WO2017021270A1

WO2017021270A1 - Process for the synthesis of ravidasvir

Info

Publication number: WO2017021270A1
Application number: PCT/EP2016/068019
Authority: WO
Inventors: Graziano Castaldi; Alessandro BARUTO; Erminio Oldani; Mauro Gaboardi
Original assignee: Hc-Pharma AG
Current assignee: Hc-Pharma AG
Priority date: 2015-08-03
Filing date: 2016-07-28
Publication date: 2017-02-09
Anticipated expiration: 2018-02-03
Also published as: ITUB20152784A1; RU2018107689A; EP3331874A1; RU2018107689A3; CN108349950A; MX2018001296A

Abstract

A process for the synthesis of ravidasvir and intermediates useful in the preparation thereof are disclosed.

Description

"PROCESS FOR THE SYNTHESIS OF RAVIDASVIR"

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DESCRIPTION

The present invention relates to a process for the synthesis of ravidasvir and intermediates useful in the preparation thereof.

Hepatitis C is an infectious disease caused by Hepatitis C virus (HCV), which affects first of all the liver. The infection is often asymptomatic, but its chronicity can lead to cicatrization of the liver and at the end to cirrhosis, which generally results evident after many years. In some cases liver cirrhosis may develop in liver failure, liver cancer, esophageal and gastric varices. HCV is primarily transmitted by direct contact with infected blood, often due to the use of intravenous drugs, not sterilized medical devices and blood transfusions.

Hepatitis C virus leads to a chronic infection in 50-80% of people who contract it, of whom about 40-80% is treated. In general, drug treatment is recommended for patients with hepatic changes caused by the virus; the reference treatment is a combination of pegylated interferon-a and ribavirin, to be taken over a period of 24 or 48 weeks, depending on the genotype of the HCV virus. It is noted that this therapy leads to improvements in 50-60% of the cases. In the phenotypes which are more difficult to be treated, these two drugs are supported by boceprevir and telaprevir, bringing the healing rate from 40% to 70%. The side effects of the treatment are frequent, half of the patients feel flu-like symptoms, and a third of the patients has emotional problems. Moreover, the treatment carried out during the first six months is more effective than when hepatitis C becomes chronic.

Ravidasvir, a drug useful in the treatment of hepatis C, is the compound of formula (I)

disclosed in WO 201 1/149856 (Presidio Pharmaceuticals Inc.). WO 201 1/149856 discloses the following processes for the synthesis of ravidasvir, reported in the schemes 1 , 2, 3 and 4:

Scheme 1

RAVIDASVIR

Scheme 2

RAVIDASVIR

30 Scheme 4

The processes disclosed above are however difficult to apply on macro scale and/or at industrial level, mainly because of the low selectivity, yields and formation of byproducts difficult to be removed by conventional purification techniques.

We have now found a process for the preparation of ravidasvir that overcomes the drawbacks reported above and that can be applied to the preparation of ravidasvir at industrial level.

It is object of the present invention a process for the synthesis of ravidasvir comprising the reaction of the compound of formula (II)

(II)

X

wherein X is a halogen atom, preferably bromine, or a boronic group of formula - BO2 1 wherein Ri is a pinacolic or glycolic group, preferably a pinacolic group; with a compound of formula (III)

wherein Y is a halogen atom, preferably bromine, or a -OSO2R2 group, wherein R2 is a straight or branched Cns alkyl group, an optionally substituted aryl group, a -CF3 group or a halogen atom, preferably a -CF3 group, or Y is a boronic group of formula -BO2R1 wherein Ri is a pinacolic or glycolic group, preferably a pinacolic group.

The process object of the present invention is carried out in the presence of a suitable palladium catalyst, preferably selected among tetrakis(triphenylphosphine)palladium(0) and [1 ,1 '-bis(diphenylphosphino)ferrocene]- dichloropalladium(ll) complexed with methylene chloride (Pd(dppf)Cl2.CH2Cl2), in the presence of a suitable base selected among potassium phosphate, potassium carbonate, sodium phosphate, sodium carbonate, in a solvent selected among tetrahydrofuran, acetonitrile, dioxane, methanol, isopropanol, toluene, N,N- dimethylformamide, optionally in the presence of water.

