Process for making a avenciguat, a soluble guanylate cyclase activator

Abstract

The invention relates to processes for making 5-ethoxy-1-[6-(3-methyl-2-{[5-methyl-2-(oxan-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl]methoxy}phenyl)-pyridin-2-yl]-1H-pyrazole-4-carboxylic acid (1): The invention also relates to methods for making certain intermediates useful for making 1.

Description

[0001] PROCESS FOR MAKING A SOLUBLE GUANYLATE CYCLASE ACTIVATOR FIELD OF THE INVENTION

[0002] The invention relates to processes for making 5-ethoxy-1-[6-(3-methyl-2-{[5-methyl-2-(oxan-4-yl)-1 ,2,3,4-tetrahydroisoquinolin-6-yl]methoxy}phenyl)-pyridin-2-yl]-1 H-pyrazole-4-carboxylic acid (1). The invention also relates to methods for making certain intermediates useful for making 1.

[0003] BACKGROUND OF THE INVENTION

[0004] Compound 1 has the structure shown below:

[0005]

[0006] 1.

[0007] Compound 1 is also known as avenciguat. Compound 1 is useful for treating a number of kidney- and liver-related disorders including, for example, chronic kidney disease, diabetic kidney disease, metabolic dysfunction-associated steatohepatitis (MASH, previously referred to as nonalcoholic steatohepatitis (NASH)), liver cirrhosis, and portal hypertension. Other diseases and diseases that may be treated with 1 are described, for example, in WO 2014 / 039434 and WO 2020011804. The preparation of 1 is described in WO 2014 / 039434 (see compound 111). However, the process described in WO 2014 / 039434 is not amenable to large-scale production. Disclosed herein are improved processes for making Compound 1. The processes described herein produce Compound 1 in higher yields, utilize milder reaction conditions, and utilize fewer reaction steps than the process described in WO 2014 / 039434.

[0008] BRIEF SUMMARY OF THE INVENTIONThe present invention relates to methods for making 1.

[0009] In one embodiment (Embodiment 1), the invention relates to a method for making Compound 1, the method comprising:

[0010] reacting Compound 2 with Compound INT-A to provide the ether Compound 4, where X is OH, Cl or Br:

[0011]

[0012] and

[0013] treating Compound 4 with base to provide Compound 1.

[0014]

[0015] In another embodiment, the invention relates to Embodiment 1, wherein the reaction of 2 with INT-A is carried out in the presence of phosphine (e.g., triphenyl phosphine) and

[0016] azodicarboxylate.In another embodiment, the invention relates to any of the embodiments above, wherein INT-A is Compound 3a.

[0017] In another embodiment, the base used in any of the embodiments above is an aqueous base; in another embodiment, the aqueous base is aqueous KOH or NaOH.

[0018] In another embodiment (Embodiment 2), the invention relates to a method for purifying Compound 1 obtained by any of the embodiments described above. In one embodiment, the purification method comprises:

[0019] (i) treating Compound 1 with aqueous acid to provide a first process stream,

[0020] (ii) filtering the first process stream to provide a filtrate,

[0021] (iii) treating the filtrate from step (ii) with aqueous citric acid to provide a second process stream,

[0022] (iv) treating the second process stream from step (iii) with water to provide a third process stream,

[0023] (v) maintaining the third process stream for a time and at a temperature sufficient to form a mixture, and

[0024] (vi) isolating the solid form of Compound 1 from the mixture.

[0025] In another embodiment, the aqueous acid used in step (i) in Embodiment 2 is hydrochloric acid or citric acid; in another embodiment, the aqueous acid is citric acid.

[0026] In another embodiment, the solid form of Compound 1 described in any of the embodiments above is a crystalline solid. In another embodiment, step (v) of Embodiment 2 is preceded by a seeding step. In another embodiment, the solid form of Compound 1 obtained in step (vi) of Embodiment 2 is crystalline. In another embodiment, the solid form of Compound 1 obtained in step (vi) of Embodiment 2 is further processed by grinding or milling.

[0027] The present invention also relates to intermediates useful in the process for making 1.

[0028] In one embodiment, the invention relates to INT-A wherein:

[0029] X is OH (Compound 3a); or

[0030] X is Cl (Compound 3b) and its hydrochloric acid salt (Compound 3b * HCI); or

[0031] X is Br (Compound 3c) and its hydrobromic acid salt (Compound 3c * HBr).

[0032]

[0033] In another embodiment, the invention relates to a method for making Compound 3a, the method comprising reacting Compound 5 with acetic acid to provide the acetate salt 5 * HOAc followed by reaction with Compound 6 under reducing conditions to provide Compound 3a:

[0034]

[0035] In another embodiment, the invention relates to a method for making Compound 3a, the method comprising reacting Compound 5 with Compound 6 and NaBH(OAC)3to provide Compound 3a:

[0036]

[0037] In another embodiment, the invention relates to a method for making Compound 3b, the method comprising reacting Compound 3a with a chlorinating agent to provide Compound 3b:

[0038]

[0039] In another embodiment, the invention relates to a method for making Compound 3c, the method comprising reacting Compound 3a with a brominating agent to provide Compound 3c:

[0040]

[0041] In another embodiment, the invention relates to a method for making Compound 5, the method comprising, reacting Compound 7 with paraformaldehyde in acetic anhydride and formic acid to provide Compound 5,

[0042]

[0043] In another embodiment, the invention relates to a method for making Compound 5, the method comprising reacting Compound 8 with paraformaldehyde in formic acid to provide Compound 5,

[0044]

[0045] In another embodiment, the invention relates to a method for making Compound 7, the method comprising:

[0046] reacting (3-Bromo-2-methylphenyl)methanol with N-vinylformamide to provide Compound 9, and

[0047] hydrogenating 9 to provide Compound 7,

[0048]

[0049] In another embodiment, the invention relates to a method for making Compound 8, the method comprising reacting Compound 12 with A / -formylformamide sodium salt to provide Compound 8,

[0050]

[0051] Applicant believes that Compounds 3b and 3b * HCI, 3c and 3c * HBr, 7, and 8 are novel. Accordingly, in another embodiment, the invention relates to Compound 3b, in anotherembodiment, the invention relates to 3c; in another embodiment, the invention relates to Compound 5; in another embodiment, the invention relates to Compound 7; in another embodiment, the invention relates to Compound 8.

