ITUB20150064A1 - PROCESS FOR THE PREPARATION OF SOFOSBUVIR - Google Patents

Description

Patent application for industrial invention entitled:

Process for preparing sofosbuvir

DESCRIPTION

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

Sofosbuvir? a prodrug used to treat hepatitis C.

Hepatitis C? an infectious disease caused by the Hepatitis C virus (HCV), which primarily affects the liver. The infection? often asymptomatic, but its chronicity can? lead to scarring of the liver and ultimately to cirrhosis, which is generally evident after many years. In some cases, liver cirrhosis may be lead to developing liver failure, liver cancer, esophageal and gastric varices. The HCV? transmitted primarily 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, the drug treatment? recommended in patients with liver disorders caused by the virus; the reference treatment? a combination of pegylated interferon-a and ribavirin, to be taken for a period of 24 or 48 weeks, depending on the genotype of the HCV virus. Yup ? observed that this therapy leads to improvements in 50-60% of cases.

In the phenotypes pi? difficult to treat, these two drugs are joined by boceprevir and telaprevir, bringing the cure rate from 40% to 70%. The side effects of the treatment are frequent, met? of patients experience flu-like symptoms and a third have emotional problems. In addition, the treatment carried out during the first six months is more? effective compared to when hepatitis C becomes chronic.

Sofosbuvir? a drug for the treatment of hepatitis C recently approved by the EMA. It is taken orally and acts with a direct mechanism of action on the life cycle of the virus, suppressing its replication, since, being a pan-genotypic inhibitor prodrug of the NS5B RNA-dependent HCV RNA polymerase, it can? be incorporated into HCV RNA by NS5B polymerase and act as a chain terminator. Sofosbuvir also showed a reduced number of liver disease complications and a reduced number of side effects, compared to patients treated with other treatments.

chemically known as isopropyl (2S) -2 - [[[(2R, 3R, 4R, 5R) -5- (2,4-dioxopyrimidin-1-yl) -4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran -2-yl] methoxyphenoxy-phosphoryl] amino] propanoate, marketed as Sovaldi <? > and described in US 8,563,530.

US 8,563,530 describes a process for the synthesis of sofosbuvir as reported in the following schemes 1 and 2.

Chem. Rev. 2014, 114, 9154-9218 describes an approach used in the past for the synthesis of nucleoside phosphoroamidate prodrugs, which was based on the reaction of a nucleoside with a diarylphosphite followed by the reaction with an amino acid. This process showed some problems, in particular the dimerization reaction of the diarylphosphite if it was used in excess and the obtaining of a 1: 1 mixture of the RP and SP diastereoisomers of the prodrugs, which were difficult to separate by flash chromatography and other common purification techniques. . The subsequent discovery that the two diastereomers exhibited different activities? biological in vitro had led to the search for new synthetic routes that would allow an easy separation of the mixture that was obtained. We have now surprisingly found a process for the synthesis of sofosbuvir in which the reaction of a suitable intermediate with a diarylphosphite followed by the reaction with an amino acid preferentially leads to the sofosbuvir diastereomer having the desired activity. biological, without the formation of an equimolar mixture of diastereomers difficult to separate from each other, thus obtaining? a clean and simple process that allows to obtain sofosbuvir in high yields.

The result obtained with this process, in addition to being advantageous for the reasons already? reported,? particularly unexpected and surprising as it contrasts with what is reported as a general teaching in Chem. Rev.

2014, 114, 9154-9218.

Therefore, the object of the present invention is a process for the synthesis of sofosbuvir which comprises:

R1 represents a hydrogen atom or a linear or branched C2-18 alkenyl group, preferably an allyl group;

R2 represents a linear or branched C1-18 alkyl group, a linear or branched C2-18 alkenyl group or an optionally substituted aryl group, preferably methyl; or an OR3 group in which R3? a linear or branched C1-18 alkyl group, a linear or branched C2-18 alkenyl group or an optionally substituted aryl group, preferably methyl;

with diphenylphosphite of formula (VI)

b) the reaction of the compound of formula (IVa) with a base in an alcoholic solvent, to give sofosbuvir of formula (I), when R1? a hydrogen atom, or the group removal reaction

alkenyl followed by the reaction with an organic base in an alcoholic solvent, to give sofosbuvir of formula (I), when R1? a linear or branched C2-18 alkenyl group.

In the process object of the present invention, the amine used? choice between triethylamine, diisopropylethylamine, tributylamine, phenylethylamine, butylamine, benzylamine, dibenzylamine, diisopropylamine, diethylamine, morpholine, piperidine, dicyclohexylamine, preferably triethylamine.

The chlorinated compound used? chosen between carbon tetrachloride and hexachloroethane.

