Process for the preparation of relugolix intermediates

Abstract

The present invention relates to a process for the preparation of a compound of formula (I), comprising the steps of: a) hydrogenating a compound of formula (VI) using a metal catalyst; b) N-protecting a compound of formula (V) with phthalic anhydride to form a compound of formula (IV); c) brominating the compound of formula (IV) using a suitable brominating agent to form a compound (III); d) dimethylaminating compound (III) by treatment with dimethylamine to form a compound of formula (II); e) deprotecting formula (II) using a suitable amine solution to form a compound of formula (I); and f) optionally converting the compound of formula (I) to an acid addition salt. TIFF2025542554000017.tif48170

Description

[Technical Field]

[0001] The present invention relates to 5-(4-aminophenyl)-2-{carboxy[(2,6-difluorophenyl)methyl]amino}-4-[(dimethylamino)methyl]thiophene-3-carboxylic acid derivatives, and more particularly to a process for the preparation of ethyl 5-(4-aminophenyl)-2-{[(2,6-difluorophenyl)methyl](ethoxycarbonyl)amino}-4-[(dimethylamino)methyl]thiophene-3-carboxylate and its salts. [Background technology]

[0002] Ethyl 5-(4-aminophenyl)-2-{[(2,6-difluorophenyl)methyl](ethoxycarbonyl)amino}-4-[(dimethylamino)methyl]thiophene-3-carboxylate of Formula I is an important key intermediate used in the preparation of Relugolix. [ka]

[0003] Relugolix is ​​a thienopyrimidine compound developed by Takeda Pharmaceutical Company Limited that belongs to a class of drugs called gonadotropin-releasing hormone (GnRH) receptor antagonists. It is used to treat advanced prostate cancer.

[0004] Relugolix works by binding to the GnRH receptor in the pituitary gland, reducing the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which reduces the amount of testosterone produced and helps slow or stop the spread of cancer cells that depend on this hormone for growth.

[0005] The compound of formula (I) is a key intermediate for relugolix. Cost-effective synthesis of pure compound of formula (I) is crucial for achieving ICH purity of relugolix.

[0006] Chinese Patent Application Publication No. 113717149 (Weiven et al.) discloses the preparation of formula (I) as shown in Scheme 1 below. [ka]

[0007] This reaction involves the reduction of a nitro compound followed by tert-butyloxycarbonyl (Boc) protection of the amino group. The Boc-protected compound is then subjected to bromination. In the final step, the brominated compound is treated with dimethylamine, followed by Boc deprotection. However, the bromination yield is 8–10%. Instead of selective alkyl bromination, N-bromination, N-BOC cleavage, and bromination on the benzene were observed in this reaction. The starting material was completely consumed. However, LC-MS of the reaction showed the formation of N-bromo and bromobenzene impurities (collectively known as "bromo impurities"). The bromination step did not yield more than 8–10% of the desired product, even after N-BOC protection.

[0008] Due to the above-mentioned technical difficulties of the processes cited in the prior art, there is a need for an improved process for the preparation of compound (I) that avoids the formation of impurities in the bromination step and makes compound (I) cost-effective. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] Chinese Patent Application Publication No. 113717149 Summary of the Invention [Means for solving the problem]

[0010] The present invention describes a multi-step process for the preparation of a compound of formula (I). The process includes a first step of hydrogenating a compound of formula (VI) using a metal catalyst. The second step involves N-protecting a compound of formula (V) with phthalic anhydride to form a compound of formula (IV). The third step involves brominating the compound of formula (IV) using a suitable brominating agent to form compound (III). Then, the fourth step involves dimethylamination of compound (III) by treatment with dimethylamine to form a compound of formula (II). The next step, i.e., the fifth step, involves deprotecting compound (II) using a suitable amine solution to form a compound of formula (I). The final step, i.e., the sixth step, optionally involves converting the compound of formula (I) to an acid addition salt. DETAILED DESCRIPTION OF THE INVENTION

[0011] References herein to "one embodiment" or "an embodiment" mean that a particular feature, structure, characteristic, or function described in connection with an embodiment is included in at least one embodiment of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment.