[0052] Compound 2 may be prepared according to the method described in WO 2014 / 039434 (see Example 3, Compound 3-15) or the methods described herein. Compound 6 is available from commercial sources or can be prepared according to methods described in the literature.

[0053] BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS Figure 1 shows the process for preparing Compound 1 as described in WO 2014 / 039434. Figure 2 shows a process for preparing an ether analog of Compound 1 according to one embodiment of the invention.

[0054] Figures 3a and 3b show processes for converting the ether analog of Compound 1 into Compound 1 according to one embodiment of the invention. The process depicted in Figure 3a requires an isolation step of a crude intermediate prior to conversion to Compound 1. The process depicted in Figure 3b can be carried out without isolation of the intermediate.

[0055] DETAILED DESCRIPTION OF THE INVENTION

[0056] Abbreviations:

[0057] ACN Acetonitrile

[0058] AcOH Acetic acid

[0059] Aq Aqueous

[0060] BIDIME (S)-3-(tert-Butyl)-4-(2,6-dimethoxyphenyl)-2,3- dihydrobenzo[d][1 ,3]oxaphosphole

[0061] Cy Cyclohexyl

[0062] Dba benzylideneacetone

[0063] DCM Dichloromethane

[0064] Dppf 1 ,1'-Bis(diphenylphosphino)ferrocene

[0065] DMF Dimethylformamide

[0066] EtOAc Ethyl acetate

[0067] EtOH Ethanol

[0068] h Hour(s)

[0069] I PA Isopropyl alcohol

[0070] MeOH Methanol

[0071] MsCI Methanesulfonyl chloride

[0072] MTBE Methyl-t-butyl ether

[0073] NaBH(OAc)3Sodium triacetoxyborohydride

[0074] NMP 1 -Methyl-2-pyrrolidone

[0075] Ns 4-Nitrobenzenesulfonate

[0076] PCy3T ricyclohexylphosphine

[0077] PPh3 Triphenylphoshine

[0078]

[0079] PPTS Pyridinium p-toluenesulfonateP(t-Bu)3tert-Butylphospine

[0080] TBABr Tetra butylammonium bromide

[0081] TEA Triethylamine

[0082] THF Tetrahydrofuran

[0083]

[0084] THP Tetrahydropyranyl

[0085] As used herein, the symbol means approximately.

[0086] GENERAL SYNTHETIC METHODS

[0087] Compound 1 may be prepared by the methods and examples described herein.

[0088] Figure 1 shows a process for preparing Compound 1 as described in WO 2014 / 039434. As shown in Figure 1 , Compound 1 is prepared from Compound 2 in a three-step process. In a first step tert-butyl 6-(bromomethyl)-5-methyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (A) is reacted with Compound 2 to provide intermediate tert-butyl 6-[(2-{6-[5-ethoxy-4-(ethoxycarbonyl)-l H-pyrazol-1 -yl]pyridin-2-yl}-6-methylphenoxy)methyl]-5-methyl-1 ,2,3,4-tetrahydroisoquinoline-2-carboxylate (B). Intermediate (B) is saponified and hydrolyzed to provide intermediate 5-ethoxy-1 -(6-{3-methyl-2-[(5-methyl-1 ,2,3,4-tetrahydroisoquinolin-6-yl)methoxy]phenyl}pyridin-2-yl)-1 H-pyrazole-4-carboxylic acid (C). Intermediate (C) is then reacted with Compound 6 to provide Compound 1. The yield of Compound 1 (based on Compound 2) is typically about 65%.

[0089] One embodiment of the present invention is depicted in Figure 2, which shows that Compound 1 is prepared from Compound 2 in a two-step process. In contrast, the process described in WO 2014 / 03943 (Figure 1) requires three-steps to carry out the same conversion. The change in reagents and elimination of one of the process steps results in fewer process impurities and higher yields as compared to the process described in WO 2014 / 03943. For example, the yield of Compound 1 (based on Compound 2) is about 80 %. Furthermore, the improved process depicted in Figure 2 avoids the use of halide A required in the process described in WO 2014 / 039434.

[0090] The present invention provides a process for preparing Compound 1 in two steps from Compound 2 (see Figures 2, 3a and 3b). In the first step of the improved process, (Figure 2) Compound 2 is reacted with Compound 3a in a Mitsunobu reaction to provide Compound 4, which is typically carried out in an anhydrous solvent such as THF in the presence of phosphine (e.g., triphenyl phosphine) and azodicarboxylate (e.g. DEAD, DIAD). Compound 1 is obtained by saponification of Compound 4 (see Figures 3a and 3b). Typically, the saponification is carried out by dissolving Compound 4 in organic solvent (for example, ethanol), heating the solution toabout 70 °C, and treating the heated solution with aqueous base such as sodium hydroxide or potassium hydroxide to provide Compound 1. Then, aqueous acid is added to the heated solution. The solution is then further treated with aqueous acid, optionally treated with seed crystals of Compound 1 , and finally cooled. The resulting solids are then collected to provide Compound 1 as a crystalline solid. The process depicted in Figure 3a requires an isolation step of a crude intermediate prior to conversion to Compound 1. The process depicted in Figure 3b can be carried out without isolation of the intermediate.