Preferably, the process of the present invention is carried out with [1 ,1 - bis(diphenylphosphino)ferrocene]-dichloropalladium(ll) complexed with methylene chloride (Pd(dppf)Cl2.CH2Cl2), in the presence of sodium carbonate in dioxane. The compounds of formula (II) are known or can be prepared with known methods, for example as disclosed in WO201 1/149856. Alternatively, the compound of formula (II) wherein X is bromide or a boronic group can be prepared according to a process which is a further object of the present invention, comprising:

a) the reaction of the

with 4-bromo-1 ,2-diaminobenzene in the presence of a suitable condensing agent to give the compound of formula (V)

b) the reaction of the compound of formula (V) with an organic acid in a polar aprotic solvent to give the compound of formula (II), wherein X is bromine; c) the optional reaction of the resultant compound of formula (II) with a boro reagent, in the presence of a suitable catalyst, of a binding agent and of a base, to give a compound of formula (II), wherein X is a boronic group of formula -BO2 1 wherein Ri is a pinacolic o glycolic group, preferably a pinacolic group.

In step a) the condensing agent is selected among 2,4,6-tri-n-propyl-2,4,6-trioxo- 1 ,3,5,2,4,6-trioxa-triphosphorinane (T3P), dicyclohexylcarbodiimide (DCC), N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCI), preferably N- (3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride.

The solvent is an apolar solvent, selected among methylene chloride, hexane, toluene, or aprotic polar selected among tetrahydrofuran, ethyl acetate, acetonitrile, Ν,Ν-dimethylformamide, preferably tetrahydrofuran.

In step b) the organic acid is selected among acetic, tartaric, butyric and formic acid, preferably acetic acid.

The solvent is selected among tetrahydrofuran, methylene chloride, ethyl acetate, toluene, tetrahydrofuran, isopropanol, methanol, acetonitrile, methyl-tertbutylether, preferably ethyl acetate.

The intermediate of formula (V) can be isolated or directlly converted into the compound of formula (II) through an one-pot process.

The intermediate of formula (V) is new and is a further object of the present invention.

In step c), the boro reagent is selected among diboronic bis-pinacolate and bis(neopentylglycolate)diboronic, preferably diboronic bis-pinacolate.

The catalyst is a palladium catalyst preferably selected among [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (Pd(dppf)Cl2), palladium acetate, palladium chloride, preferably palladium acetate.

The binding agent is selected among triphenylphosphine, 4,5- bis(diphenylphosphino)-9,9-dimethylxantene (xantphos), 2,2 - bis(diphenylphosphino)-1 ,1 ^'— binaftyl (BINAP), preferably triphenylphosphine.

The base is selected among potassium phosphate, potassium acetate, potassium carbonate, sodium phosphate, sodium carbonate, preferably potassium acetate.

The solvent is selected among tetrahydrofuran, acetonitrile, dioxane, methanol, isopropanol, toluene, Ν,Ν-dimethylformamide optionally in the presence of water. Preferably, a mixture of dioxane and water is used.

Also the compounds of formula (III) wherein Y is a halogen atom or a boronic group are known in the art or can be prepared with known methods, for example as disclosed in WO201 1/149856.

Alternatively, the compounds of formula (III) can be prepared according to a process which is a further object of the present invention, comprising:

d) the reaction of the compound of formula (VI)

with a sulfonated agent in the presence of a base and of a suitable solvent to give the compound of formula (VII)

O wherein Y is a -OSO2 2 group, wherein R2 is a straight or branched C1-18 alkyl group, an optionally substituted aryl group, a -CF3 group, a halogen atom, preferably a -CF3 group;

e) the reaction of the compound of formula (VII) with a brominating agent in a suitable solvent to give the compound of formula (VIII)

wherein Y has the above reported meanings;

f) the reaction of the compound of formula (VIII) with the compound of formula (IV)

in the presence of a base in a suitable solvent, to give a compound of formula (IX)

wherein Y has the above reported meanings;

g) the reaction of the compound of formula (IX) with ammonium acetate in a suitable solvent to give a compound of formula (III), wherein Y is a -OSO2R2 group, wherein R2 is a straight or branched Ci-ie alkyl group, an optionally substituted aryl group, a -CF3 group, a halogen atom, preferably a -CF3 group;

h) the optional reaction of the compound of formula (III), wherein Y is a

-OSO2R2 group, with a boro reagent, in the presence of a suitable catalyst, of a binding agent and of a base, to give a compound of formula (III) wherein Y is a boronic group of formula -BO2 1 wherein Ri is a pinacolic or glycolic group, preferably pinacolic group.