[0012] Reference to a "preferred embodiment" in this specification means that certain features, structures, characteristics, or functions are described in detail, thereby omitting well-known configurations and functions for the purpose of clearly explaining the present invention.

[0013] The foregoing descriptions of specific embodiments of the present invention have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teachings.

[0014] While working on prior art processes for the preparation of Compound (I), it was found that there is the formation of various bromo impurities in the process due to multiple bromination. The inventors of the present invention have developed a process that provides a higher yield of Compound (I) without the formation of bromo impurities. This process is cost-effective due to selective bromination, even in large-scale production.

[0015] The process for the preparation of compounds of formula (I) comprises several steps. a) A first step comprising hydrogenating a compound of formula (VI) in a predefined solvent in the presence of a metal catalyst at a predefined temperature and a predefined pressure to form a compound of formula (V). [ka] b) A second step comprising N-protecting the compound of formula (V) by reacting with phthalic anhydride in a pre-defined solvent at a pre-defined temperature to form a compound of formula (IV). [ka] c) A third step of brominating the compound of formula (IV) by reacting it with a pre-defined brominating agent in a pre-defined solvent in the presence of a catalyst at a pre-defined temperature to form a compound of formula (III). [ka] d) A fourth step of dimethylamination of the compound of formula (III) by reaction with dimethylamine in a predefined solvent at a predefined temperature to form a compound of formula (II). [ka] e) A fifth step of deprotecting the compound of formula (II) by reacting with a pre-defined alkali in a pre-defined solvent to form a compound of formula (I).

[0016] The process optionally includes a sixth step of converting the compound of formula (I) into an acid addition salt. [ka]

[0017] A schematic diagram of the process of the present invention is shown below. [ka]

[0018] Multiple bromination is avoided by removing the proton on the nitrogen with phthalamide protection, which was not possible with BOC protection.

[0019] In one embodiment of the present invention, the metal catalyst used in the hydrogenation in step (a) is selected from palladium, platinum, and nickel. The hydrogenation is carried out in an alcohol solvent selected from (1-4C) alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and isobutanol, and in ethyl acetate. The hydrogenation is carried out at a predetermined temperature of 20-75°C, preferably 20-30°C, under a predetermined pressure of 1-10 kg.

[0020] In a preferred embodiment, the hydrogenation is carried out in the presence of Raney nickel in ethanol or ethyl acetate at 20-50° C. under a pressure of 1-10 kg.

[0021] In one embodiment of the present invention, the solvent used in step (b) is selected from trifluoroacetic acid and acetic acid. In this embodiment, the reaction proceeds at a temperature of 80 to 140°C, preferably 90 to 130°C, and more preferably 100 to 115°C.

[0022] In a preferred embodiment, the acid is selected from trifluoroacetic acid and acetic acid, especially acetic acid.

[0023] In one embodiment of the present invention, the predefined brominating agent in step (c) is selected from N-bromosuccinamide, 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), liquid bromine, and the like.

[0024] In a preferred embodiment, the bromination is carried out in the presence of a catalyst selected from azobisisobutyronitrile (AlBN), hydrogen peroxide and benzoyl peroxide.

[0025] The bromination is carried out in a solvent selected from ethyl acetate and halogenated solvents such as chloroform, dichloromethane, benzotrifluoride, carbon tetrachloride, and the like.

[0026] In a preferred embodiment, the brominating agent and catalyst are added in small portions (lot wise), which ensures that the reaction is completed in a shorter time. The bromination is carried out at a predetermined temperature of 40-80°C, preferably 70-75°C.

[0027] In one embodiment, the dimethylamination in step (d) is carried out in a solvent selected from dimethylformamide, ethanol, tetrahydrofuran, and dichloromethane.

[0028] Step (d) is carried out in the presence of a combination of triethylamine and dimethylamine hydrochloride, the hydrochloride decomposing to produce dimethylamine, which participates in the dimethylamination. The reaction preferably proceeds at room temperature.

