of eluxadoline, said salt showing an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by main peaks at:
v. 8.88°, 10.68°, 13.24°, 21 .44° and 31 .84° ± 0.2° 20; or
vi. 7.00°, 8.88°, 10.68°, 13.24°, 17.72°, 21 .44°, 26.40° and 31 .84° ± 0.2° 20.
More preferably said crystalline salt of eluxadoline contains an amount of chloride (as determined, e.g., by argentometric titration) from 18 to 19% w/w (e.g. 18.5% w/w) and shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1 .5406 A), is characterized by at least 5 peaks (± 0.2° 20) selected from Table 3A or 3B:
Figure imgf000025_0002
Figure imgf000025_0003
According to a further embodiment thereof, this aspect of the invention provides a process for the preparation of said crystalline hydrochloride salt of eluxadoline, said process comprising the steps of treating a sodium salt of formula (7G):
Figure imgf000025_0001
in which R5 and R10 are H and Pg is fe/f-butyloxycarbonyl, (i.e. a compound of formula (7F) in which R1 is methyl and n=2), preferably the sodium salt of formula (7G) of ix., x., Table 5A, 5B, Figure 4, with hydrogen chloride or hydrochloric acid, optionally in the presence of at least one organic solvent, preferably a nitrile (more preferably acetonitrile) thus forming a dispersion; and maintaining said dispersion under stirring so as to cause precipitation of the crystalline hydrochloride salt of eluxadoline (v., vi., Table 3A, 3B, Figure 5), preferably for at least 1 hour, more preferably for a period from 2 to 20 hours, more preferably from 3 to 15 hours.
A further object of the present invention relates to another crystalline hydrochloride salt of eluxadoline, said salt showing an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by main peaks at:
vii. 17.28°, 19.72°, 26.28°, 29.60° and 31.72° ± 0.2° 20; or
viii. 17.28°, 19.72°, 21.08°, 23.68°, 26.28°, 27.04°, 29.60°, and 31.72° ± 0.2° 20.
More preferably said further crystalline salt of eluxadoline contains an amount of chloride
(as determined, e.g., by argentometric titration) from 15 to 16% w/w (e.g. 15.3% w/w) and shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by at least 5 peaks (± 0.2° 20) selected from Table 4A or 4B:
Figure imgf000026_0001
Figure imgf000026_0002
According to a further embodiment thereof, this aspect of the invention provides a process for the preparation of this further crystalline hydrochloride salt of eluxadoline, said process comprising the steps of dispersing a crystalline form of eluxadoline containing an amount of chloride from 18 to 19% w/w (v., vi., Table 3A, 3B, Figure 5) in at least one organic solvent, preferably an alcohol (more preferably methanol, ethanol, 1 -propanol, 2-propanol, tert- butanol and mixtures thereof) or a mixture thereof with water; and maintaining the resulting dispersion under stirring so as to cause precipitation of the crystalline hydrochloride salt of eluxadoline (vii., viii., Table 4A, 4B, Figure 6), preferably for at least 1 hour, more preferably for a period from 2 to 20 hours, more preferably from 3 to 15 hours.
A further object of the present invention relates to a sodium salt of formula (7G) reported above, in which R5 and R10 are hydrogen and Pg is tert- butyloxycarbonyl, which shows an X- ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by main peaks at:
ix. 10.16°, 16.72°, 17.68°, and 23.16° ± 0.2° 20; or
x. 7.68°, 10.16°, 11.96°, 16.72°, 17.68°, 19.96° and 23.16° ± 0.2° 20.
More preferably said sodium salt of formula (7G), in which in which R5 and R10 are hydrogen and Pg is tert- butyloxycarbonyl, shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by at least 4 peaks (± 0.2° 20) selected from Table 5A or 5B:
Figure imgf000027_0001
Figure imgf000027_0002
According to a further embodiment thereof, this aspect of the invention provides a process for the preparation of a crystalline form of said sodium salt of formula (7G), in which R5 and R10 are hydrogen and Pg is tert- butyloxycarbonyl, said process comprising the steps of dispersing a sodium salt of 5-(((S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6- dimethylphenyl)-/V-((S)-1-(4-phenyl-1 /-/-imidazol-2-yl)ethyl)propanamido)methyl)-2- methoxybenzoate in at least one organic solvent, preferably an alcohol (more preferably methanol, ethanol, 1 -propanol, 2-propanol, tert- butanol and mixtures thereof) or a mixture thereof with water; and maintaining the resulting dispersion under stirring so as to cause precipitation of the crystalline sodium salt of formula (7G), (ix., x., Table 5A, 5B, Figure 4), preferably for at least 1 hour, more preferably for a period from 2 to 20 hours, more preferably from 3 to 15 hours.
A further object of the present invention relates to a protected carbamoyl phenyl propanoate of formula (5B), in which R5 and R10 are hydrogen, R2 is methyl and Pg is tert- butyloxycarbonyl, which shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by main peaks at:
xi. 1 1.48°, 20.76°, 22.28°, and 22.84° ± 0.2° 20; or
xii. 1 1.48°, 18.12°, 19.40°, 20.76°, 22.28°, and 22.84° ± 0.2° 20.
More preferably said protected carbamoyl phenyl propanoate of formula (5B), in which R5 and R10 are hydrogen, R2 is methyl and Pg is tert- butyloxycarbonyl, shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by at least 4 peaks (± 0.2° 20) selected from Table 6A or 6B:
Figure imgf000028_0001
Figure imgf000028_0002
According to a further embodiment thereof, this aspect of the invention provides a process for the preparation of this crystalline form of the protected carbamoyl phenyl propanoate of formula (5B), in which R5 and R10 are hydrogen, R2 is methyl and Pg is tert- butyloxycarbonyl, said process comprising the step of the crystallizing the protected carbamoyl phenyl propanoate of formula (5B) in a medium comprising, or preferably consisting of, an alcohol. More preferably said medium is an alcohol selected from the group comprising, even more preferably consisting of, methanol, ethanol, 1 -propanol, 2-propanol, tert- butanol and mixtures thereof.
Said crystallization is generally performed by heating a solution of the protected carbamoyl phenyl propanoate of formula (5B) to a temperature next to the boiling point of the used medium, followed by cooling to a temperature between 0 and 30 °C optionally after having added a seed of the desired crystalline form (xi., xii., Table 6A, 6B, Figure 7). A further object of the present invention relates to a diethylamine salt of a protected alanine derivative of formula (6B), in which R5 and R10 are hydrogen and Pg is tert- butyloxycarbonyl, which shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by main peaks at:
xiii. 8.32°, 13.16° and 21.24° ± 0.2° 2Q; or
xiv. 8.32°, 1 1.84°, 13.16°, 15.44°, 18.16° and 21.24° ± 0.2° 20.