Step a) is preferably carried out in an aprotic polar solvent selected from tetrahydrofuran, ethyl acetate, and acetonitrile, preferably tetrahydrofuran.

The possible removal of the alkenyl group is carried out according to the procedure reported in the Italian patent application n.

102015000007696, filed on March 5, 2015 or by selecting appropriate conditions as described in step b).

In step b) of the process object of the present invention, the base used? choice from sodium carbonate, sodium methoxide, guanidine, benzylguanidine, dimethylaminopyridine, preferably guanidine, optionally in its salified form in the presence of an inorganic base selected from sodium bicarbonate and potassium bicarbonate, preferably sodium bicarbonate.

Choosing the right base? It is possible to carry out in step b) of the process object of the present invention also the removal of the alkenyl group.

The alcohol solvent used? selected from methanol, ethanol, isopropanol, butanol, preferably methanol.

A further object of the present invention is a process for the synthesis of sofosbuvir which comprises:

R2 represents a linear or branched C1-18 alkyl group, a linear or branched C2-18 alkenyl group or an optionally substituted aryl group, preferably methyl; or an OR3 group in which R3? a linear or branched C1-18 alkyl group, a linear or branched C2-18 alkenyl group or an optionally substituted aryl group, preferably methyl;

R4 and R5, the same or different from each other, represent a hydrogen atom, a linear or branched C1-18 alkyl group or a? OCOR2 group;

In step a) of the process object of the present invention, the amine used? choice between triethylamine, diisopropylethylamine, tributylamine, phenylethylamine, butylamine, benzylamine, dibenzylamine, diisopropylamine, diethylamine, morpholine, piperidine, dicyclohexylamine, preferably triethylamine.

The chlorinated compound used? chosen between carbon tetrachloride and hexachloroethane.

Step a) is carried out in an aprotic polar solvent selected from tetrahydrofuran, ethyl acetate and acetonitrile, preferably tetrahydrofuran.

In step b) of the process object of the present invention, the deprotection process is carried out according to the techniques reported in the state of the art.

In step b) of the process object of the present invention, the base used? choice from sodium carbonate, sodium methoxide, guanidine, benzylguanidine, dimethylaminopyridine, preferably guanidine, optionally in its salified form in the presence of an inorganic base selected from sodium bicarbonate and potassium bicarbonate, preferably sodium bicarbonate.

The alcohol solvent used? selected from methanol, ethanol, isopropanol, butanol, preferably methanol.

Although the invention has been described in its characteristic aspects, modifications and equivalents which are apparent to one skilled in the art are included in the following invention.

The present invention will be now illustrated by means of some examples, which are not to be seen as limiting the scope of the invention.

EXAMPLE 1

Synthesis of 5- (3-allyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-2- (hydroxymethyl) -4-methyltetrahydrofuran-3-yl acetate

(3-acetoxy-5- (3-allyl-2,4-dioxos3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-4-methyltetrahydrofuran-2-yl) methyl acetate (51.00g, 0.1325 mol), ethanol (250ml), CALB lipase (2.5g), the temperature? was brought to about 35-40 ° C and the reaction mixture? was kept in this condition for about one night. When the reaction is over, the temperature? been brought to that environment, the mixture? been filtered, the solvent? been removed by vacuum distillation and? methylterbutyl ether (MTBE, 100 ml) was added; you filter and the mixture? was washed with methylterbutyl ether (MTBE, 2 x 20 ml). The combined organic phases were reduced to residue by vacuum distillation to give 42.00 g of 5- (3-allyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro- 2- (hydroxymethyl) -4-methyltetrahydrofuran-3-yl acetate.

<1> H-NMR (DMSO, 300 MHz): 8.09 (d, 1H), 6.13 (d, 1H), 5.88 (m, 2H), 5.07 (m, 2H), 5.06 (m, 2H), 4.41 (m, 2H), 4.12 (m, 1H), 3.80 (m, 1H), 3.60 (m, 1H), 2.14 (s, 3H) , 1.29 (d, 3H).

EXAMPLE 2

Synthesis of (2S) -isopropyl-2 - (((3-acetoxy-5- (3-allyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-4- methyltetrahydrofuran-2-yl) methoxy) (phenoxy) -phosphorylamino) propanoate

Diphenylphosphite (0.51 g, 2.20 mmol), tetrahydrofuran (5 ml), triethylamine (40 mg) were loaded into a reaction flask, the temperature? been brought to about -5? C and? dropped 5- (3-allyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-2- (hydroxy-methyl) -4-methyltetrahydrofuran-3-yl acetate ( 0.50 g, 1.46 mmol), the reaction mixture? was kept in these conditions for about 30 minutes. ? L-alanine isopropyl ester hydrochloride (0.27 g, 1.60 mmol), triethylamine (0.60 ml) was then added and a solution of carbon tetrachloride (0.80 g, 5.25 mmol) in methylene (3 ml); the reaction mixture? was kept at a temperature of about -5 ° C all night. When the reaction is over, the temperature? been brought to that environment,? water (5 ml) was added and the aqueous phase? was extracted with methylene chloride (2 x 10 ml). The combined organic phases were reduced to residue by vacuum distillation and the purified product by column chromatography to give 0.70 g of (2S) -isopropyl-2 - (((3-acetoxy-5- (3-allyl-2 , 4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) -phosphorylamino) propanoate.

