WO2007140989A2

WO2007140989A2 - Process for the manufacture of 2-butyl-3- (4-methoxybenzoyl) -5-nitrobenzofurane and use thereof in the production of of medicaments

Info

Publication number: WO2007140989A2
Application number: PCT/EP2007/004984
Authority: WO
Inventors: Lars Eklund
Original assignee: Cambrex Karlskoga Ab
Priority date: 2006-06-07
Filing date: 2007-06-05
Publication date: 2007-12-13
Also published as: GB0611210D0; WO2007140989A3

Abstract

A process for the production of 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofurane by reaction of 2-butyl-5-nitrobenzofuran, characterised by the exclusive use of non-halogenated solvents in the reaction and/or extraction by crystallisation of the product. There is also proidde a method of making Dronedarone including the step of making the intermediate 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofurane in the presence of non-halogenated solvents.

Description

PROCESS

The present invention relates to a process for the manufacture of 2-butyl-3-(4- methoxybenzoyl)-5-nitrobenzofurane and its use as an intermediate in the manufacture of Dronedarone (N-[2-(n-butyl)-3-[4-[3-(dibutylamino)propoxy] benzoyl]-5-benzofuranyl] methane-sulphonamide).

Dronedarone is a Class III anti-arrhythmic drug for the prevention of cardiac arrhythmias such as atrial fibrillation (AF). AF is a condition characterised by an irregular heart beat and occurs when the atria (the upper chambers of the heart) contract very rapidly. This causes the lower chambers of the heart, the ventricles, to contract chaotically so that blood is inefficiently pumped to the body which can lead to tissue damage and even death.

Dronedarone is prepared via a stepwise procedure which involves the synthesis of a ^" number of intermediates, of which one example is 2-butyl-3-(4- methoxybenzoyl)-5-nitrobenzofurane.

2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofurane is conventionally synthesised by Friedel-Craft acylation of 2-butyl-5-nitrobenzofuran in the presence of a halogenated solvent. US 5,223,510 describes the synthesis of 2-butyl-3-(4- methoxybenzoyl)-5-nitrobenzofurane from 2-butyl-5-nitrobenzofuran in the presence of the solvent dichloro ethane. US 5,854,282 and JP2002-371076 both teach the synthesis of 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofurane from 2- butyl-5-nitrobenzofuran in the solvent, methylene chloride.

The current methods of production of both Dronedarone and its intermediates (such as 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofurane) are characterised by high costs, poor yields and are hazardous to . either or both humans and the environment (see US 6,984,741). In summary, none of the previous approaches to production of Dronedarone and its intermediates are wholly satisfactory and there is a need for improved methods of synthesis.

The listing or discussion of a prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or common general knowledge.

The present invention provides a new process for the manufacture of the intermediate 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofurane and also Dronedarone.

In a first aspect of the invention there is provided a process for the production of 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofurane by reaction of 2-butyl-5- nitrobenzofuran, characterised by the exclusive use of non-halogenated solvents in the reaction and/or extraction (e.g. by crystallization) of the product.

By 'exclusive use' we mean that only non-halogenated solvents are used and no halogenated solvents are present.

The reaction of the invention is a Friedel-Craft acylation reaction. This reaction type is part of electrophilic aromatic substitution whereby acylation of aromatic rings is conducted with an acyl chloride and using a strong Lewis acid catalyst.

Previous studies have attempted to use non-halogenated solvents such as nitrobenzene to reduce the environmental impact of Friedel-Craft acylation in reactions other than synthesis of 2-butyl-3-(4-methoxybenzoyl)-5- nitrobenzofurane. For example, US 2005-0171385 describes the use of nitrobenzene as a solvent in the acylation of isobutylbenzene to p- isobutylacetophenone.

However, the recommended limit for nitrobenzene in a working space is as low as lppm (Occupational Exposure Limits (1985) UK health and safety executive (HSE) Guidance note EH 40/85). Therefore, whilst nitrobenzene is environmentally less-toxic than halogenated solvents, it is hazardous for those working with it in the chemical plant.

Preferably the process comprises reacting 2-butyl-5-nitrobenzofuran with 4- methoxybenzoylchloride in solution with a first non-halogenated solvent and in the presence of a catalyst, to produce 2-butyl-3-(4-methoxybenzoyl)-5- nitrobenzofurane in solution.

It should be appreciated that the various reactants may be conveyed to the reaction mixture as a single combined feed or the)' may be conveyed as two or more separate feeds.