In step d) the sulfonated agent is selected among triflic anhydride, mesyl chloride, tosyl chloride, preferably triflic anhydride.

The base is a tertiary amine selected among triethylamine, tributylamine, diisopropylethylamine, preferably trimethylamine.

The solvent is selected among methylene chloride, tetrahydrofuran, acetonitrile, dioxane, toluene, Ν,Ν-dimethylformamide, preferably methylene chloride.

In step e), the brominating agent is selected among bromine, tetrabutylammonium tribromide, N-bromosuccinimide and N-bromophthalimide, preferably tetrabutylammonium tribromide.

The solvent is selected among methylene chloride, tetrahydrofuran, toluene, ethyl acetate, or mixtures thereof; preferably toluene is used.

In step f) the base is a tertiary amine selected among triethylamine, tributylamine, diisopropylethylamine, preferably trimethylamine.

The solvent is selected among methylene chloride, tetrahydrofuran, toluene, ethyl acetate, or mixtures thereof; preferably ethyl acetate is used.

In step g) the solvent used is selected among methylene chloride, tetrahydrofuran, toluene, ethyl acetate, or mixtures thereof; preferably toluene is used.

In step h), the catalyst is a palladium catalyst, selected among [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium(l l) ((Pd(dppf)CI2), palladium acetate, palladium chloride, preferably [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium(l l) (Pd(dppf)Cl2).

The solvent is selected among tetrahydrofuran, acetonitrile, dioxane, methanol, isopropanol, toluene, Ν,Ν-dimethylformamide optionally in the presence of water. Preferably a mixture of dioxane and water is used.

The compounds of formula formula (IX) and (I I I) wherein Y is a -OSO2R2 group, wherein R2 is a straight or branched CMS alkyl group, an optionally substituted aryl group, a -CF3 group, a halogen atom, preferably a -CF3 group, are novel and are a further object of the present invention.

Even if the invention have been disclosed with its characteristic embodiments, changes and equivalents which are evident to the skilled man fall within the scope of th e present invention.

The present invention is herein disclosed through some examples that cannot be considered as limiting the scope of the invention.

All the terms used in this patent application, except different indications, are to be intended in their common meaning, as known in the art.

Other more specific definitions of some terms, as used in this patent application, are shown more ahead and constantly apply to all the description and claims, unless a different definition explicitly provides a broader definition.

EXAMPLE 1

Synthesis of methyl (R)-1-((S)-2-(2-amino-4-bromophenylcarbamoyl)pyrrolidin-1-yl)- 3-methyl-1 -oxobutan-2-yl-carbamate.

In a reaction flask (S)-1-((R)-2-(metoxycarbonylamino)-3-methylbutanoyl)pyrrolidin- 2-carboxylic acid (100.00 g, 0.366 mol), 4-bromo-1 ,2-diaminobenzene (68.45 g, 0.366 mol), tetrahydrofuran (500.00 ml) were loaded; the temperature is brought to about 0°C and N-(3-dimethylaminopropyl)-N'-ethylcarbodimide hydrochloride (EDC.HCI, 73.61 g, 0.384 mol) was added. The temperature was brought to about 25°C and the reaction mixture maintained in these conditions for about one hour and a half. At the end of the reaction, the solvent was removed through vacuum distillation, ethyl acetate (600.00 ml) was added, the organic phase was washed with water (2x250.0 ml), a water solution saturated with sodium bicarbonate (1x300.00 ml) and a saturated sodium chloride solution (1x150.00 ml). The collected organic phases were reduced to residue through vacuum distillation to obtain 153.45 g of methyl (R)-1 -((S)-2-(2-amino-4-bromophenylcarbamoyl)pyrrolidin-1-yl)-3- methyl-1-oxobutan-2-yl-carbamate.

