WO2019020508A1

WO2019020508A1 - Method for the preparation of high-purity rucaparib

Info

Publication number: WO2019020508A1
Application number: PCT/EP2018/069740
Authority: WO
Inventors: Gianluca Belogi; Andrea Mazzoni; Stefano Serra; Barbara NOVO
Original assignee: Olon SpA
Current assignee: Olon SpA
Priority date: 2017-07-26
Filing date: 2018-07-20
Publication date: 2019-01-31
Anticipated expiration: 2020-01-26
Also published as: IT201700085789A1

Abstract

The present invention relates to a novel process with low environmental impact for the synthesis of rucaparib with high yield and purity, which comprises a regioselective coupling reaction between an indole and an iodo-aryl, performed in water in the presence of a catalyst. The process is advantageous from the industrial standpoint because in the key coupling step, high regioselectivity is obtained without the use of complex intermediates or the use of solvents which are potentially toxic and environmentally harmful.

Description

METHOD FOR THE PREPARATION OF HIGH-PURITY RUCAPARIB

Field of invention

The present invention relates to a novel process for the synthesis of high-purity rucaparib with a low environmental impact.

Background to the invention

Rucaparib (I) is a poly(ADP ribose) polymerase (PARP) inhibitor used as an antitumoral for the treatment of ovarian cancer.

The preparation of rucaparib (I) and its camphorsulphonic acid salt (II) is disclosed in US 6977298. Said synthesis involves, starting with intermediate III, closing to give indol-azepine IV, followed by a bromination reaction to generate bromo-indole V, which is used in a Suzuki coupling with boronic acid VI to give aldehyde VII. Rucaparib I can then be obtained in two steps from aldehyde VII by a reductive amination reaction (Scheme 1).

Scheme 1

VIII

This synthesis method suffers from poor atom economy as a halogen is introduced into the molecule which does not appear in the end product, and requires the use of toxic, environmentally harmful reagents such as pyridinium tribromide for the bromination reaction and environmentally harmful solvents such as dichloromethane in the Suzuki reaction step.

The formation of an azepine ring on the indole structure by a procedure similar to the conversion step from intermediate III to intermediate IV (Scheme 1) had been described in the literature, for example in Arch. Pharm. (Weinheim) 328, 329-332 (1995) and Chem.Pharm.BuU. 36 (3) 1162-1168 (1988).

The synthesis method reported in US 6977298 was subsequently disclosed in great detail in Organic Process Research & Development, 2012, 16, 1897-1904. That publication indicated, in particular, a variation for the preparation of intermediate IV comprising alkylative reduction of indole IX to give intermediate X followed by deprotection and closing to obtain intermediate IV (Scheme 2). Scheme 2

IX X

The main step of a second rucaparib synthesis method, disclosed in US 7323562, comprises coupling with the Sonogashira reaction between triflate XII and alkyne XIII, followed by reduction of the nitro group to amine and ring closure to give the indole structure. After a series of further steps designed to construct the azepine ring, including Raney nickel reduction, rucaparib I is obtained (Scheme 3).

Scheme 3

w in

This synthesis method suffers from a number of drawbacks, including the use of strongly corrosive reagents such as triflic anhydride for the preparation of intermediate XII, poor atom economy, and two reduction steps requiring reactions performed at a high hydrogen pressure. Description of the invention

We have unexpectedly found that the process can be performed in high yields, producing high-purity rucaparib with greater atom economy and avoiding the use of environmentally harmful organic solvents in the key step of the process. In particular, the use of the bromine atom employed in the synthesis method previously described is avoided, as the coupling reaction is conducted starting directly from the indole with a palladium-catalyzed regioselective coupling reaction. In this reaction, the solvent dichloromethane normally used in the Suzuki reaction is replaced with water. The process is advantageous from the industrial standpoint as it provides high regioselectivity without the use of complex intermediates or potentially toxic, environmentally harmful solvents.

