A process for the preparation of 2-amino-3,5-difluoropyridine or a salt thereof

Abstract

This invention provides a method for preparing 2-amino-3,5-difluoropyridine (compound F) or its salts from 2,3,5-trichloropyridine (compound A), the method involving 3,5-difluoro-2-pyridinecarboxynitrile (compound D) and 3,5-difluoro-2-pyridinecarboxamide (compound E). This method features high purity and high yield, and is suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and in particular to a method for preparing 2-amino-3,5-difluoropyridine or its salts. Background Technology

[0002] 2-Amino-3,5-dihalopyridines constitute synthetic intermediates or structural components of many bioactive compounds. Their preparation typically involves halogenating agents such as bromine (WO2016183116), iodine / periodic acid (Angewandte Chemie, International Edition (2013), 52(38), 10093-10096), N -Chlorosuccinimide (European Journal of Organic Chemistry (2012), 2012(28), 5595-5604) is used in the presence of a parent 3 or 5-monohalo-2-aminopyridine or 2-aminopyridine via halogenation, or in the presence of a suitable reducing agent via reduction of 2-nitro (Collection of Czechoslovak Chemical Communications (1991), 56(11A), 2420-9) or 2-hydrazino (US20060047124) 3,5-dihalopyridine, or in less common cases via nucleophilic substitution of 2-fluoro-3,5-dihalopyridine with a nucleophilic reagent such as ammonia (Bioorganic & Medicinal Chemistry Letters (2015), 25(17), 3436-3441) or alkylamidinium followed by hydrolysis (Organic & Biomolecular Chemistry (2018)). 16(41), 7564-7567) to achieve this.

[0003] In 2-amino-3,5-dihalopyridine compounds, derivatives with fluorine substituents can be used to prepare various pharmaceuticals. In particular, 2-amino-3,5-difluoropyridine can be used to prepare compounds known in WO2022 / 161972 A1.

[0004] The preparation of fluorinated 2-aminopyridines is more challenging than that of other halogenated 2-aminopyridines because the library of synthetic methods for introducing fluorine onto the pyridine ring is very limited. The most commonly used methods involve metal-halogen exchange followed by the reaction of an organometallic intermediate with a fluorinating agent such as... N-Fluorobenzenesulfonamide (Angewandte Chemie, International Edition (2010), 49(12), 2215-2218) undergoes halogen exchange reaction in the presence of fluoride salts such as potassium fluoride (US20060009643), or the amine is converted to a diazonium salt and then reacted with a fluorinating agent (such as tetrafluoroboric acid) (US20060199960).

[0005] US2006 / 0047124 A1 describes the preparation of 2-aminopyridine derivatives, particularly 2-amino-3,5-difluoropyridine. The described method involves the regioselective monodehalogenation of pentafluoropyridine to yield 2,3,5,6-tetrafluoropyridine. 2,3,5,6-tetrafluoropyridine is condensed with hydrazine monohydrate at the 2 and 6 positions sequentially, followed by reduction in the presence of copper sulfate and acetic acid, respectively, or by reduction with hydrogen in the presence of Raney nickel catalyst, to obtain 2-amino-3,5-difluoropyridine.

[0006] Although this method yields high results, it is not well-suited for large-scale production due to the use of highly reactive compounds. The sensitivity and instability of these compounds necessitate special handling processes. The reaction also involves the formation of toxic intermediates and the use of toxic reagents, both undesirable in large-scale production. Another drawback of this method is that its starting material, pentafluoropyridine, is difficult to obtain.

[0007] A method for preparing 2-amino-3,5-difluoropyridine that avoids the disadvantages described above is needed. This method should be suitable for scaling up and involve stable, non-toxic, and readily available compounds.

