WO2025093610A1

WO2025093610A1 - A process for preparing 2-amino-3,5-difluoropyridine or a salt thereof

Info

Publication number: WO2025093610A1
Application number: PCT/EP2024/080707
Authority: WO
Inventors: Christophe Pierre Alain Chassaing; Raina SEUPEL; Tanja Schweisel; Thomas Dahmen
Original assignee: Intervet International BV; Intervet Inc
Current assignee: Intervet International BV; Intervet Inc
Priority date: 2023-10-31
Filing date: 2024-10-30
Publication date: 2025-05-08
Anticipated expiration: 2026-04-30

Abstract

The present invention provides a process for preparing 2-amino-3,5-difluoropyridine (compound F) or a salt thereof from 2,3,5-trichloropyridine (compound A) involving 3,5-difluoro-2-pyridinecarbonitrile (compound D) and 3,5-difluoro-2-pyridinecarboxamide (compound E). The process is characterized by a high purity and yield and is suitable to be used in large scale production.

Description

A PROCESS FOR PREPARING 2-AMINO-3,5-DIFLUOROPYRIDINE OR A SALT THEREOF

The present invention relates to the field of organic synthesis, particularly to a process of preparing 2- amino-3,5-difluoropyridine or a salt thereof.

Background

2-Amino-3,5-dihalopyridines constitute synthesis intermediates or structural components of numerous biologically active compounds. Their preparation is usually achieved via either halogenation of parents 3 or 5 monohalogenated 2-aminopyridines or 2-aminopyridines in the presence of halogenating agents such as bromine (WO2016183116), iodine/periodic acid (Angewandte Chemie, International Edition (2013), 52(38), 10093-10096), A/-chlorosuccinimide (European Journal of Organic Chemistry (2012), 2012(28), 5595-5604) or via the reduction of 2-nitro- (Collection of Czechoslovak Chemical Communications (1991), 56(11 A), 2420-9) or 2-hydrazino- (US20060047124) 3,5-dihalopyridines in the presence of suitable reducing agents or in less frequent cases via nucleophilic substitution of 2-fluoro-3,5-dihalopyridine with nucleophiles such as ammonia (Bioorganic & Medicinal Chemistry Letters (2015), 25(17), 3436-3441) or an alkylamidine followed by an hydrolysis (Organic & Biomolecular Chemistry (2018), 16(41), 7564-7567).

Among the 2-amino-3,5-dihalopyridine class of compounds, derivatives having fluorine substituents are useful for preparation of various pharmaceutical agents. Particularly, 2-amino-3,5-difluoropyridine can be used in the preparation of compounds known from WO2022/161972 A1.

The preparation of fluorinated 2-aminopyridine is more challenging than of other halogenated 2- aminopyridines as the repertoire of synthetic methods for introducing a fluorine on the pyridine ring is very limited. The most frequently used methodologies involve metal-halogen exchange followed by reaction of the organometallic intermediate with a fluorinating agent such as A/-fluorobenzenesulfonimide (Angewandte Chemie, International Edition (2010), 49(12), 2215-2218), halogen exchange in the presence of a fluorine salt such as potassium fluoride (US20060009643) or conversion of an amine into a diazonium salt followed by reaction with a fluorinating agent such as tetrafluoroboric acid (US20060199960).

US2006/0047124 A1 describes preparation of 2-aminopyridine derivatives, in particular of 2-amino-3,5- difluoropyridine. The described method involves a regioselective mono-dehalogenation of pentafluoropyridine to deliver 2,3,5,6-tetrafluoropyridine. Sequential condensations on 2, 3,5,6- tetrafluoropyridine with hydrazine monohydrate at positions 2 and 6, followed respectively by reduction in the presence of copper sulfate and of acetic acid or with hydrogen in the presence of a Raney nickel catalyst affords 2-amino-3,5-difluoropyridine.

Although this method results in a high yield, it is less suitable for large-scale production due to the use of compounds with high reactivity. Such compounds require a special handling process due to their sensitivity and instability. The reaction also involves formation of toxic intermediates and the use of toxic reagents, both undesired in large-scale production. Another disadvantage of the method is that it starts from pentafluoropyridine, which is difficult to source.

There is a need to provide a process of preparing 2-amino-3,5-difluoropyridine, which does not suffer from the above-mentioned disadvantages. The method should be suitable for scale up and involve compounds that are stable, not toxic and easy to source.