<1> H-NMR (CDCl3, 300 MHz):? 7.47 (d, 1H), 7.34-7.29 (m, 2H), 7.25-7.20 (m, 3H), 6.21 (d, 1H), 5.88-5, 79 (m, 1H), 5.56 (d, 1H), 5.22-5.14 (m, 3H), 5.20-4.98 (m, 1H), 4.53-4.49 ( m, 3H), 4.31-4.28 (m, 1H), 4.25-4.18 (m, 1H), 4.02-3.90 (m, 1H), 3.79-3, 72 (m, 1H), 2.17 (s, 3H), 1.37-1.20 (m, 12H).

EXAMPLE 3

Synthesis of (S) -isopropyl 2 - ((S) - (((2R, 3R, 4R, 5R) -3-acetoxy-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) - il) -4-fluoro-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) -phosphorylamino) propanoate

(2S) -isopropyl-2 - (((3-acetoxy-5- (3-allyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) - 4-fluoro-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphorylamino) propanoate (0.2 g, 0.33 mmol), 2-butanol (2 ml) and ruthenium chloride monohydrate (10 mg, 0.05 mmol), the reaction mixture? was brought to the reflux temperature of the solvent and maintained under these conditions for about 15-18 hours. When the reaction is over, the temperature? has been brought to room value, the solvent? been removed by vacuum distillation and the residue? was purified by column chromatography to give 0.2 g of (S) -isopropyl 2 - ((S) - (((2R, 3R, 4R, 5R) -3-acetoxy-5- (2,4-dioxo- 3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) -phosphorylamino) -propanoate.

<1> H-NMR (CDCl3, 300 MHz):? 7.41 (d, 1H), 7.33-7.26 (m, 2H), 7.25-7.12 (m, 3H), 6.17 (d, 1H), 5.51 (d, 1H), 5.21-5.11 (m, 1H), 5.06-4.93 (m, 1H), 4.57-4.51 (m, 1H), 4.30-4.18 ( m, 2H), 4.08-3.93 (m, 2H), 2.16 (s, 3H), 1.41-1.13 (m, 12H).

EXAMPLE 4

Synthesis of 5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-2- (hydroxymethyl) -4-methyltetrahydrofuran-3-yl acetate

(3-acetoxy-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-4-methyltetrahydrofuran-2-yl) methyl acetate were charged (45.62 g, 0.1325 mol), ethanol (250 ml), acetonitrile (225 ml), CALB lipase (4.5 g), the temperature? was brought to about 35-40 ° C and the reaction mixture? was kept in these conditions for about three days. When the reaction is over, the temperature? been brought to that environment, the mixture? been filtered, the solvent? was removed by vacuum distillation to give 40.05 g of 5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-2- (hydroxymethyl) -4-methyltetrahydrofuran-3 - acetate.

<1> H-NMR (CDCl3, 300 MHz):? 11.53 (s, 1H), 7.99 (d, 1H), 6.05 (d, 1H), 5.72 (d, 1H), 5.34 (s, 1H), 5.24 (m , 1H), 4.11 (d, 1H), 3.79 (m, 1H), 3.57 (m, 1H), 2.14 (s, 3H), 1.28 (d, 3H).

EXAMPLE 5

Synthesis of (2S) -isopropyl-2 - (((3-acetoxy-5- (2,4-dioxo-3,4-dihydro-pyrimidine-1 (2H) -yl) -4-fluoro-4-methyltetrahydrofuran- 2-yl) methoxy) (phenoxy) -phosphorylamino) propanoate

Diphenylphosphite (0.51 g, 2.20 mmol), tetrahydrofuran (5 ml), triethylamine (40 mg) were loaded into a reaction flask, the temperature? been brought to about -5? C and? 5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-2- (hydroxymethyl) 4-methyltetrahydrofuran-3-yl acetate (0.44 g, 1, 46 mmol), the reaction mixture? was kept in these conditions for about 30 minutes. ? L-alanine isopropyl ester hydrochloride (0.27 g, 1.60 mmol), triethylamine (0.60 ml) was then added and a solution of carbon tetrachloride (0.80 g, 5.25 mmol) in methylene (3 ml); the reaction mixture? was kept at a temperature of about -5 ° C all night. When the reaction is over, the temperature? been brought to that environment,? water (5 ml) was added and the aqueous phase? was extracted with methylene chloride (2 x 10 ml). The combined organic phases were reduced to residue by vacuum distillation and the purified product by column chromatography to give 0.58 g of (2S) -isopropyl-2 - (((3-acetoxy-5- (2,4-diox -3,4-dihydro-pyrimidine-1 (2H) -yl) -4-fluoro-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) -phosphorylamino) propanoate.