[0091] In another embodiment, the invention relates to methods for making Compound 3a. In a first step, Compound 5 is treated with acid (such as acetic acid) to provide the salt 5 * HOAc. This salt is then reacted with tetrahydropyran-4-one and hydrogen in the presence of a hydrogenation catalyst (for example, palladium on charcoal) to provide Compound 3a.

[0092] In another embodiment, Compound 3a is prepared by reacting Compound 5 with Compound 6 and NaBH(OAC)3to provide Compound 3a.

[0093] In another embodiment, the invention relates to Compound 3b. Compound 3b may be obtained by reacting Compound 3a with a chlorinating agent to provide 3b. Nonlimiting examples of chlorinating agents include methanesulfonyl chloride with ammonium chloride salt, thionyl chloride, and PCh. In another embodiment, the chlorinating agent is methanesulfonyl chloride. Another embodiment of the invention relates to Compound 3c. Compound 3c may be obtained by reacting Compound 3a with a brominating agent to provide 3c. Nonlimiting examples of brominating agents include HBr (when used under acidic conditions) and PBr3.

[0094] In another embodiment, the invention relates to Compound 5. One method for making Compound 5 involves reacting Compound 7 with paraformaldehyde in acetic anhydride and formic acid to provide Compound 5. Another method for making Compound 5 involves reacting Compound 8 with paraformaldehyde in formic acid to provide Compound 5.

[0095] EXAMPLES

[0096] Unless otherwise described herein, seed crystals of Compound 1 are prepared by the method described in WO2024123847 (crystalline Form I).

[0097] Example 1

[0098] Preparation of ({5-ethoxy-1-[6-(2-hydroxy-3-methylphenyl)pyridin-2-yl]-1 H-pyrazol-4-yl}ethylperoxy)one (2)

[0099] Method 1 :

[0100]

[0101] Ethyl 1-(6-chloro-2-pyridinyl)-5-ethoxy-1 H-pyrazole-4-carboxylate (20,00 g) (13) prepared as described in WO 2014 / 039434), (2-hydroxy-3-methylphenyl)boronic acid (13,87 g, and potassium carbonate (14,02 g) are suspended in isopropanol (100 ml) and deionized water (80 ml) in a jacketed reaction vessel under argon atmosphere. Palladium(ll) acetate (110 mg) and triphenylphosphine (270 mg) are added at room temperature. The reactor is evacuated and charged with argon. The reaction mixture is heated to 75-80 °C and maintained at slight reflux for at least 1 hour. The reaction mixture is transferred into a second reactor. The first reactor is rinsed with isopropanol (20 ml), the rinse is transferred to the second reactor, and the contents of the second reactor are cooled 60-65 °C. A / -acetylcysteine (280 mg) is added to the reactor and the contents stirred at 65 °C for 30 min. Deionized water (40 ml) and seeding crystals of Compound 2 (100 mg) (prepared as described in WO2014039434) are added, and the mixture is stirred for another 20 min. at 60 °C. Another portion of deionized water (120 ml) is added at 50-60 °C and the mixture is stirred for further 30 min. The mixture is cooled to 20 °C within 60 min., held at 20 °C for 30 min., and filtered. The collected solids are washed with deionized water (40 ml) and isopropanol (40 ml) and dried at 50 °C under reduced pressure to provide 23,7 g of 2 (95,4%).

[0102] Method 2:

[0103] An alternative method for preparing Compound 2 can be carried out as described above in Method 1 except palladium(ll) acetate in Step 1 is replaced by PdCl2(PPh3), PdCl2(dppf), Pd(OAc)2( / P(t-Bu)3»HBF4, PdCl2P(Cys)3, or BIDIME-precatalyst with 0.5% to 1.0 mol% catalyst loading.

[0104] Example 2

[0105] Preparation of [5-methyl-2-(oxan-4-yl)-1 ,2,3,4-tetrahydroisoquinolin-6-yl]methanol (3a) Method 1 :OH

[0106] * AcOH

[0107]

[0108] 5 * HOAc

[0109] Step 1 : Compound 5 (20 g) and methanol (70 ml) are mixed and heated to 60 °C. Acetic acid (7,15 g) is added slowly, and the mixture is cooled to 55-60 °C. MTBE (50 ml) is added at 50-55 °C within 10 min. The suspension is cooled to room temperature within 45 min. and another portion of MTBE (30 ml) is added. The mixture is then cooled to ~8 °C and stirring is continued for 30 min. at ~8 °C. The solids are filtered, washed with MTBE (30 ml), and dried at 70 °C under reduced pressure to provide 25,0 g of Compound 5*HOAc (93,2%).

[0110]

[0111] Step 2. Compound 5 * HOAc from Step 1 above (20 g), tetrahydropyran-4-one (6) (11.5 g) and palladium on carbon (10%, 1.5 g) is mixed with methanol (160 ml) and hydrogenated at 2-4 bar hydrogen pressure for 3-6 hours at 25-35 °C. The mixture is then treated with deionized water (60 ml) and acetic acid (2.5 g). The suspension is filtered and the solid washed with 30 ml of deionized water. The combined filtrate is concentrated to about 90 ml under reduced pressure, treated with deionized water (20 ml), and heated to 50-60 °C. Within at least 15 min. the solution is treated with 25 % aqueous ammonia solution (15.0 g) and deionized water (10 ml) at 50-60 °C. The suspension is cooled to 0-10 °C, and stirred for 30 min. The solids are filtered, washed with deionized water (30 ml), and dried at 80 °C under reduced pressure to provide 21.2 g of Compound 3a. (Yield: 96 %.)