1 H-NMR (DMSO, 300 MHz): δ 9.33 (s, 1 H), 7.34 (d, 1 H), 6.98 (d, 1 H), 6.87 (s, 1 H), 6.64 (d, 1 H), 5.19 (s, 2H), 4.40 (t, 1 H), 3.81 (t, 1 H), 3.50 (m, 5H), 2.15 (m, 1 H), 1.94 (m, 4H), 0.91 (d, 6H).

EXAMPLE 2

Synthesis of methyl (R)-1-((S)-2-(6-bromo-1 H-benzordlimidazol-2-yl)pyrrolidin-1 -yl)- 3-methyl-1 -oxobutan-2-yl-carbamate.

In a reaction flask methyl (R)-1-((S)-2-(2-amino-4-bromophenylcarbamoyl)pyrrolidin- 1-yl)-3-methyl-1-oxobutan-2-yl-carbamate (153.45 g, 0.347 mol), ethyl acetate (850.00 ml), acetic acid (45.05 g, 0.750 mol) were added. The temperature was brought to the reflux temperature of the solvent and the mixture was maintained in these conditions for about two hours. At the end of the reaction, the temperature was brought to about 25°C, water (250.00 ml), sodium bicarbonate (100.00 g) were added and the organic phase washed with water (1 x200.00 ml) and a with saturated sodium chloride solution (1 x250.00 ml). The collected organic phases were reduced to residue through vacuum distillation and methyl-terbutylether (300.00 ml) was added. The mixture was dripped in heptane (1300.00 ml) and the formed solid was filtered, washed with the mixture of heptane and methyl - terbutylether (250.00 ml) and the solvent evaporated through vacuum distillation, to obtain 12.49 g of methyl (R)-1-((S)-2-(6-bromo-1 H-benzo[d]imidazol-2-yl)pyrrolidin-1 -yl)-3-methyl-1- oxobutan-2-yl-carbamate.

1 H-NMR (DMSO, 300 MHz): δ 12.35 (s, 1 H), 7.69 (d, 1 H), 7.45 (s, 1 H), 7.31 (t, 2H), 5.16 (t, 1 H), 4.10 (d, 1 H), 3.85 (d, 2H), 3.54 (s, 3H), 2.22 (m, 1 H), 1 .98 (m, 4H), 0.83 (d, 6H).

EXAMPLE 3

Synthesis of methyl 3-methyl-1-oxo-1-(2-(6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-1 H-benzordlimidazol-2-yl)pyrrolidin-1-yl)butan-2-yl-carbamate.

In a reaction flask methyl (R)-1-((S)-2-(6-bromo-1 H-benzo[d]imidazol-2-yl)pyrrolidin- 1-yl)-3-methyl-1-oxobutan-2-yl-carbamate (100.00 g, 0.236 mol), diboronic bis- pinacolate (66.02 g, 0.260 mol), potassium acetate (46.33 g, 0.472 mol), triphenylphosphine (14.97 g, 0.057 mol), dioxane (500.00 ml), palladium acetate (4.26 g, 0.019 mol) were loaded. The temperature was brought to about 90°C and the reaction mixture was maintained in these conditions for about two hours and a half. At the end of the reaction, ethyl acetate (300.00 ml and water (100.00 ml) were added. The organic phase was washed with a water solution of sodium bicarbonate (1x100.00 ml), water (2x50.00 ml) and a saturated sodium chloride solution (1 x50.00 ml). The collected organic phases were reduced to residue through vacuum distillation to obtain 91.00 g of 3-methyl-1-oxo-1-(2-(6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-yl-carbamate. 1 H-NMR (DMSO, 300 MHz): δ 12.22 (s, 1 H), 7.76 (d, 1 H), 7.48 (m, 2H), 7.31 (d, 1 H), 5.16 (t, 1 H), 4.10 (d, 1 H), 3.85 (d, 2H), 3.54 (s, 3H), 2.22 (m, 1 H), 1.98 (m, 4H), 1.29 (s, 12H), 0.83 (d, 6H)

EXAMPLE 4

Synthesis of 6-acetylnaphtalen-2-yl trifluoromethanesulfonate.