A preferred first non-halogenated solvent is one selected from three isomers of nitrotoluene i.e. ortho-nitrotoluene (2-nitrotoluene); para-nitrotoluene (4- nitrotoluene) and meta-nitrotoluene (3=nitrotoluene).-

Nitrotoluenes are produced commercially, as a mixture, by nitration of toluene. Typical end-use markets for the Nitrotoluenes and their derivatives are main materials for the synthesis of imaging products like pigment, dyestuffs, photographic chemicals, antioxidants, agricultural, and rubber chemicals.

Advantageously the first non-halogenated solvent is ortho-nitrotoluene (2- nitrotoluene). Ortho-nitrotoluene (ONT) has a recommended limit 5 times the limit for nitrobenzene. (Occupational Exposure Limits (1985) HSE Guidance note EH 40/85)

Preferably the catalyst for this reaction is FeCb. An alternative catalyst would be tin tetrachloride.

The reaction may be conducted at any temperature in the range of (-1O⁰C to 50⁰C). However, it is preferable if the temperature of the reaction mixture is maintained at approximately 19⁰C. Preferably the concentration of the starting material, 2-buryl-5-nitrobenzofuran, in the reaction mixture is between 30 and 60% w/w. Most preferably the concentration of 2-butyl-5-nitrobenzofuran is approximately 30% w/w.

It is preferred if the number of molecules of 2-butyI-5-nitrobenzofuran and 4- methoxybenzoylchloride are in a ratio of between 1 : 1.1 to 1 : 1.5. Most preferably the ratio is 1 :1.1.

Also preferred is that the number of molecules of 2-butyl-5-nitrobenzofuran and the catalyst are in a ratio of between 1:1.1 to 1:1.5. Most preferably the ratio is 1:1.1.

Advantageously, the process of the first aspect of the invention further comprises the additional step of extraction of 2-butyl-3-(4-methoxybenzoyl)-5- nitrobenzofurane by crystallisation from solution using a second non-halogenated solvent.

Preferably the mixture is cooled after adding the second non-halogenated solvent. Conveniently, the mixture is cooled to between -5 and 15⁰C. A preferred temperature is -5⁰C (minus five degrees Celsius).

The mixture may be cooled using any suitable cooling systems well known to those skilled in the art and include, for example, heat exchangers.

The second non-halogenated solvent may also be used to wash the crystallised product providing it has been pre-cooled. Possible temperatures to which the solvent may be pre-cooled are between -5°C to 5°C. If there is no pre-cooling of the washing solvent, yield drops. Most preferred is the temperature of -5⁰C.

Preferably the second non-halogenated solvent is one selected from methanol ethanol, iso-propanol and 1-propanol. Most preferred the solvent is methanol. In a preferred embodiment, the purified 2-butyl-3-(4-methoxybenzoyl)-5- nitrobenzofurane product will have a chromatographic purity (HPLC, 254 nm) greater than 99 %, more preferably greater than 99.5 %, particularly greater than 99.6 % pure, and especially greater than 99.8 % pure, e.g. greater than 99.9 % pure based on the total amount of peaks in the chromatogram.

It should be appreciated that the purified 2-butyl-3-(4-methoxybenzoyl)-5- nitrobenzofurane product may also contain materials other than those specified above.

This product may be further purified using any suitable separation/purification technique or combination of techniques including further crystallisation, distillation, phase separation, adsorption, e.g. using molecular sieves and/or activated carbon, and scrubbing.

Optionally, the pfocess of the first aspect of the invention further comprises using a raw material containing 2-methyl-3-propyl-5-nitro benzofuran in mixture with the starting material, 2-butyl-5-nitrobenzofuran. The 2-methyl-3-propyl-5-nitro benzofuran and 2-butyl-5-nitrobenzofuran may be provided together as a mixture obtained from the synthesis of 2-butyl-5-nitrobenzofuran.

Preferably, the number of molecules of 2-butyl-5-nitrobenzofuran and 2-methyl-3- propyl-5-nitro benzofuran are in a ratio of 1 :0 to 1:2, preferably 1:0 to 1 :1.

In a second aspect of the invention there is provided a process of producing Dronedarone comprising the step of making 2-butyl-3-(4-methoxybenzoyl)-5- nitrobenzofurane using a process as described in the first aspect of the invention.

Dronedarone can be made using any standard route of synthesising alkyJaminoaalkyl derivatives of benzofuran, such as those described in US 5,223,510. In a third aspect of the invention there is provided the use of a non-halogenated solvent in the manufacture of 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofurane from 2-butyl-5-nitrobenzofuran.