The object of the present invention is a process for the preparation of rucaparib having the following formula (I) or a pharmaceutically acceptable salt thereof:

I

wherein said process comprises the following steps:

a) coupling reaction between a compound of formula IX:

IX

wherein Ri is straight or branched Ci-C₆ alkyl, and a compound of formula XIX:

XIX wherein X is halogen and R₂ is straight or branched Ci-C₆ alkyl, to obtain a compound of formula X

wherein Ri and R₂ are as defined above; and

b) reaction of compound of formula XX obtained in step a) with

N-phthalimido-ethylamino-acetaldehyde to obtain compound of formula XXI:

XXI

wherein Ri and R₂ are as defined above; and

c) conversion of compound of formula XXI, obtained in the preceding step, to compound of formula XXII:

XXII

wherein R₂ is as defined above; and

d) hydrolysis of compound of formula XXII obtained in the preceding step to obtain rucaparib of formula (I), and optionally

e) transformation of rucaparib of formula (I) obtained in the preceding step to a pharmaceutically acceptable salt. Detailed description of the invention

In compounds of Formula IX, XX and XXI, Ri is preferably methyl, ethyl, n-propyl, sec-propyl, n-butyl or tert-butyl, more preferably methyl.

In compounds of Formula XIX, XX and XXI, R₂ is preferably methyl, ethyl, n-propyl, sec-propyl, n-butyl or tert-butyl, more preferably tert-butyl.

In compound XIX, X is F, CI, Br or I, more preferably I.

The preferred salt of rucaparib of formula (I) is the camphorsulphonic acid salt. Indole IX and iodo-aryl XIX are commercially available.

Step a): regioselective coupling reaction between compound of formula IX and compound of formula XIX to give compound of formula XX

The reaction can be conducted using palladium or a salt or complex thereof, such as palladium acetate and palladium chloride, as catalyst. The reaction can preferably be performed using palladium acetate as catalyst. The palladium acetate catalyst is preferably used in a ratio ranging from 0.05 to 0.001 to compound IX.

The reaction can be conducted using a monodentate or bidentate phosphine as ligand, such as triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tri-ortho-toluylphosphine, 2,2'-bis(diphenylphosphino)-l, -binaphthyl (BINAP), tri(2-furyl)phosphine (TFP), 4-(N,N-dimethylamino)phenyl)di-tert-butyl phosphine (APhos), l,2,3,4,5-pentaphenyl- -(di-tert-butylphosphino)ferrocene (QPhos),

1 , 1 '-ferrocenediyl-bis(diphenylphosphine) (dppf), 1 ,4-bis(diphenylphosphino)butane (dppb), l,2-bis(dicyclohexylphosphino)ethane (dcpe), bis(diphenylphosphino)methane (dppm), l,l,l-tris(diphenylphosphinomethyl)ethane (Triphos),

1.2- bis(dimethylphosphino)ethane (dmpe), l,2-bis(diphenylphosphino)ethane (dppe) and

1.3- bis(diphenylphosphino)-propane (dppp).

The reaction can preferably be performed using dppm as ligand. The bidentate ligand dppm is preferably used in a stoichiometric ratio to palladium acetate ranging from 1.1 to 1.

The reaction can be performed using potassium acetate and sodium acetate as base.

The reaction can preferably be performed using potassium acetate as base. Potassium acetate is preferably used in a stoichiometric ratio to compound IX ranging from 10 to 1.

The reaction is preferably performed using compound XIX in a stoichiometric ratio to compound IX ranging from 1.5 to 1.

The reaction can be performed in water or protic organic solvents such as ethanol, methanol, isopropanol or mixtures thereof, and preferably using water as the solvent. The reaction can be performed at a temperature from room temperature to 120°C.

The regioselectivity of the reaction can be obtained to a surprisingly high extent by operating at a temperature ranging from 80°C to 110°C. The reaction time is from 2 to 48 hours, preferably from 12 to 36 hours, and more preferably from 16 to 30 hours. The reaction can be performed at a pressure ranging from 1 to 2 bars, preferably from 1 to 1.2 bars.

To isolate compound XX, the reaction mixture is extracted in ethyl acetate.

The ethyl acetate solution is concentrated under vacuum, preferably at a pressure of less than 100 mBars and in a time of less than 2 hours.

The product is obtained as an oil, and it is purified by silica-gel column chromatography to obtain a white solid.

Step b): reaction of compound XX with N-phthalimido-ethylamino-acetaldehyde by alkylative reduction to give compound XXI

Compound XXI is prepared by reacting compound XX with N-phthalimido- ethylamino-acetaldehyde in an aprotic solvent at a controlled temperature in the presence of an acid and a reducing agent which are suitable to promote the reaction.