It is therefore an object of the present invention to provide a manufacturing process for preparation of 2- amino-3,5-difluoropyridine that does not involve toxic or instable reagents or intermediates, or the use of reducing agents. Preferably, the process achieves a high yield and a high purity of the target compound, and is suitable for large-scale production. Summary of invention

The present invention provides a process for preparing 2-amino-3,5-difluoropyridine (compound F) or a salt thereof from 2,3,5-trichloropy ridi ne (compound A) involving 3,5-difluoro-2-pyridinecarbonitrile (compound D) and 3,5-difluoro-2-pyridinecarboxamide (compound E) as synthetic intermediates.

Brief description of the drawings

Figure 1 shows a schematic representation of the reaction steps according to an embodiment of the present invention.

Detailed description

Surprisingly it was found that 2-amino-3,5-difluoropyridine (compound F) can be obtained with a high yield and purity from 2,3 ,5-trichloropy ridine (compound A) that is relatively easy to source, by a process which does not involve prohibitively toxic or unstable compounds and is amenable to production at a large scale. The process involves compounds 3,5-difluoro-2-pyridinecarbonitrile, also known as 2-amido-3,5- difluoropyridine (compound E) as synthetic intermediates.

For reference:

Compound A = 2,3,5-trichloropy ridine

Compound B = 2-fluoro-3,5-dichoropyridine

Compound C = 3,5-dichloro-2-pyridinecarbonitrile

Compound D = 3,5-difluoro-2-pyridinecarbonitrile

Compound E = 3,5-difluoro-2-pyridinecarboxamide

Compound F = 2-amino-3,5-difluoropyridine

Compound G = a salt of 2-amino-3,5-difluoropyridine

The method according to the invention preferably comprises the steps of

(a) converting compound A to compound D,

(b) subjecting compound D to hydrolysis to obtain compound E,

(c) subjecting compound E to Hofmann rearrangement to obtain compound F.

In step (a), compound A is converted to compound D. This can be done by methods known to the person skilled in the art of organic synthesis. Preferably, step (a) comprises the following steps:

(a1) reacting compound A with a fluoride source under conditions of nucleophilic aromatic fluorination to obtain compound B,

(a2) reacting compound B with a cyanide source to obtain compound C,

(a3) reacting compound C with a fluoride source under conditions of nucleophilic aromatic fluorination to obtain compound D. In step (a1) the chlorine atom in the position 2 of compound A is substituted for a fluorine atom by nucleophilic aromatic fluorination. To achieve this transformation, compound A is reacted with a fluoride source under suitable conditions. Typically, this reaction is performed in a polar aprotic solvent at an elevated temperature. Suitable aprotic solvents include, for example, dimethyl sulfoxide (DMSO), N,N- dimethyl formamide (DMF), acetonitrile, A/,A/-dimethyl acetamide (DMA), A/-methylpyrrolidin-2-one (NMP). Preferably, dimethyl sulfoxide (DMSO) is used.

It is further preferred to avoid the presence of water and therefore the solvent is preferably dried before the reaction. Drying is preferably achieved by azeotropic distillation. The water content of the solvent is preferably less than 1 wt.%, more preferably less than 0.5 wt.%.

The fluoride source can be a salt. Examples of suitable salts include potassium fluoride (KF), cesium fluoride (CsF), sodium fluoride (NaF), or other fluorides such as tetramethylammonium fluoride. Preferably, potassium fluoride is used.

The temperature of the reaction can be in the range 80-180°C, preferably 120-140°C.

In step (a2) the fluorine in compound B is exchanged for a cyano group by reacting compound B with a cyanating agent. The reaction can be performed at room temperature. Generally, no catalyst is necessary. The cyanating agent (cyanide source) is preferably a cyanide salt, such as potassium cyanide or sodium cyanide, preferably potassium cyanide.

The reaction (a2) is performed in a suitable solvent. Advantageously, the same solvent as in step (a1) can be used. However also a different solvent can be used, e.g. methyl te/Y-butylmethyl ether (MTBE).

Preferably, steps (a1) and (a2) are performed in one pot, meaning that no intermediate reaction product is isolated or purified. This means that, preferably, the reagents of step (a2) are added to the same vessel, containing the reaction mixture obtained in step (a1).