More preferably said diethylamine salt of a protected alanine derivative of formula (6B), in which R5 and R10 are hydrogen and Pg is tert- butyloxycarbonyl, shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by at least 3 peaks (± 0.2° 20) selected from Table 7 A or 7B:
Figure imgf000029_0001
Figure imgf000029_0002
According to a further embodiment thereof, this aspect of the invention provides a process for the preparation of diethylamine salt of a protected alanine derivative of formula (6B), in which R5 and R10 are hydrogen and Pg is tert- butyloxycarbonyl, said process comprising the steps of dispersing a said protected alanine derivative of formula (6B), preferably (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)propanoate in a medium (preferably comprising a ketone, more preferably comprising acetone); mixing the resulting dispersion with diethylamine; and maintaining under stirring at a temperature normally from 0 to 50 °C (preferably from 20 to 35 °C), preferably for at least 10 minutes, more preferably for a period from 30 minutes to 20 hours, even more preferably from 1 to 15 hours so as to cause precipitation of the crystalline diethylamine salt of compound of formula (6B), (xiii., xiv., Table 7A, 7B, Figure 8).
A further object of the present invention relates to a protected alanine derivative of formula (6B), in which R5 and R10 are hydrogen and Pg is tert- butyloxycarbonyl, which shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by main peaks at:
xv. 16.12°, 20.72° and 25.56° ± 0.2° 20; or
xvi. 16.12°, 17.96°, 20.72°, 21.96° and 25.56° ± 0.2° 20.
More preferably said protected alanine derivative of formula (6B), in which R5 and R10 are hydrogen and Pg is tert- butyloxycarbonyl, shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by at least 3 peaks (± 0.2° 20) selected from Table 8A or 8B:
Figure imgf000030_0001
Figure imgf000030_0002
According to a further embodiment thereof, this aspect of the invention provides a process for the preparation of protected alanine derivative of formula (6B), in which R5 and R10 are hydrogen and Pg is tert- butyloxycarbonyl, said process comprising the steps of dispersing a diethylamine salt of said protected alanine derivative of formula (6B), preferably a diethylamine salt of (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6- dimethylphenyl)propanoate, more preferably the diethylamine salt of xiii., xiv., Table 7 A, 7B, Figure 8) in a medium (preferably water); treating the resulting dispersion with an acid (preferably an organic acid, more preferably formic acid); and maintaining under stirring at a temperature normally from 0 to 50 °C (preferably from 20 to 35 °C), preferably for at least 10 minutes, more preferably for a period from 30 minutes to 20 hours, even more preferably from 1 to 15 hours so as to cause precipitation of the crystalline compound of formula (6B), (xv., xvi., Table 8A, 8B, Figure 9),
When anyone of the compounds described in the present application are obtained with a degree of chemical purity not suitable for the inclusion in a medicament, the processes object of the present invention entails a further step of purification, for example by means of chromatography or crystallization, optionally after formation of an addition compound, such as for example a salt (preferably a hydrochloride salt) or a co-crystal, or by washing with an organic solvent or an aqueous solution, optionally adjusting the pH.
The invention will be further illustrated by the following examples.
Examples
XRPD: Analyses were performed on an APD 2000 Ital Structures diffractometer at 25 °C, using a Cu Ka tube (35 kV, 30 mA, l = 1 .5406 A) as the X-ray source. Data collection was made in step scan mode and in Bragg-Brentano configuration, at a scan speed of 0.027s in the range of 5° to 40° in theta/2theta. Samples were accurately ground and placed in the hollow of an aluminium sampler. The instrument was previously calibrated by means of zinc oxide, then allowing acquisition and elaboration of data by means of WinAcq32 software. In some of the XRPD traces reported below the person skilled in the art may recognise the peak corresponding to the aluminium of the sampler. RH (relative humidity) in the cabin: 28-30%.
Argentometric titration: Chloride content was determined using a Series DL67 titrator (Mettler Toledo) equipped with Glass electrode DM141 -SC (KNO3 in water 1 M). To a solution of an accurately weighed amount of the sample to be tested (40 ± 2 mg) dissolved in MeOH (20 ml.) and water (40 ml_), 1 ml. of nitric acid 70% was added. Then titrate with 0.1 N silver nitrate. Before each analysis, perform a blank determination.
High Performance Liquid Chromatography-Ultraviolet Detection (HPLC-UV): Analyses were performed according to the following method
Column: Symmetry C18 250 x 4.6 mm, 3.5 pm (Waters)
Mobile Phase A: 0.1 % (V/V) phosphoric acid aqueous solution
Mobile Phase B: acetonitrile
Diluent: 1 :1 (V/V) mixture of Mobile Phases A and B
Flow Rate: 1 .0 mL/min
Runtime: 70 min
Column Temperature 30 °C
Autosampler Temperature: Ambient
Injection Volume: 5 pL
Detection: 210 nm
Sample concentration: 0.25 mg/ml_
Gradient Program:
Figure imgf000031_0001
Figure imgf000032_0001
Example 1
Preparation of methyl (S)-2-((fe/f-butoxycarbonyl)amino)-3-(2,6-dimethyl-4- (((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate, compound of formula (2) wherein n is 2, R1 and R2 are methyl, R3 is -OTf, and Pg is tert- butyloxycarbonyl.
This example is representative of operation d) of the process of the invention.
Figure imgf000032_0002
To a suspension of methyl (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-hydroxy-2,6- dimethylphenyl)propanoate monohydrate (2.05 g, 6.0 mmol) in acetonitrile (15 ml_), 4- methylmorpholine (0.91 g, 9.0 mmol) and trifluoromethanesulfonic anhydride (2.20 g, 12.6 mmol) were added under stirring monitoring that the internal temperature did not exceed 10 °C. The mixture was maintained under stirring at the same temperature until complete conversion (about 1 hour). Glacial acetic acid (0.18 g, 3.0 mmol) was added thereto up to obtain a pH lower than 6.0 (determined by means of a pH strips). The mixture was concentrated under reduced pressure to residue, which was dispersed in toluene (5 ml.) and water (2.5 ml_). The resulting phases were separated and the organic layer was concentrated under reduced pressure up to obtaining an oily residue (2.85 g, quantitative yield).