[0029] In one embodiment, the fifth deprotection step (e) is carried out in a solvent selected from alcoholic solvents such as methanol, ethanol, and isopropyl alcohol (IPA). The deprotection is carried out in the presence of a predefined alkali selected from monomethylamine or hydrazine hydrate.

[0030] In a preferred embodiment, the deprotection is carried out using monomethylamine in the solvent ethanol.

[0031] In another embodiment, the salt prepared in step f) is a salt of hydrochloric acid or trifluoroacetic acid.

[0032] These and other embodiments will become apparent to those skilled in the art and others upon consideration of the following detailed description of several embodiments. However, it should be understood that this summary and detailed description provide only some examples of various embodiments and are not intended to limit the invention as claimed. The following examples illustrate, but do not limit, the invention. [Example]

[0033] Example 1 Preparation of ethyl 2-[(2,6-difluorophenyl)methyl-ethoxycarbonyl-amino]-4-methyl-5-(4-aminophenyl)thiophene-3-carboxylate (Compound V) Ethyl 2-[(2,6-difluorophenyl)methyl-ethoxycarbonyl-amino]-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate (100 g) was added to ethanol (1000 ml) at room temperature. Raney Ni (10 g) was added to the mixture, and 1 kg of hydrogen pressure was applied at room temperature. The mixture was maintained for 6-7 hours, filtered, and washed with ethanol (200 ml). The filtrate was distilled under vacuum, and ethyl 2-[(2,6-difluorophenyl)methyl-ethoxycarbonyl-amino]-4-methyl-5-(4-aminophenyl)thiophene-3-carboxylate was isolated as an oil (93 g; yield 98%). HPLC purity: 97.5%

[0034] Example 2 Preparation of ethyl 2-[(2,6-difluorophenyl)methyl-ethoxycarbonyl-amino]-4-methyl-5-(4-aminophenyl)thiophene-3-carboxylate (Compound V) Ethyl 2-[(2,6-difluorophenyl)methyl-ethoxycarbonyl-amino]-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate (40 g) was added to ethanol (280 ml) at 25-30°C. 10% Pd / C (0.8 g) was added to the reaction mixture. 5 kg / cm 3 A H2 pressure of 1000 kJ / ml was applied, and the reaction mixture was stirred and maintained at 25-30°C for 30 minutes. The mixture was maintained for 20-22 hours, and then the whole was filtered. The filtrate was distilled under vacuum, and ethyl 2-[(2,6-difluorophenyl)methyl-ethoxycarbonyl-amino]-4-methyl-5-(4-aminophenyl)thiophene-3-carboxylate was isolated as an oil (37 g; yield 98.5%). (96.5% purity)

[0035] Example 3 Preparation of ethyl 2-[(2,6-difluorophenyl)methyl-ethoxycarbonyl-amino]-4-methyl-5-(4-aminophenyl)thiophene-3-carboxylate (Compound V) Ethyl 2-[(2,6-difluorophenyl)methyl-ethoxycarbonyl-amino]-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate (25 g) was added to ethyl acetate (225 ml) at room temperature. Raney Ni (2.5 g) was added to the mixture, and 5 kg of hydrogen pressure was applied at room temperature. The mixture was stirred for 30 minutes and maintained for 20-24 hours. The whole was filtered, and the filtrate was distilled under vacuum to isolate ethyl 2-[(2,6-difluorophenyl)methyl-ethoxycarbonyl-amino]-4-methyl-5-(4-aminophenyl)thiophene-3-carboxylate as an oil (22.5 g; yield 95.7%). (Purity: 97%)

[0036] Example 4 Preparation of ethyl 2-[(2,6-difluorophenyl)methyl](ethoxycarbonyl)amino-5-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]-4-methylthiophene-3-carboxylate (Compound IV) Acetic acid (300 ml) was added to ethyl 2-[(2,6-difluorophenyl)methyl-ethoxycarbonyl-amino]-4-methyl-5-(4-aminophenyl)thiophene-3-carboxylate (100 g) isolated in Example 1. Phthalic anhydride (31.21 g) was added to this mixture at room temperature. The mixture was heated to 115-120°C and stirred for 1 hour. After completion of the reaction, the mixture was quenched in cold water (500 ml). The solid was filtered and washed with water (500 ml). The isolated ethyl 2-[(2,6-difluorophenyl)methyl](ethoxycarbonyl)amino-5-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]-4-methylthiophene-3-carboxylate was suction dried and further dried under vacuum at 40-50°C for 5-6 hours. Dry weight (120 g, 94% yield) HPLC purity: 99.2%