Preferably, compound C is isolated from the reaction mixture obtained in step (a2). The obtained suspension from step (a2) typically contains a mixture of inorganic salts (e.g. KCN; KCI) and a liquid that consists of a solution of 2-cyano-3,5-dichloropyridine. Compound C can be isolated by known methods, e.g. by liquid-liquid separation. Liquid-liquid separation can be performed e.g. by extraction using water and an organic solvent (e.g. MTBE).

This optional separation step after step (a2) has an advantage that it may provide for a higher yield in the following step (a3) because of less byproduct formation. Inventors have found that there is also no need for (further) purification of the compound at this stage, which simplifies the whole process considerably.

In step (a3) compound C is reacted with a fluoride source under conditions of nucleophilic aromatic fluorination to obtain compound D. Suitably, the reaction conditions, solvent and/or the fluoride source from step (a1) may be used for step (a3). Preferably, a lower temperature may be used, such as 110-130°C. The resulting compound is 3,5-difluoro-2-pyridinecarbonitrile (compound D). Compound may be subjected to purification, e.g. using charcoal, to obtained purified product for the next step.

In step (b), compound D is subjected to hydrolysis to obtain compound E. Hydrolysis is preferably performed in the presence of either a strong acid or a strong base, or in the presence of metal catalysts or periodo reagents under neutral conditions. Preferably, hydrolysis in this case is performed in the presence of a strong acid.

Strong acid in this application is an acid with a pKa in water of less than 3, preferably less than 0, more preferably less than -2. Examples of suitable strong acids include hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid. Preferably, hydrochloric acid is used, which allows to achieve the highest yield and purity compared to other acids. Hydrochloric acid is preferably used as a concentrated solution in water. Also, gaseous HCI in water or an organic solvent can be used.

Hydrolysis in step (b) can be done in a mixture of water and an organic solvent (e.g. the solvent present in the reaction mixture from previous steps). In other embodiments, the hydrolysis in step (b) is performed in the absence of organic solvents. In that case, only water is present as a liquid medium. It can be advantageous because it allows to obtain compound E as a solid, as described herein-further.

The product of step (b) is preferably isolated. This can be done by known methods. For example, it can be extracted by liquid-liquid extraction using an organic solvent (e.g. ethyl acetate). If no organic solvent was used in step (b), then the product of step (b) (compound E) is obtained in the solid form, which makes its isolation easier.

In some embodiments, compound E obtained in step (b) might be purified. Purification can be done by adding a solvent, heating to an elevated temperature and cooling down. The side products remain in solution, while pure compound E precipitates from the mother liquor. The solvent is then removed by suitable means (e.g. filtration followed by drying under reduced pressure). Any suitable solvent can be used, e.g. an ether, preferably methyl fe/Y-butylether (MTBE).

In step (c), compound E is subjected to Hofmann rearrangement to obtain compound F. Hofmann rearrangement is typically performed in the presence of a hypohalite source and a strong base. Preferred hypohalite sources in this case include sodium hypochlorite (NaCIO), periodo reagents (e.g. iodobenzene diacetate, (bis(trifluoroacetoxy)iodo)benzene), A/-bromosuccinimide, A/-chlorosuccinimide or bromine. Preferably sodium hypochlorite is used. The advantage is that it is a relatively cheap and accessible reagent. Bromine is less convenient to handle at scale as it may generates toxic vapours. Hypervalent iodine reagents such as iodobenzene diacetate are more expensive than NaCIO and are not atom economic. As a strong base, inorganic hydroxides or salts can be used such as KOH or NaOH, or organic bases such as 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Preferably, an inorganic hydroxide such as NaOH is used. The reaction can be carried out between 50 and 90°C. The reaction in step (c) can be performed in water or in an organic solvent, depending on the reagents selected for performing the reaction. A skilled person is able to select a suitable reaction medium for a particular mixture of reagents. As an example, the reaction of step (c) is done in water, using NaOH as the strong base and NaCIO as the hypochlorite source.

As a result of step (c), compound F is obtained as a free base. Since compound F is relatively volatile, it can be advantageously converted to a less volatile salt for the ease of further handling, especially when handling at scale. Therefore, the method according to the invention preferably further comprises:

(d) reacting compound F with a strong acid to form a salt of compound F.