Example 2
Preparation of methyl (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6- dimethylphenyl)propanoate, compound of formula (5) wherein n is 2, R1 and R2 are methyl, R5 and R10 are H, and Pg is tert- butyloxycarbonyl.
This example is representative of operations e.1 ) and e.2) of the process of the invention.
Figure imgf000032_0003
The oily residue prepared as described in example 1 (6.0 mmol theoretical) was dissolved in /V,/V-dimethyl formamide (56 ml_). /V-formylsaccarin (1 .90 g, 9.0 mmol), Xantphos (0.16 g, 0.3 mmol), potassium fluoride (8.70 g, 15.0 mmol), and palladium (II) acetate (0.04 g, 0.2 mmol) were added. The resulting mixture was subjected to 3 cycles of vacuum/nitrogen, then maintained under stirring at 80-85 °C until complete conversion (about 16 hours). The reaction was cooled to 20-25 °C and subjected to 3 cycles of vacuum! nitrogen (in order to remove the formed carbon monoxide) then it was further cooled to 0-5 °C and triethylamine (2.43 g, 24.0 mmol) and ammonia (0.15 g, 9.0 mmol) were added thereto. When the conversion was complete, the mixture was evaporated under reduced pressure in order to remove most of L/,/V-di methyl formamide, then water (42 ml.) and isopropyl acetate (8.5 ml.) were added. The mixture was heated to 45 °C, then filtered on a pad of celite and charcoal. The phases were separated, then a 5% (w/w) aqueous solution of sodium carbonate (4.80 g) was added to the organic phases. After having separated the resulting layers, the organic phase is concentrated under reduced pressure so as to obtain an oily residue (2.85 g, quantitative yield).
An aliquot of the residue was crystallized from acetone and the resulting solid analysed by XRPD, obtaining the diffractogram shown in Figure 1.
A further aliquot of the residue was crystallized from 2-propanol and the resulting solid analysed by XRPD, obtaining the diffractogram shown in Figure 7.
Example 3
Preparation of (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6- dimethylphenyl)propanoic acid, compound of formula (6) wherein n is 2, R1 is methyl, R5 and R10 are H, and Pg is tert- butyloxycarbonyl.
This example is representative of operation g) of the process of the invention.
Figure imgf000033_0001
To the oily residue prepared as described in example 1 (6.0 mmol theoretical) dispersed in tetrahydrofuran (8.6 ml.) and water (8.6 ml_), a 30% (w/w) solution of sodium hydroxide in water (1.4 g, 10.8 mmol) was slowly added monitoring that the internal temperature did not exceed 10 °C. The mixture was maintained under stirring at 5 °C for 1 hour then toluene (1.7 ml.) and formic acid (0.57 g, 12.4 mmol) were subsequently added thereto. The phases were separated so as to cause precipitation of a solid. The mixture was filtered, the solid washed with water and dried at 40 °C under reduced pressure so as to obtain 1.14 g of the desired compound.
An aliquot of the residue was crystallized from a 2:1 (V/V) mixture of DMF and water and the product was analysed by XRPD, obtaining the diffractogram shown in Figure 2.
Example 4
Preparation of the hemi-oxalate salt of methyl (S)-2-methoxy-5-(((1-(4-phenyl-1 H- imidazol-2-yl)ethyl)amino)methyl)benzoate, i.e. the hemi-oxalate salt of the compound of formula (8B).
Figure imgf000033_0002
A solution of oxalic acid (0.24 g, 2.7 mmol) in isopropyl acetate (10 ml.) was added under stirring to a solution of methyl (S)-2-methoxy-5-(((1-(4-phenyl-1 H-imidazol-2- yl)ethyl)amino)methyl)benzoate (1.97 g, 5.4 mmol) in isopropyl acetate (10 ml.) previously heated to 65 °C. The mixture was maintained under stirring at the same temperature for 1 hour, then cooled to 25 °C in about 2 hours. The resulting solid was filtered, washed with isopropyl acetate and dried at 50 °C under reduced pressure, thus affording 2.2 grams of the desired hemi-oxalate salt.
The attained product was analysed by XRPD, obtaining the diffractogram shown in
Figure 3.
Example 5
Preparation of methyl (S)-2-methoxy-5-(((1-(4-phenyl-1 H-imidazol-2- yl)ethyl)amino)methyl)benzoate, compound of formula (8B).
Figure imgf000034_0001
To the oxalate salt of methyl (S)-2-methoxy-5-(((1-(4-phenyl-1 H-imidazol-2- yl)ethyl)amino)methyl)benzoate (10.53 g, 23.1 1 mmol), prepared according to the procedure described in IPCOM000247658D, a solution of potassium carbonate (5.75 g, 41.60 mmol) in water (80 ml.) and methanol (63 ml.) was added. The resulting suspension was heated to 45 °C, maintained under stirring at the same temperature for 30 minutes, then isopropyl acetate
(53 ml.) was added thereto. After having maintained the mixture at 45 °C for 3 hours, the phases were separated. The aqueous layer was extracted with isopropyl acetate and the combined organic phases were concentrated under reduced pressure (monitoring that internal temperature did not exceed 45 °C) up to achieve a residual volume of 30 ml_. Isopropyl acetate (40 ml.) was added thereto and the resulting mixture maintained under stirring at 45 °C for 15 minutes. The phases were separated, the organic phase was washed with water and concentrated under reduced pressure up to achieve a residual volume of 15 ml_. The resulting residue was co-evaporated with ethyl acetate in order to remove residual isopropyl acetate, water and methanol, then ethyl acetate (21 ml.) was added thus leading to 33 g of a solution suitable to be used in example 7.
Example 6
Preparation of methyl (S)-2-methoxy-5-(((1-(4-phenyl-1 H-imidazol-2- yl)ethyl)amino)methyl)benzoate, compound of formula (8B).
Figure imgf000034_0002
To the hemi-oxalate salt of methyl (S)-2-methoxy-5-(((1-(4-phenyl-1 H-imidazol-2- yl)ethyl)amino)methyl)benzoate (9.49 g, 23.12 mmol), prepared according to the procedure described in example 4, a solution of potassium carbonate (2.88 g, 20.81 mmol) in water (80 ml.) and methanol (32 ml.) was added. The resulting suspension was heated to 45 °C, maintained under stirring at the same temperature for 30 minutes, then isopropyl acetate (53 ml.) was added thereto. After having maintained the mixture at 45 °C for 3 hours, the phases were separated. The aqueous layer was extracted with isopropyl acetate and the combined organic phases were concentrated under reduced pressure (monitoring that internal temperature did not exceed 45 °C) up to achieve a residual volume of 30 ml_. Isopropyl acetate (40 ml.) was added thereto and the resulting mixture maintained under stirring at 45 °C for 15 minutes. The phases were separated, the organic phase was washed with water and concentrated under reduced pressure up to achieve a residual volume of 15 ml_. The resulting residue was co-evaporated with ethyl acetate in order to remove residual isopropyl acetate, water and methanol, then ethyl acetate (21 ml.) was added thus leading to 33 g of a solution suitable to be used in example 7.
