BR112022008892B1 - PROCESS AND INTERMEDIATE FOR THE PREPARATION OF OXETAN-2-ILMETHANAMINE, COMPOUND AND ITS USE - Google Patents

Abstract

The present invention relates to a process and intermediate for the preparation of a compound of formula (I), or its salt. (I)

Description

[0001] The present invention relates to a process and intermediate for the preparation of oxetan-2-yl methanamine, which is a key intermediate in the preparation of certain glucagon-like peptide-1 receptor agonists.

[0002] Oxetan-2-yl methanamine is a key intermediate in the preparation of certain glucagon-like peptide-1 receptor agonists, including certain 1-[2-oxetan-2-ylmethyl]-1H-benzimidazole compounds disclosed in WO2018/109607. The process disclosed in WO2018/109607 for the preparation of (S)-oxetan-2-yl methanamine is a five-step process starting from (S)-2-((benzyloxy)methyl) oxirane. The first step is a ring expansion step which expands the oxirane to an oxetane. In the penultimate step, the nitrogen of the amine group is introduced using sodium azide and in the final step, the azide intermediate is reduced to provide the amine group. Azide compounds are highly toxic. Certain azide compounds also present significant physical hazards because they can be sensitive to heat and shock and can decompose explosively with little external energy input. As such, the final two steps of this process are significantly unstable and require extensive and costly safety measures.

[0003] There is a need for an improved process that is less resource intensive, cheaper and/or facilitates more efficient production. In particular, there is a need for a process that avoids the use of toxic and hazardous azide compounds. In addition, there is a need for a simpler process that requires less manipulation.

[0004] The process of the present invention addresses these needs by introducing protected nitrogen prior to the ring expansion step. The nitrogen is protected by two benzyl groups.

[0005] Likewise, in one embodiment, the present invention provides a process for preparing a compound of the formula: or its salt, comprising the steps of:i. combining dibenzyl amine and a compound of the formula: then adding a base to produce a compound of the formula: ii. taking trimethyl sulfuxonium halide in the presence of a base and combining with a solution of the compound resulting from step (i) and heating above 40oC to produce a compound of the formula: iii. . deprotection of compound resulting from step (ii).

[0006] In one embodiment, the compound of Formula I is: or its salt. This formula represents the S-enantiomer.

[0007] In one embodiment, the compound of Formula I is the hydrochloride salt of:

[0008] In one embodiment, the trimethyl sulfuxonium halide is trimethyl sulfuxonium iodide.

[0009] In one embodiment, the base in step (ii) is a different base than the base used in step (i). In one embodiment, the base in step (ii) is selected from an alkali metal hydride, a sterically hindered alkali metal alkoxide, a hindered lithium alkyl in alcohol solvent, an alkali metal hexamethyl disilylazane. In a particular embodiment, the base in step (ii) is selected from: potassium t-butoxide, lithium t-butoxide, sodium t-butoxide, potassium t-amylate, lithium t-amylate, sodium t-amylate, lithium potassium hydride, sodium hydride, potassium hydride, lithium n-butyl in alcohol solvent, lithium hexamethyl disilazide, sodium hexamethyl disilazide, or potassium hexamethyl disilazide. In a preferred embodiment, the base is potassium tert-butoxide.

[0010] In one embodiment, the solution in step (ii) comprises a solvent selected from: a polar aprotic solvent or a hindered alcohol. In a particular embodiment, the solvent is selected from: t-butanol, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N-methyl-2-pyrrolidone, or t-amyl alcohol. In a preferred embodiment, the solvent is tert-butanol.

[0011] In one embodiment, step (ii) is carried out at a temperature greater than 70oC. In a preferred embodiment, step (ii) is carried out at a temperature greater than 80oC. In another preferred embodiment, step (ii) is carried out at a temperature between 80 and 90oC. In another preferred embodiment, step (ii) is carried out at a temperature between 80 and 85oC.

[0012] In one embodiment, step (iii) is carried out using a palladium catalyst. In a preferred embodiment, the palladium catalyst is palladium on carbon.

[0013] The process may further comprise the step (here step (iv)) of combining a base and a compound of the formula

[0014] where R is H or an acid protecting group, with a solution of a compound of the formula: to produce a compound of the formula:

[0015] In an embodiment of step (iv), R in the compounds of Formulas V and VI is H or C1-4 alkyl. In one embodiment, R is H. In another embodiment, R is C1-4 alkyl, preferably methyl.

[0016] In one embodiment, R is H and step (iv) comprises combining a 3-fluoro-4-nitrobenzoic base with a solution of a compound of the formula:

[0017] to produce a compound of the formula:

[0018] In one embodiment, R is methyl and step (iv) comprises adding a base and methyl 3-fluoro-4-nitrobenzoate to a solution of a compound of the formula: to produce a compound of the formula:

[0019] Following step (iv), the process may further comprise the step (here step (v)) of reducing the nitro group of the compound of formula: to produce a compound of the formula:

[0020] In one embodiment of step (v), R in the compounds of Formulas VI and VII is H. In another embodiment of step (v), R in the compounds of Formulas VI and VII is C1-4 alkyl, preferably methyl.