[0112] 1H NMR (500 MHz, CDCI3): 57.12 (d, J= 7.7 Hz, 1H), 6.88 (d, J= 7.7 Hz, 1 H), 4.66 (s, 2H), 4.06 (dd, J= 11.5, 3.8 Hz, 2H), 3.76 (s, 2H), 3.42 (t, J= 11.5 Hz, 2H), 2.87 (t, J= 5.8 Hz, 2H), 2.78 (t, J = 5.8 Hz, 2H), 2.63 (tt, J= 11.2, 3.7 Hz, 1H), 2.2 (s, 3H), 1.87 (d, J= 12.4 Hz, 2H), 1.71 (dt, J= 12.0, 4.3 Hz, 2H), 1.65 (br s, 1H);13C NMR (500 MHz, CDCI3): 6 136.7, 134.9, 133.7, 125.7, 124.4 (2C), 67.6, 64.2, 60.3, 52.6, 47.0, 29.8, 27.9, 14.1; HRMS (ESI): Exact mass calcd for CI6H24O2N [M+H]+, 262.1802, found 262.1803.

[0113] Method 2:A suspension of Compound 5 (56.8 g) in IPA (850mL) is stirred at a temperature of 20-25°C under nitrogen atmosphere. The reactor is then charged with 6 (1.3 eq) and solid NaBH(OAc)s (1.5 eq.), and the reaction mixture is stirred for 3 h at 20-25°C. If the reaction is less than 98% complete, another portion of NaBH(OAc)s (0.3 eq.) and 6 (0.2 eq.) is added, and the reaction mixture is stirred at 20-25°C for 1 h. (Additional tetrahydro-pyran-4-one and sodium triacetoxyborohydride are added to drive the reaction to completion as needed). The reactor is then charged with water (300 ml) and stirred at 22°C until a clear solution is obtained. IPA is removed by distillation and the aqueous residue is slowly treated with 4N NaOH (~500mL) to adjust the pH to ~9. The crude product precipitates as free base from the mixture. The resulting slurry is stirred for 0.5 h at 22°C and filtered. The filter cake is washed with water (100 ml) and dried.

[0114] The crude product, IPA (500mL) and water (100 ml) are added to a reactor, and the mixture is stirred at 60°C for 0.5 hr. The reactor contents are then cooled to 20-25 °C, stirred for 1 h at this temperature, cooled again to 5 °C, and stirred for another 1 h at 5 °C. The resulting slurry is filtered the filter cake is washed with 60 ml IPA / water (5:1 v / v) and dried to provide 3a (107.0 g) as a light yellow solid: 65.4% yield; purity >99.5 area % by HPLC.

[0115] Example 3

[0116] Preparation of 6-(chloromethyl)-5-methyl-2-(oxan-4-yl)-1 ,2,3,4-tetrahydroisoquinoline (3b):

[0117]

[0118] Compound 3a (100.0 g, 55 wt%) is charged to a 2 L reactor under nitrogen atmosphere followed by THF (500 ml). The reactor contents are cooled to 0-3 °C. MsCI (36.1 g, 1.5 equiv) and TEA (37.3 g, 1.75 eq.) are added, and the reactor mixture is stirred for 1 h. Bu4NCI (73.1 , 1.25 eq.) is added, and the mixture is warmed to 20-25 °C and stirred for 2 h to complete the reaction. Water (400 ml) is added and the mixture stirred for 1 h. The mixture is distilled under reduced pressure at <30 °C to remove about 450 ml solvent. The resulting slurry is stirred for 1 h and filtered. The filter cake is washed with water (200 ml) and heptane (200 ml). The filter cake is then dried at 50 °C under vacuum to provide 3b in 92 % yield.

[0119] 1H NMR (500 MHz, ( -DMSO): 67.08 (d, J= 7.7 Hz, 1H), 6.83 (d, J= 7.7 Hz, 1H), 4.70 (s, 2H), 3.84 (dd, J= 11.1 , 3.0 Hz, 2H), 3.61 (s, 2H), 3.24 (t, J = 11.1 Hz, 2H), 2.72 (br m, 2H), 2.61 (m,3H), 2.44 (brs, 1 H), 2.14 (s, 3H), 1.72 (d, J= 11.9 Hz, 2H), 1.43 (dddd, J= 11.8, 11.8, 11.8, 3.8 Hz, 1H);13C NMR (500 MHz, c -DMSO): 0 135.3, 133.8, 133.1, 127.3, 124.1 (2C), 66.4, 59.3, 51.7, 46.2, 45.8, 29.2, 27.3, 13.8; HRMS (ESI): Exact mass calcd for CI6H23ONCI [M+H]+, 280.1463, found 280.1464.

[0120] If desired, 3b can be equilibrated with aqueous HCI to provide the hydrogen chloride salt of 3b (3b * HCI).

[0121] Example 4

[0122] Preparation of 6-(bromomethyl)-5-methyl-2-(oxan-4-yl)-1 ,2,3,4-tetrahydroisoquinoline (3c)

[0123]

[0124] Compound 3a (15.96 g, 50 wt%, 30.53 mmol) and AcOH (16 ml) are charged to a 250 ml flask under nitrogen atmosphere, and the contents of the reactor are slowly treated with 33% HBr in HOAc (37.47 g, 152.28 mmol) over 15 min while keeping the internal temperature below 55 °C. The mixture is stirred at 55 °C for 50 min to complete the reaction, cooled to room temperature, treated with MTBE (80 ml), and stirred at room temperature for 30 min. The mixture is filtered, and the filter cake is washed with MTBE (14 ml). The filter cake is air-dried for 30 min, reslurried in water (70 ml) for 30-60 min and filtered. The filter cake is washed with water (15 ml) and dried under reduced pressure at 45 °C to provide 3c (11.1 g, 98.8%) in 90% yield.