[0008] Therefore, the object of this invention is to provide a method for preparing 2-amino-3,5-difluoropyridine that does not involve toxic or unstable reagents or intermediates, nor does it involve the use of reducing agents. Preferably, this method achieves high yield and high purity of the target compound and is suitable for large-scale production. Summary of the Invention

[0009] The present invention provides a method for preparing 2-amino-3,5-difluoropyridine (compound F) or a salt thereof from 2,3,5-trichloropyridine (compound A), the method involving 3,5-difluoro-2-pyridinecarboxynitrile (compound D) and 3,5-difluoro-2-pyridinecarboxamide (compound E) as synthetic intermediates. Attached Figure Description

[0010] Figure 1 A schematic diagram of the reaction steps according to an embodiment of the present invention is shown. Detailed Implementation

[0011] Surprisingly, it was discovered that 2-amino-3,5-difluoropyridine (compound F) can be obtained in high yield and high purity from relatively readily available 2,3,5-trichloropyridine (compound A) through a process that does not involve highly toxic or unstable compounds and is suitable for large-scale production. This method involves compound 3,5-difluoro-2-pyridinecarboxynitrile, also known as 2-amino-3,5-difluoropyridine (compound E), as a synthetic intermediate.

[0012] For reference: Compound A = 2,3,5-trichloropyridine Compound B = 2-fluoro-3,5-dichloropyridine Compound C = 3,5-dichloro-2-pyridinecarboxynitrile Compound D = 3,5-difluoro-2-pyridinecarboxynitrile Compound E = 3,5-difluoro-2-pyridinecarboxamide Compound F = 2-amino-3,5-difluoropyridine Compound G = salt of 2-amino-3,5-difluoropyridine The method according to the present invention preferably includes the following steps: (a) Convert compound A into compound D, (b) Hydrolyze compound D to obtain compound E. (c) Compound E is subjected to Huffman rearrangement to obtain compound F.

[0013] In step (a), compound A is converted into compound D. This can be achieved by methods well known to those skilled in the art of organic synthesis. Preferably, step (a) includes the following steps: (a1) Compound A is reacted with a fluorine source under nucleophilic aromatic fluorination conditions to obtain compound B. (a2) React compound B with a cyanide source to obtain compound C. (a3) Compound C is reacted with a fluorine source under nucleophilic aromatic fluorination conditions to obtain compound D.

[0014] In step (a1), the chlorine atom at position 2 of compound A is replaced by a fluorine atom via nucleophilic aromatic fluorination. To achieve this conversion, compound A is reacted with a fluorine source under suitable conditions. Typically, this reaction is carried out at high temperatures in a polar aprotic solvent. Suitable aprotic solvents include, for example, dimethyl sulfoxide (DMSO). N,N -Dimethylformamide (DMF), acetonitrile, N,N -Dimethylacetamide (DMA) N2-Methylpyrrolidone (NMP). Preferably, dimethyl sulfoxide (DMSO) is used.

[0015] To further avoid the presence of water, the solvent is preferably dried before the reaction. Drying is preferably carried out by azeotropic distillation. The water content of the solvent is preferably less than 1 wt.%, more preferably less than 0.5 wt.%.

[0016] The fluorine source can be a salt. Suitable examples of salts include potassium fluoride (KF), cesium fluoride (CsF), sodium fluoride (NaF), or other fluorides such as tetramethylammonium fluoride. Potassium fluoride is preferred.

[0017] The reaction temperature can be in the range of 80-180℃, preferably 120-140℃.

[0018] In step (a2), the fluorine in compound B is exchanged for cyano groups by reacting compound B with a cyaniding agent. This reaction can be carried out at room temperature. Typically, no catalyst is required. The cyaniding agent (cyanide source) is preferably a cyanide salt, such as potassium cyanide or sodium cyanide, with potassium cyanide being more preferred.

[0019] Reaction (a2) is carried out in a suitable solvent. Advantageously, the same solvent as in step (a1) can be used. However, different solvents can also be used, for example, methyl tert-butyl ether (MTBE).

[0020] Preferably, steps (a1) and (a2) are carried out in a one-pot process, which means that there is no need to separate or purify the intermediate reaction products. Preferably, this means that the reagent of step (a2) is added to the same container containing the reaction mixture obtained in step (a1).

