WO2020038812A1

WO2020038812A1 - New process for the preparation of amenamevir

Info

Publication number: WO2020038812A1
Application number: PCT/EP2019/071880
Authority: WO
Inventors: Alexander Stephan Siegfried DÖMLING; Tryfon ZARGANIS-TZITZIKAS
Original assignee: Telesispharma BV; Rijksuniversiteit Groningen
Current assignee: Telesispharma BV; Rijksuniversiteit Groningen
Priority date: 2018-08-20
Filing date: 2019-08-14
Publication date: 2020-02-27
Anticipated expiration: 2021-02-20

Abstract

The present invention relates to an improved process for the preparation of Amenamevir and derivatives thereof via a four component Ugi reaction.

Description

New process for the preparation of Amenamevir

Amenamevir is a helicase-primase inhibitor that is active against varicella-zoster virus and herpes simplex virus types 1 and 2. Amenamevir stabilizes the interaction between the helicase-primase and its DNA substrates, preventing the progression through helicase or primase catalytic cycles, thus interfering with viral DNA replication and viral growth. Amenamevir is marketed under the name Amenalief· by the company Maruho Co., Ltd for the treatment of herpes zoster (shingles) in Japan.

A synthesis of Amenamevir and derivatives thereof is e.g. disclosed in EP 1 844 775 B1. Since the technical synthesis of Amenamevir is rather long and inefficient, it has been the object of the present invention to provide an improved process for the preparation of Amenamevir and derivatives thereof.

The present invention provides a process for the preparation of a compound of formula

(I):

wherein

R¹ is a phenyl group which phenyl group is substituted by at least one methyl group and which phenyl group may further have one or two substituents selected from the group consisting of a methyl group and halogen atoms; ora 5-indanyl group; and R² is a 1,2,4-oxadiazol-3-yl or 4-oxazolyl group; which process is characterized in that compounds of formulas (II), (III), (IV) and (V) are reacted with each other.

The process of the present invention is preferably based on a four component Ugi reaction.

The formaldehyde of formula (II) is preferably used in the form of paraformaldehyde.

The term "halogen atoms" refers to F, Cl, Br and I.

Preferably, R¹ is a phenyl group which is substituted by two methyl groups.

Especially preferably, R¹ is a group of formula

Preferably, R² is a 1 ,2,4-oxadiazol-3-yl group:

A preferred compound of formula (I) is the following compound:

The most preferred compound of formula (I) is the following compound (Amenamevir):

Preferably, the compounds of formulas (II), (III), (IV) and (V) are reacted with each other in a one-pot reaction; preferably In a simultaneous one-pot reaction.

The process of the present invention can be carried out in any solvent suitable for a four component Ugi reaction. Examples of suitable solvents include 2,2,2- trifluoroethanol (TFE), methanol, ethanol, butanol, n-propanol, isopropanol, glycol, glycerine, water, mixtures of one or more of the above alcohols and water, biphasic solvent mixtures such as water mixed with DMF, HMPT, DCM, chloroform, toluene, benzene or chlorobenzene as well as mixtures of one or more of these solvents.

Preferred solvents include polar solvents such as methanol, ethanol, 2,2,2- trifluoroethanol, n-propanol, isopropanol, water or mixtures thereof. Methanol is an especially preferred solvent.

The process of the present invention can be performed in a temperature range from -40 °C to up to 100 °C. Preferably, the process is performed between room temperature and 50 °C. Most preferably the process is performed at room temperature (such as about 20-25 °C) since this does not require any cooling or heating efforts. Typically, the process is performed over a time period of at least 24 hours, preferably 1-4 days, preferably at room temperature.

The relative amounts of the 4 starting compounds of formulas (II), (III), (IV) and (V) are not particularly limited. Good results can be obtained when using about equimolar amounts. For example, each of the compounds of formulas (II), (IV) and (V) may initially be present in an amount of 0.9-1.3 equivalents relative to the amount of the amine of formula (III). Preferably, the components are added in equal or small excess amounts (1.0-1.2 eq) in relation to the amine of formula (III).

The process of the present invention can also be performed with the formamide precursor of the isocyanide with an in situ formation of the isocyanide and subsequent addition of the other components, thus allowing for a "one-pot" process.