[0125] If desired, 3b can be equilibrated with aqueous HBr to provide the hydrogen bromide salt of 3b (3b* HBr).

[0126] Example 5

[0127] Preparation of ({5-ethoxy-1 -[6-(3-methyl-2-{[5-methyl-2-(oxan-4-yl)-1 ,2,3,4-tetrahydroisoquinolin-6-yl]methoxy}phenyl)pyridin-2-yl]-1 H-pyrazol-4-yl}ethylperoxy)one (4)

[0128] Compound 4 may be prepared as described in WO 2014 / 039434 or by the methods described below.

[0129] Method 1 :

[0130]

[0131] Compound 2, (20.0 g), Compound 3a (21 ,4 g) and triphenylphosphine (24,8 g) are suspended in THF (200 ml) under argon atmosphere. The reactor content is cooled to -5 °C, and the resulting mixture is treated dropwise with diisopropylazodicarboxylate (19,2 g) at -5 to 0 °C within 210 minutes. The reactor content is warmed to room temperature over 120 min and stirred at room temperature for at least 1 h. The solution is concentrated under reduced pressure at 90 °C until about 180 ml of solvent is removed. Acetonitrile (120 ml) is added to the residue and 110 ml of solvent is distilled off under reduced pressure at 90 °C. A further portion of acetonitrile (100 mL) is added, and the solution is cooled to 80 °C and stirred for 30 min. The solution is further cooled to 65-70° C and treated with seed crystals of Compound 4 (prepared as described in WO 2014 / 039434). The mixture is cooled to 10 °C and stirred for 1 hour. The solids are collected by filtration, washed with 2x 40 ml of cold acetonitrile, and dried at 65 °C under reduced pressure to provide 28,6 g of 4 (85,9%) as off-white crystals.

[0132] Method 2:

[0133]

[0134] A 2 liter flask is charged with 3b * HCI (43.5 g), 2 (56.1g), Cs2C0s( 69.9 g), TBABr (2.3 g) and DMF (330 ml) at 20-25 °C under nitrogen atmosphere. The mixture is heated with stirring to 40-45 °C and maintained at that temperature for 1 h to complete the reaction. The mixture is cooled to 20-25 °C and treated with water (495 ml) and MTBE (495 ml). The mixture is stirred for 1 h and filtered. The filter cake is washed with water (165 ml) and MTBE (165 ml). The filter cake is then dried under reduced pressure at 20-25 °C to provide the crude product (4) as an off-white solid (100 g). The crude product is dissolved in DMF (693 ml) at 60-65 °C, slowly treated with water (198 ml), and stirred at 60-65 °C for 0.5 h. The mixture is cooled to 20-25 °C, stirred for 1 h, and filtered. The filter cake is washed with I PA (110 ml) and dried under reduced pressure at 50-55 °C to provide 4 (81.2 g) in 92 % yield.

[0135] Method 3:

[0136] Compound 4 can be prepared in a manner similar to that described in Method 2 except Compound 3b is used instead of 3b * HCI.

[0137] Method 4:

[0138]

[0139] A 500 mL reactor is charged with 2 (10.00 g, 27.22 mmol), BnEtsNCI (0.31 g, 1 .36 mmol), CS2CO3 (39.91 g, 122.49 mmol) and NMP (100 ml) and stirred at 27-30 °C. The mixture is then treated with 3c * HBr (11.58 g, 28.58 mmol) in ten portions every 15-20 minutes. The resulting slurry is stirred at 27-30 °C for 15-20 min, heated to 45-50 °C for 30 min, and filtered. The filter cake is washed with NMP (40 ml). The combined filtrates are warmed to 35 °C, cooled to 25 °C, and treated with water (15 ml) over 2 min while keeping internal temperature below 35 °C. A seed crystal of 2 (0.01 g) (prepared as described in Method 1 above) is added, and the contents of the vessel are stirred for 10 min. Water (55 ml) is added with stirring over 20-40 min while maintaining an internal temperature below 47 °C. The mixture is cooled to 28-30 °C over 30min, stirred for 1 -16 h at 28-30 °C, and filtered. The filter cake is washed with EtOH (40 ml) and dried under reduced pressure while keeping the temperature below 45 °C to provide 4 (14.12 g) in 85 % yield.

[0140] Example 6

[0141] Preparation of (5-methyl-1 ,2,3,4-tetrahydroisoquinolin-6-yl)methanol (5) or its HCI salt (5 * HCI):

[0142] Method 1 :

[0143]

[0144] Compound 7 (40g), paraformaldehyde (13.64 g), formic acid (240 ml), and acidic acid anhydride (31.68 g) are charged to a 1 liter flask under N2atmosphere. The mixture is stirred at about 22 °C for 2 h then heated to 90-95 °C for 3h. The mixture is distilled at 45-50 °C under reduced pressure to minimum volume. The distillation residue is treated with EtOAc (240 ml) and water (100 ml), stirred at 40 °C for 1 h, and cooled to room temperature. The aqueous phase is removed and the organic phase washed with brine (100 ml) and distilled at 35 °C under reduced pressure to a minimum volume. The distillation residue is treated with MeOH (40 ml) and distilled to a minimum volume. The distillation residue is treated with MeOH (100 ml) and 5N NaOH (165 ml), and the stirred mixture is heated to 60-65 °C for 2h. The mixture is cooled to about 22 °C and stirred for 2 h. The resulting slurry is distilled to remove MeOH and filtered. The filter cake is then washed with water (40 ml) and isopropyl acetate (120 ml) and dried at 50 °C under reduced pressure to provide 5 (26 g) as white solid in about 70% yield.