[0021] Preferably, compound C is separated from the reaction mixture obtained in step (a2). The suspension obtained from step (a2) typically contains a mixture of an inorganic salt (e.g., KCN; KCl) and a liquid consisting of a solution of 2-cyano-3,5-dichloropyridine. Compound C can be separated by known methods (e.g., by liquid-liquid separation). Liquid-liquid separation can be carried out, for example, by extraction using water and an organic solvent (e.g., MTBE).

[0022] The advantage of the optional separation step following step (a2) is that, due to the formation of fewer byproducts, a higher yield can be provided in the subsequent step (a3). The inventors have found that no further purification of the compound is required at this stage, which greatly simplifies the entire process.

[0023] In step (a3), compound C reacts with a fluorine source under nucleophilic aromatic fluorination conditions to obtain compound D. Suitably, the reaction conditions, solvent, and / or fluorine source of step (a1) can be used in step (a3). Preferably, a lower temperature, such as 110-130°C, can be used. The resulting compound is 3,5-difluoro-2-pyridinecarboxynitrile (compound D). The compound can be purified, for example, using charcoal, to obtain a purified product for the next step.

[0024] In step (b), compound D is hydrolyzed to obtain compound E. Preferably, the hydrolysis is carried out in the presence of a strong acid or a strong base, or under neutral conditions in the presence of a metal catalyst or periodic acid reagent. Preferably, in this case, the hydrolysis is carried out in the presence of a strong acid.

[0025] In this application, a strong acid is defined as an acid with a pKa in water of less than 3, preferably less than 0, and more preferably less than -2. Suitable examples of strong acids include hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid. Preferably, hydrochloric acid achieves the highest yield and purity compared to other acids. Preferably, hydrochloric acid is used in the form of a concentrated solution in water. Alternatively, gaseous HCl in water or an organic solvent can be used.

[0026] The hydrolysis in step (b) can be carried out in a mixture of water and an organic solvent (e.g., a solvent present in the reaction mixture of the previous steps). In other embodiments, the hydrolysis in step (b) is carried out in the absence of an organic solvent. In this case, only water is present as a liquid medium. This may be advantageous because it allows the production of compound E in solid form, as further described herein.

[0027] Preferably, the product of step (b) is separated. 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 is used in step (b), the product of step (b) (compound E) can be obtained in solid form, which makes it easier to separate.

[0028] In some embodiments, the compound E obtained in step (b) can be purified. Purification can be accomplished by adding a solvent, heating to a high temperature, and then cooling. The byproducts remain in solution, while the purified compound E precipitates from the mother liquor. The solvent is then removed by a suitable method (e.g., filtration followed by drying under reduced pressure). Any suitable solvent can be used, such as diethyl ether, preferably methyl tert-butyl ether (MTBE).

[0029] In step (c), compound E undergoes a Hoffmann rearrangement to obtain compound F. The Hoffmann rearrangement is typically carried out in the presence of a hypohalite source and a strong base. In this case, preferred hypohalite sources include sodium hypochlorite (NaClO), periodic acid reagents (e.g., iodophenyldiacetic acid, (bis(trifluoroacetoxy)iodo)benzene), N -bromosuccinimide, N -Chlorosuccinimide or bromine. Sodium hypochlorite is preferred due to its relatively inexpensive and readily available nature. Bromine is less convenient for large-scale processing because it can produce toxic vapors. High-valent iodine reagents, such as iodophenyldiacetic acid, are more expensive than NaClO and do not offer atom economy.

[0030] As a strong base, inorganic hydroxides or salts, such as KOH or NaOH, or organic bases, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), can be used. Preferably, inorganic hydroxides, such as NaOH, are used. The reaction can be carried out between 50 and 90°C. The reaction in step (c) can be carried out in water or in an organic solvent, depending on the reagents chosen for the reaction. Those skilled in the art can select suitable reaction media for a particular mixture of reagents. As an example, the reaction in step (c) is carried out in water, using NaOH as a strong base and NaClO as a hypochlorite source.