In a reaction flask 1-(6-hydroxynaphtalen-2-yl)ethanone (100.00 g, 0.537 mol), triethylamine (65.20 g, 0.644 mol), methylene chloride (500.00 ml) were loaded. The temperature was brought to about 15°C, triflic anhydride (159.08 g, 0.564 mol) was added. The temperature was brought to about 25°C and the reaction mixture was maintained for about two hours. At the end of the reaction water (200.00 ml) was added, the organic phase was washed with a saturated sodium bicarbonate solution (1x200.00 ml), 2N hydrochloric acid (1x200.00 ml) and 2N sodium chloride (1x200.00 ml). The collected organic phases were reduced to residue through vacuum distillation to obtain 162.36 g of 6-acetylnaphtalen-2-yl trifluoromethanesulfonate.

1 H-NMR (CDCI3, 300 MHz): δ 8.45 (s, 1 H), 8.00 (q, 2H), 7.85 (d, 1 H), 7.77 (s, 1 H), 7.44 (d, 1 H), 2.73 (s, 3H).

EXAMPLE 5

Synthesis of 6-(2-bromoacetyl)naphtalen-2-yl trifluoromethanesulfonate.

In a reaction flask 6-acetylnaphtalen-2-yl trifluoromethanesulfonate (100.00 g, 0.314 mol), toluene (500.00 ml) were loaded; the temperature was brough to 20°C, tetrabutylammonium tribromide (166.59 g, 0.345 mol) was added and the reaction mixture was maintained in these conditions for about two hours.

At the end of the reaction, water (200.00 ml) was added. The organic phase was washed with water (3x200.00 ml) and with a saturated sodium chloride solution (1x200.00 ml). The collected organic phases were reduced to residue through vacuum distillation to obtain 1 18.45 g of 6-(2-bromoacetyl)naphtalen-2-yl trifluoromethanesulfonate.

1 H-NMR (CDCI3, 300 MHz): δ 8,52 (s, 1 H), 8,05 (q, 2H), 7,90 (d, 1 H), 7,80 (s, 1 H), 7,48 (d, 1 H), 4, 55 (t, 2H).

EXAMPLE 6

Synthesis of 2-oxo-2-(6-(trifluoromethylsulfonyloxy)naphtalen-2-yl)ethyl 2-(2- (methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-1 -carboxylate.

In a reaction flask 6-(2-bromoacetyl)naphtalen-2-yl trifluoromethanesulfonate (1 18.45 g, 0.298 mol), ethyl acetate (500.00 ml), (S)-1-((R)-2- (methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-carboxylic acid (85.82 g, 0.314 mol), triethylamine (96.42 ml, 0.690 mol) were loaded and the reaction mixture maintained under stirring for about sixteen hours. At the end of the reaction, water (200.00 ml) was added, the organic phase was washed with 2N hydrochloric acid (1 x100.00 ml), a saturated sodium bicarbonate solution (1x100.00 ml) and a saturated sodium chloride solution (1 x100.00 ml). The collected organic phases were reduced to residue through vacuum distillation to obtain 140.31 g of 2-oxo-2- (6-(trifluoromethysulfonyloxy)naphtalen-2-yl)ethyl 2-(methoxycarbonylamino)-3- methylbutanoyl)pyrrolidin-1 -carboxylate.

1 H-NMR (DMSO, 300 MHz): δ 8.80 (s, 1 H), 8.26 (m, 1 H), 8.14 (m, 1 H), 8.04 (m, 2H), 7.64 (d, 1 H), 7.40 (d, 1 H), 5.70 (dd, 2H), 4.55 (t, 1 H), 4.01 (t, 1 H), 3.80 (m, 2H), 3.49 (s, 3H), 2.18 (m, 2H), 2.00 (m, 3H), 0.93 (d, 6H).