According to a preferred embodiment, the isocyanide (IV) is prepared in situ from the corresponding formamide of formula (VI):

This procedure avoids the Isolation of the noxious isocyanide, is shorter and saves synthetic steps. In this embodiment the formamide is first converted in situ to the isocyanide using a suitable dehydrating agent and a base. Then, the other starting materials of the Ugi reaction (add, aldehyde and amine), preferably In a suitable cosolvent, are added.

Accordingly, in one embodiment the process of the invention comprises reacting a formamide precursor (VI) of a compound of formula (IV) in the presence of a dehydrating agent and a base to produce in situ the compound of formula (IV), followed by adding the compounds of formula (II), (III) and (V) (preferably in a suitable cosolvent) to initiate the Ugi reaction.

Exemplary dehydrating agents are phosphorous oxychloride, thionyl chloride, tosylchloride, phosgene, diphosgene, triphosgene. Suitable bases include TEA, pyridine, Hunig's, KOtBu base, NaOH or KOH. Suitable solvents for the dehydration reaction are DCM, chloroform, toluene, xylene, benzene or 1 ,3-dimethyl benzene. Examples of suitable co-solvents for the Ugi reaction include methanol, ethanol, propanol, butanol, glycol, glycerine, trifluoroethanol or aqueous mixtures thereof.

The dehydration part of the reaction can be performed under cooling with an ice bath or any other suitable cooling mixture.

EXAMPLES

1. Synthesis of compound (V):

1.1 Synthesis of 3,3-Dimethyl-2,4-dioxa-9-thiaspiro[5.5]undecane-1 ,5-dione-9,9- dioxide:

Divinylsulfone (5.89 g, 49.8 mmol) was charged to refluxing tert-butanol (80 °C, 100 mL, 1070 mmol) followed by addition of K2CO3 (1.72 g, 12.5 mmol, reagent grade powder, -325 mesh). 2,2-Dimethyl-1 ,3-dioxane-4,6-dione (8.60 g, 59.8 mmol) was added in five portions over 30 min to the reaction solution at 80 °C. The reaction was stirred at 80 °C for 1 h or until HPLC showed complete consumption of the divinylsulfone. The reaction was cooled to 35 °C, and MtBE (20.0 mL, 168 mmol) was added. The slurry was stirred at 35 °C for 12 h and then filtered; the cake was dried in a vacuum oven at 60 °C, with N2 bleed, overnight. The desired adduct was isolated as a white solid in near quantitative yield (13.0 g, 496 mol, >98% yield). The ¹H NMR of the product was consistent with that reported in the literature for this compound.

Ref: E. Carton , R. W. Draper, R. Friary (1977) A Brief Preparation of Thian-4- Carboxylic Acid 1 ,1 -Dioxide, Organic Preparations and Procedures International: The New Journal for Organic Synthesis, 1977, 9, 94-96.

1.2 Thian-4-carboxylic Acid 1 ,1 -Dioxide:

3,3-Dimethyl- 2, 4-dioxa-9-thiaspiro[5.5]undecane-1 ,5-dione-9, 9-dioxide 1 (20.0 g, 76.3 mmol) and then 6 N hydrochloric acid (60 mL) and Antifoam 204 (200 mg, 1 wt % relative to 1) were charged to a 250-mL, three-neck round-bottom flask, equipped with a mechanical stirrer and a thermocouple. The reaction was then heated to reflux and the distillate collected until the internal temperature reached 100 ^eC; thereafter the reaction was allowed to reflux for an additional 8 h or until LC/MS showed complete conversion of 1 to 2. The reaction was then cooled to room temperature and held for ~12 h, during which time the product crystallized from solution. The slurry was cooled to 0 °C for 1 h and then filtered. The cake was dried in a vacuum oven at 60 ^eC, with nitrogen bleed, overnight to give the product as a white, crystalline solid (8.84 g, 49.6 mmol, 65% yield, >98 wt % by quantitative ¹H NMR vs benzyl benzoate standard).’H NMR of compound (V) was consistent with that reported in the literature.