This step is performed by the method described in Righi et al., Journal of Organic

Chemistry, 2012, 77,14, 6351-6357.

The reaction can be performed using trifluoroacetic acid, trichloroacetic acid and acetic acid, for example, as the acid. Trifluoroacetic acid is preferably used as the acid. The reaction can be performed using triethylsilane, diphenylsilane, triethoxysilane or tetramethyldisiloxane, for example, as reducing agent, preferably triethylsilane.

The stoichiometric ratio of N-phthalimido-ethylamino-acetaldehyde to compound XX is from 2.0 to 1.0, preferably from 1.5 to 1.0, and more preferably from 1.2 to 1.0. The molar ratio of the acid to compound XX usually ranges from 10.0 to 1.0; preferably from 8.0 to 2.0, and more preferably from 6.0 to 3.0. The molar ratio of reducing agent to compound XX usually ranges from 6.0 to 1.0; preferably from 5.0 to 1.0, and more preferably from 4.0 to 1.0.

The reaction can be performed in aprotic solvents including dichloromethane, ethyl acetate, toluene, acetonitrile, dimethylformamide, tetrahydrofuran, dioxane or mixtures thereof. The reaction is preferably performed in dichloromethane.

The sequence of operations preferably involves adding the acid and the reducing agent in succession to a solution of compound XX in the reaction solvent.

The mixture of compound XX with the acid and the reducing agent is maintained at a temperature ranging from 0°C to the boiling point of the solvent, preferably from 10 to 30°C, and more preferably from 15 to 25°C. The reaction mixture is kept under stirring for a time ranging from 1 hour to 36 hours, preferably from 2 to 24 hours. At the end of the reaction the reaction mixture is cooled to a temperature ranging from -10 to 10°C, preferably from -5 to 5°C.

The reaction mixture is neutralised by adding an organic base such as triethylamine, pyridine or diisopropylethylamme or an inorganic base such as sodium bicarbonate, sodium carbonate, potassium bicarbonate or potassium carbonate, preferably sodium bicarbonate.

The solution of compound XXI in dichloromethane is concentrated under vacuum, preferably at a pressure of less than 100 mBars and in a time of less than 2 hours.

Compound XXI can be isolated by crystallisation from organic solvent. Step c): conversion of compound XXI to compound XXII by removal of the phthalimido group and formation of a lactam

Compound XXII is prepared by deprotection of the phthalimido group followed by formation of lactam to give the azepine ring.

The reaction is performed in a pro tic solvent such as water, ethanol, methanol or isopropanol. The reaction is preferably performed in water.

The reaction is performed using a reagent such as methylamine, hydrazine, phenylhydrazine, methylhydrazine or hydroxylamine, preferably methylamine.

The stoichiometric ratio of methylamine to compound XXI ranges from 10 to 50, preferably from 20 to 40.

The reaction is performed at a temperature generally ranging from 0 to 40°C, preferably from 15°C to 30°C, and more preferably from 20°C to 30°C. The reaction is performed for a time ranging from 0.5 to 4 hours, preferably from 0.5 to 2 hours.

The reaction is performed by adding compound XXI to the methylamine solution. Compound XXII is recovered by filtration from the reaction mixture.

Compound XXII can be purified by crystallisation from water or organic solvents.

Step d): hydrolysis of the protecting group of XXII to give rucaparib (I)

The hydrolysis reaction of the tert-butyloxycarbonyl (BOC) protecting group of compound XXII is preferably performed in a mixture of an aprotic solvent such as dichloromethane, ethyl acetate, toluene or THF with a protic solvent such as methanol, ethanol or isopropanol. The reaction is preferably performed in a mixture of dichloromethane and methanol.

The reaction is promoted by an acid such as trifluoroacetic acid or hydrochloric acid in methanol. The stoichiometric ratio of hydrochloric acid to compound XXII ranges from 20 to 5, preferably from 10 to 5.

The reaction is performed by adding hydrochloric acid dissolved in methanol to the solution of compound XXII in dichloromethane and methanol. The reaction is performed at a temperature generally ranging from 0 to 40°C, preferably from 15°C to 30°C, and more preferably from 20°C to 30°C. The reaction is performed for a time ranging from 1 to 24 hours, preferably from 2 to 6 hours.