Example 7
Preparation of methyl 5-(((S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6- dimethylphenyl)-/V-((S)-1-(4-phenyl-1 /-/-imidazol-2-yl)ethyl)propanamido)methyl)-2- methoxybenzoate, compound of formula (7) wherein n is 2, R1 and R7 are methyl, R5 and R10 are H, R6 is methyl 2-methoxy-5-(A3-methyl)benzoate, D is 2-(A3-ethyl)-4-phenyl-1 /-/-imidazole and Pg is tert- butyloxycarbonyl.
This example is representative of operation b) of the process of the invention.
Figure imgf000035_0001
To the solution of methyl (S)-2-methoxy-5-(((1-(4-phenyl-1 H-imidazol-2- yl)ethyl)amino)methyl)benzoate in ethyl acetate prepared as described in example 5 or 6 (33 g of the solution containing 8.45 g, 23.12 mmol of (S)-2-methoxy-5-(((1-(4-phenyl-1 H-imidazol- 2-yl)ethyl)amino)methyl)benzoate in ethyl acetate), (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4- carbamoyl-2,6-dimethylphenyl)propanoic acid prepared as described in example 3 (7.00 g, 20.81 mmol), ethyl acetate (64 ml.) and subsequently triethylamine (7.95 g, 78.60 mmol) were added at 25 °C under stirring. The resulting mixture was cooled to -15 °C and a 50% w/w solution of T3P in ethyl acetate (22.07 g, 34.68 mmol) added thereto monitoring that the internal temperature did not exceed -10 °C. The mixture was maintained under stirring at -15/- 10 °C until complete conversion was achieved (about 1 hour) then water (34 ml.) was added thereto monitoring that internal temperature did not exceed 0 °C. The resulting phases were heated to 25 °C, maintained under stirring at this temperature for 1 hour then separated. The organic layer was washed with water and the combined organic phases concentrated under reduced pressure up to achieve a residual volume of 20 ml_. The resulting residue was co- evaporated with isopropanol in order to remove residual ethyl acetate, then isopropanol (34 ml.) was added thus leading to 41 g of a solution suitable to be used in example 8.
A portion of the product was subjected to HPLC analysis, giving rise to the results reported below:
Figure imgf000036_0002
Example 8
Preparation of sodium 5-(((S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6- dimethylphenyl)-/V-((S)-1-(4-phenyl-1 /-/-imidazol-2-yl)ethyl)propanamido)methyl)-2- methoxybenzoate, compound of formula (7G) wherein R5 and R10 are H and Pg is tert- butyloxycarbonyl.
This example is representative of optional operation b’) of the process of the invention.
Figure imgf000036_0001
To the solution of methyl 5-(((S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6- dimethylphenyl)-/V-((S)-1-(4-phenyl-1 /-/-imidazol-2-yl)ethyl)propanamido)methyl)-2- methoxybenzoate prepared as described in example 7 (41 g of solution containing 14.23 g, 23.12 mmol), isopropanol (80 ml.) was added at 25 °C under stirring. The resulting solution was heated under stirring to 70 °C, then a 10 % w/w solution of sodium hydroxide in water (12.50 g, 34.68 mmol) was added. The reaction mixture was maintained under stirring at the same temperature until complete conversion was achieved (about 3 hours) then it was cooled to 25 °C and maintained at this temperature for additional 3 hours. The resulting solid was filtered, washed with isopropanol and dried under reduced pressure at 40 °C so as to obtain 12.40 g of the desired compound.
The attained product was analysed by XRPD, obtaining the diffractogram shown in Figure 4. Example 9
Preparation of eluxadoline hydrochloride salt, i.e. the hydrochloride salt of a compound of formula (9) wherein n is 2, R1 and R7 are methyl, R5 and R10 are H, R6 is methyl 2-methoxy- 5-(A3-methyl)benzoate and D is 2-(A3-ethyl)-4-phenyl-1 /-/-imidazole.
Figure imgf000037_0001
To a suspension of sodium 5-(((S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6- dimethylphenyl)-/V-((S)-1 -(4-phenyl-1 /-/-imidazol-2-yl)ethyl)propanamido)methyl)-2- methoxybenzoate prepared as described in example 8 (12.40 g, 17.92 mmol) in acetonitrile (75 ml.) hydrochloric acid (12N, 18.37 g, 186.40 mmol) was added at 25 °C under stirring. The resulting mixture was maintained under stirring at the same temperature until complete conversion was achieved (about 3 hours) then it was cooled to -15 °C and maintained at this temperature for additional 3 hours. The resulting solid was filtered, washed with acetonitrile, dried under reduced pressure at 40 °C thus affording 13.91 g of a solid which was analysed by XRPD yielding the diffractogram shown in Figure 5 and a chloride content - as per argentometric titration - of 18.5% w/w.
Then it was suspended in isopropanol (52 ml.) and water (52 ml.) and maintained under stirring at 25 °C until a solution is achieved. A 10% w/w solution of sodium hydroxide in water (7.99 g, 19.96 mmol) was added thereto monitoring that internal temperature did not exceed 30 °C. The resulting solution is concentrated under reduced pressure up to achieve a residual volume of 45 ml_. The resulting residue was co-evaporated with isopropanol in order to remove most of the water, then isopropanol (130 ml.) was added. The so-obtained mixture was maintained under stirring at 45 °C for about 1 hour then cooled to 20 °C and maintained under stirring for additional 2 hours. The resulting solid was filtered, washed with isopropanol and dried under reduced pressure at 40 °C so as to obtain 1 1 ,80 g of the desired compound with a chloride content - as per argentometric titration - of 15.3% w/w.
The attained product was analysed by XRPD, obtaining the diffractogram shown in Figure 6.
Example 10
Preparation of methyl (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6- dimethylphenyl)propanoate, compound of formula (5) wherein n is 2, R1 and R2 are methyl, R5 and R10 are H, and Pg is tert- butyloxycarbonyl.
This example is representative of operations e.1 ) and e.2) of the process of the invention.