Ref: Matthew. M. Bio, Karl B. Hansen, John Gipson (2008) A Practical, Efficient Synthesis of 1 ,1-Dioxo-hexahydro-1A^e-thiopyran-4-carbaldehyde. Organic Process Research & Development 12, 892-895

1 H NMR (500 MHz, CDCIa) 6 7.33 (dt, J = 8.3, 5.4 Hz, 4H), 7.05 (td, J = 8.5, 3.3 Hz, 4H), 5.63 (s, 1 H), 5.52 (s, 1 H), 4.29-4.16 (m, 2H), 3.73 (dt, J = 19.5, 10.8 Hz, 2H), 3.58- 3.41 (m, 2H), 3.38-3.17 (m, 2H), 2.88 (dq, J = 13.0, 6.5 Hz, 2H), 2.64-2.49 (m, 2H), 2.47-2.34 (m, 2H), 1.38 (d, J = 4.7 Hz, 7H), 1.34 (s, 5H), 1.20 (d, J = 7.0 Hz, 5H), 1.17- 1.12 (m, 12H).

2. Synthesis of the isocvanide PNL:

2.1 Synthesis of N-Hydroxy-4-nitro-benzamidine:

Hydroxyiamine hydrochloride 1.9 g, 27.2 mmol) and then sodium carbonate (2.2 g, 20.4 mmol) were added to a stirred solution of 4-nitro-benzonitrile (1 g, 6.8 mmol) in ethanol (20 mL) and water (8 mL). The resulting mixture was refluxed at 85°C under an atmosphere of nitrogen for 2 hours. The volatiles were then evaporated and the residue was extracted with ethyl acetate. The organic phases were washed with brine solution, dried over N32S04 and evaporated to afford 1.2 g (98%) of /V-Hydroxy-4-nitro- benzamidine. ¹H NMR: (DMSO-de): d 10.2 (s,1H), 8.24 (d,2H), 7.97 (d,2H), 6.03 (s,

2H).

2.2 Synthesis of 3-(4-Nitro-phenyl)-{1 ,2,41oxadlazole:

Triethyl orthoformate (2.93 g, 19.8 mmol) was added to a stirred solution of N-hydroxy- 4-nitro-benzamidine (1.2g, 6.6 mmol) in THF (15 mL). The mixture was cooled to 0°C. Boron trifluoride dimethyl ether (900 mg, 7.9 mmol) was then added drop wise. The mixture was maintained at room temperature for three hours. The volatiles were evaporated and the residue was washed with ether and dried to afford 650 mg (55%) of 3-(4-nitro-phenyi)-[1 ,2,4]oxadiazole.

2.3 Synthesis of 4-[1 ,2,4]Oxadiazol-3-yl-phenylamine:

Ammonium chloride (214 mg, 4 mmol) in water (5 mL) was added to a stirred solution of 3-(4-nitro-phenyl)-[1 ,2,41oxadiazole (200 mg, 1 mmol) in THF (15 mL). Zinc powder (262 mg, 4 mmol) was then added portion wise. The reaction was stirred at room temperature for 1 hour and then refluxed at 65°C for 5 hours. The mixture was filtered over celite, the filtrate was evaporated and the residue was extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2S04 and evaporated to afford 155 mg (92%) of 4-[1_l2_l4]oxadiazol-3-yl-phenyiamine.

¹H NMR: (DMSO-de): 6 9.5 (s,1H), 7.7 (d,2H), 6.7 (d,2H), 5.8 (s, 2H).

2.4 Synthesis of /V-(4-(1 ,2,4-oxadiazol-3-yl)phenyl)formamide:

A solution of 4-(1 ,2,4-oxadiazol-3-yl)aniline (322 mg, 2 mmol) in ethyl formate (50 mL) was refluxed for 18 hours. The reaction was concentrated in vacuo and further dried under high vacuum.