EXAMPLE 7

Synthesis of 6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)- pyrrolidin-2-yl)-1 H-imidazol-5-yl)naphtalen-2-yl trifluoromethanesulfonate.

In a reaction flask 2-oxo-2-(6-(trifluoromethylsulfonyloxy)naphtalen-2-yl)ethyl 2-(2- (methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-1 -carboxylate (140.31 g, 0.238 mol), toluene (500.00 ml), ammonium acetate (72.60 g, 0.942 mol) were loaded; the temperature was brought to the reflux temperature of the solvent and the reaction mixture was maintained in these conditions for about two hours. At the end of the reaction, the mixture was washed with a saturated sodium bicarbonate solution (2x100,00 ml), the organic phase was washed with a solution of 2N phosphoric acid (2x157.00 ml), to extract the product in water phase. Ethyl acetate (200.00 ml), sodium carbonate (73.22 g) and a saturated sodium chloride solution (50.00 ml) were added. The organic phases were reduced to residue through vacuum distillation to obtain 106.35 g of 6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3- methylbutanoyl)-pyrrolidin-2-yl)-1 H-imidazol-5-yl)naphtalen-2-yl

trifluoromethanesulfonate.

1 H-NMR (DMSO, 300 MHz): δ 1 1.86 (s, 1 H), 8.24 (d, 2H), 7.28 (m, 3H), 7.64 (m, 2H), 5.12 (t, 1 H), 4.01 (t, 1 H), 3.80 (m, 2H), 3.49 (s, 3H), 2.18 (m, 2H), 2.00 (m, 3H), 0.93 (d, 6H).

EXAMPLE 8

Synthesis of methyl (SV3-methyl-1 -oxo-1 -((SV2-(5-(6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)naphtalen-2-yl)-1 H-imidazol-2-yl)pyrrolidin-1 -yl)butan-2-yl carbamate.

In a reaction flask 6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)- pyrrolidin-2-yl)-1 H-imidazol-5-yl)naphtalen-2-yl trifluoromethanesulfonate (10.00 g, 0.019 mol), diboronic bis-pinacolate (5.43 g, 0.021 mol), potassium acetate (3.73 g, 0.038 mol), dioxane (60.00 ml), [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (1.1 1 g, 0.0015 mol) were loaded. The temperature was brought to about 90°C and the reaction mixture was maintained in these conditions for about three hours. At the end of the reaction, the temperature was brought to about 25°C, ethyl acetate (50.00 ml) and water (30.00 ml) were added; the organic phase was washed with water (1 x20.00 ml), with a saturated sodium bicarbonate solution (1x25.00 ml) and the collected organic phases were reduced to residue through vacuum distillation to obtain 7.27 g of methyl (S)-3-methyl-1-oxo-1 -((S)-2-(5-(6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)naphtalen-2-yl)-1 H-imidazol-2-yl)pyrrolidin-1 -yl)butan-2-yl carbamate.

1 H-NMR (DMSO, 300 MHz): δ 1 1.86 (s, 1 H), 8.24 (d, 2H), 7.28 (m, 3H), 7.64 (m, 2H), 5.12 (t, 1 H), 4.01 (t, 1 H), 3.80 (m, 2H), 3.49 (s, 3H), 2.18 (m, 2H), 2.00 (m, 3H), 1.33 (s, 12H), 0.93 (d, 6H).

EXAMPLE 9

Synthesis of ravidasvir.

In a reaction flask methyl 3-methyl-1-oxo-1 -(2-(6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-benzo[d]imidazol-2-yl)-pyrrolidin-1-yl)butan-2-yl-carbamate (10.00 g, 0.021 mol), 6-(2-((S)-1-((S)-2-(methoxyicarbonylamino)-3- methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)naphtalen-2-yl

trifluoromethanesulfonate (12.09 g, 0.021 mol), sodium carbonate (6.67 g, 0.063 g), dioxane (100.00 ml), water (30.00 ml), palladium tetrakis (2.31 g, 0.002 mol) were loaded; the temperature was brought to about 70°C and the reaction mixture was maintained in these conditions for about two hours and a half. At the end of the reaction, the temperature was brought to about 25 °C, ethyl acetate (50.00 ml) and water (20.00 ml) were added; the organic phase was washed with water (1 x20.00 ml) and the collected organic phases were filtered, the solvent was removed through vacuum distillation to obtain 13.73 g of ravidasvir.