<1> H-NMR (CDCl3, 300 MHz):? 7.41 (d, 1H), 7.33-7.26 (m, 2H), 7.25-7.12 (m, 3H), 6.17 (d, 1H), 5.51 (d, 1H), 5.21-5.11 (m, 1H), 5.06-4.93 (m, 1H), 4.57-4.51 (m, 1H), 4.30-4.18 ( m, 2H), 4.08-3.93 (m, 2H), 2.16 (s, 3H), 1.41-1.13 (m, 12H).

EXAMPLE 6

Sofosbuvir synthesis

(2S) -isopropyl-2 - (((3-acetoxy-5- (2,4-dioxo-3,4-dihydro-pyrimidine-1 (2H) -yl) -4- fluoro-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) -phosphorylamino) propanoate (0.19 g, 0.33 mmol), guanidine nitrate (0.08 g, 0.65 mmol), sodium bicarbonate (0, 02 g, 0.33 mmol), methanol (2 ml) and the reaction mixture? was kept in these conditions for about two hours. At the end of the reaction, the solvent? been removed by vacuum distillation,? been added methylene chloride (2 ml) and the organic phase? was washed with water (1 x 2 ml). Have the assembled organic fakes been cooled? was methylene chloride added and the solid formed? filtered under vacuum to give 0.16 g of Sofosbuvir.

Claims (7)

CLAIMS 1) A process for the synthesis of sofosbuvir which includes: a) the reaction of the compound of formula (Va) in which R1 represents a hydrogen atom or a linear or branched C2-18 alkenyl group, preferably an allyl group; R2 represents a linear or branched C1-18 alkyl group, a linear or branched C2-18 alkenyl group or an optionally substituted aryl group, preferably methyl; or an OR3 group in which R3? a linear or branched C1-18 alkyl group, a linear or branched C2-18 alkenyl group or an optionally substituted aryl group, preferably methyl; with diphenylphosphite of formula (VI) in the presence of an amine and, subsequently, with L-alanine isopropyl ester free base or hydrochloride in the presence of chlorinated compounds to give the compound of formula (IVa) where R1 and R2 have the meanings reported above; b) the reaction of the compound of formula (IVa) with a base in an alcoholic solvent, to give sofosbuvir of formula (I), when R1? a hydrogen atom, or the alkenyl group removal reaction followed by the reaction with an organic base in an alcoholic solvent, to give sofosbuvir of formula (I), when R1? a linear or branched C2-18 alkenyl group. 2) A process for the synthesis of sofosbuvir which includes: a) the reaction of the compound of formula (Vb) in which R2 represents a linear or branched C1-18 alkyl group, a linear or branched C2-18 alkenyl group or an optionally substituted aryl group, preferably methyl; or an OR3 group in which R3? a linear or branched C1-18 alkyl group, a linear or branched C2-18 alkenyl group or an optionally substituted aryl group, preferably methyl; R4 and R5, the same or different from each other, represent a hydrogen atom, a linear or branched C1-18 alkyl group or a in which R2, R4 and R5 have the meanings reported above; b) the reaction of the compound of formula (IVb) with a base in an alcoholic solvent, to give sofosbuvir of formula (I). 3) A process according to claim 1 or 2 wherein in step a) the amine? choice between triethylamine, diisopropylethylamine, tributylamine, phenylethylamine, butylamine, benzylamine, dibenzylamine, diisopropylamine, diethylamine, morpholine, piperidine, dicyclohexylamine, preferably triethylamine. 4) A process according to claim 1 or 2 in which the chlorinated compound? chosen between carbon tetrachloride and hexachloroethane. 5) A process according to claim 1 or 2 in which step a) is carried out in an aprotic polar solvent selected from tetrahydrofuran, ethyl acetate and acetonitrile, preferably tetrahydrofuran. 6) A process according to claim 1 or 2 wherein in step b) the base? choice from sodium carbonate, sodium methoxide, guanidine, benzylguanidine, dimethylaminopyridine, preferably guanidine, optionally in its salified form in the presence of an inorganic base selected from sodium bicarbonate and potassium bicarbonate, preferably sodium bicarbonate. 7) A process according to claim 1 or 2 wherein in step b) the alcoholic solvent? selected from methanol, ethanol, isopropanol, butanol, preferably methanol.