[0031] As a result of step (c), compound F is obtained in the form of a free base. Since compound F is relatively volatile, it can be advantageously converted into a less volatile salt, thereby facilitating further processing, particularly on a large scale. Therefore, the method according to the invention preferably further comprises: (d) React compound F with a strong acid to form a salt of compound F.

[0032] Suitable strong acids for forming the salt of compound F include, for example, hydrochloric acid, hydrobromic acid, and sulfuric acid. Hydrochloric acid is preferably used. Step (d) involves adding a strong acid to the mixture obtained as a result of step (c). Preferably, the strong acid is used in the form of an aqueous solution or an organic solution of (gaseous) hydrochloric acid (e.g., 1,4-dioxane). The salt precipitate can be filtered out and optionally washed with a solvent (e.g., MTBE).

[0033] The method according to the invention is characterized by having sufficiently high purity (>90%, preferably >95%, up to 99%) and yield to be suitable for large-scale production.

[0034] Starting compound A is relatively easy to obtain. The method does not involve highly toxic or unstable reagents or intermediates. Another advantage is that compound F can be obtained in high yield and purity even without cumbersome intermediate purification steps.

[0035] The invention will now be further described by way of the following non-limiting examples.

[0036] Example HPLC Method A: The Agilent UHPLC / MS 1290 series consists of the following components: Including the high-speed pump G7120A for the degasser G4226A Orifice Plate Sampler Column oven G7116B, MCT Diode array detector G7117B G6105B quadrupole LC / MS mass detector equipped with ESI-Jetstream source Chromatographic system: Column information: XBridge BEH C18 from Waters, 2.1 50 mm, 2.5 µ Solvent A: Water / Ammonia: 99.9 / 0.1 % vol. / vol. Solvent B: Acetonitrile / Ammonia: 99.9 / 0.1 % vol. / vol. Gradient: from 2% MeCN to 100% MeCN in 1.2 min, then to 100% MeCN in 0.5 min. Flow rate: 0.8 mL / min Incubator temperature: 40℃ Injection volume: 0.3 µL Runtime: 2.2 min (including 0.4 min balancing time) Detection methods: UV @254 nm and 210 nm ESI / MS (100-1000 m / z), positive ions HPLC Method B: The Agilent UHPLC / MS 1290 series consists of the following components: Including the high-speed pump G7120A for the degasser G4226A Orifice Plate Sampler Column oven G7116B, MCT Diode array detector G7117B G6135B XT quadrupole LC / MS mass detector equipped with ESI-Jetstream source Chromatographic system: Column information: XBridgeP BEH C18+ from Waters, 2.1 50 mm, 2.5 µ Solvent A: Water / Ammonia: 99.9 / 0.1 % vol. / vol. Solvent B: Acetonitrile / Ammonia: 99.9 / 0.1 % vol. / vol. Gradient: from 2% MeCN to 100% MeCN in 1.2 min, then to 100% MeCN in 0.5 min. Flow rate: 0.8 mL / min Incubator temperature: 40℃ Injection volume: 0.3 µL Runtime: 2.2 min (including 0.4 min balancing time) Detection methods: UV @254 nm and 210 nm ESI / MS (100-1000 m / z), positive ions HPLC Method C: The Agilent UHPLC / MS 1290 series consists of the following components: Including the high-speed pump G7120A for the degasser G4226A Orifice Plate Sampler Column oven G7116B, MCT Diode array detector G7117B G6105B quadrupole LC / MS mass detector equipped with ESI-Jetstream source Chromatographic system: Column information: XBridge BEH C18 from Waters, 2.1 50 mm, 2.5 µ Solvent A: Water / Ammonia: 99.9 / 0.1 % vol. / vol. Solvent B: Acetonitrile / Ammonia: 99.9 / 0.1 % vol. / vol. Gradient: from 2% MeCN to 100% MeCN in 1.2 min, then to 100% MeCN in 0.5 min. Flow rate: 0.8 mL / min Incubator temperature: 40℃ Injection volume: 0.3 µL Runtime: 2.2 min (including 0.4 min balancing time) Detection methods: UV @254 nm, 225 nm and 210 nm ESI / MS (100-1000 m / z), positive ions Example Example 1: Preparation of 3,5-dichloro-2-pyridinecarboxynitrile (compound C) Dry dimethyl sulfoxide (240 mL) and potassium fluoride (47.3 g, 814 mmol) were added to a jacketed reactor (500 mL) equipped with a reflux condenser with a reflux partial pressure head, a mechanical stirrer, an internal thermometer, and placed under a nitrogen atmosphere. The temperature was raised to approximately 100 °C, and approximately 20% of the solvent volume was distilled off under reduced pressure (approximately 10 mbar). After cooling the dried solution to room temperature, 2,3,5-trichloropyridine (30 g, 163 mmol) was added under a weak nitrogen flow, 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 tert-butyl methyl ether (750 mL). The organic layer was washed with brine (300 mL), filtered through a pad consisting of magnesium sulfate (100 g) and Celite® (25 g), and then rinsed with methyl tert-butyl methyl ether (150 mL). The filtrate was concentrated to obtain 3,5-dichloro-2-pyridinium nitrile (22.79 g, 115 mmol, 71% yield) as a brown solid.