EXAMPLE 10

Synthesis of ravidasvir

In a reaction flask methyl (R)-1 -((S)-2-(6-bromo-1 H-benzo[d]imidazol-2-yl)pyrrolidin- 1-yl)-3-methyl-1-oxobutan-2-yl-carbamate (10.00 g, 0.024 mol), methyl (S)-3-methyl- 1-oxo-1 -((S)-2-(5-(6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphtalen-2-yl)-1 H- imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (12.91 g, 0.024 mol), sodium carbonate (5.09 g, 0.048 g), dioxane (60.00 ml), water (30.00 ml), palladium tetrakis (2.31 g, 0.002 mol) were loaded, the temperature was brought to about 70°C and th e reaction mixture maintained in these conditions for about two hours and a half. At the end of the reaction, the temperature was brought to about 25°C, ethyl acetate (50.00 ml) and water (20.00 ml) were added; the organic phase was washed with water (1x20.00 ml) and the collected organic phases filtered, the solvent was removed through vacuum distillation to obtain 10.00 g of ravidasvir.

Claims

1 ) A process for the synthesis of ravidasvir comprising the reaction of the compound of formula (II)

wherein X is a halogen atom, or a boronic group of formula

-BO2 I wherein Ri is a pinacolic or glycolic group;

with a compound of formul

wherein Y is a halogen atom, or a -OSO2R2 group, wherein R2 is a straight or branched CMS alkyl group, an optionally substituted aryl group, a -CF3 group or a halogen atom, or Y is a boronic group of formula -BO2R1 wherein Ri is a pinacolic or glycolic group;

in the presence of a suitable palladium catalyst, in the presence of a suitable base selected among potassium phosphate, potassium carbonate, sodium phosphate, sodium carbonate, in a solvent selected among tetrahydrofuran, acetonitrile, dioxane, methanol, isopropanol, toluene, N,N-dimethylformamide, optionally in the presence of water.

2) A process according to claim 1 wherein the palladium catalyst is selected among tetrakis(triphenylphosphine)palladium(0) and [1 ,1 - bis(diphenylphosphino)ferrocene]-dichloropalladium(ll) complexed with methylene chloride (Pd(dppf)Cl2.CH₂CI₂).

3) A process according to claim 1 or 2 wherein the catalyst is [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complexed with methylene chloride (Pd(dppf)Cl2.CH2Cl2), in the presence of sodium carbonate in dioxane.

4) A process according to any of claims from 1 to 3 further comprising the preparation of the compounds of formula (II) wherein X is bromine or a boronic group according to a process comprising:

a) the reaction of the compound of formula (IV)

5) A process according to claim 4 wherein, in step a), the condensing agent is selected among 2,4,6-tri-n-propyl-2,4,6-trioxo-1 ,3,5,2,4,6-trioxa-triphosphorinane (T3P), dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (EDC.HCI) and the solvent is an apolar solvent, selected among methylene chloride, hexane, toluene, or aprotic polar selected among tetrahydrofuran, ethyl acetate, acetonitrile, Ν,Ν-dimethylformamide; in step b), the organic acid is selected among acetic, tartaric, butyric and formic acid, and the solvent is selected among tetrahydrofuran, methylene chloride, ethyl acetate, toluene, tetrahydrofuran, isopropanol, methanol, acetonitrile, methyl-tertbutylether; in step c), the boro reagent is selected among diboronic bis-pinacolate and bis(neopentylglycolate)diboronic, and the catalyst is a palladium catalyst, and the binding agent is selected among triphenylphosphine, 4,5-bis(diphenylphosphino)-9,9-dimethylxantene (xantphos), 2,2 - bis(diphenylphosphino)-1 ,1 ^'— binaftyl (BINAP), and the base is selected among potassium phosphate, potassium acetate, potassium carbonate, sodium phosphate, sodium carbonate, and the solvent is selected among tetrahydrofuran, acetonitrile, dioxane, methanol, isopropanol, toluene, N,N- dimethylformamide optionally in the presence of water.

