ITUB20152784A1 - PROCESS FOR RAVIDASVIR SYNTHESIS - Google Patents

Description

"Process for the synthesis of ravidasvir"

DESCRIPTION

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

Hepatitis C is an infectious disease caused by the Hepatitis C virus (HCV), which primarily affects the liver. The infection is often asymptomatic, but its chronicization can lead to scarring of the liver and, finally, to cirrhosis, which is generally evident after many years. In some cases, liver cirrhosis can lead to liver failure, liver cancer, esophageal and gastric varices. HCV is mainly transmitted by direct contact with infected blood, often due to intravenous drug use, unsterilized medical devices, and blood transfusions.

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

Ravidasvir, a drug useful for the treatment of hepatitis C, is the compound of formula (I)

^ r \ ~ r \ ì

(THE)

described in WO 2011/149856 (Presidium Pharmaceuticals Ine.).

WO 2011/149856 describes the following processes for the synthesis of ravidasvir, reported in schemes 1, 2, 3 and 4:

Scheme 1

NBoc

Br

Pd (dppf) CI2y NaHC03DME / H20

RAVIOASVIR

Scheme 2

1) 4N HO / dioxane

2 HATLf, DIPELA, DMF

Boc <'>

4N HCI

MH dioxane

Λ <> τ>

RAVIDASVIR

Scheme 3

Oxidation

NBoc

NaBH

Et OH

1) 4N HCI / dioxane 2) HATU, DIPEA, DMF (BOC) 20

K2C03

OR RAVIDASVIR

Scheme 4

1) 4N HCI / dioxane

2) HATU, DIPEA, DM F

Gr

Br

f

J NH

ντ Λ_ / Ίί

--N

T ^

cA?

The processes described above are however difficult to apply on a macroscale and / or at an industrial level, above all due to low selectivity and yields and the formation of by-products which are difficult to eliminate with conventional purification techniques.

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

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

H3co

(II) N NH

X

wherein X is a halogen atom, preferably a bromine atom, or a boronic group of formula -BO2R1 wherein RT is a pinacol or glyconeum group, preferably pinacol;

with a compound of formula (III)

V / I

wherein Y is a halogen atom, preferably a bromine atom, or a -OSO2R2 group, where R2 is a branched CriBlinear O 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 -B02Ri where R1 is a pinacol or glycol group, preferably pinacol.

The process object of the present invention is carried out in the presence of a suitable palladium-based catalyst, preferably selected from tetraki s (triphenylphosphine) palladium (0) and [1, T-bis (diphenylphosphino) ferrocene] -dichloropalladium (11) complexed with methylene chloride (Pd (dppf) CI2.CH2CI2), in the presence of an appropriate base chosen from potassium phosphate, potassium carbonate, sodium phosphate, sodium carbonate, in a solvent selected from tetrahydrofuran, acetonitrile, dioxane, methanol, isopropanol, toluene , Μ, Ν-dimethylformamide, optionally in the presence of water. Preferably, the process object of the present invention is carried out with [1, 1 '-bi s (d if en i Ifosfi n o) f errocen e] dichloropalladium (11) complexed with methylene chloride (Pd (dppf) CI2.CH2CI2), 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 described in WG 2011/149856.

Alternatively, the compounds of formula (II) in which X is bromine or a boronic group can be prepared according to a process, which constitutes a further object of the present invention, which comprises:

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

H, CO (IV)

COOH

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

(V)

H2N

b) the reaction of the compound of formula (V) with an organic acid in an aprotic polar solvent to give the compound of formula (II), in which X is a bromine atom;

c) the possible reaction of the compound of formula (II) thus obtained with a boron-based reagent, in the presence of a suitable catalyst, of a ligand and of a base, to give a compound of formula (II), in which X is a boronic group of formula -BO ^ where R1 is a pinacol or glycolic group, preferably pinacol. In step a), the condensing agent is selected from 2,4,6-tri-n-propyl-2,4,6-tri-oxo- 1,3, 5, 2, 4, 6-trioxa-triphosphorin (T3P ), dicyclohexylcaithiodimide (DCC), M- (3-dimethylaminopropyl) -N'-ethylcarbodimide hydrochloride (EDC.HCI), preferably N- (3-dimethylaminopropyl) -N'-ethylcarbodimide hydrochloride.