When the reaction to the solution in dichloromethane and methanol is complete, an inorganic base such as sodium hydroxide, potassium hydroxide or sodium bicarbonate is added. Sodium hydroxide, added in the form of a concentrated aqueous solution, is preferably used as inorganic base. The stoichiometric ratio of inorganic base to hydrochloric acid added to the reaction is from 1.5 to 1.

The resulting precipitate is recovered by filtration.

Step e): optional salification of rucaparib (I) to the corresponding camphorsulphonic acid salt

This step is performed, for example, by the method described in Gillmore et al, Organic Process Research & Development, 2012, 16, 1897-1904.

The formation of the camphorsulphonic acid salt of rucaparib (I) is performed in a mixture of water with protic solvents, such as methanol, ethanol or isopropanol.

The formation of the camphorsulphonic acid salt of rucaparib (I) is preferably performed in a water and isopropanol mixture. A solution of camphorsulphonic acid in water is added to a suspension of rucaparib (I) in water and isopropanol. The suspension is heated to a temperature ranging from 60 to 80°C until completely dissolved. The solution is cooled to a temperature ranging from 50 to 20°C to precipitate the product. The suspension is cooled to a temperature ranging from 0 to 20°C. The precipitated product is isolated by filtration.

A further object of the invention is the reaction intermediate of formula XXI:

XXI

wherein Ri is straight or branched Ci-C₆ alkyl and R₂ is straight or branched Ci-C₆ alkyl, and its use in processes for the preparation of rucaparib of formula (I) or a pharmaceutically acceptable salt thereof.

The process will now be further illustrated by the following examples.

EXAMPLES

EXAMPLE 1

Compound (XX)

Pd(OAc)₂ (8.7 mg, 0.04 mmol, 5 mol%), dppm (14.8 mg, 0.04 mmol, 5 mol%) and AcOK (227 mg, 2.3 mmol) are added to a suspension of compound XIX (250 mg, 0.78 mmols) and compound IX (400 mg, 1.16 mmols) in water. The resulting suspension is maintained under vigorous stirring for 24 hours at 110°C. After 24 hours the reaction mixture is cooled to room temperature. IN HCl (10 mL, 10 mmols) and ethyl acetate (20 mL) are added. The organic phase is separated and the aqueous phase is further extracted with ethyl acetate (2 x 10 mL). The combined organic phases are concentrated at low pressure.

After chromatographic purification (Si02, hexane/ethyl acetate 9/1), compound XX (195 mg, 0.46 mmols, 60%) is obtained.

EXAMPLE 2

Compound (XXI)

A solution of trifluoroacetic acid (0.38 mL, 5 mmols) and triethylsilane (0.48 mL, 3 mmols) in dichloromethane (3 mL) is added to a solution of compound XX (420 mg, 1.0 moles) and N-phthalimido-ethylamino-acetaldehyde (225 mg, 1.1 mmols) in dichloromethane (3 mL).

The resulting mixture is kept under stirring at room temperature for 3-16 hours. The reaction is cooled to 0°C, carefully neutralised with a sodium bicarbonate saturated solution (15 mL) and diluted with dichloromethane (20 mL).

The organic phase is extracted and evaporated under vacuum to a residue.

Compound XXI is isolated (350 mg, 0.60 mmols, 60%) by silica-gel column chromatography (Si02, hexane/ethyl acetate 9/1).

EXAMPLE 3

Compound (XXII)

A solution of methylamine in water (40%wt, 3.0 mL, 35 mmols) is added to compound XXI (300 mg, 0.51 mmols). The resulting suspension is kept under stirring at room temperature for 24 hours. Water (5 mL) is added to the reaction. The resulting solid is filtered and washed with water. After drying, compound XXII is obtained (175 mg, 0.41 mmols, 80%).

EXAMPLE 4

Rucaparib (I)

TFA (0.5 mL) and TIPS (0.2 mL) are added to compound XXII (150 mg, 0.38 mmols) in dichloromethane (5 mL) at the temperature of 0°C. The solution is brought to room temperature and kept under stirring for 12 hours.

The solvent is evaporated at low pressure. The residue is dissolved in methanol

(10 mL); water (15 mL) and concentrated hydrochloric acid (2 mL) are added, and the mixture is kept under stirring for 1 hour. THF is added (10 mL). The solution is concentrated to obtain a suspension, which is filtered. After washing with water (5 mL) a solid is obtained, which is isolated. Said solid is added to a solution of sodium hydroxide (40 mg, 1.0 mmols) in water (10 mL). The resulting suspension is filtered. The solid is washed with water to obtain rucaparib (I) (100 mg, 0.30 mmols, 80%>).

