Process for preparation of 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)-phenoxy)-3, 7-dihydro-1h-purine-2, 6-dione

Abstract

The present invention relates to a novel process for the preparation of 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy) phenoxy)-3, 7-dihydro-1h-purine-2, 6-dione (compound (I)): # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a novel process for the preparation of 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-3,7-dihydro-1H-purine-2,6-dione (Compound (I)):

[0002] Background Art

[0003] Compound I is a potent and selective inhibitor of transient receptor potential (TRP) cation channel superfamily member 5 (TRPC5) and was first described in WO2014 / 143799 (Example 7a, page 441; Example 356, page 612). Further, the following process for the preparation of Compound (I) was disclosed in WO2014 / 143799 (Scheme 1)

[0004]

[0005] Scheme 1. Process for the preparation of Compound (I) as disclosed in WO2014 / 143799.

[0006] However, the synthetic method as disclosed in WO2014 / 143799 is not suitable for large-scale preparation processes due to the following problems:

[0007] 1) Low yields,

[0008] 2) Involvement of protecting group chemistry (expensive reagents and additional process steps increase the preparation cost),

[0009] 3) Use of toxic solvents and reagents (safety issues and risk of residual impurities in the drug substance (I)),

[0010] 4) Requirement of liquid chromatography for the separation of Compound (I).

[0011] Therefore, the object of the present invention is to provide an efficient process for the preparation of Compound (I) which is suitable for industrial scale operation. Detailed Description

[0012] The present invention provides the following process for the preparation of Compound (I) (Scheme 2).

[0013]

[0014] Scheme 2. Process for the preparation of Compound (I) according to the present invention.

[0015] The process according to the present invention uses commercially available bulk chemicals which are easy to handle safely.

[0016] In one embodiment, the present invention relates to a method for preparing compound (I)

[0017]

[0018] which comprises the following steps:

[0019] (1) Reacting 8-bromo-3-methylxanthine

[0020]

[0021] with 4-chlorobenzyl chloride in a suitable solvent in the presence of a suitable base to produce compound (II):

[0022]

[0023] (2) Reacting compound (II) with 3-chloro-1-propanol in a suitable solvent in the presence of a suitable base and a suitable additive to produce compound (III):

[0024] and

[0025] (3) Reacting compound (III) with 3-(trifluoromethoxy)phenol in a suitable solvent in the presence of a suitable base and a suitable additive to produce compound (I).

[0026] Optionally, the method of the present invention further comprises the following step:

[0027] (4) Recrystallizing the compound (I) obtained in step (3) in a suitable solvent.

[0028] Thus, in a second embodiment, the present invention relates to a method according to the foregoing embodiment, the method further comprising an additional step (4), which is the recrystallization of compound (I) in a suitable solvent.

[0029] The method of the present invention relates to the separation and purification of the respective (intermediate) reaction products in crystalline form. That is, compounds (I), (II) and (III) can be separated from their respective reaction mixtures by crystallization. In one embodiment, compound (I) can be easily separated from the reaction mixture by crystallization.

[0030] Compound (I) is obtained by the method of the present invention in an excellent overall yield of 79% (over 3 steps) and high purity (98.5%).

[0031] Compound (I) is obtained by the method of the present invention in an excellent overall yield of 75% (over 4 steps) and high purity of 99.8% after recrystallization.

[0032] Compound (I) is obtained by the process of the present invention (in 3 steps or in 4 steps) in the form of a stable polymorph (which is the same polymorphic form of compound (I) obtainable by the process disclosed in WO2014 / 143799).

[0033] When referring to the crystallization or recrystallization of any of the compounds obtained during or by the process of the present invention, the crystallization process can be assisted by using an anti-solvent or by adding seed crystals of the respective compound.

[0034] In a preferred embodiment, compound (II) is separated by using an anti-solvent at the end of reaction step (1), and compounds (III) and (I) are crystallized by adding seed crystals at the end of reaction steps (2) and (3), respectively. Even more preferably, compound (I) is recrystallized by adding seed crystals in step (4).

[0035] Suitable solvents in step (1) include DMAc, DMF, NMP, acetonitrile, acetone, sulfolane, DMSO, chlorinated hydrocarbons such as dichloromethane, cyclic ureas such as DMPU, HMPT, THF, Et2O, nitromethane, dimethyl carbonate and diethyl carbonate, and ionic liquids; preferably DMAc, DMF, NMP, sulfolane, DMSO and acetonitrile; most preferably DMAc.