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

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

The solvent is selected from tetrahydrofuran, methylene chloride, ethyl acetate, toluene, tetrahydrofuran, isopropanol, methanol, acetonitrile, methyltertbutyl ether, preferably ethyl acetate.

The intermediate of formula (V) can be isolated or converted directly into the compound of formula (II) by a one-pot process. The intermediate of formula (V) is new and represents a further object of the present invention.

In step c), the boron-based reagent is selected from bis-p in diboronic acolate and bis (neopentylglycolate) diboronic, preferably diboronic bispinacolate.

The catalyst is based on palladium, preferably selected from [1,1 -bis (diphenylphosphino) ferrocene] dichloropalladium (II) (Pd (dppf) CI2), palladium acetate, palladium chloride, preferably palladium chloride.

The binder is selected from triphenylphosphine, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (xantphos), 2,2 - bis (diphenylphosphino) - 1.1-diphenylphosphine (BINAP), preferably triphenylphosphine.

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

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

The compounds of formula (III) in which Y is a halogen atom or a boronic group are also known or can be prepared with known methods, for example as described in WO 2011/149856.

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

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

(VI) or

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

CH3 (VII) or

wherein Y is a -0SO2R2 group, where R2 is a linear 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)

γ

(VIII) Br

or

where Y has the above meanings;

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

H, co

(IV) COOH

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

(IX)

OR

where Y has the above meanings;

g) the reaction of the compound of formula (IX) with ammonium acetate in a suitable solvent to give a compound of formula (III), in which Y is a -0SO2R2 group, where R2 is a linear or branched 01-1Β alkyl group, a optionally substituted aryl, a -CF3 group, a halogen atom, preferably a -CF3 group.

h) the possible reaction of the compound of formula (III), in which Y is a -0S02R2 group, with a boron-based reagent, in the presence of a suitable catalyst, a ligand and a base, to give a compound of formula (III) wherein Y is a boronic group of formula -B02RI wherein Ri is a pinacol or glycolic group, preferably pinacol.

In step d), the sulfonate reagent is selected from triflic anhydride, mesyl chloride, tosyl chloride, preferably triflic anhydride.

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

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

In step e), the brominating agent is selected from bromine, tetrabutyl ammonium tribromide, N-bromosuccinimide and N-bromophthalimide, preferably tetrabutyl ammonium tribromide.

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

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

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

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

In step h), the catalyst is based on palladium, selected from [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (ll) ((Pd (dppf) CI2), palladium acetate, palladium chloride, preferably [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (Pd (dppf) CI2) The base is chosen from potassium phosphate, potassium acetate, potassium carbonate, sodium phosphate, sodium carbonate, preferably potassium acetate.

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

The compounds of formula (IX) and (III) in which Y is an -OSO2R2 group, where R2 is a branched C1-18 linear O alkyl group, an optionally substituted aryl group, a -CF3 group, a halogen atom, preferably a -CF3, are new and represent a further object of the present invention.

Although the invention has been described in its characteristic aspects, modifications and equivalents that are evident to those skilled in the art are included in the following invention.

The present invention will now be illustrated by means of some examples, which should not be seen as limiting the scope of the invention. All the terms used in the present application, unless otherwise indicated, must be understood in their common meaning as known in the art. Other more specific definitions for some terms, as used in this question, are highlighted below and consistently apply throughout the description and claims, unless a different definition explicitly provides a broader definition.

EXAMPLE 1

Synthesis of fR) -1-ffS) -2-f2-amino-4-bromophenylcarbamoinpyrrolidin-1-in-3-m eti I - 1 -oxob utan -2-i 1-carbamate

(S) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine-2-carboxylic acid (100.00 g, 0.366 mol), 4-bromine-1 was charged into a reaction flask , 2-diaminobenzene (68.45 g, 0.366 mol), tetrahydrof urane (500.00 ml); the temperature was 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 was kept under these conditions for about an hour and a half. At the end of the reaction, the solvent was removed by vacuum distillation, ethyl acetate (600.00 ml) was added, the organic phase was washed with water (2x250.00 ml), a saturated aqueous solution of sodium bicarbonate (1x300 ml). 00 ml) and a saturated sodium chloride solution (1x150.00 ml). The combined organic phases were reduced to residue by vacuum distillation to give 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, 1H), 7.34 (d, 1H), 6.98 (d, 1H), 6.87 (s, 1H) , 6.64 (d, 1H), 5.19 (s, 2H), 4.40 (t, 1H), 3.81 (t, 1H), 3.50 (m, 5H), 2.15 ( m, 1H), 1.94 (m, 4H), 0.91 (d, 6H).