[0037] Example 5 Preparation of ethyl 4-(bromomethyl)-2-[(2,6-difluorophenyl)methyl](ethoxycarbonyl)amino-5-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]thiophene-3-carboxylate (Compound III) Ethyl 2-[(2,6-difluorophenyl)methyl](ethoxycarbonyl)amino-5-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]-4-methylthiophene-3-carboxylate (100 g) was added to ethyl acetate (1000 ml) at room temperature. The mixture was heated to 70-75°C. The first lot of NBS (14.1 g) and AIBN (1.25 g) were added to the reaction mixture, and the whole was maintained at 70-75°C for 30 minutes.

[0038] A second lot of NBS (14.1 g) and AIBN (1.25 g) were added to the reaction mixture, and the whole was maintained at 70-75°C for 30 minutes.

[0039] A third lot of NBS (14.1 g) and AIBN (1.25 g) were added to the reaction mixture, and the whole was maintained at 70-75°C for 30 minutes.

[0040] A fourth lot of NBS (14.1 g) and AIBN (1.25 g) were added to the reaction mixture, and the whole was maintained at 70-75°C for 30 minutes.

[0041] The mixture was heated to reflux and stirred for 3 hours. The whole was cooled to 30-35°C. The layers were settled and separated. The organic layer was distilled under vacuum at 45-50°C, and IPA (500 ml) was added. The mixture was cooled to room temperature and stirred for 1 hour. The solid was filtered and washed with IPA (50 g × 2). The resulting compound, ethyl 4-(bromomethyl)-2-[(2,6-difluorophenyl)methyl](ethoxycarbonyl)amino-5-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]thiophene-3-carboxylate, was dried by suction and further dried under vacuum. (Dry weight: 93g; yield 82%) HPLC purity - 98.5%

[0042] Example 6 Preparation of ethyl 2-[(2,6-difluorophenyl)methyl](ethoxycarbonyl)amino-4-[(dimethylamino)methyl]-5-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]thiophene-3-carboxylate (Compound II) Ethyl 4-(bromomethyl)-2-[(2,6-difluorophenyl)methyl](ethoxycarbonyl)amino-5-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]thiophene-3-carboxylate (100 g) was added to dimethylformamide (500 ml) at 25-30°C and stirred for 10 minutes.

[0043] Dimethylamine hydrochloride (36 g) and triethylamine (60 g) were added to the above mixture and stirred at 25-30°C for 30 minutes. The reaction mixture was quenched with cold water (2000 ml). The mixture was stirred at 0-5°C for 30 minutes. The solid was filtered, and the wet solid was poured into toluene (800 ml) at 25-30°C. The mixture was stirred for 10 minutes, and the layers were separated. The organic layer was distilled under vacuum, and n-heptane (200 ml) was added to the resulting oil. The mixture was stirred at 25-30°C for 60 minutes. The solid was filtered and poured into IPA (70 ml) at 25-30°C. The mixture was stirred for 60 minutes and filtered. The resulting wet cake was washed with IPA (25 ml). The solid was further dried under vacuum at 40-45°C. Dry weight 70g; Yield % - 73% HPLC purity - 97%

[0044] Example 7 Preparation of ethyl 5-(4-aminophenyl)-2-[(2,6-difluorophenyl)methyl](ethoxycarbonyl)amino-4-[(dimethylamino)methyl]thiophene-3-carboxylate dihydrochloride (Compound I) IPA (400 ml) was added to ethyl 2-[(2,6-difluorophenyl)methyl](ethoxycarbonyl)amino-4-[(dimethylamino)methyl]-5-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]thiophene-3-carboxylate (100 g) isolated in Example 5 at 25-30°C and stirred for 10 minutes. Monomethylamine (100 ml) was slowly added to the mixture, and the temperature was raised to 40-45°C. The mixture was stirred for 1 hour until the solution became clear. The solvent was removed under vacuum. Dichloromethane (600 ml) was added at 25-30°C and stirred for 10 minutes. The layers were separated, and the organic layer was set aside.