Figure imgf000038_0001
The oily residue prepared as described in example 1 (6.0 mmol theoretical) was dissolved in L/,/V-dimethyl formamide (56 ml_). /V-formylsaccarin (1.90 g, 9.0 mmol), Xantphos (0.16 g, 0.3 mmol), potassium fluoride (8.70 g, 15.0 mmol), and palladium (II) acetate (0.04 g, 0.2 mmol) were added. The resulting mixture was subjected to 3 cycles of vacuum/nitrogen, then maintained under stirring at 80-85 °C until complete conversion (about 16 hours). The reaction was cooled to 20-25 °C and subjected to 3 cycles of vacuum/nitrogen (in order to remove the formed carbon monoxide) then it was further cooled to 0-5 °C and potassium phosphate (2.80 g, 13.2 mmol) and ammonium acetate (0.70 g, 9.0 mmol) were added thereto. When the conversion was complete, water (168 ml.) and isopropyl acetate (8.5 ml.) were added to the mixture maintaining the internal temperature below 10 °C. The mixture was heated to 25 °C, then filtered on a pad of celite and charcoal. A 15% (w/w) aqueous solution of sodium chloride (25 g) was added to the filtrate then the phases were separated. The aqueous phase was extracted with isopropyl acetate, then a 0.2% (w/w) aqueous solution of potassium hydrogen carbonate was added to the collected organic phases previously heated to 45 °C. After having separated the resulting layers, the organic phase is concentrated under reduced pressure so as to obtain an oily residue (2.85 g, quantitative yield).
An aliquot of the residue was crystallized from acetone or from 2-propanol and analysed by XRPD, giving rise to diffractograms corresponding to that obtained in example 2.
Example 11
Preparation of potassium (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6- dimethylphenyl)propanoate, compound of formula (6) wherein n is 2, R1 is methyl, R5 and R10 are H, and Pg is tert- butyloxycarbonyl.
This example is representative of operation g’) of the process of the invention.
Figure imgf000038_0002
Potassium hydrogen carbonate (1.49 g, 14.90 mmol) was added to a suspension of (S)- 2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)propanoic acid (5.00 g, 14.86 mmol) in 2-propanol (50 ml_). The resulting mixture was maintained under stirring under reflux conditions until complete conversion (about 4 hours). The mixture was then allowed to cool down to 25 °C and maintained under stirring at the same temperature for 30 minutes. The solid was filtered by means of a Buchner funnel and washed with 2-propanol. The wet cake was oven-dried at 45 - 50 °C under reduced pressure until constant weight, thus giving 5.40 g of the title salt.
Example 12
Preparation of diethylamine salt (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6- dimethylphenyl)propanoate, compound of formula (6) wherein n is 2, R1 is methyl, R5 and R10 are H, and Pg is tert- butyloxycarbonyl.
This example is representative of operation g’) of the process of the invention.
Figure imgf000039_0001
Diethylamine (2.20 g, 30.00 mmol) was added to a suspension of ( S)-2-((tert - butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)propanoic acid (9.00 g, 26.75 mmol) in acetone (45 ml.) at 20-25 °C. The resulting mixture was maintained under stirring at the same temperature until abundant precipitation (at least 1 hour). The mixture was then heated to reflux and maintained under stirring at the same temperature for at least 2 hours. The resulting suspension was cooled to 20-25 °C in 3 hours and maintained under stirring at the same temperature for 1 additional hour. The solid was filtered by means of a Buchner funnel and washed with acetone. The wet cake was oven-dried at 45 - 50 °C under reduced pressure until constant weight, thus giving 10.50 g of the title salt.
A portion of the product was analysed by XRPD, obtaining the diffractogram shown in Figure 8.
Example 13
Preparation of (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6- dimethylphenyl)propanoate, compound of formula (6) wherein n is 2, R1 is methyl, R5 and R10 are H, and Pg is tert- butyloxycarbonyl.
This example is representative of operation g”) of the process of the invention.
Figure imgf000039_0002
A solution of the diethylamine salt of (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl- 2,6-dimethylphenyl)propanoic acid, prepared according to example 12 (10.50 g, 26.75 mmol), in water (52 ml.) was slowly added (in about 1 hour) at 20-25 °C to a solution of formic acid 95-97% (1.60 g, 34.78 mmol) in water (21 ml_). The resulting mixture was maintained under stirring at the same temperature until abundant precipitation (at least 2 hours). The solid was filtered by means of a Buchner funnel and washed with water. The wet cake was oven-dried at 45 - 50 °C under reduced pressure until a residual moisture content (determined by Karl Fischer titration) lower than 0.5% (w/w), thus giving 8.9 g of the title compound.
A portion of the product was analysed by XRPD, obtaining the diffractogram shown in Figure 9.
Comparative Example 1
Preparation of methyl 5-(((S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6- dimethylphenyl)-/V-((S)-1-(4-phenyl-1 /-/-imidazol-2-yl)ethyl)propanamido)methyl)-2- methoxybenzoate, compound of formula (7) wherein n is 2, R1 and R7 are methyl, R5 and R10 are H, R6 is methyl 2-methoxy-5-(A3-methyl)benzoate, D is 2-(A3-ethyl)-4-phenyl-1 /-/-imidazole and Pg is tert- butyloxycarbonyl.
This procedure is considered a fair representation of the procedure described in Bioorganic & Medicinal Chemistry Letters 2012, vol. 22, no. 14, pages 4869-4872 or in WO 2017/191650 A1 modified so as to include use of T3P, according to Organic Letters 2011 , vol. 13, no. 19, pages 5048-5051.