EXAMPLE 2

Synthesis of methyl (R) -1 - ((S) -2- (6-bromo-1H-benzo [d1imidazol-2-yl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl- carbamate

Methyl (R) -1 - ((S) -2- (2-amino-4-bromophenylcarbamoyl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl- were added to a reaction flask carbamate (153.45 g, 0.347 mol), ethyl acetate (850.00 ml), acetic acid (45.05 g, 0.750 mol); the temperature was brought to the reflux temperature of the solvent and the reaction mixture was kept under 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) was added and the organic phase was washed with water (1x200.00 ml) and a saturated solution of sodium chloride (1x250.00 ml). The combined organic phases were reduced to residue by vacuum distillation and methylterbutyl ether (300.00 ml) was added; the mixture was dropped in heptane (1300.00 ml) and the solid formed was filtered, washed with a mixture of heptane and methyl-terbutyl ether (250.00 ml) and the solvent evaporated by vacuum distillation, to give 12, 49 g of methyl (R) -1 - ((S) -2- (6-bromo-1H-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, 1H), 7.69 (d, 1H), 7.45 (s, 1H), 7.31 (t, 2H ), 5, 16 (t, 1H), 4, 10 (d, 1H), 3.85 (d, 2H), 3.54 (s, 3H), 2.22 (m, 1H), 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-benzo [d1imidazol- 2-yl) pyrrolidin-1-yl) butan-2-ylcarbamate

Methyl (R) -1 - ((S) -2- (6-bromo-1H-benzo [d] imidazol-2-yl) pyrrolidin-1-yl) -3-methyl- were charged into a reaction flask 1-oxobutan-2-yl-carbamate (100.00 g, 0.236 mol), bis-p in diboronic acolate (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 on carbon at 10% wet with 50% water (40.43 g, 0.019 mol); the temperature was brought to about 90 ° C and the reaction mixture was kept under these conditions for about two and a half hours. At the end of the reaction, ethyl acetate (300.00 ml) and water (100.00 ml) were added, the organic phase was washed with an aqueous solution of sodium bicarbonate (1x100.00 ml), water (2x50.00 ml) ml) and a saturated sodium chloride solution (1x50.00 ml). The combined organic phases were reduced to residue by vacuum distillation to give 91.00 g of methyl 3-methyl-1-oxo-1- (2- (6- (4,4,5,5-tetramethyl-1, 3 , 2-d i ossab now an-2-i I) - 1 H-b enz o [d] i m i daz ol -2-i I) p i rrol i d i n- 1 -i I) butan-2-i I-carbamate.

<1> H-NMR (DMSO, 300 MHz): δ 12.22 (s, 1H), 7.76 (d, 1H), 7.48 (m, 2H), 7.31 (d, 1H) , 5.16 (t, 1H), 4.10 (d, 1H), 3.85 (d, 2H), 3.54 (s, 3H), 2.22 (m, 1H), 1.98 (m, 4H), 1.29 (s, 12H), 0.83 (d, 6H)

EXAMPLE 4

Synthesis of 6-acetylnaphthalen-2-yl trifluoromethanesulfonate

1- (6-hydroxynaphthalene-2-yl) ethanone (100.00 g, 0.537 mol), triethylamine (65.20 g, 0.644 mol), methylene chloride (500.00 ml) were charged to a reaction flask. ; the temperature was raised to about 15 ° C, triflic anhydride (159.08 g, 0.564 mol) was added, the temperature was raised to about 25 ° C and the reaction mixture was kept for about two hours. At the end of the reaction, water (200.00 ml) was added, the organic phase was washed with a saturated solution of sodium bicarbonate (1x200.00 ml), 2N hydrochloric acid (1x200.00 ml) and 2N sodium chloride (1x200 ml) .00 mi). The combined organic phases were reduced to residue by vacuum distillation, to give 162.36 g of 6-aceti I naphthal and n-2-i I 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, 1H), 2.33 (s, 3H).

EXAMPLE 5

Synthesis of 6- (2-bromoacetyl) naphthalen-2-yl trifluoromethanesulfonate

Into a reaction flask were charged 6-acetyls I n aftal and n-2-I trifluoromethanesulfonate (100.00 g, 0.314 mol), toluene (500.00 ml); the temperature was brought to about 20 ° C, tetrabutylammonium tribromide (166.59 g, 0.345 mol) was added and the reaction mixture was kept under these conditions for about two hours.