Preferably the non-halogenated solvent is one selected from three isomers of nitro toluene, ortho-nitro toluene (2 -nitro toluene); para-nitro toluene (4- nitrotoluene) and meta-nitrotoluene (3 -nitro toluene). Advantageously, the solvent is ortho-nitrotoluene.

The process of the present invention may be operated as a batch process or operated as a continuous process and may be conducted on any scale.

Preferred Embodiments

Examples embodying certain preferred aspects of the invention will now be described. All equipment, reagents and solvents used were standard laboratory equipment, e.g. glassware, heating apparatus and HPLC apparatus.

Example 1 - Synthesis of 2-Butyl-5-nitrobenzofuran

To a solution of 277g hydroxylamine x HCl in 400 ml water is added 380g 2- hexanone. NaOH is then added until pH is 8-11, keeping the temperature at less than 5O⁰C. The product is extracted with 130 ml toluene and the water phase separated.

After stripping the toluene the residue is diluted with 2200 ml DMF (dimethylformamide) and 538 g 4-chloro nitrobenzene is added. The temperature is adjusted to approx. 35⁰C and NaOH is added in portions at a maximum of 50⁰C. After stirring for 5 hours at 35-50⁰C, 2200 ml of water is added, and the product extracted with 1900 ml toluene.

The toluene phase is concentrated until no water separates in the distillate and then the toluene phase is diluted with 1550 ml ethanol. The solution is cooled to approx. 25°C and 895g sulphuric acid is carefully added. The resulting slurry is heated to reflux and stirred for 12 h or until > 95 % conversion is achieved. Water, 490 ml, is added and the water phase separated.

The toluene phase is washed with 980 ml water containing 29 g NaOH and the water phase again separated. The toluene is removed at reduced pressure leaving a viscous dark oil containing 356g 2-butyl-5-nitrobenzofuran in mixture with 192g 2-methyl-3-propyl-5-nitrobenzofuran. The product can be used as raw material in the Friedel-Craft reaction without further purification or alternatively may be purified using standard methods.

Example 2 - Friedel-Craft acylation of 2-butyl-5-nitrobenzofuran without halogenated solvents

2-Butyl-5-nitrobenzofuran (5g, 22.8 mmol) was dissolved in ONT (11.6 g, giving a concentration of 30-% w/w) and 4-methoxy benzoylchloride (4.-3 gr 25.1 mmol, 1.1 equivalents) was added.

FeC13 (4.1 g, 25.1 mmol, 1.1 equivalents.) was added in portions and was accompanied with an exotherm thereby raising the temperature of the reaction mixture to 48⁰C, thus indicating that a reaction was taking place.

After approximately 20 minutes a sample was withdrawn, diluted with methanol and analyzed with HPLC. The analysis revealed that a new peak had developed in the chromatogram with a retention time corresponding to 2-butyl-3-(4- methoxybenzoyl)-5-nitrobenzofurane.

During the time, a small amount of colourless crystals had also separated from the methanol solution thus indicating the ability to crystallize the product directly from the reaction mixture by dilution with methanol, contrary to prior art methods. Hence, methanol (60 ml) was added in one portion and after a few minutes crystals start to separate. The slurry was stirred for 30 minutes at approx. 25⁰C and then cooled to 3⁰C, filtered and the filter cake washed with 20 ml methanol.

The filtered material was dried at 60⁰C to constant weight. A lH NMR spectrum was recorded and found to be identical with an authentic control sample of. 2- butyl-3-(4-methoxybenzoyl)-5-nitrobenzofurane.

This process gave rise to a yield of 5.7 g, 71 % of theoretical, with a purity measured by HPLC (254 run) as 99.9 %.

This method clearly shows that ONT is a good substitute for halogenated solvents in the Friedel-Craft reaction to obtain 2-butyl-3-(4-methoxybenzoyl)-5- nitrobenzofurane.

Since no^'extractive^" work-up Is performed in the synthesis it was expected the product would be substantially contaminated with iron, since FeCl₃ is used in excess to the substrate. Surprisingly, iron was showed to only be present in the product at a level less then 0.05 % w/w.

Example 3 - Running synthesis at 46 % concentration and using more methanol in crystallization

2-Butyl-5-nitrobenzofuran (5g, 22.8 mmol) and 4-methoxybenzoylchloride (4.3 g,

25.1 mmol, 1.1 equivalents) was dissolved in ONT (5.8 g, cone. 46 % w/w).