[0045] Dichloromethane (200 ml) was added to the aqueous layer and stirred for 10 minutes at 25-30° C. The layers were separated and the organic layers were combined.

[0046] The organic layer was distilled under vacuum, and toluene (400 ml) was added to the resulting oil. The mixture was cooled and filtered at 0-5°C. 5% dilute HCl (500 ml) was added to the filtrate at 25-30°C and stirred for 10 minutes. The layers were settled and separated, and the pH of the aqueous layer was adjusted to 8 using saturated sodium bicarbonate solution. The mixture was stirred for 10 minutes. Toluene (300 ml) was added at 25-30°C, and the mixture was stirred for 10 minutes. The layers were separated, and the organic layer was passed through sodium sulfate. The solvent was distilled under vacuum at 40-45°C to give a degassed oil.

[0047] Ethyl acetate (300 ml) was added to the degassed oil, followed by Dhalcot activated carbon (10 g). The solution was stirred at 25-30°C for 30 minutes. The mixture was filtered through a hyflow. The filtrate, containing ethyl 5-(4-aminophenyl)-2-[(2,6-difluorophenyl)methyl](ethoxycarbonyl)amino-4-[(dimethylamino)methyl]thiophene-3-carboxylate, was cooled to 5-10°C. IPA HCl (100 ml) was added, and the mixture was stirred for 30 minutes. The resulting solid was filtered and poured into methanol (150 ml) at 25-30°C, and the temperature was raised to 40-45°C. Ethyl acetate (300 ml) was slowly added to the mixture.

[0048] The whole was gradually cooled to 5-10°C and stirred for 30 minutes. The solid was filtered and dried under vacuum for 7-8 hours. (Dry weight: 65g, yield 71.4%) (HPLC purity:) - 99.3%

[0049] In accordance with the present invention, the process of the present invention provides higher yields of compound (I) without the formation of bromo impurities. This process is cost-effective due to selective bromination even in large-scale production.

[0050] The embodiments have been chosen and described to best explain the principles of the invention and its practical application, and thereby enable others skilled in the art to best utilize the invention and its various embodiments with various modifications as suited to the particular uses contemplated.

[0051] It is understood that various omissions and substitutions of equivalents are contemplated as circumstances may suggest or render expedient, and that such are intended to encompass applications or implementations without departing from the scope of the invention.

Claims

1. A process for preparing a compound of formula (I) comprising: 【Chemistry 1】 a) a first step comprising hydrogenating a compound of formula (VI) in a predefined solvent in the presence of a metal catalyst at a predefined temperature and a predefined pressure to form a compound of formula (V); 【Chemistry 2】 b) a second step comprising N-protecting the compound of formula (V) by reacting with phthalic anhydride in a predefined solvent at a predefined temperature to form a compound of formula (IV); 【Transformation 3】 c) a third step of brominating the compound of formula (IV) by reacting with a predefined brominating agent in a predefined solvent in the presence of a catalyst at a predefined temperature to form a compound of formula (III); 【Chemistry 4】 d) a fourth step of dimethylamination of compound (III) by reaction with dimethylamine in a predefined solvent at a predefined temperature to form a compound of formula (II); 【Transformation 5】 e) a fifth step of deprotecting the compound of formula (II) by reacting with a predefined alkali in a predefined solvent to form a compound of formula (I); f) optionally a sixth step of converting the compound of formula (I) into its acid addition salt; 【Transformation 6】 A method comprising:

2. 10. The process of claim 1, wherein the metal catalyst for the first step hydrogenation is selected from palladium, platinum, and nickel.

3. 3. The process of claim 1 or claim 2, wherein the metal catalyst for the first step hydrogenation is Raney nickel.