[0037] HPLC Method A: Retention Time: 1.03 min 1 H-NMR (600 MHz, d6-DMSO) δ (ppm): 8.83 (d, J = 2.1 Hz, 1H), 8.66 (d, J =2.0 Hz, 1H).

[0038] Example 2: Preparation of 3,5-difluoro-2-pyridinecarboxynitrile (compound D) Add dry dimethyl sulfoxide (195 mL) and potassium fluoride (33.3 g, 573 mmol) to a 500 mL three-necked round-bottom flask equipped with a reflux condenser with a reflux partial pressure head, a mechanical stirrer, an internal thermometer, and placed under a nitrogen atmosphere. Raise the temperature to approximately 100 °C and distill off approximately 20% of the solvent volume under reduced pressure (approximately 10 mbar). After cooling the dried solution to room temperature, add 3,5-dichloro-2-pyridinium nitrile (22.79 g, 115 mmol) and heat the resulting mixture to 115 °C (internal). After a reaction time of 4.5 h, cool the temperature to 15 °C. Dilute the reaction mixture with water (300 mL), extract with methyl tert-butyl methyl ether (300 mL), and dry with magnesium sulfate (50 g). After filtration, add activated carbon (3.5 g) to the solution and heat the resulting suspension under reflux for 5 min. After cooling to room temperature, the suspension was filtered through a silica gel plunger (30 g) and washed with methyl tert-butyl methyl ether (50 mL). The filtrate was concentrated at 40 °C and 200 mbar, then at 100 mbar for 15 min to obtain a brown, oily 3,5-difluoro-2-pyridinium carbide (16.05 g, 86 mmol, 75% yield) containing approximately 10 mol% residual methyl tert-butyl methyl ether. The product was used in Example 3 or 4 without further purification.

[0039] HPLC Method B: Retention Time: 0.814 min 1 H NMR (300 MHz, d6-DMSO) δ (ppm): 8.76 (d, J = 2.3 Hz, 1H), 8.38 (td, J =9.1, 2.3 Hz, 1H).

[0040] 19 F NMR (283 MHz, d6-DMSO) δ (ppm): -112.59 – -112.81 (m).

[0041] Example 3: Preparation of 3,5-difluoro-2-pyridinecarboxamide (compound E) The 3,5-difluoropyridinecarboxamide (94.3 g, 0.57 mol) isolated from Example 2 was dissolved in a 37% wt. aqueous hydrochloric acid solution (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 precisely adjusted to pH 9.0 by adding 4 N sodium hydroxide aqueous solution while maintaining the temperature below 10 °C. The aqueous solution was saturated by adding sodium chloride and extracted with ethyl acetate (2 × 8 L and 2 L). The combined organic layers were filtered through a sodium sulfate (500 g) pad and concentrated under reduced pressure at 40 °C to give a beige solid. The crude product was ground in warm methyl tert-butyl methyl ether (860 mL), filtered over a No. 3 sintered glass funnel, and dried under reduced pressure to give a beige solid of 3,5-difluoro-2-pyridinecarboxamide (74.1 g, 0.47 mol, yield 83%).