[0145] 1H NMR (500 MHz, c -DMSO): 67.08 (d, J= 7.7 Hz, 1H), 6.80 (d, J= 7.7 Hz, 1H), 4.46 (s, 2H), 3.79 (s, 2H), 2.96 (t, J= 5.8 Hz, 2H), 2.53 (t, J= 5.8 Hz, 2H), 2.08 (s, 3H);13C NMR (500 MHz, t^-DMSO): 6137.3, 135.0, 133.7, 133.3, 124.4, 123.1 , 61.7, 48.4, 43.8, 26.7, 13.3; HRMS (ESI): Exact mass calcd for CnHieON [M+H]+, 178.1227, found 178.1226

[0146] Method 2H

[0147]

[0148] 8 5 * HCI The oily residue of 8 from Example 8 (about 31.8 g) is treated with paraformaldehyde (8.60 g, 286.6 mmol) and formic acid (100ml). The mixture is heated to 100 °C, maintained at 100 °C with stirring for 1 h, and cooled to 25 °C. The mixture is concentrated by distillation to a minimum volume (-1 / 3 of volume). The concentrated residue is treated with EtOAc (200 ml) and water (200 ml), stirred for 5 min, and the organic phase is collected. The aqueous phase is extracted with EtOAc (100 ml) and the combined organic layers are washed with 100 ml saturated NaHCOs. The combined organic layers are concentrated to a minimum volume (~10% of total volume), treated with 100 ml EtOH, and distilled to a minimum volume. The concentrated residue is treated with EtOH (200 ml) and 4N NaOH (115 ml, 458.4 mmol, 4 eq.), heated at reflux for 1-2 h, and cooled to 25 °C. The mixture is concentrated by distillation to a minimum volume (-1 / 3 of total volume) and extracted with DCM (200 ml). The aqueous layer is further extracted with DCM (200ml), and the combined organic phases are washed with brine (50 ml). The combined organic phases are treated with I PA (100 ml) and concentrated by distillation to 1 / 6 of total volume to provide a yellow oil. The oil is treated with IPA (100 ml) and the resulting mixture is concentrated to 1 / 2 of total volume by distillation. The concentrated residue is then treated with HCI / IPA (5N) (45.8 ml, 229.2 mmol) and MTBE (292 ml), stirred at room temperature for 0.5 h, and filtered. The filter cake is washed with 1 :2 IPA / MTBE (60 ml) and dried at 60 °C under reduced pressure to provide 5 * HCI as an off white solid (13.0 g) in about 92 % yield.

[0149] The salt can be used directly for next reaction step. If desired, the salt form can be treated with inorganic or organic bases to provide the free-base form of 5.

[0150] Example 7

[0151] Preparation of N-{2-[3-(hydroxymethyl)-2-methylphenyl]ethyl}formamide (7)

[0152]

[0153] Step 1 : Preparation of N-(3-(hydroxymethyl)-2-methylstyryl)formamide (9)

[0154] (3-Bromo-2-methylphenyl)methanol (120 g), benzyltriethylammonium chloride (67.97 g), Pd2(dba)s (0.68 g) and P(t-Bu3)*BF4(0.43 g) are charged under nitrogen atmosphere to a 5 liter flask equipped with an overhead stirrer. The reaction mixture is purged with inert gas (such as nitrogen or argon) for 10 min. In a separate reaction vessel, NMeCy2(139.95 g), N-vinylformamide (53.02 g) and dioxane (600 ml) are combined, and the resulting solution is degassed for 10 min.

[0155] The dioxane solution is then charged to the 5 liter flask and the resulting mixture heated at 75 °C for 5 h to complete the reaction. The reaction is cooled to room temperature, water (1200 ml) and 1 N NaOH (1200 ml) are charged to the reaction mixture, and the content of the reactor is stirred at room temperature for 1 h. The slurry is filtered, and the filter cake is washed with water / IPA (120 ml 1 :1 , v / v) and I PA (120 ml). The wet cake is then dried under reduced pressure at 55-60 ° to provide 9. (78.5 g) in about 68% yield.

[0156] Step 2: Preparation of Compound 7

[0157] Compound 9 (20.0 g), a 200 ml solution of EtOH containing 5 % MeOH and 5 % IPA, and palladium on charcoal (2.0 g, 10 % wet) are charged to a hydrogenation reactor, and the mixture is hydrogenated at 70 °C / 400 psi for 5 h. The mixture is filtered and washed with EtOH (100 ml). The filtrate is distilled under vacuum to a minimum volume, treated with MTBE (100 ml), stirred at room temperature for 1 h, and filtered. The resulting filter cake is washed with MTBE (25 ml) and dried under vacuum at 50 °C to provide 7 (16.5 g) in 85-95% yield.

[0158] 1H NMR (500 MHz, CDCI3): 57.94 (s, 1 H), 7.21 (d, J= 7.3 Hz, 1 H), 7.10 (dd, J= 7.7, 7.7 Hz, 1 H), 7.04 (d, J = 7.3 Hz, 1 H), 6.23 (br s, 1 H), 4.62 (s, 2H), 3.43 (dt, J = 6.8 Hz, 6.8 Hz, 2H), 2.83 (t, J= 7.1 Hz, 2H), 2.26 (s, 3H);13C NMR (500 MHz, CDCh): 6 161.6, 139.5, 137.2, 134.6, 129.2, 126.6, 125.8, 63.7, 38.4, 33.2, 14.2; HRMS (ESI): Exact mass calcd for CnHi6O2N [M+H]+, 194.1176, found 194.1177.Example 8