2.5 Synthesis of 3-(4-isocyanophenyl)-1 , 2, 4-oxadiazole:

To a solution of /V-(4-(1 _l2,4-oxadiazol-3-yl)phenyl)formamide (374 mg, 2 mmol) in CH2CI2 (50 mL) was added EfeN (10 mmol, 5.0 equiv.). The mixture was cooled to -5 °C at which POCb (1.8 mmol, 0.9 equiv.) was added drop wise over 60 minutes maintaining the temperature below 0 °C. After the addition the reaction was stirred at 0°C for an additional hour. An aqueous solution of Na2C03 (0.6 M, 30 mL) was added carefully while the temperature increased to 20^eC. Additional water was added until all salts were dissolved (~50 mL). The mixture was transferred to a separatory funnel and the organic layer was separated. The water layer was extracted with dichloromethane (100 mL). The combined organic layers were washed with brine (50 mL), dried over MgS04, and concentrated in vacuo. The crude product was purified by filtration over silica (100% CH2CI2) and after evaporation of the solvent obtained as a brown solid (69 %).

3. Synthesis of N-f2-ff4-M .2.4-oxadiazol-3-vhDhenvnaminoV-2-oxoethvh-N-f2.6- dimethviphenvh tetrahvdro-2H-thioDvran-4-carboxamide 1.1 -dioxide:

Paraformaldehyde (1.2 eq), 2,6-dimethylaniline (1.0 eq), tetrahydro-2H-thiopyran-4- carboxylic acid 1 ,1-dioxide (1.2 eq) and 3-(4-isocyanophenyl)-1 ,2,4-oxadiazole (1.2 eq) were added together along with MeOH and stirred at room temperature for 72h. The solvent was evaporated under reduced pressure and the residue was purified using flash chromatography to obtain the desired bisamide product.

Other solvents which were successfully used for this reaction include ethanol, 2,2,2- trifluoroethanol, propanol, isopropanol, water and mixtures thereof.

Ή NMR (500 MHz, CDCIs) d 10.21 (d, J = 9.8 Hz, 1 H), 8.69 (dd, J = 9.3, 3.7 Hz, 1H), 7.64 (d, J = 2.8 Hz, 1H), 7.46 (td, J = 9.0, 5.5 Hz, 2H), 7.23 (dd, J = 9.3, 2.8 Hz, 1 H), 7.14 (td, J = 9.0, 4.6 Hz, 2H), 5.59 (d, J = 4.9 Hz, 1 H), 4.27-4.16 (m, 1 H), 3.86 (s, 3H), 3.78 (m, 1H), 3.69-3.61 (m, 1H), 3.61-3.49 (m, 1H), 3.45-3.31 (m, 1H), 3.01-2.90 (m, 1H), 2.46-2.36 (m, 2H), 2.34-2.21 (m, 2H), 1.46 (s, 12H), 1.41 (s, 4H), 1.38-1.32 (m, 4H), 1.24-1.17 (m, 9H).

4. In situ one-pot procedure:

To a stirred solution of /V-(4-(1 ,2,4-oxadiazol-3-yl)pheny1)formamide (1.0 mmol) in dichloromethane (1 mL), trimethylamine (2.4 mmol) was added at 0°C. After 10 min, triphosgene (0.4 mmol) was added dropwise over 30 min. The reaction mixture was stirred at 0°C for an additional 20 min and then paraformaldehyde (1.2 eq), 2,6- dimethylaniline (1.0 eq), tetrahydro-2/-/-thiopyran-4-carboxylic acid 1,1 -dioxide (1.2 eq) and methanol (2 mL) were added. The solution was stirred for 48 h. The solvent was evaporated under reduced pressure and the residue was purified using flash chromatography to obtain the desired bisamide product. The analytical data was equivalent to Example 3. 5. Synthesis of further compounds of formula :

The following compounds of formula (I) were prepared according to the procedures described above using appropriate starting materials:

N-(2-((4-{1_l2,4-oxadlazol-3-yl)phenyl)amlno)-2-oxoethyl)-A/-{p-tolyl)tetrahydro-

2H-thlopyran-4-carboxamlde 1,1 -dioxide

HRMS (ESI) Calcd for C23H25N4O5S: [M+H]*: 469.1546; found 469.1580.

^2-((4-(1_l2,4-oxadiazol-3-yl)phenyl)amlno)-2-oxoethyl)-N-(m-tolyl)tBtrahydro- 2H-thlopyran-4-carboxamlde 1,1 -dioxide

HRMS (ESI) Calcd for C23H25N4O5S: [M+H]⁺: 469.1546; found 469.1544.