[0042] HPLC Method B: Retention Time: 0.532 min 1 H NMR (300 MHz, d6-DMSO) δ (ppm): 8.56 (d, J = 2.3 Hz, 1H), 8.12 – 7.93(m, 2H), 7.71 (s, 1H).

[0043] Example 4: Preparation of 3,5-difluoro-2-pyridinecarboxamide (compound E) A 37% wt. aqueous hydrochloric acid solution (35.3 mL) was added to 3,5-difluoropyridinecarboxamide (16.05 g, 86 mmol). The resulting mixture was stirred at 50 °C for 4 h, and then stirred 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 a temperature below 5 °C. The resulting suspension was filtered through a No. 3 sintering funnel, the wet cake was washed with water (2 × 20 mL) and dried under reduced pressure at 40 °C to give 3,5-difluoro-2-pyridinecarboxamide (11.369 g, 66.2 mmol, yield 77%) as a beige solid.

[0044] HPLC Method B: Retention Time: 0.532 min 1 H NMR (300 MHz, d6-DMSO) δ (ppm): 8.56 (d, J = 2.3 Hz, 1H), 8.12 – 7.93(m, 2H), 7.71 (s, 1H). Example 5: Preparation of 3,5-difluoropyridine-2-ammonium chloride (a salt of compound F) Sodium hydroxide (35.2 g, 0.88 mol) was dissolved in water (740 mL). Sodium hypochlorite (272 mL, 0.44 mol) aqueous solution (10 wt.%) and 3,5-difluoro-2-pyridinecarboxamide (74 g, 0.44 mol) were added, and the 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 precipitate, the organic layer was collected, washed with brine (200 mL), dried over magnesium sulfate, and concentrated to approximately 250 mL. The resulting solution was diluted with methyl tert-butyl methyl ether (750 mL), and a solution of 4 M hydrochloric acid in 1,4-dioxane (115 mL, 0.46 mol) was added with stirring. The resulting suspension was stirred at ambient temperature for 30 min, filtered, and dried under reduced pressure to obtain a beige solid of 3,5-difluoropyridine-2-ammonium chloride (65.5 g, 0.39 mol, yield 89%, purity 98% by area at 254 nm). 1 The H-NMR content was 96 wt.%.

[0045] HPLC Method C: Retention Time: 0.69 min 1 H NMR (300 MHz, d4-MeOD) δ (ppm): 8.18 – 7.98 (m, 1H), 7.98 – 7.81 (m, 1H).

Claims

1. A method for preparing 2-amino-3,5-difluoropyridine (compound F) or a salt thereof from 2,3,5-trichloropyridine (compound A), which involves 3,5-difluoro-2-pyridinecarboxynitrile (compound D) and 3,5-difluoro-2-pyridinecarboxamide (compound E).

2. The method according to claim 1, comprising the following steps: (a) Convert compound A into compound D, (b) Hydrolyze compound D to obtain compound E. (c) Perform Hoffmann rearrangement on compound E to obtain compound F or its salt.

3. The method according to claim 2, wherein step (a) comprises the following steps: (a1) Compound A is reacted with a fluorine source under nucleophilic aromatic fluorination conditions to obtain 2-fluoro-3,5-dichloropyridine (compound B). (a2) React compound B with a cyaniding agent to obtain 3,5-dichloro-2-pyridinecarboxynitrile (compound C). (a3) Compound C is reacted with a fluorine source under nucleophilic aromatic fluorination conditions to obtain compound D.

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

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

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

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

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

9. The method according to any one of claims 2-8, wherein step (b) is carried out in the absence of an organic solvent.

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

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

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

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