[0159] Preparation of N-(2-{2-methyl-3-[(oxan-2-yloxy)methyl]phenyl}ethyl)formamide (8)

[0160]

[0161] Compound 12 (50.00 g; 114.8 mmol), / V-formylformamide sodium salt (14.18 g; 149.3 mmol) and DMF (100 ml) are charged to a 2 liter reactor under nitrogen atmosphere. The mixture is heated to 55-56 °C over 45 min and stirred at 55-56 °C for 60 min. The mixture is then treated with MeOH (13 ml) and stirred at 55 °C for 30 min. The mixture is cooled to 22-25 °C with stirring and treated with MTBE (195 ml). The mixture is filtered and the filter cake washed with MTBE (65 ml). The combined filtrates are treated with 5% Na2CO3aq. (195 ml) and stirred for 5 min. The aqueous layer is collected and extracted with MTBE (95 ml). The organic layers are combined, washed with 5% NaCI aq. (95 ml), and distilled to a minimum volume (-10% of total volume) to provide 8 as an oily residue (about 31.8 g).

[0162] Example 9

[0163] Preparation of 2-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenethyl 4-nitrobenzenesulfonate (12)

[0164]

[0165] Step 1 : Synthesis of 10

[0166] (3-Bromo-2-methylphenyl)methanol (34.90 g, 173.6 mmol), pyridinium p-toluenesulfonate (4.36 g, 17.4 mmol) and DCM (230 ml) are charged to a reactor, and the mixture is azeotropically distilled until a Karl-Fischer titration provides a water content of less than 0.02 %. The mixture isthen charged with 3,4-dihydro-2H-pyran (18.98 g, 225.7 mmol) and stirred at 18-25 °C for 3 h. The mixture is distilled to 1 / 5 of its original volume under reduced pressure while keeping the internal temperature below 40 °C. The concentrated mixture is treated with heptane (130 ml) and concentrated under reduced pressure to 1 / 3 of its original volume while keeping the internal temperature below 40 °C. The concentrated mixture is treated with heptane (250 mL), cooled to 15-18 °C, and stirred at that temperature for 1-16 h. The mixture is filtered and the filter cake washed with heptane (45 ml). The filtrates are collected and distilled under reduced pressure to 1 / 10 of the original volume while keeping internal temperature below 40 “C to provide 10 as a concentrated residue.

[0167] Step 2: Synthesis of 11

[0168] The concentrated residue 10 from Step 1 is treated with THF (180 ml) and the system is flushed with nitrogen three times. The mixture is cooled to 0 °C and slowly treated with ethylene oxide (9.48 g, 215.2 mmol) by bubbling in over 30 min. The mixture is cooled to -8 °C and treated with a THF solution of / -PrMgCI (2.0 M, 43.4 ml, 86.8 mmol) while keeping the internal temperature below -2 °C. The mixture is further cooled to -8 °C and slowly treated with a n-BuLi hexane solution (2.5 M, 62.5 ml, 156.2 mmol) over 1 hour while keeping the internal temperature between -8 °C and ~-2 °C. The mixture is warmed to 40 °C in 40 min and stirred at 40 °C for 20 min to complete the reaction. The mixture is cooled to 35 °C, treated with 7% NH4CI aqueous solution (200 ml) and heptane (100 ml), and stirred for 5 min. The aqueous phase is discarded and the organic phase washed with 3% NaCI aqueous solution (100 ml). The organic phase is then distilled to 1 / 7 of its original volume under reduced pressure while keeping the internal temperature below 40 °C. The concentrated mixture is treated with THF (200 ml) and distilled to 1 / 5 of its original volume under reduced pressure while keeping the internal temperature below 40 °C to provide 11 as a concentrated residue.

[0169] Step 3: Synthesis of 12

[0170] The concentrated residue 11 from Step 2 is treated with triethylamine (23.71 g, 234.3 mmol) and 4-nitrobenzenesulfonyl chloride (50.01 g, 225.65 mmol) in THF (160 ml) in 1 min. The mixture is then heated at 40-25 °C for 3 h. The mixture is filtered and the filter cake washed with 5:1 heptane / THF (120ml). The combined filtrates are mixed with 5% of NagCOs (300 ml) at 20-25 °C for 20 min, the aqueous layer is discarded, and the organic layer is washed with 3% NaCI aqueous solution (150 ml). The organic phase is distilled to 1 / 2 of its original volume under reduced pressure while keeping the internal temperature below 40 °C. I PA (270 ml) is added slowly during reduced pressure distillation to keep the same internal volume while keeping internal temperature between 28° and -35 °C. The mixture is then treated with MeOH (80 I), cooled to 30 °C, and stirred for 5 min. The mixture is slowly treated with IPA (200 ml), over20-30 min, cooled to 25 °C in 30 min, stirred at 25 °C for 1 -16 h, and filtered. The filter cake is washed with IPA / MeOH (20:1 , v / v, 126 ml) and dried under reduced pressure at < 25 °C to provide 12.

[0171] Compound 12 can also be prepared as described above except the cooled methanol solution is seeded with 0.01 of Compound 12 (prepared as described above) to provide 12 (59.3 g, 99.5 % pure) in 78% yield.