[0021] Following step (v), the process may further comprise the steps of: vi carrying out an amide coupling reaction with a compound of the formula: and a compound of the formula: to produce a compound of the formula: or its salt;vii carrying out a cyclization reaction on the compound resulting from step (vi) to produce a compound of the formula: and optionally reacting to form a pharmaceutically acceptable salt thereof.

[0022] In one embodiment of steps (vi) and (vii), R in the compounds of Formulae VII, IX, and X is H. In another embodiment of steps (vi) and (vii), R in the compounds of Formulae VII, IX, and X is C1-4 alkyl, preferably methyl.

[0023] In one embodiment, R in the compounds of Formulae VI, VII, IX and X is an acid protecting group and the process further comprises the step (herein step (viii)) of hydrolyzing the ester group to produce the acidic compound of Formula (X) where R is H.

[0024] and optionally reacting to form a pharmaceutically acceptable salt thereof.

[0025] In one embodiment, the compound formed in step (vii) or step (viii) is the t-butyl amine salt of: Preferably, the compound is the t-butyl amine salt of:

[0026] In one embodiment, there is provided a compound of the formula: or its salt.

[0027] In a preferred embodiment, the compound is a compound of the formula: or its salt. This formula represents the S-enantiomer.

[0028] Further provided herein is the use of the compound of the formula: in the preparation of a compound of the formula: or a pharmaceutically acceptable salt thereof.

[0029] The formation of the epoxide in step (i) is known, for example, from Scheme 1 of Synthetic Communications, 45:2576-2582, 2015 and Example 1 in WO 2012/153155. Those skilled in the art will appreciate that a number of bases and solvents may be employed in this step. Suitable solvents include sterically hindered alcohols, in particular 2-propanol. There are a number of suitable bases including sodium hydroxide, potassium hydroxide and lithium hydroxide. This step may be carried out by addition of epichlorohydrin to dibenzyl amine and 2-propanol at a low temperature, preferably below 5°C. The reaction mixture may then be warmed to room temperature, preferably between 20 and 25°C, and stirred. The solution may then be cooled to below 5°C before addition of base and then rewarming to room temperature, preferably about 20°C. Alternatively, the addition of epichlorohydrin to dibenzyl amine and 2-propanol may be carried out at a temperature between 10 and 20°C, followed by addition of the base and stirring at 20 to 25°C.

[0030] The deprotection step (step (iii)) may be carried out by a number of different methods known in the art, "Protective groups in organic synthesis" by T. W. Greene and P. G. M. Wuts, Wiley, 3rd Ed, 1999, Hoboken, NJ, pp 579-580. For example, a palladium catalyst may be used. If the compound of Formula I is the hydrochloride salt, then it is preferable to use between 0.8 and 1 molar equivalent of hydrochloric acid, preferably about 0.9 molar equivalent. A number of solvents may be used in this step including, for example, ethanol or methanol. In one embodiment, the compound resulting from step (ii) is taken forward to step (iii) in solution, for example, in ethanol solution.

[0031] Optional step (iv) may be carried out using methods taught in the art, see for example the method for the preparation of Intermediate 24 in WO 2018/109607. In one embodiment of step (iv), the oxetan-2-yl methanamine, or its salt, is dissolved in dimethyl formamide. In an alternative embodiment, the oxetan-2-yl methanamine may be used in, for example, a lower alkyl alcohol solution, in particular an ethanol solution. This solution may be carried forward directly from the previous step (iii).

[0032] In another embodiment of step (iv), the step is performed at room temperature. In an alternative embodiment, the step is performed at a temperature of 110 to 120°C.

[0033] A preferred base in step (iv) is triethyl amine.

[0034] Methods of carrying out reduction of the nitro group to form the amine in step (v) are well known in the art. For example, it can be carried out using a palladium catalyst such as palladium on carbon.

[0035] The amide coupling reaction in step (vi) may be carried out using methods known in the art. In one embodiment, the coupling may be carried out using 1,1-carbonyl diimidazole. It is preferred to first add 1,1-carbonyl diimidazole to 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluoro-5-methylphenyl)acetic acid in a solvent, e.g., tetrahydrofuran, and allow adequate time for generation of an active intermediate prior to addition of compound of Formula VII. Alternatively, the amide coupling step may be carried out using other coupling conditions, e.g., using HATU (1-(bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate).

[0036] The cyclization reaction in step (vii) may be carried out by heating, for example, to above 80°C, optionally in the presence of an acid.

[0037] As shown above, when R in the compounds of Formulas VI, VII, IX and X in steps (iv), (v), (vi) and (vii) is an acid protecting group, the process may further comprise the step (step (viii)) of hydrolyzing the ester compound to provide the final acid compound (Formula X'). This step may be carried out, for example, by heating the ester in the presence of a base, such as lithium hydroxide.