Figure imgf000040_0001
To the solution of methyl (S)-2-methoxy-5-(((1-(4-phenyl-1 H-imidazol-2- yl)ethyl)amino)methyl)benzoate in ethyl acetate prepared as described in example 5 or 6 (33 g of the solution containing 8.45 g, 23.12 mmol of (S)-2-methoxy-5-(((1-(4-phenyl-1 H-imidazol- 2-yl)ethyl)amino)methyl)benzoate in ethyl acetate), (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4- carbamoyl-2,6-dimethylphenyl)propanoic acid prepared as described in example 3 (7.00 g, 20.81 mmol), ethyl acetate (64 mL) and subsequently triethylamine (7.95 g, 78.60 mmol) were added at 25 °C under stirring. A 50% w/w solution of T3P in ethyl acetate (22.07 g, 34.68 mmol) added to the mixture monitoring that the internal temperature did not exceed 30 °C. The mixture was maintained under stirring at 25 °C until complete conversion was achieved (about 1 hour) then water (34 mL). The resulting phases were maintained under stirring at 25 °C for
1 hour then separated. The organic layer was washed with water and the combined organic phases concentrated under reduced pressure up to achieve a residual volume of 20 mL. The resulting residue was co-evaporated with isopropanol in order to remove residual ethyl acetate. A portion of the product was subjected to HPLC analysis, giving rise to the results reported below:
Figure imgf000041_0002
Comparative Example 2
Preparation of methyl 5-(((S)-2-((fe/f-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6- dimethylphenyl)-/V-((S)-1-(4-phenyl-1 /-/-imidazol-2-yl)ethyl)propanamido)methyl)-2- methoxybenzoate, compound of formula (7) wherein n is 2, R1 and R7 are methyl, R5 and R10 are H, R6 is methyl 2-methoxy-5-(A3-methyl)benzoate, D is 2-(A3-ethyl)-4-phenyl-1 /-/-imidazole and Pg is tert- butyloxycarbonyl.
This procedure is considered a fair representation of the procedure described in Bioorganic & Medicinal Chemistry Letters 2012, vol. 22, no. 14, pages 4869-4872 or in WO 2017/191650 A1 modified so as to include use of T3P and of a temperature of 0 °C, according to Organic Letters 2011 , vol. 13, no. 19, pages 5048-5051.
Figure imgf000041_0001
To the solution of methyl (S)-2-methoxy-5-(((1-(4-phenyl-1 H-imidazol-2- yl)ethyl)amino)methyl)benzoate in ethyl acetate prepared as described in example 5 or 6 (33 g of the solution containing 8.45 g, 23.12 mmol of (S)-2-methoxy-5-(((1-(4-phenyl-1 H-imidazol- 2-yl)ethyl)amino)methyl)benzoate in ethyl acetate), (S)-2-((fe/f-butoxycarbonyl)amino)-3-(4- carbamoyl-2,6-dimethylphenyl)propanoic acid prepared as described in example 3 (7.00 g, 20.81 mmol), ethyl acetate (64 mL) and subsequently triethylamine (7.95 g, 78.60 mmol) were added at 25 °C under stirring. The resulting mixture was cooled to 0 °C and a 50% w/w solution of T3P in ethyl acetate (22.07 g, 34.68 mmol) added thereto monitoring that the internal temperature did not exceed 5 °C. The mixture was maintained under stirring at 0 °C until complete conversion was achieved (about 1 hour) then water (34 mL). The resulting phases were heated to 25 °C, maintained under stirring at this temperature for 1 hour then separated. The organic layer was washed with water and the combined organic phases concentrated under reduced pressure up to achieve a residual volume of 20 mL. The resulting residue was co-evaporated with isopropanol in order to remove residual ethyl acetate. A portion of the product was subjected to HPLC analysis, giving rise to the results reported below:
Figure imgf000042_0001

Claims

1. Process for the preparation of a mixed pOR agonist/60R antagonist (9) or a salt thereof:
Figure imgf000043_0001
said process comprising the following operations:
a) providing a protected alanine derivative of formula (6) or a salt thereof:
Figure imgf000043_0002
b) reacting the protected alanine derivative of formula (6) or a salt thereof with an amine of formula (8) or a salt thereof in the presence of 1-propanephosphonic anhydride (T3P) at a temperature lower than 0 °C so as to provide a protected amide (7) or a salt thereof:
Figure imgf000043_0003
c) converting the protected amide (7) or the salt thereof into a mixed pOR agonist/60R antagonist (9) or a salt thereof:
Figure imgf000043_0004
wherein:
- n is 1 , 2, 3 or 4;
- each R1 is independently selected from (C1-C6)alkyl, (C1-C6)alkoxy and fluoro;
- R5 and R10 are independently selected from hydrogen and (C1-C4)alkyl; alternatively, R5 and R10 taken together with the nitrogen atom to which they are bound form a five to seven membered heterocyclic radical;
- Pg is a nitrogen protecting group;
- R6 is selected from hydrogen, (C1 -C6)alkyl, (C3-C8)cycloalkyl, aryl(C1 -C6)alkyl- and heteroaryl(C1 -C6)alkyl-, wherein the aryl and the heteroaryl group can be further substituted with at least one group selected from the group consisting of OH, CN, NO2, CO2H, halogen, (C1 -C6)alkyl, (C1 -C6)alkoxy-, and (C1 -C6)alkoxycarbonyl-;
- R7 is C1 -C4 alkyl;
Figure imgf000044_0001
- p is 0, 1 or 2;
- R8 is selected from hydrogen and (C1 -C4)alkyl; and
- R9 is selected from (C1 -C6)alkyl, aryl, aryl(C1 -C6)alkyl-, aryl(C2-C6)alkenyl-, aryl(C2- C6)alkynyl-, heteroaryl, heteroaryl(C1 -C6)alkyl-, heteroaryl(C2-C6)alkenyl-, heteroaryl(C2-C6)alkynyl-, amino, (C1 -C6)alkylamino-, (C1 -C6)2-alkylamino-, arylamino-, heteroarylamino-, aryloxy-, heteroaryloxy-, trifluoromethyl and halogen.
2. Process according to claim 1 , in which step b) is carried out at a temperature of or lower than -5 °C.
3. Process according to any one of claims 1 and 2, in which step b) is carried out at a temperature of or lower than -10 °C.
4. Process according to any one of claims 1 to 3, in which step b) is carried out at a temperature of or higher than -40 °C.
5. Process according to any one of claims 1 to 4, in which step b) is carried out at a temperature of or higher than -30 °C.
6. Process according to any one of claims 1 to 5, in which step b) is carried out at a temperature of or higher than -25 °C.
7. Process according to any one of claims 1 to 6, in which step b) is carried out at a temperature of or higher than -20 °C.
8. Process according to any one of claims 1 to 7, in which step b) is carried out at a temperature of or higher than -15 °C.