FeC13 (4.1 g, 25.1 mmol 1.1 equivalents) was added in portions at 22°C to 36°C.

HPLC analysis after 20 minutes showed that conversion to 2-butyl-3-(4- methoxybenzoyl)-5-nitrobenzofuran was 94 % (HPLC). Methanol (70 ml) was added in one portion and after a few minutes crystals start to separate. The slurry was stirred for 30 minutes at approx. 25°C and then cooled to 3°C, filtered and the filter cake washed with 20 ml methanol. The material was dried at 6O⁰C to constant weight.

The yield in this process was 6.4 g, 80 % of theoretical.

Example 4 - Running synthesis in the presence of 2-MethyI-3-propyl-5-nitro benzofurane at 52 % w/w concentration using 1.3 equivalents FeCB and at a higher temperature.

2-Butyl-5-nitrobenzofuran (5g, 22.8 mmol), 2-Methyl-3 -propyl- 5 -nitro benzofiiran (2.1g, 12.3 mmol) and 4-Methoxy benzoylchloride (4.3 g, 25.1 mmol, 1.1 equivalents) were dissolved in ONT (4.6 g, cone. 52 % w/w).

FeC13 (4.8 g, 29.6 mmol, 1.3 equivalents) was added in portions. HPLC analysis after 10 minutes showed that conversion to 2-butyl-3-(4-methoxybenzoyl)-5- nitrobenzofuran was 99 % (HPLC).

Methanol (66 ml) and water (6.5 ml) was added in one portion and after a few minutes an oil separated. Another portion of methanol (10 ml) was added and the mixture was brought to solution by heating to 55°C.

The solution was allowed to cool and crystallized after seeding at 46°C. The slurry was cooled to 15 ⁰C over 75 minutes. The product was filtered and the cake washed with 10 % v/v aqueous methanol (20 ml) followed by water (20 ml). The material was dried at 7O⁰C to constant weight.

The yield in this process was 6.6 g, 82 % of theoretical, and a purity (HPLC) of 99.3 % was achieved. Example 5 -Optimising the synthesis

In order to optimise the synthesis of the product, variations of reaction conditions were considered.

To a mixture of 2-butyl-5-nitro benzofurane (46.8g, 0.214 mol) and 2-methyl-3- propyl-5-nitro benzofuran (24,1 g, 0.110 mol) was added Ortho-nitrotoluene (75g) giving a concentration of 2-butyl-5-nitro benzofuran of 32 % w/w.

4-Methoxybenzoylchloride (40. Ig, 0.235 mol, 1.1 equivalents) was then charged and the temperature adjusted to 11°C. FeC13 (45.1g, 0.278 mol, 1.3 equivalents) was added in portions at such rate that the temperature due to exothermic reaction did not exceed 19⁰C.

The mixture was stirred at 17-19°C for 2.5 h and then diluted with 618 ml metfiaήol7ATπiild exoffiermTaised the temperature to 28^oe during-rhe dilution and after a few minutes at approx. 28⁰C crystals started to separate.

After stirring at approx 25°C for 40 minutes the slurry was cooled to -5⁰C over 90 minutes. The product was filtered and the cake washed with 188 ml methanol pre- cooled to 5°C.

The wet cake (68.4g) was dried to constant weight at 60⁰C, 20 mbar, giving 61.6g 2-butyl-3- (4-methoxybenzoyl)-5-nitrobenzofuran.

The yield in this process was 61.6g (81.5 % of theoretical) and a purity (HPLC) of 99.6 % was achieved.

Example 6 - Synthesis of Dronedarone

Dronedarone is synthesised using standard synthetic route incorporating the use of Ortho-nitrotoluene in the step of converting 2-butyl-5-nitrobenzofuran to 2-butyl- 3-(4-methoxybenzoyl)-5-nitrobenzofurane. Dronedarone can be made using any standard route of synthesising alkylaminoaalkyl derivatives of benzofuran, such as those described in US 5,223,510.

Claims

CLAIMS:

1. A process for the production of 2-butyl-3-(4-methoxybenzoyl)-5- nitrobenzofurane by reaction of 2-butyl-5-nitrobenzofuran, characterised by the exclusive use of non-halogenated solvents in the reaction and/or extraction by crystallisation of the product.

2. A process as claimed in claim 1 wherein 2-butyl-5-nitrobenzofuran is reacted with 4-methoxybenzoylchloride in a first non-halogenated solvent and in the presence of a catalyst, to produce 2-butyl-3-(4- methoxybenzoyl)-5-nirrobenzofurane in solution.