6) A process according to claim 5 wherein in step a) the condensing agent is N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and the solvent is tetrahydrofuran.

7) A process according to claim 5 wherein in step b) the organic acid is acetic acid and the solvent is ethyl acetate.

8) A process according to claim 5 wherein in step c) the boro reagent is diboronic bis-pinacolate, the palladium catalyst is selected among [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(l I) (Pd(dppf)Cl2), palladium acetate, palladium chloride, the binding agent is triphenylphosphine and the base is potassium acetate.

9) A process according to claim 1 , 2 or 3 further comprising the preparation of the compounds of formula (III) according to a process comprising:

d) the reaction of the compound of formula (VI)

with a sulfonated agent in the presence of a base and of a suitable solvent to give the compound of formula

wherein Y is a -OSO2 2 group, wherein R2 is a straight or branched C1-18 alkyl group, an optionally substituted aryl group, a -CF3 group, a halogen atom, preferably a -CF3 group; e) the reaction of the compound of formula (VII) with a brominating agent in a suitable solvent to give the compound of formula (VIII)

wherein Y has the above reported meanings;

the reaction of the compound of formula (VIII) with the compound of formula (IV)

wherein Y has the above reported meanings;

g) the reaction of the compound of formula (IX) with ammonium acetate in a suitable solvent to give a compound of formula (III), wherein Y is a -OSO2 2 group, wherein R2 is a straight or branched C1-18 alkyl group, an optionally substituted aryl group, a -CF3 group, a halogen atom, preferably a -CF3 group.

h) the optional reaction of the compound of formula (III), wherein Y is a - OSO2R2 group, with a boro reagent, in the presence of a suitable catalyst, of a binding agent and of a base, to give a compound of formula (III) wherein Y is a boronic group of formula -BO2R1 wherein Ri is a pinacolic or glycolic group, preferably pinacolic group.

10) A process according to claim 9 wherein, in step d), the sulfonated agent is selected among triflic anhydride, mesyl chloride, tosyl chloride, and the base is a tertiary amine selected among triethylamine, tributylamine, diisopropylethylamine, and the solvent is selected among methylene chloride, tetrahydrofuran, acetonitrile, dioxane, toluene, Ν,Ν-dimethylformamide; in step e), the brominating agent is selected among bromine, tetrabutylammonium tribromide, N-bromosuccinimide and N-bromophthalimide, and the solvent is selected among methylene chloride, tetrahydrofuran, toluene, ethyl acetate, or mixtures thereof; in step f), the base is a tertiary amine selected among triethylamine, tributylamine, diisopropylethylamine, and the solvent is selected among methylene chloride, tetrahydrofuran, toluene, ethyl acetate, or mixtures thereof; in step g), the solvent is selected among methylene chloride, tetrahydrofuran, toluene, ethyl acetate, or mixtures thereof; in step h), the catalyst is a palladium catalyst, selected among [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(l I) ((Pd(dppf)Cl2), palladium acetate, palladium chloride, and the base is selected among potassium phosphate, potassium acetate, potassium carbonate, sodium phosphate, sodium carbonate, and the solvent is selected among tetrahydrofuran, acetonitrile, dioxane, methanol, isopropanol, toluene, Ν,Ν-dimethylformamide optionally in the presence of water.

1 1 ) A process according to claim 10 wherein in step d) the solfonated agent is triflic anhydride, the base is triethylamine and the solvent is methylene chloride and in step e) the brominating agent is tetrabutylammonium tribromide and the solvent is toluene.

12) A process according to claim 10 wherein in step f) the base is triethylamine and the solvent is ethyl acetate.

13) A process according to claim 10 wherein in step g) the solvent is toluene and in step h) the palladium catalyst is 1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(l l) (Pd(dppf)C ) and the base is potassium acetate.

14) Compounds of formula (IX) and (III)

wherein Y is a -OSO2R2 group, wherein R2 is a straight or branched C1-18 alkyl group, an optionally substituted aryl group, a -CF3 group, a halogen atom, preferably a -CF3 group.

15) Compound of formula (V)