9. Process according to any one of claims 1 to 8, in which, in step b), the protected alanine derivative of formula (6) or the salt thereof is reacted with an amine of formula (8’) or a salt thereof:
Figure imgf000045_0001
10. Process according to any one of claims 1 to 8, in which, in step b), the protected alanine derivative of formula (6) or the salt thereof is reacted with an amine of formula (8”) or a salt thereof:
Figure imgf000045_0002
1 1 . Process according to any one of claims 1 to 8, in which, in step b), the protected alanine derivative of formula (6) or the salt thereof is reacted with an amine of formula (8’”) or a salt thereof:
Figure imgf000045_0003
12. Process according to any one of claims 1 to 8, in which, in step b), the protected alanine derivative of formula (6) or the salt thereof is reacted with an amine of formula (8A’) or a salt thereof:
Figure imgf000045_0004
13. Process according to any one of claims 1 to 8, in which, in step b), the protected alanine derivative of formula (6) or the salt thereof is reacted with an amine of formula (8A) or (8B) so as to provide a protected amide of formula (7C), (7D) respectively, or a salt of any one of them:
Figure imgf000045_0005
Figure imgf000046_0001
14. Process according to claim 13, comprising a subsequent step b’) in which the protected amide of formula (7C) or (7D) or the salt thereof is converted into a protected amide of formula (7E) or (7F) respectively, or a salt thereof:
Figure imgf000046_0002
15. Process according to any one of claims 13 and 14, in which, in step c), the protected amide of formula (7C), (7D), (7E) or (7F) or the salt thereof is converted into a mixed pOR agonist/60R antagonist of formula (9A), (9B), (9E) or (9F) respectively, or a salt of any one of them:
Figure imgf000046_0003
Figure imgf000047_0001
16. Process according to any one of claims 1 to 15, in which step b) is carried out in the presence of a base, said base being other than the amine of formula (8), (8’), (8”), (8’”), (8A’), (8A) or (8B).
17. Process according to claim 16, in which the base is an aliphatic tertiary amine.
18. Process according to any one of claims 16 and 17, in which the base is cyclic or acyclic.
19. Process according to any one of claims 16 to 18, in which the base is selected from the group consisting of triethylamine, /V,/V-diisopropylethylamine, N,N- diisopropylmethylamine, /V-methylpyrrolidine, /V-methylmorpholine, N,N- dicyclohexylmethylamine, L/,/V-diethylaniline, 2,2,6,6-tetramethylpiperidine and N- ethylmorpholine.
20. Process according to any one of claims 1 to 19, in which, in step a), it is provided a protected alanine derivative of formula (6A) or (6B):
Figure imgf000047_0002
21 . Process according to claim 20, in which the protected alanine derivative of formula (6A) or (6B) are prepared starting from a salt thereof.
22. Process according to any one of claims 21 and 22, in which the protected alanine derivative of formula (6A) or (6B) are prepared starting from a salt thereof with sodium, potassium, benzylamine, tributylamine, triethylamine or diethylamine.
23. Process according to any one of claims 1 to 22, in which, in step b), 1 - propanephosphonic anhydride (T3P) is used in a stoichiometry from 100 to 200 mol% compared to the molar quantity of the protected alanine derivative of formula (6), (6A) or (6B).
24. Process according to any one of claims 16 to 23, in which, in step b), the base is used in a stoichiometry from 200 to 600 mol%, compared to the molar quantity of the protected alanine derivative of formula (6), (6A) or (6B).
25. Process according to any one of claims 1 to 19 and 23 to 24, in which the protected alanine derivative of formula (6) or the salt thereof is prepared according to the following steps:
d) providing a protected phenyl propanoate of formula (2):
Figure imgf000048_0001
e) subjecting the protected phenyl propanoate of formula (2) to a metal-catalysed carbonylation by treatment with gaseous CO or at least one CO surrogate in the presence of a transition metal-comprising catalytic system and, subsequently or concurrently, with at least one nucleophile:
1) gaseous CO or CO surrogate
2) Nucleophile
Figure imgf000048_0002
Figure imgf000048_0003
f) optionally, when in the phenyl propanoate of formula (4) R4 is different from R10R5N, converting said phenyl propanoate of formula (4) into a protected carbamoyl phenyl propanoate of formula (5) by treatment with an amine of formula R10-NH-R5:
Figure imgf000048_0004
g) converting the protected carbamoyl phenyl propanoate of formula (5) into the protected alanine derivative of formula (6) or a salt thereof:
Figure imgf000048_0005
wherein the substituents assume the meanings reported above and
- R2 is selected from (C1-C4)alkyl;
- R3 is a leaving group able to undergo a nucleophilic aromatic substitution; and
- R4 is halogen, (C1-C6)alkoxy-, hydroxy, amino, (C1-C4)alkylamino-, (C1-C4)2- alkylamino-.
26. Process according to any one of claims 1 to 25, in which, in the compounds of formula (2), (4), (5), (6), (7) and (9) n is 2.
27. Process according to any one of claims 25 and 26, in which operation e) includes: e.1 ) subjecting the protected phenyl propanoate of formula (2) to a metal-catalysed carbonylation by treatment with gaseous CO or at least one CO surrogate in the presence of a transition metal-comprising catalytic system; and
e.2) converting the resulting oxidative insertion adduct into a phenyl propanoate of formula (4) by treatment with at least one nucleophile;
said steps e.1 ) and e.2) being carried out subsequently or concurrently.
28. Process according to any one of claims 25 and 27, in which, in step e) or e.1 ), the transition metal-comprising catalytic system comprises ruthenium, rhodium, iridium, nickel, platinum or palladium.
29. Process according to any one of claims 25 to 28, in which, in step e) or e.1 ), the transition metal-comprising catalytic system has oxidation state 0 (zero) or II (two).
30. Process according to any one of claims 25 to 29, in which, in step e) or e.1 ), the transition metal-comprising catalytic system comprises a mono- or a bi-dentate ligand.
31 . Process according to claim 30, in which the mono- or bi-dentate ligand is selected from the group consisting of triphenyl phosphine (PPI73), tri(o-tolyl)phosphine (P(o-tol)s), 1 ,1 - bis(diphenylphosphino)methane (DPPM), 1 ,1 '-bis(diphenylphosphino)ferrocene (DPPF), 1 ,2-bis(diphenylphosphino)ethane (DPPE), 1 ,3- bis(diphenylphosphino)propane (DPPP), 1 ,4-bis(diphenylphosphino)butane (DPPB), 1 ,2-bis(diphenylphosphino)benzene (DPPBz), racemic-2,2'-bis(diphenylphosphino)- 1 ,1 '-binaphthyl (rac-BINAP), tri-fe/f-butylphosphonium tetrafluoroborate (P(f- Bu)3*HBF4), (oxydi-2,1 -phenylene)bis(diphenylphosphine) (DPEphos), and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos).
32. Process according to any one of claims 25 to 31 , in which, in step e) or e.1 ), the at least one CO surrogate is selected from the group consisting of phenyl formates and N- formylsaccharin.