Suitable strong acids for forming a salt of compound F include for example hydrochloric acid, hydrobromic acid, sulphuric acid. Preferably, hydrochloric acid is used. Step (d) includes addition of a strong acid to the mixture obtained as a result of step (c). The strong acid is preferably used in the form of an aqueous solution or in an organic solution of (gaseous) hydrochloric acid in e.g. 1 ,4-dioxane. The salt precipitate can be filtered out and optionally rinsed with a solvent, e.g. MTBE.

The process according to the invention is characterized by a sufficiently high purity (>90%, preferably more than 95%, up to 99%) and yield to be suitable for large scale production.

The starting compound A is relatively easy to source. The described process does not involve prohibitively toxic or unstable reagents or intermediates. Another advantage is that compound F is obtained in high yield and purity, even without the need of tedious intermediate purification steps.

The invention will now be further described by the following, non-limiting, examples.

Examples

HPLC Method A:

Agilent UHPLC/MS 1290 series composed of: High speed pump G7120A included degasser Well plate sampler G4226A

Column oven G7116B, MCT

Diode array detector G7117B

Mass detector G6105B Quadrupole LC/MS with ESI-Jetstream-source

Chromatographic systems:

Column information: Xbridge BEH C18 from Waters, 2.1*50 mm, 2.5 p

Solvent A: water / ammonia: 99.9 / 0.1 % vol. / vol.

Solvent B: acetonitrile / ammonia: 99.9 / 0.1 % vol. I vol.

Gradient: from 2 % MeCN to 100 % MeCN in 1 .2 min, 0.5 min 100 % MeCN

Flow: 0.8 mL / min Oven temperature: 40 °C

Injection volume: 0.3 pL

Run time: 2.2 min (0.4 min equilibration time included)

Detection method: UV @254 nm and 210 nm

ESI/MS (100-1000 m/z), positive ions

HPLC Method B:

Aqilent UHPLC/MS 1290 series composed of:

High speed pump G7120A included degasser

Well plate sampler G4226A

Column oven G7116B, MCT

Diode array detector G7117B

Mass detector G6135B XT Quadrupole LC/MS with ESI-Jetstream-source

Chromatographic systems:

Column information: XbridgeP BEH C18+ from Waters, 2.1*50 mm, 2.5 p

Solvent A: water / ammonia: 99.9 / 0.1 % vol. I vol.

Solvent B: acetonitrile / ammonia: 99.9 / 0.1 % vol. I vol.

Gradient: from 2 % MeCN to 100 % MeCN in 1 .2 min, 0.5 min 100 % MeCN

Flow: 0.8 mL / min

Oven temperature: 40 °C

Injection volume: 0.3 pL

Run time: 2.2 min (0.4 min equilibration time included)

Detection method: UV @254 nm and 210 nm

ESI/MS (100-1000 m/z), positive ions

HPLC Method C:

Aqilent UHPLC/MS 1290 series composed of:

High speed pump G7120A included degasser

Well plate sampler G4226A

Column oven G7116B, MCT

Diode array detector G7117B

Mass detector G6105B Quadrupole LC/MS with ESI-Jetstream-source

Chromatographic systems:

Column information: Xbridge BEH C18 from Waters, 2.1*50 mm, 2.5 p

Solvent A: water / ammonia: 99.9 / 0.1 % vol. I vol.

Solvent B: acetonitrile / ammonia: 99.9 / 0.1 % vol. I vol.

Gradient: from 2 % MeCN to 100 % MeCN in 1 .2 min, 0.5 min 100 % MeCN

Flow: 0.8 mL / min

Oven temperature: 40 °C

Injection volume: 0.3 pL

Run time: 2.2 min (0.4 min equilibration time included) Detection method: UV @254 nm, 225 nm and 210 nm

ESI/MS (100-1000 m/z), positive ions

Examples

Example 1. Preparation of 3,5-dichloro-2-pyridinecarbonitrile (Compound C)

A jacketed reactor (500 mL) equipped with a reflux condenser with a reflux divider head, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with dry dimethylsulfoxide (240 mL) and with potassium fluoride (47.3 g, 814 mmol). The temperature was raised to about 100 °C and approximately 20 % of the solvent volume was distilled off under reduced pressure (about 10 mbar). After cooling the dry solution to room temperature, 2,3,5-trichloropyridine (30 g, 163 mmol) was added under a light nitrogen stream and the resulting mixture was stirred at 152 °C for 4 h. The temperature was lowered to room temperature and potassium cyanide (14.84 g, 228 mmol) was added. The resulting mixture was stirred at ambient temperature for 18 h. The reaction mixture was cooled to 13 °C, diluted with water (900 mL) and extracted with methyl te/Y-butylmethyl ether (750 mL). The organic layer was washed with brine (300 mL), filtered over a pad composed of magnesium sulfate (100 g) and of Celite® (25 g) which was rinsed with methyl te/Y-butylmethyl ether (150 mL). The filtrate was concentrated to afford 3,5-dichloro- 2-pyridinecarbonitrile as a brown solid (22.79 g, 115 mmol, 71 % yield).