Claims

1. A process for the preparation of rucaparib having the following formula (I):

I

or a pharmaceutically acceptable salt thereof,

wherein said process comprises the following steps:

a) coupling a compound of formula IX:

IX

wherein Ri is straight or branched Ci-C₆ alkyl, with a compound of formula XIX:

XIX

wherein X is halogen and R₂ is straight or branched Ci-C₆ alkyl, to obtain a compound of formula XX:

XX wherein Ri and R₂ are as defined above; and

b) reacting compound of formula XX obtained in step a) with N-phthalimido amino acetaldehyde to obtain compound of formula XXI:

XXI

wherein Ri and R₂ are as defined above; and

c) converting compound of formula XXI, obtained in the previous step, to compound of formula XXII:

XXII

wherein R₂ is as defined above; and

d) hydrolyzing compound of formula XXII, obtained in the previous step, to obtain rucaparib of formula (I), and optionally

e) transforming rucaparib of formula (I) obtained in the previous step into a pharmaceutically acceptable salt thereof.

2. The process according to claim 1 wherein:

Ri in compounds of Formula IX, XX and XXI is methyl, ethyl, n-propyl, sec-propyl, n-butyl or tert-butyl;

R₂ in compounds of Formula XIX, XX and XXI is methyl, ethyl, n- propyl, sec-propyl, n-butyl or tert-butyl; and

X in compound XIX is F, CI, Br or I.

3. The process according to claim 1 wherein:

Ri in compounds of Formula IX, XX and XXI is methyl;

R₂ in compounds of Formula XIX, XX and XXI is tert-butyl; and

X in compound XIX is I.

4. The process according to any one of the preceding claims wherein the pharmaceutically acceptable salt of the rucaparib of formula (I) is the camphorsulphonic acid salt.

5. The process according to any one of the preceding claims wherein step a) is carried out in the presence of a palladium catalyst or a salt or a complex thereof, a monodentate or bidentate phosphine and a base, in a solvent selected from water, protic organic solvents and mixtures thereof.

6. The process according to claim 5 wherein the catalyst is palladium acetate and the base is an alkali metal or alkaline earth metal acetate.

7. The process according to claim 5 or 6 wherein the monodentate or bidentate phosphine is selected from the group consisting of triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tri-ortho-toluylphosphine, BINAP, TFP, APhos, QPhos, dppf, dppb, dcpe, dppm, Triphos, dmpe, dppe and dppp.

8. The process according to any one of claims 5 to 7 wherein the solvent is water.

9. The process according to any one of claims 5 to 8 wherein step a) is carried out at a temperature from 80°C to 1 10°C.

10. The process according to any one of the preceding claims wherein step b) is carried out in the presence of a reducing agent selected from the group consisting of triethylsilane, diphenylsilane, triethoxysilane and tetramethyldisiloxane and an acid in a protic organic solvent.

1 1. The process according to claim 10 wherein the acid is trifluoroacetic acid, trichloroacetic acid or acetic acid and the organic solvent is selected from the group consisting of dichloromethane, ethyl acetate, toluene, acetonitrile, dimethylformamide, tetrahydrofuran, dioxane and mixtures thereof.

12. The process according to claim 10 or 1 1 wherein the reducing agent is triethylsilane, the acid is trifluoroacetic acid and the solvent is dichloromethane.

13. The process according to any one of claims 10 to 12 wherein step b) is carried out at a temperature ranging from 15°C to 25°C.

14. The process according to any one of the preceding claims wherein step c) is carried out in the presence of a base selected from a primary amine, hydroxylamine and hydrazine, in water or in a protic organic solvent.

15. The process according to claim 14 wherein the base is methylamine and the solvent is water.

16. The process according to any one of claims 14 and 15 wherein step c) is carried out at a temperature ranging from 20°C to 30°C.

17. The process according to any one of the preceding claims wherein step c) is carried out in the presence of an acid in a protic or aprotic organic solvent or a mixture thereof.

18. A compound of formula XXI :

XXI

wherein Ri is straight or branched Ci-C₆ alkyl and R₂ is straight or branched Ci-C₆ alkyl.