[0036] Suitable bases in step (1) include tertiary amines such as triethylamine, diisopropylethylamine, alkylated piperidines, alkylated pyrrolidines, inorganic bases such as Na2CO3, K2CO3, Cs2CO3, K3PO4, Na3PO4, K2HPO4, Na2HPO4, NaOH, NaOtBu, KOtBu, NaOtAmyl, KOtAmyl or amidines such as DBU and DBN; preferably diisopropylethylamine, Na2CO3, K2CO3 and K3PO4, Na3PO4; most preferably diisopropylethylamine.

[0037] The reaction temperature range in step (1) should be 50 - 160 °C; preferably 75 - 95 °C; most preferably 80 - 90 °C.

[0038] The reaction in step (1) is monitored by process control analysis. The reaction time range in step (1) is generally between 2 - 12 h, more preferably between 3 - 6 h.

[0039] The suitable solvents in step (2) include DMF, DMAc, NMP, acetonitrile, acetone, sulfolane, DMSO, chlorinated hydrocarbons such as dichloromethane, cyclic ureas such as DMPU, HMPT, THF, nitromethane, dimethyl carbonate and diethyl carbonate, and ionic liquids; preferably DMAc, DMF, NMP, sulfolane, DMSO and acetonitrile; most preferably DMAc.

[0040] The suitable bases in step (2) include inorganic bases such as NaHCO3, KHCO3, Na2CO3, K2CO3, Cs2CO3, K3PO4, Na3PO4, K2HPO4, Na2HPO4, NaOH, NaOAc; alcoholates such as NaOtBu, KOtBu, NaOtAmyl, KOtAmyl; and tertiary amines such as diisopropylethylamine, triethylamine, alkylated piperidines, alkylated pyrrolidines, and amidines such as DBU and DBN; preferably NaHCO3, KHCO3, Na2CO3, K2CO3, K3PO4, Na3PO4, K2HPO4, Na2HPO4, diisopropylethylamine; most preferably NaHCO3.

[0041] The suitable additives in step (2) include quaternary ammonium salts such as tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, benzyltriethylammonium bromide or benzyltriethylammonium chloride, methyltributylammonium bromide or methyltributylammonium chloride, methyltrioctylammonium bromide or methyltrioctylammonium chloride, and organic phosphonium salts such as cetyltributylphosphonium bromide or cetyltributylphosphonium chloride; preferably tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, benzyltriethylammonium bromide or benzyltriethylammonium chloride, methyltributylammonium bromide or methyltributylammonium chloride; most preferably tetra-n-butylammonium bromide.

[0042] The reaction temperature range in step (2) should be 80 - 160 °C, preferably 100 - 120 °C, most preferably 105 - 115 °C.

[0043] The reaction in step (2) is monitored by process control analysis. The reaction time range in step (2) is usually 2 - 12 h, more preferably 4 - 6 h.

[0044] The reaction pressure in step (2) should be maintained at 100 - 1000 mbar (abs.), preferably at 200 - 400 mbar (abs.), most preferably 250 - 350 mbar (abs.).

[0045] The suitable solvents in step (3) include DMAc, DMF, NMP, acetonitrile, acetone, sulfolane, DMSO, hydrocarbon chlorides such as dichloromethane, cyclic urea solvents such as DMPU, HMPT, THF, Et2O, nitromethane, dimethyl carbonate and diethyl carbonate, and ionic liquids; preferably DMAc, DMF, NMP, sulfolane, DMSO and acetonitrile; most preferably NMP.

[0046] The suitable bases in step (3) include inorganic bases such as Na2CO3, K2CO3, Cs2CO3, K3PO4, Na3PO4, K2HPO4, Na2HPO4, NaOH, NaOAc, NaOtBu, KOtBu, NaOtAmyl, KOtAmyl, tertiary amines such as diisopropylethylamine, triethylamine, alkylated piperidines, alkylated pyrrolidines and amidines such as DBU and DBN; preferably diisopropylethylamine, Na2CO3, K2CO3, K3PO4 and Na3PO4; most preferably Na2CO3.

[0047] The suitable additives in step (3) include quaternary ammonium salts such as tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, benzyltriethylammonium bromide or benzyltriethylammonium chloride, methyltributylammonium bromide or methyltributylammonium chloride, methyltrioctylammonium bromide or methyltrioctylammonium chloride and organic phosphonium salts, such as cetyltributylphosphonium bromide or cetyltrioctylphosphonium chloride; preferably tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, benzyltriethylammonium bromide or benzyltriethylammonium chloride, methyltributylammonium bromide or methyltributylammonium chloride; most preferably tetra-n-butylammonium bromide.