[0172] Example 10

[0173] Preparation of Compound 1

[0174] Method 1 :

[0175]

[0176] Compound 4 (20 g), 120 ml ethanol and 40 ml deionized water are charged to a reactor. The resulting suspension is treated with aqueous potassium hydroxide solution (45%, 4,2 ml) at room temperature. The reaction mixture is heated to 80 °C and maintained at that temperature for 3 hours. The mixture is cooled to room temperature and treated with ammonium citrate (4,0 g). The content of the reactor is heated to 70 °C, filtered into a crystallizing vessel, and the reactor rinsed with deionized water (20 ml). The filtrate is heated to 70 °C and 25% aqueous citric acid solution (9,6 ml) is added at 65-75 °C within 10 min. The solution is seeded with Compound 1 (50 mg) (prepared as described in Example 11) and stirred for an additional 30 min at about 70 °C. The suspension is cooled to 55 °C and treated with an additional portion of 25% aqueous citric acid solution (5,8 ml) within 10 min. and stirred for another 30 min. at 55 °C. Deionized water (100 ml) is added within 10 min. and the mixture is stirred for 30 min. at 55 °C. The suspension is cooled to room temperature within 60 min. and stirred for additional 60 min.at this temperature. The solids are filtered, and the filter cake washed subsequently with 40 ml of deionized water followed by 40 ml ethanol. The solids are then dried at 65 °C under reduced pressure to provide 17,9 g of Compound 1 in 93,8%. (The process is depicted in Figure 3b). Method 2: An alternative method for preparing Compound 1 can be carried out as described above in Method 1 except hydrochloric acid is used in the work-up and a crude form of Compound 1 is isolated after HCI treatment. The crude product is dissolved again in aqueous ammonia and acidified with citric acid to provide Compound 1. (The process is depicted in Figure 3a).

[0177] Method 3:

[0178] Compound 4 (10 g) and 60 ml ethanol are charged to a reactor. The resulting suspension is treated with 12.1 ml of aqueous potassium hydroxide (1.3174 equivalents) over 10 min. The mixture is then treated with 10 ml of deionized water (1 V), heated to 79 °C over 15 min. and heated at reflux for 1 hour. The contents of the reactor are cooled to 70° C. over 24 min. and treated with 4.63 g of HC1 10% (0.78 eq) over 39 sec. The mixture is seeded with 50 mg of Compound 1 and stirred for an additional 50 min. at 70° C. The mixture is treated with 3.66 g of HCI 10% (0.61 eq) over about 100 min and the held at 70° C for 30 minutes. The mixture is then treated with 60 ml of deionized water over about 50 min at 70° C, and held for an additional 30 min. at 70° C. The mixture is then cooled to 20° C over 1 hour, held for 30 min at 20° C and treated with 2.11 ml of potassium hydroxide solution. The solids are collected using suction filtration (filter diameter: 40 mm) and the solids washed with a mixture of 10 ml ethanol and 10 ml of deinonized water. The solids are then dried at 65° C under reduced pressure (100 mbar vacuum) to provide 8.61 g of Compound 1. Relative yield: 90.6%.

Claims

ClaimsWhat is claimed is:

1. A method for making Compound 1,the method comprising :reacting Compound 2 with Compound INT-A to provide the ether Compound 4,wherein X is OH, Cl or Br, andtreating Compound 4 with base to provide Compound 1.

2. The method of claim 1 , wherein the in the base is an aqueous base selected from the group consisting of aqueous potassium hydroxide (KOH) and sodium hydroxide (NaOH).

3. The method of claim 1 or 2, wherein the reaction of 2 with INT-A is carried out in the presence of triphenyl phosphine and azodicarboxylate.

4. The method of any of the preceding claims, further comprisingtreating Compound 1 with an ammonium citrate to provide a first process stream, filtering the first process stream to obtain a filtrate,treating the filtrate with aqueous citric acid to provide a mixture, andcollecting the solids from the mixture to provide a solid form of Compound 1.

5. The method of any of claims 1 to 3, further comprisingtreating Compound 1 with aqueous acid to provide a first mixture,isolating the solids from the mixture,dissolving the solids in aqueous ammonia to provide a solution,filtering the solution to obtain a filtrate,treating the filtrate with aqueous citric acid to provide a mixture, andisolating the solids from the mixture to provide a solid form Compound 1.

6. The method of claim 5, wherein the aqueous acid is selected from the group consisting of hydrochloric acid and citric acid.

7. The method of any of claim 4 or 5, wherein the solid form of Compound 1 is a crystalline solid.

8. A method for making Compound 3a, the method comprising:(i) reacting Compound 5 with acetic acid to provide the acetate salt 5 * HOAC, and (ii) Reaction 5 * HOAC with Compound 6 under reducing conditions to provide Compound 3a:5a * HOAc9. A method for making Compound 3a, the method comprising reacting Compound 5 with Compound 6 and NaBH(OAC)3to provide Compound 3a:

10. A method for making Compound 3b, the method comprising reacting Compound 3a with a chlorinating agent to provide Compound 3b:

11. The method of claim 11 , wherein the chlorinating agent is selected from the group consisting of methanesulfonyl chloride ammonium chloride salt, thionyl chloride, and PCh.

12. The method of claim 12 or 13, wherein the chlorinating agent is methanesulfonyl chloride.

13. A method for making Compound 3c, the method comprising reacting Compound 3a with a brominating agent to provide Compound 3c:

14. The method of claim 15, wherein the brominating agent is selected from the group consisting of HBr and PBrs.

15. The method of claim 15 or 16, wherein the brominating agent is HBr.

16. A method for making Compound 5, the method comprising reacting Compound 7 with paraformaldehyde in acetic anhydride and formic acid to provide Compound 5:

17. A method for making Compound 5, the method comprising reacting Compound 8 with paraformaldehyde in formic acid to provide Compound 5:

18. A method for making Compound 7, the method comprising:reacting (3-Bromo-2-methylphenyl)methanol with A / -Vinylformamide to provide Compound 9, andhydrogenating 9 to provide Compound 7,19. A method for making Compound 8, the method comprising reacting Compound 12 with A / -Formylformamide sodium salt to provide Compound 8,20. Compound 3b,21. Compound 3c,22. Compound 7,23. Compound 8,

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