N-(2-{(4-(1,2_l4-oxadlazol-3-yl)phenyl)amino)-2-oxoethy1)-AHo-tolyl)tetrahydro- 2H-thiopyran-4-carboxamlde 1,1 -dioxide

HRMS (ESI) Calcd for C23H25N4O5S: [M+H]⁺: 469.1546; found 499.1598.

Af-(2-((4-(1,2_l4-oxadlazol-3-yl)phenyl)amlno)-2-oxoethyl)-Af-(2,3-dlmethylphenyl) tetrahydro-2H-thlopyran-4-carboxamlde 1 ,1 -dioxide

HRMS (ESI) Calcd for C24H27N4O5S: [M+HG: 483.1702; found 483.1711.

N-(2-((4-(1,2,4-oxadlazol-3-yl)phenyl)amino)-2-oxoethyl)-AH2,4-dlmethylphenyl) tetrahydro-2H-thlopyran-4-carboxamlde 1 ,1-dioxide

HRMS (ESI) Calcd for C24H27N4O5S: [M+H]*: 483.1702; found 483.1700. N-(2-((4-(1,2,4-oxadlazol-3-yl)phenyl)amlno)-2-oxoethyl)-AM2,S-dImethy1phenyl) tetrahydro-2/V-thiopyran-4-carboxamlde 1,1 -dioxide

HRMS (ESI) Calcd for C24H27N4O5S: [M+H]⁺: 483.1702; found 483.1703.

^2-((4-(1,2,4-oxadlazol-3-yl)phenyl)amlno)-2-oxoethyl)-Af-(2,6-dlmethylphenyl) tetrahydro-2H-thlopyran-4-carboxamlde 1 ,1 -dioxide

HRMS (ESI) Calcd for C24H27N4O5S: [M+H]⁺: 483.1702; found 483.1800. N-(2-((4-(1,2,4-oxadlazol-3-yl)phenyl)amino)-2-oxoethyl)-M-(3_l4-dlmethylphenyl) tetrahydro-2H-thiopy ran-4-carboxamlde 1 ,1 -dioxide

HRMS (ESI) Calcd for C24H26N4O5S: [M+HG: 483.1702; found 483.1714. N-(2-((4-(1,2,4-oxadiazol-3-yl)phenyl)ainino)-2-oxoethyl)-W-(3_f5-dimethylphenyl) tetrahydro-2H-thlopyran-4-carboxamlde 1 ,1 -dioxide

HRMS (ESI) Calcd for C24H26N4O5S: [M+H]⁺: 483.1702; found 483.1704.

/V-(2-((4-(1,2,4-oxadlazol-3-yl)phenyl)amlno)-2-oxoethy1)-A/-mesltyltetrahydro- 2H-thiopyran-4-carboxamide 1,1 -dioxide

HRMS (ESI) Calcd for C25H29N4O5S: [M+H]*: 497.1859; found 497.1955.

N-(2-((4-(1,2,4-oxadlazol-3-yl)phenyl)amlno)-2-oxoethyl)-A/-(4-#luoro-2,6- dimethy1phenyl)tetrahydro-2H-thlopyran-4-carboxamide 1 ,1 -dioxide

HRMS (ESI) Calcd for C24H2eFN40sS: [M+HJ+: 501.1608; found 501.1601.

Af-(2-((4-(1,2_l4-oxadlazol-3-yl)phenyl)amlno)-2-oxoethyl)-Af-(4-fluoro-3- methylphenyl)tetrahydro-2H-thlopyran-4-carboxamide 1 ,1 -dioxide

HRMS (ESI) Calcd for C23H24FN4O5S: [M+HJ⁺: 487.1451; found 487.1455.

A/-(2-((4-(1 ,2,4-oxadiazol-3-yl)phenyl)amlno)-2-oxoethyl)-A/-(2_l3-dlhydro-1 H- inden-5-yl)tetrahydro-2H-thiopyran-4-carboxamide 1 ,1-dioxide

HRMS (ESI) Calcd for C25H27N4O5S: [M+H]*: 495.1702; found 495.1700.

Af-(2-((4-(1,2,4-oxadiazol-3-yl)phenyl)amlno)-2-oxoethyl)-Af-(3-bromo-4- methylphenyl)tetrahydro-2H4hlopyran-4-carboxamide 1,1 -dioxide

HRMS (ESI) Calcd for C23H24BrN40sS: [M+H]⁺: 547.0651; found 547.0666.