[0048] The reaction temperature range in step (3) should be 80 - 160 °C; preferably 100 - 130 °C; most preferably 115 - 125 °C.

[0049] The reaction time range in step (3) is generally 4 - 12 h; more preferably 8 - 10 h.

[0050] The reaction pressure in step (2) should be maintained at 100 - 1000 mbar (abs.); preferably at 200 - 400 mbar (abs.); most preferably 250 - 350 mbar (abs.).

[0051] Another embodiment of the present invention relates to a method for preparing compound (I)

[0052]

[0053] which comprises reacting compound (III)

[0054]

[0055] The step of reacting 3-(trifluoromethoxy)phenol in a suitable solvent in the presence of a suitable base and a suitable additive to produce compound (I), and optionally further including recrystallizing the obtained compound (I) in a suitable solvent.

[0056] Another embodiment of the present invention relates to a method for preparing compound (III)

[0057]

[0058] which comprises reacting compound (II)

[0059]

[0060] with 3-chloro-1-propanol in a suitable solvent in the presence of a suitable base and a suitable additive to produce compound (III):

[0061]

[0062] The method according to the present invention is superior to the method described in WO2014 / 143799 in that

[0063] 1) It produces compound (I) with high purity without chromatographic separation and purification steps, having a significantly higher yield of 79% (or 75% after recrystallization) compared to a 46%

[0064] yield (route A) or 9% yield (route B) [Table 1],

[0065] 2) It does not require protection group chemistry operations,

[0066] 3) It limits the use of toxic solvents and reagents.

[0067] Table 1. Comparison of the yields and purities of compound (I) obtained in the methods described in WO2014 / 143799 and the present invention

[0068]

[0069] In another embodiment, the present invention thus relates to a method for preparing compound (I) as defined above, wherein compound (I) is obtained with a purity of 98.5% or higher, preferably 99.8% or higher.

[0070] In another embodiment, the present invention relates to compound (I) obtained by the method described herein and characterized by a purity of 98.5% or higher, preferably 99.8% or higher.

[0071] The method according to the invention is suitable for the conventional industrial-scale production of compound (I) in batches of 150 kg and above. The data in Table 2 demonstrate that the method according to the invention is robust and scalable without affecting the yield and the quality of the drug substance.

[0072] Table 2. Comparison of Yields and Purities at Laboratory Scale and Production Scale

[0073]

[0074] Experimental Section

[0075] List of Abbreviations:

[0076] APCI Atmospheric Pressure Chemical Ionization

[0077] abs. absolute

[0078] aq. aqueous

[0079] BHT 3,5-Di-tert-butyl-4-hydroxytoluene

[0080] conc concentrated

[0081] DCM Dichloromethane

[0082] DIPEA N-Ethyl-diisopropylamine

[0083] DMAc Dimethylacetamide

[0084] DMF Dimethylformamide

[0085] DMSO Dimethylsulfoxide

[0086] equiv. equivalent

[0087] ESI Electrospray Ionization

[0088] EtOAc Ethyl Acetate

[0089] g gram

[0090] h hour

[0091] HOAc Acetic Acid

[0092] HPLC High Performance Liquid Chromatography

[0093] iPr Isopropyl

[0094] kg kilogram

[0095] NMP N-Methyl-2-pyrrolidone

[0096] NMR Nuclear Magnetic Resonance

[0097] MeCN Acetonitrile

[0098] MeOH Methanol

[0099] min Minute

[0100] mg Milligram

[0101] mL Milliliter

[0102] M Mole (mol / L)

[0103] TBABr Tetra-n-butylammonium bromide

[0104] THF Tetrahydrofuran

[0105] NMR method: The NMR spectra were recorded on a Bruker AVANCE III instrument, respectively, 1 The experimental frequency of 1H-NMR was 600 MHz, 13 The experimental frequency of 13C-NMR was 150 MHz and TopSpin 3.2 pl6 software was used for analysis. Chemical shifts are given in parts per million (ppm) and are expressed in δ units downfield from the internal standard trimethylsilane. The selected data are reported in the following way: chemical shift (multiplicity, coupling constant (J), number of hydrogens). Abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), spt (septet), m (multiplet), br (broad).