3. A process as claimed in any previous claim wherein the first non- halogenated solvent is one selected from three isomers of nitrotoluene, ortho-nitrotoluene (2 -nitrotoluene); para-nitrotoluene (4-nitrotoluene) and meta-nitrotoluene (3-nitrotoluene).

4. A process as claimed in claim 3 wherein the non-halogenated solvent is ortho-nitrotoluene.

5. A process as claimed in any of claims 2 to 4 wherein the catalyst is FeCl₃ or tin tetrachloride.

6. A process as claimed in claim 5 wherein the catalyst is FeCl₃

7. A process as claimed in any previous claim wherein the temperature of the reaction mixture is maintained at between approximately -10⁰C to 5O⁰C.

8. A process as claimed in claim 7 wherein the temperature of the reaction mixture is maintained at approximately 19⁰C.

9. A process as claimed in any previous claim wherein the concentration of 2-butyl-5-nitrobenzofuran in the reaction mixture is between 30 and 60% w/w.

10. A process as claimed in claim 9 wherein the concentration of 2-butyl-

5-nitrobenzofuran is approximately 30% w/w.

1 1. A process as claimed in any of claims 2 to 10 wherein the number of molecules of 2-butyl-5-nitrobenzofuran and 4-Methoxybenzoylchloride are in a ratio of between 1 :1.1 to 1 : 1.5.

12. A process as claimed in claim 11 wherein the ratio is 1 : 1.1

13. A process as claimed in any of claims 2 to 12 wherein the number of molecules of 2-butyl-5-nitrobenzofuran and the catalyst are in a ratio of between 1: 1. ^"1 to 1^": 175.

14. A process as claimed in claim 13 wherein the ratio is 1: 1.1

15. A process as claimed in any previous claim, further comprising the step of extraction of 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofurane by crystallisation from solution using a second non-halogenated solvent.

16. A process as claimed in claim 15 wherein the mixture is cooled after adding the second non-halogenated solvent.

17. A process as claimed in claim 16 wherein the mixture is cooled to between -5 and 15⁰C.

18. A process as claimed in claim 17 wherein the mixture is cooled to -5⁰C

(minus five degrees Celsius).

19. A process as claimed in any of claims 15 to 18 wherein the second non-halogenated solvent is one selected from methanol, ethanol, iso- propanol and 1-propanol.

20. A process as claimed in claim 19 wherein the second non-halogenated solvent is methanol.

21. A process as claimed in any of claims 2 to 20 comprising the step of washing the product obtained by extraction using the second non- halogenated solvent.

22. A process as claimed in any of claims 2 to 21 further comprising adding 2-methyl-3-propyl-5-nitro benzofuran to the reaction mixture with 2-butyl-5-nitrobenzofuran and 4-methoxybenzoylchloride.

23. ^~ A-process as claimed in any of claim 22- wherein -the -number of- molecules of 2-butyl-5-rdtrobenzofuran and 2-methyl-3-propyl-5-nitro benzofuran are in a ratio of between 1:0 and 1: 1.

24. A process as claimed in any previous claim wherein the purified 2- butyl-3-(4-methoxybenzoyl)-5-nitrobenzofurane product has a chromatographic purity (HPLC, 254 nm) greater than 99% based on the total amount of peaks in the chromatogram.

25. A process as claimed in claim 24 wherein the purified 2-butyl-3-(4- methoxybenzoyl)-5-nitrobenzofurane product has a chromatographic purity (HPLC, 254 nm) greater than 99.9% based on the total amount of peaks in the chromatogram.

26. A process of producing Dronedarone comprising the step of making 2- butyl-3-(4-methoxybenzoyl)-5-nitrobenzofurane using a process as claimed in any of claims 1 to 25.

27. Use of a non-halogenated soh'ent in the manufacture of 2-butyl-3-(4- methoxybenzoyl)-5-nitrobenzofurane from 2-butyl-5-nitrobenzofuran.

28. A use as claimed in 27 wherein the non-halogenated solvent is one selected from three isomers of nitrotoluene, ortho-nitrotoluene (2- nitrotoluene); para-nitrotoluene (4-nitrotoluene) and meta-nitrotoluene (3-nitrotoluene).

29. A use as claimed in 28 wherein the non-halog ce-nated solvent is ortho- nitrotoluene.

30. A process substantially as described herein with reference to the examples.

31. A use substantially as described herein with reference to the examples.