N-(2-((4-(1_l2,4-oxadiazol-3-yl)pheny1)amino)-2-oxoethyl)-AZ-(3-fluoro-4- methylphenyl)tetrahydro-2H-thlopyran-4-carboxamlde 1 ,1 -dioxide

HRMS (ESI) Calcd for C23H24FN4O5S: [M+H]⁺: 487.1451; found 487.1455.

N-(2-((4-(i,2,4-oxadiazol-3-yl)phenyl)amino)-2-oxoethyl)-Af-(3-chloro-4- methy1phenyl)tetrahydro-2H-thlopyran-4-carboxamide 1 ,1 -dioxide

HRMS (ESI) Calcd for C23H24CIN4O5S: [M+H]⁺: 503.1156; found 503.1154. /V-(2-((4-(1,2,4-oxadlazol-3-yl)phenyl)amlno)-2-oxoethyl)-Af-(4-chloro-3- methylphenyl)tetrahydro-2H-thiopyran-4-carboxamide 1 ,1 -dioxide

HRMS (ESI) Calcd for C23H24CIN4O5S: [M+HJ⁺: 503.1156; found 503.1157.

N-(2-{(4-{1,2_l4-oxadiazol-3-yl)phenyf)amino)-2-oxoethyl)-A/-{4-fluoro-3_l5- dimethylphenyl)tetrahydro-2H-thiopyran-4-carboxamlde 1 ,1 -dioxide

HRMS (ESI) Calcd for CwHzeFI^OsS: [M+H]*: 501.1608; found 501.1625.

N-(2-((4-(1,2_l4-oxadiazol-3-yl)phenyl)amlno)-2-oxoethyi)-Af-(3-fluoro-2,4- dimethylphenyl)tetrahydro-2H-thiopyran-4-carboxamkie 1 ,1 -dioxide

HRMS (ESI) Calcd for C24H2eFN40₅S: [M+H]*: 501.1608; found 501.1611.

^2-((4-(1,2,4-oxadlazol-3-yl)phenyl)amlno)-2-oxoethyl)-A/-(2-fluoro-4- methylphenyl)tetrahydro-2H-thlopyran-4-carboxamide 1,1 -dioxide

HRMS (ESI) Calcd for C23H23FN4O5S: [M+H]*: 487.1451 ; found 487.1455.

Claims

1. A process for the preparation of a compound of formula (I):

wherein

R¹ is a phenyl group which phenyl group is substituted by at least one methyl group and which phenyl group may further have one or two substituents selected from the group consisting of a methyl group and halogen atoms; or a 5-indanyl group; and R² is a 1 ,2,4-oxadiazol-3-yl or 4-oxazolyl group;

which process is characterized in that compounds of formulas (II), (III), (IV) and (V) are reacted with each other:

wherein the formaldehyde of formula (II) may be used in the form of paraformaldehyde.

2. The process of claim 1 , wherein R¹ is a phenyl group which is substituted by two methyl groups.

3. The process of claim 1 or 2, wherein R¹ is a group of formula

4. The process of any one of the preceding claims, wherein R² is a 1 ,2,4-oxadiazol-

3-yl group:

5. The process of any one of the preceding claims, wherein the compound of formula (I) is the following compound:

6. The process of any one of the preceding claims, wherein the compound of formula (I) is the following compound (Amenamevir):

7. The process of any one of the preceding claims, wherein the reaction is carried out in a polar solvent, preferably selected from methanol, ethanol, 2,2,2- trifluoroethanol, n-propanol, isopropanol, water or mixtures thereof.

8. The process of any one of the preceding claims, wherein the reaction is carried out in a temperature range of from -40°C to up to 100°C; preferably, between room temperature and 50°C; most preferably at room temperature.

9. The process of any one of the preceding claims, wherein each of the compounds of formulas (II), (IV) and (V) are initially present in an amount of 0.9-1.3 molar equivalents relative to the amount of the amine of formula (III).

10. The process of any one of the preceding claims, wherein the isocyanide (IV) is prepared in situ from the corresponding fbrmamide of formula (VI):