[0106] X-ray powder diffraction (XRPD) pattern:

[0107] X-ray powder diffraction patterns were generated in reflection mode using a Bruker D8 Advance diffractometer equipped with a LynxEye position-sensitive detector and a Cu-anode as the X-ray source with CuKα1 radiation ( 40 kV, 40 mA). The standard error range of the 2θ values was ±0.2°.

[0108] Example:

[0109] Preparation of compound (I)

[0110] Step (1): Preparation of 8-bromo-7-(4-chlorobenzyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione (II):

[0111]

[0112] 8-Bromo-3-methylxanthine (20.0 g, 81.6 mmol, 1.0 eq) and BHT (0.8 g, 3.6 mmol, 0.04 eq) were dissolved in dimethylacetamide (210 mL). The mixture was heated to 85 °C. A solution of 4-chlorobenzyl chloride (15.8 g, 97.9 mmol, 1.2 eq) in dimethylacetamide (20 mL) was added and rinsed with dimethylacetamide (10 mL). Diisopropylethylamine (11.1 g, 85.7 mmol, 1.05 eq) was added and rinsed with dimethylacetamide (10 mL). The reaction was stirred at 85 °C until the starting material was consumed (8-bromo-3-methylxanthine <0.3%). Optionally, a further dose of diisopropylethylamine (0.5 g, 4.1 mmol, 0.05 eq) could be implemented to complete the reaction. After complete conversion, hydrochloric acid (4 M, 0.8 g, 8.2 mmol, 0.1 eq) was added. The reaction solvent was partially removed via vacuum distillation (until approximately 150 mL of the reaction mixture volume remained). Acetonitrile (150 mL) was added, and the product suspension was slowly cooled to 20 °C. The product was separated by filtration, and the filter cake was washed twice with acetonitrile (50 mL). The separated material was dried at 50 °C under reduced pressure to give compound (II) as a colorless solid (28.7 g, 78.0 mmol, 95% yield, 99.9% purity). Melting point: 270 - 271 °C.

[0113] Analytical data:

[0114] 1 1H NMR (DMSO-d6) δ: 11.37 (s, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 5.48 (s, 2H), 3.34 (s, 3H); 13 13C NMR (DMSO-d6) δ: 154.0, 150.5, 149.3, 134.5, 132.6, 129.0, 128.7, 127.9, 108.6, 48.6, 28.5; HRMS (ESI): m / z 369, ([M+H] + , predicted 368.9763, calculated 368.9748.

[0115] Step (2): Preparation of 8-bromo-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione (III):

[0116]

[0117] Compound (II) (20.0 g, 54.1 mmol, 1.0 equiv), sodium bicarbonate (6.8 g, 81.2 mmol, 1.5 equiv), and tetrabutylammonium bromide (0.8 g, 2.7 mmol, 0.05 equiv) were suspended in dimethylacetamide (170 mL). The mixture was heated to 110 °C. 3-Chloro-1-propanol (7.7 g, 81.5 mmol, 1.5 equiv) was added and rinsed with dimethylacetamide (10 mL). Then a vacuum (200 - 400 mbar) was applied. The reaction was stirred at 110 °C until the starting material was consumed (Compound (II) < 0.5%). After complete conversion, the reaction mixture was cooled to 80 °C, filtered, and rinsed with dimethylacetamide (30 mL). Water (160 mL) was added to the filtrate at 90 °C, then sodium bicarbonate (0.5 g, 5.4 mmol, 0.1 equiv). The mixture was cooled to 70 °C and seed crystals (47 mg) were added. The crystal suspension was cooled to 40 °C over 60 min, heated to 70 °C, held at 70 °C for at least 15 min, cooled to 20 °C over 150 min, and stirred for 1 h. The product was separated by filtration and the filter cake was washed with water (160 mL). The separated material was dried at 60 °C under reduced pressure to give Compound (III) (16.1 g, 37.7 mmol, 91% yield, 98.7% purity) as a colorless solid. Melting point: 148 - 149 °C.

[0118] Analysis data:

[0119] 1 1H NMR (DMSO-d6) δ: 7.43 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 5.52 (s, 2H), 4.48 (t, J = 5.2 Hz, 1H), 3.89 - 3.96 (m, 2H), 3.43 - 3.48 (m, 2H), 3.38 (s, 2H), 1.65 - 1.74 (m, 2H); 13 13C NMR (DMSO-d6) δ: 153.5, 150.3, 147.9, 134.5, 132.6, 129.0, 128.7, 128.2, 108.2, 58.7, 48.7, 38.5, 30.8, 29.5; HRMS (ESI): m / z 427, ([M+H] + , predicted value 427.0188, calculated value 427.0167.