At the end of the reaction, water (200.00 ml) was added, the organic phase was with water (3x200.00 ml) and with a saturated sodium chloride solution (1x200.00 ml). The combined organic phases were reduced to residue by vacuum distillation to give 118.45 g of 6- (2-bromoacetyl) naphthalen-2-yl trifluoromethanesulfonate.

<1> H-NMR (CDCls, 300 MHz): δ 8.52 (s, 1H), 8.05 (q, 2H), 7.90 (d, 1H), 7.80 (s, 1 H) , 7.48 (d, 1H), 4.55 (t, 2H).

EXAMPLE 6

Synthesis of 2-oxo-2- (6- (trifluoromethylsulfonyloxy) naphthalen-2-yl) ethyl 2- (2- (methoxycarbonylaminoK3-methylbutane pyrrolidin-1-carboxylate

6- (2-bromoacetyl) naphthalen-2-yl trifluoromethanesulfonate (118.45 g, 0.298 mol), ethyl acetate (500.00 ml), acid (S) -1 - (( R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine-2-carboxylic (85.82 g, 0.314 mol), triethylamine (96.42 ml, 0.690 mol) and the reaction mixture was stirred for approx. sixteen hours. At the end of the reaction, water (200.00 ml) was added, the organic phase was washed with hydrochloric acid solution 2N (1x100.00 ml), a saturated solution of sodium bicarbonate (1x100.00 ml) and a saturated solution of sodium chloride (1x100.00 ml). The combined organic phases were reduced to residue by vacuum distillation to give 140.31 g of 2-oxo-2- (6- (trifl u orom eti I su Ifon i I oxi) n aftal en-2-i I) eti I 2- (2- (methoxycarbonylamino) -3-m eti I butan oi I) pi rrol i of n - 1 -carb oxy side.

<1> H-NMR (DMSO, 300 MHz): δ 8.80 (s, 1H), 8.26 (m, 1H), 8.14 (m, 1H), 8.04 (m, 2H) , 7.64 (d, 1H), 7.40 (d, 1H), 5.70 (dd, 2H), 4.55 (t, 1H), 4.01 (t, 1H), 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 - ((Sl-1-i (YES-2- (methoxycarbonylamino) -3-methylbutane pyrrolidin-2-in-1 H-imidazol-5-yl) naphthalen-2-trifluoromethanesulfonate

In a reaction flask 2-oxo-2- (6- (trifl u orom eti I on Ifon i I oxi) n aftal en-2-i I) eti I 2- (2- (methoxycarbonylamino) -3 were loaded -m eti I b utan oi I) pi rrol i of n - 1 -carb oxy I ato (140.31 g, 0.238 mol), toluene (500.00 ml), ammonium acetate (72.60 g, 0.942 mol) ; the temperature was brought to the reflux temperature of the solvent and the reaction mixture was kept under 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 2N phosphoric acid solution (2x157.00 ml), to extract the product in the aqueous phase . Ethyl acetate (200.00ml), sodium carbonate (73.22g) and saturated sodium chloride solution (50.00ml) were added. The combined organic phases were reduced to residue by vacuum distillation to give 106.35 g of 6- (2 - ((S) -1 - ((S) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin-2- il) -1 H-i m i d az ol -5-i I) n aftal en-2-i I trifluoromethanesulfonate.

<1> H-NMR (DIVIDED, 300 MHz): δ 11, 86 (s, 1H), 8.24 (d, 2H), 7.28 (m, 3H), 7.64 (m, 2H), 5.12 (t, 1H), 4.01 (t, 1H), 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 (S P3-m eti I - 1 -osso- 1 - ((S) -2- (5- (6- (4, 4,5, 5-tetram ethyl-1, 3,2-dioxaborolan- 2-yl) naphthalen-2-yl) -1H-imidazol-2-yl) pyrrolidin-1-inbutan-2-carbamate.

6- (2 - ((S) -1 - ((S) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin-2-yl) -1 H-imidazol-5-yl were charged into a reaction flask ) naphthalene-2-yl trifluorometanesulfonate (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 (II) (1.11 g, 0.0015 mol); the temperature was brought to about 90 ° C and the reaction mixture was kept under 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 (1x20.00 ml), with a saturated sodium bicarbonate solution (1x25.00 ml) and the combined organic phases were reduced to residue by vacuum distillation, to give 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) naphthalen-2-yl) -1 H-imidazol-2-yl) pyrrolidin-1-yl) butan-2-yl carbamate.