4. 4. The method of any one of claims 1 to 3, wherein the first step hydrogenation is carried out in a predefined solvent selected from ethyl acetate and alcohol solvents.

5. 5. The method according to claim 4, wherein the alcohol solvent is selected from (1-4C) alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, etc.

6. 6. The method according to any one of claims 1 to 5, wherein the hydrogenation in the first step is carried out at a predefined temperature of 20 to 75°C and under a predefined pressure of 1 to 10 kg of hydrogen pressure.

7. The method according to claim 6, wherein the hydrogenation in the first step is carried out at 20 to 30°C under a hydrogen pressure of 4 to 7 kg.

8. 2. The method of claim 1, wherein the predefined solvent for N-protection in the second step is selected from trifluoroacetic acid and acetic acid.

9. The method of claim 1 or claim 8, wherein the solvent for N-protection in the second step is acetic acid.

10. 2. The method of claim 1, wherein the N-protection in the second step is carried out at 80 to 140°C.

11. The method of claim 1 or claim 10, wherein the N-protection in the second step is carried out at 90 to 130°C.

12. The method of claim 1, claim 10 or claim 11, wherein the N-protection in the second step is carried out at 100 to 115°C.

13. 2. The method according to claim 1, wherein the brominating agent in the third step of bromination is selected from N-bromosuccinamide, 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), and liquid bromine.

14. The method according to claim 1 or claim 13, wherein the brominating agent in the third step of bromination is N-bromosuccinamide.

15. 15. The method of claim 13 or claim 14, wherein the bromination in the third step is carried out in the presence of a catalyst selected from azobisisobutyronitrile (AIBN), hydrogen peroxide and benzoyl peroxide.

16. 16. The method of claim 15, wherein the third step bromination is carried out in the presence of azobisisobutyronitrile (AIBN).

17. 14. The method of claim 1 or claim 13, wherein the predefined solvent used in the third step bromination is selected from ethyl acetate and halogenated solvents such as chloroform, dichloromethane, benzotrifluoride, carbon tetrachloride, etc.

18. 18. The method of claim 1 or claim 17, wherein the solvent used in the third step bromination is ethyl acetate.

19. 19. The method of claim 1, claim 17 or claim 18, wherein the bromination in the third step is carried out at a predefined temperature of 40 to 80°C.

20. The method according to any one of claims 1 and 17 to 19, wherein the bromination in the third step is carried out at 70 to 75°C.

21. 16. The method of claim 15, wherein the brominating agent and catalyst in the third step bromination are added in small portions.

22. 10. The method of claim 1, wherein the dimethylamination of the fourth step is carried out in a predefined solvent selected from dimethylformamide, ethanol, tetrahydrofuran, and dichloromethane.

23. 23. The method of claim 1 or claim 22, wherein the dimethylamination of the fourth step is carried out in dimethylformamide.

24. 2. The method of claim 1, wherein the deprotection of the fifth step is carried out in the presence of a predetermined alkali selected from monomethylamine or hydrazine hydrate.

25. 2. The method of claim 1, wherein the deprotection of the fifth step is carried out in a predefined solvent selected from alcoholic solvents such as methanol, ethanol, and isopropyl alcohol (IPA).

26. 26. The method of claim 25, wherein the deprotection of the fifth step is carried out in ethanol.

27. 2. The process according to claim 1, wherein the salt of the compound of formula (I) is formed by treating the compound obtained in the deprotection step with a predefined acid selected from hydrochloric acid or trifluoroacetic acid.

28. The method comprises: 【Transformation 7】 a) hydrogenating a compound of formula (VI) using Raney nickel; b) N-protecting a compound of formula (V) with phthalic anhydride to form a compound of formula (IV); c) brominating the compound of formula (IV) using N-bromosuccinamide to form compound (III); d) dimethylamination of compound (III) by treatment with dimethylamine to form a compound of formula (II); e) deprotecting formula (II) in the presence of monomethylamine to form a compound of formula (I); f) converting the compound of formula (I) into its hydrochloride salt by treatment with concentrated hydrochloric acid; 28. The method of any one of claims 1 to 27, comprising:

Images