[0120] Step (3): Preparation of crude 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-3,7-dihydro-1H-purine-2,6-dione (I):

[0121]

[0122] Suspend compound (III) (20.0 g, 46.8 mmol, 1.0 equiv), tetrabutylammonium bromide (0.8 g, 2.4 mmol, 0.05 equiv) and sodium carbonate (3.5 g, 32.7 mmol, 0.7 equiv) in N-methyl-2-pyrrolidone (135 mL). Heat the mixture to 50 °C. Add 3-(trifluoromethoxy)phenol (9.2 g, 51.7 mmol, 1.1 equiv) and rinse with N-methyl-2-pyrrolidone (10 mL). Heat the mixture to 120 °C and stir at 120 °C under reduced pressure (200 - 400 mbar) until the starting material is consumed (compound (III) < 1.0%). After complete conversion, cool the reaction mixture to 80 °C, filter and rinse with N-methyl-2-pyrrolidone (15 mL). Add acetonitrile (40 mL). Add water (110 mL) over at least 30 min. Cool the mixture to 58 °C and add seed crystals (20 mg). Continuously cool the crystal suspension to 40 °C, heat to 60 °C, hold at the same temperature for at least 15 min and cool to 20 °C. Isolate the product by filtration and wash the filter cake with water (160 mL) and n-heptane (40 mL). Dry the separated material under reduced pressure at 60 °C to obtain the crude compound (I) as a colorless solid (22.1 g, 42.1 mmol, 90% yield, 98.5% purity). Melting point: 124 - 125 °C.

[0123] Analysis data:

[0124] 1 H NMR (DMSO-d6) δ: 7.56 - 7.63 (m, 1H), 7.49 (s, 1H), 7.40 - 7.45 (m, 5H), 7.32 (br d, J = 8.3 Hz, 1H), 5.44 (s, 2H), 4.47 (t, J = 5.3 Hz, 1H), 3.87 - 3.96 (m, 2H), 3.39 - 3.48 (m, 2H), 3.29 (s, 3H), 1.63 - 1.75 (m, 2H); 13 C NMR (DMSO-d6) δ: 153.8, 153.7, 152.1, 150.5, 148.6, 145.4, 135.1, 132.5, 131.3, 129.5, 128.7, 118.8, 118.2, 119.9, 113.1, 102.5, 58.7, 45.8, 38.3, 30.9, 29.5; HRMS (ESI): m / z 525 ([M+H] + , predicted value 525.1151, calculated value 525.1147).

[0125] Step (4): Recrystallization of 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-3,7-dihydro-1H-purine-2,6-dione (I)

[0126] Suspend compound (I) (20.0 g, 38.1 mmol, 1.0 eq) in ethyl acetate (90 mL). Heat the mixture to 65 °C, filter, and add n-heptane (100 mL) to the solution. Cool the mixture to 53 °C and add seed crystals (40 mg). Stir the crystallization suspension for at least 60 min, then add n-heptane (100 mL) and stir for an additional 60 min at 53 °C. Cool the suspension to 5 °C over 90 min and stir at 5 °C for 120 min. Isolate the product by filtration and wash the filter cake with n-heptane (100 mL). Dry the separated material under reduced pressure at 50 °C to obtain compound (I) as a colorless solid (18.9 g, 36.2 mmol, 95% yield, 99.8% purity). Melting point: 124 °C.

[0127] Analysis data:

[0128] 1 H NMR (DMSO-d6) δ: 7.56 - 7.63 (m, 1H), 7.49 (s, 1H), 7.40 - 7.45 (m, 5H), 7.32 (br d, J = 8.3 Hz, 1H), 5.44 (s, 2H), 4.47 (t, J = 5.3 Hz, 1H), 3.87 - 3.96 (m, 2H), 3.39 - 3.48 (m, 2H), 3.29 (s, 3H), 1.63 - 1.75 (m, 2H); 13 C NMR (DMSO-d6) δ: 153.8, 153.7, 152.1, 150.5, 148.6, 145.4, 135.1, 132.5, 131.3, 129.5, 128.7, 118.8, 118.2, 119.9, 113.1, 102.5, 58.7, 45.8, 38.3, 30.9, 29.5; HRMS (ESI): m / z 525 ([M+H] + , predicted value 525.1150, calculated value 525.1147).