<1> H-NMR (DIVIDED, 300 MHz): δ 11, 86 (s, 1H), 8.24 (d, 2H), 7.28 (m, 3H), 7.64 (m, 2H), 5.12 (t, 1H), 4.01 (t, 1H), 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

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- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin-2-yl) -1H-imidazol-5-yl) naphthalen-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); the temperature was brought to about 70 ° C and the reaction mixture was kept under these conditions for about two and a half hours. 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 combined organic phases were filtered, the solvent removed by vacuum distillation, to give 13.73 g of ravidasvir.

EXAMPLE 10

Synthesis of ravidasvir

Methyl (R) -1 - ((S) -2- (6-bromo-1H-benzo [d] imidazol-2-yl) pyrrolidin-1-yl) -3-methyl- were charged into a reaction flask 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) naphthalen-2-yl) -1 H-imidazol-2-yl) pyrroMdin-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), the temperature is was brought to about 70 ° C and the reaction mixture was kept under these conditions for about two and a half hours. 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 combined organic phases were filtered, the solvent removed by vacuum distillation, to give 10.00 g of ravidasvir.

Claims (8)

CLAIMS 1) A process for the synthesis of ravidasvir comprising the reaction of the compound of formula (II) OR (II) X wherein X is a halogen atom, preferably a bromine atom, or a boronic group of formula -B02R ·, wherein R-, is a pinacol or glycol group, preferably pinacol; with a compound of formula (III) wherein Y is a halogen atom, preferably a bromine atom, or a -OSO2R2 group, where R2 is a branched linear Cns alkyl group, an optionally substituted aryl group, a -CF30 group a halogen atom, preferably a - CF3, or Y is a boronic group of formula -B02Ri where R1 is a pinacol or glyconeum group, preferably pinacol; in the presence of a suitable palladium-based catalyst, preferably selected from tetrakis (triphenylphosphine) palladium (0) and [1,1 -bis (diphenylphosphino) ferrocene] -dichloropalladium (ll) complexed with methylene chloride (Pd (dppf) CI2 .CH2CI2), in the presence of an appropriate base chosen from potassium phosphate, potassium carbonate, sodium phosphate, sodium carbonate, in a solvent selected from tetrahydrofuran, acetonitrile, dioxane, methanol, isopropanol, toluene, N, N-dimethylformamide, possibly in presence of water. 2) A process according to claim 1 wherein the catalyst is [1,1 -b i s (d ifen i Ifosfi n o) f errocen e] d i ci orop al I to i o (11) complexed with methylene chloride (Pd (dppf) CI2.CH2CI2), in the presence of sodium carbonate in dioxane. 3) A process according to claim 1 or 2 further comprising the preparation of the compounds of formula (II) in which X is bromine or a boronic group according to a process which comprises: a) the reaction of the compound of formula (IV) H, CO (IV) COOH with 4-bromo-1,2-diaminobenzene in the presence of a suitable condensing agent to give the compound of formula (V) hUCO (V) H2N b) the reaction of the compound of formula (V) with an organic acid in an aprotic polar solvent to give the compound of formula (II), in which X is a bromine atom; c) the possible reaction of the compound of formula (II) thus obtained with a boron-based reagent, in the presence of a suitable catalyst, of a ligand and of a base, to give a compound of formula (II), in which X is a boronic group of formula -BO ^ where R1 is a pinacol or glycolic group, preferably pinacol. 4) A process according to claim 3 wherein, in step a), the condensing agent is selected from 2,4, 6-tri-n-p rop i I -2, 4, 6-tri-oxo-1,3,5 , 2,4,6-trioxy-triphosphorinan (T3P), dicyclohexylcarbodimide (DCC), N- (3-dimethylaminopropyl) -N'-ethylcarbodimide hydrochloride (EDC.HCI), preferably N- (3-dimethylaminopropyl) -N'- ethylcarbodimide hydrochloride and the solvent is an apolar solvent, selected from methylene chloride, hexane, toluene, or aprotic polar chosen from tetrahydrofuran, ethyl acetate, acetonitrile, M, N-dimethylformamide, preferably tetrahydrofuran; in step b), the organic acid is selected from acetic, tartaric, butyric and formic acid, preferably acetic acid and the solvent is selected from tetrahydrofuran, methylene chloride, ethyl