HPLC Method A: Ret. Time: 1.03 min

¹H-NMR (600 MHz, d₆-DMSO) 5 (ppm): 8.83 (d, J = 2.1 Hz, 1 H), 8.66 (d, J = 2.0 Hz, 1 H).

Example 2. Preparation of 3,5-difluoro-2-pyridinecarbonitrile (Compound D)

A three-neck round-bottom flask (500 mL) equipped with a reflux condenser with a reflux divider head, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with dry dimethylsulfoxide (195 mL) and with potassium fluoride (33.3 g, 573 mmol). The temperature was raised to about 100 °C and approximately 20 % of the solvent volume was distilled off under reduced pressure (about 10 mbar). After cooling the dry solution to room temperature, 3,5-dichloro-2-pyridinecarbonitrile (22.79 g, 115 mmol) was added and the resulting mixture was heated to 115 °C (internal). After 4.5 h reaction time, the temperature was cooled to 15 °C. The reaction mixture was diluted with water (300 mL), extracted with methyl te/Y-butylmethyl ether (300 mL) and was dried over magnesium sulfate (50 g). After filtration activated charcoal (3.5 g) was added to the solution and the resulting suspension was heated to reflux for 5 min. After cooling to room temperature, the suspension was filtered over a plug of silica gel (30 g) which was rinsed with methyl fe/Y-butylmethyl ether (50 mL). The filtrate was concentrated at 40 °C and 200 mbar and then 100 mbar for 15 min to afford 3,5-difluoro-2-pyridinecarbonitrile as a brown oil (16.05 g, 86 mmol, 75% yield) containing about 10 mol% residual methyl fe/Y-butylmethyl ether. The product was used in Example 3 or 4 without further purification.

HPLC Method B: Ret. Time: 0.814 min

¹H NMR (300 MHz, d₆-DMSO) 5 (ppm): 8.76 (d, J = 2.3 Hz, 1 H), 8.38 (td, J = 9.1 , 2.3 Hz, 1 H).

¹⁹F NMR (283 MHz, d₆-DMSO) 5 (ppm): -112.59 - -1 12.81 (m).

Example 3. Preparation of 3,5-difluoro-2-pyridinecarboxamide (Compound E)

3,5-Difluoropicolinamide (94.3 g, 0.57 mol) isolated from Example 2 was dissolved in aqueous 37% wt. hydrochloric acid (900 mL) and the resulting mixture was stirred at ambient temperature for 16 h. The temperature of the mixture was adjusted to -10 °C and the pH was carefully set to pH 9.0 by the addition of aqueous 4N sodium hydroxide, while keeping the temperature below 10 °C. The aqueous solution was saturated by the addition of sodium chloride and was extracted with ethyl acetate (2 x 8 L and 2 L). The combined organic layers were filtrated over a pad of sodium sulfate (500 g) and were concentrated under reduced pressure at 40 °C to afford a beige solid. The crude product was triturated in warm methyl tert- butylmethyl ether (860 mL), was filtrated over a pore 3 fritt funnel and dried under reduced pressure to afford 3,5-difluoro-2-pyridinecarboxamide as beige solid (74.1 g, 0.47 mol, 83% yield).

HPLC Method B: Ret. Time: 0.532 min

¹H NMR (300 MHz, d₆-DMSO) 5 (ppm): 8.56 (d, J = 2.3 Hz, 1 H), 8.12 - 7.93 (m, 2H), 7.71 (s, 1 H).