[0129] The recrystallized compound (I) prepared according to step (4) is analyzed by X-ray powder diffraction to obtain the results as listed below and shown in Figure 1 (XRPD pattern) and Table 1.

[0130] Table I. Peak data of the XRPD pattern of compound (I),

[0131]

[0132] Preparation of 3-(trifluoromethoxy)phenol

[0133]

[0134] At room temperature, 1-bromo-3-(trifluoromethoxy)benzene (70.0 g, 290 mmol, 1.0 eq) was dissolved in THF (17 mL) and iPrMgBr·LiCl (14 wt.-% in THF, 298 g, 405 mmol, 1.4 eq) was added at 15 °C over 20 min. After the addition was complete, the reaction mixture was stirred at room temperature for 2.5 h until complete conversion (1-bromo-3-(trifluoromethoxy)benzene < 3.0%). The reaction mixture was then cooled to 0 °C and quenched successively by adding B(OMe)3 (31.8 g, 304 mmol, 1.1 eq), adding water (105 mL), and then adding aqueous HCl (4 M, 45.4 g, 461 mmol, 1.6 eq). After phase separation, the reaction solvent of the organic phase was partially removed via vacuum distillation (to approximately 80 mL of the remaining reaction mixture volume). Water (240 mL) and sodium hydroxide solution (45 wt.-%, 39.6 g, 446 mmol, 1.5 eq) were added to the mixture, and the reaction mixture was further concentrated to approximately 260 mL of the remaining reaction mixture volume with the water jacket temperature at 80 °C under reduced pressure (150 mbar). After adding water (67 mL) and cooling to 5 °C, hydrogen peroxide (35 wt.-% in water, 29.6 g, 304 mmol, 1.1 eq) was added below 30 °C. After the addition was complete, the reaction was stirred at 20 °C until complete conversion (boric acid intermediate < 0.1%) and then quenched by adding aqueous sodium sulfite solution (26.7 g, 29.0 mmol, 0.1 eq). After adding aqueous HCl (4 M, 79.2 g, 782 mmol, 2.7 eq) and dichloromethane (200 mL), the organic layer was separated. The crude mixture was distilled using a steam pipe and under reduced pressure (boiling point 72 °C at 80 mbar) to give 3-(trifluoromethoxy)phenol as a colorless liquid (46.9 g, 263 mmol, 91% yield).

[0135] Analysis data:

[0136] 1 1H NMR (DMSO-d6) δ: 10.0 (s, 1H), 7.28 (m, 1H), 6.71 - 6.80 (m, 3H); 1313C NMR (DMSO-d6) δ: 158.8, 149.2, 130.7, 120.4, 114.4, 110.9, 107.8; HRMS (neg. APCI): m / z 285 ([M + Cl] - , predicted value 285.0515, calculated value 241.0511.

[0137] Alternatively, the intermediate boric acid can be isolated and then further reacted in a method comprising two consecutive steps to produce 3-(trifluoromethoxy)phenol:

[0138] Preparation of (3-(trifluoromethoxy)phenyl)boronic acid

[0139]

[0140] At room temperature, 1-bromo-3-(trifluoromethoxy)benzene (25.0 g, 103 mmol, 1.0 equiv), BHT (0.6 g, 3 mmol, 0.02 equiv) were dissolved in THF (6 mL), and iPrMgBr·LiCl (14 wt.-% in THF, 114 g, 155 mmol, 1.5 equiv) was added at 15 °C over 15 min. After the addition was complete, the reaction mixture was stirred at 30 °C for 2 h until complete conversion (1-bromo-3-(trifluoromethoxy)benzene < 3.0%). Then the reaction mixture was cooled to 0 °C and quenched by the addition of B(OMe)3 (11.5 g, 109 mmol, 1.05 equiv) until complete conversion ((trifluoromethoxy)benzene < 2.0%) and diluted with water (38 mL) and toluene (25 mL). Then the reaction mixture was quenched by addition to aqueous HCl (4 M, 16.2 g, 164 mmol, 1.6 equiv) at 0 °C, and the phases were separated. The organic layer was washed again with aqueous HCl (1 M, 40 mL), and the resulting organic layer was diluted with toluene (78 mL) and concentrated (THF < 5.0%). After phase separation, the organic layer was successively treated with aqueous sodium hydroxide solution (6 wt.-%, 73.4 g, 68 mL, 144 mmol, 1.1 equiv), and after phase separation, the organic layer was washed again with aqueous sodium hydroxide solution (6 wt.-%, 26.7 g, 41 mL, 41 mmol, 0.4 equiv). At room temperature, the combined aqueous layers were acidified to pH 1 - 3 with aqueous HCl (4 M, 16.3 g, 165 mmol, 1.6 equiv) and cooled to 0 °C. The desired product was obtained by filtration, and the filter cake was washed with water (40 mL), dried, and the desired title compound was obtained as colorless crystals (15.3 g, 74 mmol, 72% yield). Melting point: 86 °C.