33. Process according to any one of claims 25 to 32, in which, in step e) or e.1 ), the metal- catalysed carbonylation is carried out in the presence of at least one base.
34. Process according to claim 33 in which the base is an inorganic base.
35. Process according to any one of claims 25 to 31 and 33 to 35 in which, in step e) or e.1 ), the pressure of gaseous CO is in the range of 1 (100000 Pa) to 20 bar (2000000 Pa).
36. Process according to any one of claims 25 to 35, in which the nucleophile used in step e) or e.2) is selected from the group consisting of halide ions, oxygen nucleophiles, and nitrogen nucleophiles.
37. Process according to claim 36, in which the halide ions are selected from the group consisting of fluorides (F ), chlorides (Cl ), bromides (Br) and iodides (l ).
38. Process according to claim 36, in which the oxygen nucleophiles are selected from the group consisting of hydroxide anions, alcohols and alkoxide anions.
39. Process according to claim 36, in which the nitrogen nucleophiles are selected from the group consisting of ammonia, ammonium salts, amines, amides and an amine of formula R10-NH-R5.
40. Process according to any one of claims 25 to 39 in which the phenyl propanoate of formula (4) resulting from step e) or e.2) is crystallized from an organic solvent and subsequently subjected to optional step f) or to step g).
41 . Process according to claim 40 in which said organic solvent is a nitrile.
42. Process according to any one of claims 25 to 41 further comprising a step g’), carried out after step g), said step g’) comprising converting a protected alanine derivative of formula (6), (6A) or (6B) into a salt thereof.
43. Process according to claim 42, in which the protected alanine derivative of formula (6), (6A) or (6B) is converted into a salt thereof with sodium, potassium, benzylamine, tributylamine, triethylamine or diethylamine.
44. Process according to any one of claims 42 and 43 comprising a step g”), carried out after step g’), said step g”) comprising converting the salt of the protected alanine derivative of formula (6), (6A) or (6B) into the corresponding acid.
45. Process according to any one of claims 25 to 44, in which optional step f) is carried out in the presence of a base able to ensure that the pH of mixture formed in this step is at maximum 10.
46. Process according to any one of claims 25 to 45, in which optional step f) is carried out in the presence of a base able to ensure that the pH of mixture formed in this step is from 7 to 9.
47. Process according to any one of claims 25 to 46, in which optional step f) is carried out in the presence of a base able to ensure that the pH of mixture formed in this step is from 7 to 8.
48. Process according to any one of claims 45 to 47, in which said base is selected from the group consisting of potassium phosphate (i.e. K3PO4) or potassium phosphate dibasic (i.e. K2HPO4).
49. Crystalline form of a protected carbamoyl phenyl propanoate of formula (5B):
Figure imgf000051_0001
in which R5 and R10 are hydrogen, R2 is methyl and Pg is fe/f-butyloxycarbonyl, having an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by main peaks at:
i. 5.92°, 1 1.80°, 21 .08°, 21.48° and 23.76° ± 0.2° 2Q; or
ii. 5.92°, 1 1.80°, 19.52°, 21.08°, 21 .48° and 23.76° ± 0.2° 20.
50. Crystalline form of a protected alanine derivative of formula (6B):
Figure imgf000051_0002
in which R5 and R10 are hydrogen and Pg is fe/f-butyloxycarbonyl, having an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by main peaks at:
iii. 14.60°, 15.92°, 18.20°, 20.56° and 25.48° ± 0.2° 20; or
iv. 10.80°, 14.60°, 15.92°, 18.20°, 20.56° and 25.48° ± 0.2° 20.
51 . Crystalline hydrochloride salt of eluxadoline, said salt showing an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1 .5406 A), is characterized by main peaks at:
v. 8.88°, 10.68°, 13.24°, 21 .44° and 31.84° ± 0.2° 20; or
vi. 7.00°, 8.88°, 10.68°, 13.24°, 17.72°, 21 .44°, 26.40° and 31 .84° ± 0.2° 20.
52. Crystalline hydrochloride salt according to claim 49 containing an amount of chloride, as determined by argentometric titration, from 18 to 19% w/w.
53. Crystalline hydrochloride salt of eluxadoline, said salt showing an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1 .5406 A), is characterized by main peaks at:
vii. 17.28°, 19.72°, 26.28°, 29.60° and 31 .72° ± 0.2° 20; or
viii. 17.28°, 19.72°, 21 .08°, 23.68°, 26.28°, 27.04°, 29.60°, and 31 .72° ± 0.2° 20.
54. Crystalline hydrochloride salt according to claim 51 containing an amount of chloride, as determined by argentometric titration, from 15 to 16% w/w.
55. Crystalline sodium salt of formula (7G):
Figure imgf000052_0003
in which R5 and R10 are hydrogen and Pg is tert- butyloxycarbonyl, which shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by main peaks at:
ix. 10.16°, 16.72°, 17.68°, and 23.16° ± 0.2° 20; or
x. 7.68°, 10.16°, 1 1 .96°, 16.72°, 17.68°, 19.96° and 23.16° ± 0.2° 20.
56. Crystalline protected carbamoyl phenyl propanoate of formula (5B):
Figure imgf000052_0001
in which R5 and R10 are hydrogen, R2 is methyl and Pg is fe/f-butyloxycarbonyl, which shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by main peaks at:
xi. 1 1 .48°, 20.76°, 22.28°, and 22.84° ± 0.2° 20; or
xii. 1 1 .48°, 18.12°, 19.40°, 20.76°, 22.28°, and 22.84° ± 0.2° 20.
57. Crystalline diethylamine salt of a protected alanine derivative of formula (6B):
Figure imgf000052_0002
in which R5 and R10 are hydrogen and Pg is fe/f-butyloxycarbonyl, which shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by main peaks at:
xiii. 8.32°, 13.16° and 21 .24° ± 0.2° 20; or
xiv. 8.32°, 1 1 .84°, 13.16°, 15.44°, 18.16° and 21 .24° ± 0.2° 20 ± 0.2° 20.
58. Crystalline protected alanine derivative of formula (6B):
Figure imgf000053_0001
in which R5 and R10 are hydrogen and Pg is tert- butyloxycarbonyl, which shows an X-ray powder diffraction pattern that, when collected with the Ka radiation of copper (l = 1.5406 A), is characterized by main peaks at:
xv. 16.12°, 20.72° and 25.56° ± 0.2° 20; or
xvi. 16.12°, 17.96°, 20.72°, 21 .96° and 25.56° ± 0.2° 20 ± 0.2° 20.
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