Example 4. Preparation of 3,5-difluoro-2-pyridinecarboxamide (Compound E)

Aqueous 37 %wt. hydrochloric acid (35.3 mL) was added to 3,5-difluoropicolinamide (16.05 g, 86 mmol). The resulting mixture was stirred at 50 °C for 4 h and then at ambient temperature for 16 h. The temperature was adjusted to 3 °C and the reaction mixture was diluted with water (100 mL) and toluene (16 mL), while maintaining the temperature below 5 °C. The obtained suspension was filtered over a pore 3 fritt funnel, the wet cake was washed with water (2 x 20 mL) and was dried under reduced pressure at 40 °C to afford 3,5-difluoro-2-pyridinecarboxamide as beige solid (11.369 g, 66.2 mmol, 77% yield).

HPLC Method B: Ret. Time: 0.532 min

Example 5. Preparation of 3,5-difluoropyridin-2-aminium chloride (salt of Compound F)

Sodium hydroxide (35.2 g, 0.88 mol) was dissolved in water (740 ml). Aqueous (10 wt.%) sodium hypochlorite (272 mL, 0.44 mol) and 3,5-difluoro-2-pyridinecarboxamide (74 g, 0.44 mol) were added and resulting mixture was stirred at ambient temperature for 17 h. The temperature was then raised to 65 °C and the reaction mixture was stirred at this temperature for 4 h. After cooling to ambient temperature, ethyl acetate (1.6 L) was added and the resulting mixture was stirred for 10 min. The layers were allowed to settle, the organic layer was collected, washed with brine (200 mL), dried over magnesium sulfate and concentrated to approximately 250 mL. The obtained solution was diluted with methyl fe/Y-butylmethyl ether (750 mL) and a 4M solution of hydrochloric acid in 1 ,4-dioxane (115 mL, 0.46 mol) was added under stirring. The resulting suspension was stirred at ambient temperature for 30 min, was filtered and dried under reduce pressure to afford 3,5-difluoropyridin-2-aminium chloride as a beige solid (65.5 g, 0.39 mol, 89% yield, 98% purity as area % at 254 nm, content 96 wt.% by ¹H-NMR).

HPLC Method C: Ret. Time: 0.69 min

¹H NMR (300 MHz, d₄-MeOD) 5 (ppm): 8.18 - 7.98 (m, 1 H), 7.98 - 7.81 (m, 1 H).

Claims

1. A process for preparing 2-amino-3,5-difluoropyridine (compound F) or a salt thereof from 2,3,5- trichloropyridine (compound A) involving 3,5-difluoro-2-pyridinecarbonitrile (compound D) and 3,5-difluoro- 2-pyridinecarboxamide (compound E).

2. The process according to claim 1 , comprising the steps of:

(a) converting compound A to compound D,

(b) subjecting compound D to hydrolysis to obtain compound E,

(c) subjecting compound E to Hofmann rearrangement to obtain compound F or salt thereof.

3. The process according to claim 2, wherein step (a) comprises the following steps:

(a1) reacting compound A with a fluoride source under conditions of nucleophilic aromatic fluorination to obtain 2-fluoro-3,5-dichoropyridine (compound B),

(a2) reacting compound B with a cyanating agent to obtain 3,5-dichloro-2-pyridinecarbonitrile (compound C),

(a3) reacting compound C with a fluoride source under conditions of nucleophilic aromatic fluorination to obtain compound D.

4. The process according to claim 3, wherein steps (a1) and (a2) are performed as a one-pot process.

5. The process according to claim 3 or 4, wherein the fluoride source in step (a1) or step (a3) is selected from fluoride salts, particularly, from potassium fluoride, cesium fluoride and sodium fluoride.

6. The process according to any one of claims 3-5, wherein the cyanating agent in step (a2) is selected from cyanide salts, particularly from potassium cyanide and sodium cyanide.

7. The process according to any one of claims 3-6, wherein compound C is isolated after step (a2).

8. The process according to any one of claims 2-7, wherein the hydrolysis in step (b) is performed in the presence of a strong acid, preferably selected from hydrochloric acid, sulfuric acid and phosphoric acid.

9. The process according to any one of claims 2-8, wherein step (b) is performed in the absence of organic solvents.

10. The process according to any one of claims 2-9, wherein the Hofmann rearrangement in step (c) is performed in the presence of a hypohalite source, preferably sodium hypochlorite or sodium chlorite, and a strong base, preferably NaOH.

11 . The process according to any one of claims 2-10, further comprising: (d) reacting compound F with an acid to form a salt of compound F.

12. The process according to claim 11 , wherein the acid is hydrochloric acid.

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