[0141] Analysis data:

[0142] 1 1H NMR (DMSO-d 6 ) δ: 10.05 (br s, 1H), 7.29 (t, J = 8.2 Hz, 1H), 6.82 (ddd, J = 8.2, 2.3, 0.8 Hz, 1H), 6.74 - 6.76 (m, 1H), 6.72 - 6.74 (m, 1H); 13 13C NMR (DMSO-d 6 ) δ: 159.3, 149.7, 131.1, 120.6 (q, J = 121 Hz), 114.9, 111.3, 108.3; HRMS (ESI): m / z 241 ([M + Cl] - , predicted 241.0058, calculated 241.0056.

[0143] Preparation of 3-(trifluoromethoxy)phenol from (3-(trifluoromethoxy)phenyl)boronic acid

[0144]

[0145] At room temperature, (3-(trifluoromethoxy)phenyl)boronic acid (69.2 g, 336 mmol, 1.0 equiv) was dissolved in water (250 mL) and treated with aqueous sodium hydroxide solution (50 wt.-%, 37.7 g, 471 mmol, 1.4 equiv). Hydrogen peroxide (30 wt.-% in water, 43.9 g, 38 mL, 387 mmol, 1.2 equiv) was added below 30 °C and dissolved in water (40 mL) after the addition was complete. The reaction was stirred at 15 °C until complete conversion (boronic acid intermediate <0.1%) and then quenched by successive addition of aqueous sodium sulfite solution (152 g, 165 mmol, 0.5 equiv) and aqueous HCl (4 M, 92.0 g, 908 mmol, 2.7 equiv). The mixture was diluted with dichloromethane (300 mL), and the organic layer was separated. The crude mixture was distilled using a steam bath and concentrated under reduced pressure (boiling point 72 °C at 80 mbar) to give 3-(trifluoromethoxy)phenol as a colorless solid (59.3 g, 336 mmol, >99% yield).

[0146] Analysis data:

[0147] 1 1H NMR (DMSO-d6) δ: 10.0 (s, 1H), 7.28 (m, 1H), 6.71 - 6.80 (m, 3H); 13 13C NMR (DMSO-d6) δ: 158.8, 149.2, 130.7, 120.4, 114.4, 110.9, 107.8; HRMS (neg. APCI): m / z 285 ([M + Cl]- , Predicted value 285.0515, Calculated value 241.0511.

Claims

1. A method for preparing compound (I), which comprises the following steps: (1) React 8-bromo-3-methylxanthine with 4-chlorobenzyl chloride in a suitable solvent in the presence of a suitable base, to produce compound (II) (2) React compound (II) with 3-chloro-1-propanol in a suitable solvent in the presence of a suitable base and a suitable additive, to produce compound (III) React compound (III) with 3-(trifluoromethoxy)phenol in a suitable solvent in the presence of a suitable base and a suitable additive to produce compound (I).

2. The method according to claim 1, wherein compound (I) is separated from the reaction mixture by crystallization.

3. The method according to claim 1 or 2, the method further comprising step (4), which comprises recrystallizing compound (I) in a suitable solvent.

4. The method according to any one of the preceding claims, wherein the solvent in step (1) is selected from DMAc, DMF, NMP, acetonitrile, acetone, sulfolane, DMSO, chlorinated hydrocarbons such as dichloromethane, cyclic ureas such as DMPU, HMPT, THF, Et2O, nitromethane, dimethyl carbonate and diethyl carbonate, and ionic liquids; preferably DMAc, DMF, NMP, sulfolane, DMSO and acetonitrile; most preferably DMAc.

5. The method according to any one of the preceding claims, wherein the base in step (1) is selected from tertiary amines such as triethylamine, diisopropylethylamine, alkylated piperidines, alkylated pyrrolidines, inorganic bases such as Na2CO3, K2CO3, Cs2CO3, K3PO4, Na3PO4, K2HPO4, Na2HPO4, NaOH, NaOtBu, KOtBu, NaOtAmyl, KOtAmyl or amidines such as DBU and DBN; preferably diisopropylethylamine, Na2CO3, K2CO3 and K3PO4, Na3PO4; most preferably diisopropylethylamine.