acetate, toluene, tetrahydrofuran, isopropanol, methanol, acetonitrile, methyl-tertbutyl ether, preferably ethyl acetate; in step c), the boron-based reagent is selected from diboronic bispinacolate and diboronic bis (neopentylglycolate), preferably diboronic bis-pinacolate, and the catalyst is based on palladium, preferably selected from [1,1 bis (diphenylphosphino) ferrocene ] dichloropalladium (ll) (Pd (dppf) CI2), palladium acetate, palladium chloride, preferably palladium chloride, and the binder is selected from triphenylphosphine, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (xantphos), 2 , 2 - bis (diphenylphosphino) - 1, 1 binaphthyl (BINAP), preferably triphenylphosphine, and the base is chosen from potassium phosphate, potassium acetate, potassium carbonate, sodium phosphate, sodium carbonate, preferably potassium acetate, and the solvent is selected from tetrahydrof urane, acetonitrile, dioxane, methanol, isopropanol, toluene, Ν, Ν-dimethylformamide possibly in the presence of water. 5) A process according to claim 1 or 2 further comprising the preparation of the compounds of formula (III) according to a process which comprises: d) the reaction of the compound of formula (VI) CH3 (VI) or with a sulfonated agent in the presence of a base and a suitable solvent to give the compound of formula (VII) CH3 (VII) or wherein Y is an -OSO2R2 group, where R2 is a branched C1-1B linear O 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) (VIII) Br OR where Y has the above meanings; f) the reaction of the compound of formula (VIII) with the compound of formula (IV) COOH in the presence of a base in a suitable solvent, to give a compound of formula (IX) where Y has the above meanings; g) the reaction of the compound of formula (IX) with ammonium acetate in a suitable solvent to give a compound of formula (III), in which Y is an -OSO2R2 group, where R2 is a branched linear C1-18 alkyl group, a optionally substituted aryl, a -CF3 group, a halogen atom, preferably a -CF3 group. h) the possible reaction of the compound of formula (III), in which Y is a -OSO2R2 group, with a boron-based reagent, in the presence of a suitable catalyst, a binder and a base, to give a compound of formula (III) wherein Y is a boronic group of formula -BO2R1 where R1 is a pinacol or glycol group, preferably pinacol. 6) A process according to claim 5 in which, in step d), the sulfonate reagent is selected from tritium anhydride, mesyl chloride, tosyl chloride, preferably triflic anhydride, and the base is a tertiary amine selected from triethylamine, tributylamine, diisopropylethylamine, preferably triethylamine, and the solvent is selected from methylene chloride, tetrahydrofuran, acetonitrile, dioxane, toluene, M, N-dimethylformamide, preferably methylene chloride; in step e), the brominating agent is selected from bromine, tetrabutyl ammonium tribromide, N-bromosuccinimide and M-bromophthalimide, preferably tetrabutyl ammonium tribromide, and the solvent is selected from methylene chloride, tetrahydrofuran, toluene, ethyl acetate, 0 their blends; preferably toluene; in step f), the base is a tertiary amine selected from triethylamine, tributylamine, diisopropylethylamine, preferably triethylamine, and the solvent is selected from methylene chloride, tetrahydrofuran, toluene, ethyl acetate, or their mixtures; preferably toluene; in step g), the solvent is selected from methylene chloride, tetrahydrofuran, toluene, ethyl acetate, or their mixtures; preferably toluene; in step h), the catalyst is based on palladium, selected from [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (ll) ((Pd (dppf) CI2), palladium acetate, palladium chloride, preferably [1, 1'b i s (d ifen i Ifosfi no) ferrocene] dichloropalladium (ll) (Pd (dppf) CI2), and the base is chosen from potassium phosphate, potassium acetate, potassium carbonate, sodium phosphate, sodium carbonate, preferably potassium acetate, and the solvent is selected from tetrahydrofuran, acetonitrile, dioxane, methanol, isopropanol, toluene, Ν, Ν-dimethylformamide optionally in the presence of water. 7) Compounds of formula (IX) and (III) in which Y is a -OS02R2 group, where R2 is a linear or branched C1-1B alkyl group, an optionally substituted aryl group, a -CF3 group, a halogen atom, preferably a group -CF3. 8) Compound of formula (V).