6. The method according to any one of the preceding claims, wherein the reaction temperature range in step (1) is 75 - 95 °C; most preferably 80 - 90 °C.

7. The method according to any one of the preceding claims, wherein the solvent in step (2) is selected from DMF, DMAc, NMP, acetonitrile, acetone, sulfolane, DMSO, chlorinated hydrocarbons such as dichloromethane, cyclic ureas such as DMPU, HMPT, THF, nitromethane, dimethyl carbonate and diethyl carbonate, and ionic liquids; preferably DMAc, DMF, NMP, sulfolane, DMSO and acetonitrile; most preferably DMAc.

8. The method according to any one of the preceding claims, wherein the base in step (2) is selected from inorganic bases such as NaHCO3, KHCO3, Na2CO3, K2CO3, Cs2CO3, K3PO4, Na3PO4, K2HPO4, Na2HPO4, NaOH, NaOAc; alcoholates such as NaOtBu, KOtBu, NaOtAmyl, KOtAmyl; and tertiary amines such as diisopropylethylamine, triethylamine, alkylated piperidine, alkylated pyrrolidine, and amidines such as DBU and DBN; preferably NaHCO3, KHCO3, Na2CO3, K2CO3, K3PO4, Na3PO4, K2HPO4, Na2HPO4, diisopropylethylamine; most preferably NaHCO3.

9. The method according to any one of the preceding claims, wherein the additive in step (2) is selected from quaternary ammonium salts such as tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, benzyltriethylammonium bromide or benzyltriethylammonium chloride, methyltributylammonium bromide or methyltributylammonium chloride, methyltrioctylammonium bromide or methyltrioctylammonium chloride and organic phosphonium salts such as cetyltributylphosphonium bromide or cetyltributylphosphonium chloride; preferably tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, benzyltriethylammonium bromide or benzyltriethylammonium chloride, methyltributylammonium bromide or methyltributylammonium chloride; most preferably tetra-n-butylammonium bromide.

10. The method according to any one of the preceding claims, wherein the reaction temperature range in step (2) is 100 - 120 °C; most preferably 105 - 115 °C.

11. The method according to any one of the preceding claims, wherein the solvent in step (3) is selected from DMAc, DMF, NMP, acetonitrile, acetone, sulfolane, DMSO, chlorinated hydrocarbons such as dichloromethane, cyclic urea solvents such as DMPU, HMPT, THF, Et2O, nitromethane, dimethyl carbonate and diethyl carbonate, and ionic liquids; preferably DMAc, DMF, NMP, sulfolane, DMSO and acetonitrile; most preferably NMP.

12. The method according to any one of the preceding claims, wherein the base in step (3) is selected from inorganic bases such as Na2CO3, K2CO3, Cs2CO3, K3PO4, Na3PO4, K2HPO4, Na2HPO4, NaOH, NaOAc, NaOtBu, KOtBu, NaOtAmyl, KOtAmyl, tertiary amines such as diisopropylethylamine, triethylamine, alkylated piperidine, alkylated pyrrolidine and amidines such as DBU and DBN; preferably diisopropylethylamine, Na2CO3, K2CO3, K3PO4 and Na3PO4; most preferably Na2CO3.

13. The method according to any one of the preceding claims, wherein the additive in step (3) is selected from quaternary ammonium salts such as tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, benzyltriethylammonium bromide or benzyltriethylammonium chloride, methyltributylammonium bromide or methyltributylammonium chloride, methyltrioctylammonium bromide or methyltrioctylammonium chloride, and organic phosphonium salts such as cetyltributylphosphonium bromide or cetyltributylphosphonium chloride; preferably tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, benzyltriethylammonium bromide or benzyltriethylammonium chloride, methyltributylammonium bromide or methyltributylammonium chloride; most preferably tetra-n-butylammonium bromide.

14. The method according to any one of the preceding claims, wherein the reaction temperature range in step (3) is 100 - 130 °C; most preferably 115 - 125 °C.

15. The method according to any one of the preceding claims, wherein the reaction pressure in step (2) and / or step (3) is maintained in the range of 200 - 400 mbar (abs.); most preferably 250 - 350 mbar (abs.).

16. The method according to any one of the preceding claims, wherein compound (I) is obtained with a purity of 98.5% or higher, preferably 99.8% or higher.

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