[0038] In a particular embodiment, R in the compounds of Formulas VI, VII, IX and X in steps (iv), (v), (vi) and (vii) is H and the final step (viii) is not necessary. This is advantageous because it reduces the number of synthetic steps. Furthermore, if this hydrolysis step is carried out by heating the ester in the presence of a base, this step may result in an undesirable side reaction at the nitrile group.

[0039] Steps (iv), (v), (vi), and (vii) all involve compounds having group R. In each occurrence, R is either H or an acid protecting group. As those skilled in the art will appreciate, the R group remains the same through each of these sequential steps. In one embodiment, R is H. In another embodiment, R is C1-4 alkyl, preferably methyl. In step (viii), the compound of Formula X where R is an acid protecting group is hydrolyzed to a compound of Formula X where R is H (Formula X').

[0040] The compounds of Formulae I, II, III, IV, VI, IX and X all have a chiral center at the oxirane or oxetane attachment point. While the process steps include the use of all individual enantiomers, and mixtures thereof, as well as racemates, certain configurations are preferred.

[0041] Formulas Ia, IVa, VIa, VIIa, IXa and Xa represent the S-enantiomer. Formulas IIb and IIIb represent the R-enantiomer.

[0042] The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound considered to be acceptable for clinical and/or veterinary use. Examples of pharmaceutically acceptable salts and common methodologies for their preparation can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use" P. Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and S.M. Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19. A preferred salt of the compound of Formula X is the tert-butyl amine (or erbumine) salt.

[0043] R in the compounds of formulas V, VI, VII, IX, and X described herein may be an acid protecting group. It is understood that protecting groups may be varied as appreciated by those skilled in the art depending on the particular reaction conditions and the particular transformations to be performed. Acid protecting groups, as well as protection and deprotection conditions, are well known to those skilled in the art and are described in the literature (see, for example, "Greene's Protective Groups in Organic Synthesis", Fourth Edition, by Peter G.M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

[0044] Certain abbreviations are defined as follows: "ACN" refers to acetonitrile; "DCM" refers to dichloromethane; "DMEA" refers to N,N-dimethyl ethyl amine; "DMF" refers to N,N-dimethyl formamide; "DMSO" refers to dimethyl sulfoxide; "ES-MS" refers to electrospray mass spectrometry; "EiOAc" refers to ethyl acetate; "EtOH" refers to ethanol or ethyl alcohol; "h" refers to hour or hours; "HPLC" refers to high performance liquid chromatography; "MeOH" refers to methanol or methyl alcohol; "MTBE" refers to methyl tert-butyl ether; "min" refers to minute or minutes; "m/z" refers to mass-to-charge ratio; "Pd(dppf)Cl2 refers to [1,1'-bis-(diphenylphosphino)ferrocene]dichloropalladium(II); "RT" refers to room temperature; "TFA" refers to trifluoroacetic acid; and "THF" refers to tetrahydrofuran.

[0045] X-ray sputter diffraction (XRPD) patterns of crystalline solids are obtained on a Bruker D4 Endeavor X-ray sputter diffractometer equipped with a CuKα source and a Vantec detector, operating at 35 kV and 50 mA. The sample is scanned between 4 and 40 2θ°, with a step size of 0.008 2θ° and a scan rate of 0.5 seconds/step, and using 1.0 mm divergence, 6.6 mm fixed anti-scatter, and 11.3 mm detector slits. The dried sputter is packed onto a quartz sample holder and a uniform surface is obtained using a glass slide. Crystalline diffraction patterns are collected at room temperature and relative humidity. Crystal peak positions are determined in MDI-Jade after integer standard deviation based on an internal NIST 675 standard with peaks at 8.853 and 26.774 2θ°. It is well known in crystallography that for any given crystal form, the relative intensities of diffraction peaks can vary due to preferred orientation resulting from factors such as crystal morphology and habit. Where preferred orientation effects are present, peak intensities are altered, but the characteristic peak positions of the polymorph are unchanged. See, for example, The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, it is also well known in crystallography that for any given crystal form the angular peak positions can vary slightly. For example, peak positions may shift due to a variation in the temperature at which a sample is analyzed, sample displacement, or the presence or absence of an internal standard. In the present case, a peak position variability of +/- 0.2 2θ is assumed to account for these potential variations without hindering unequivocal identification of the indicated crystal form. Confirmation of a crystal form may be made based on any unique combination of distinct peaks. Preparation 1(R)-1-chloro-3-(dibenzylamino)propane-2-ol

[0046] To a flask, add dibenzylamine (200.0 g, 0.993 moles) and 2-propanol (200 mL). Cool the solution with stirring to below 5°C in an ice/water bath. Using an addition funnel, add (R)-(-)-epichlorohydrin (95 mL, 1.21 moles) over 10 minutes. Warm the mixture to 21°C and stir for two days, then refrigerate the resulting solution containing the title compound until use in the next step. ES-MS m/z 290 (M+H). Preparation 2(R)-N,N-dibenzyl-1-(oxiran-2-yl)methanamine

[0047] Method A: Pour the (R)-1-chloro-3-(dibenzylamino)propane-2-ol solution from Preparation 1 into a mechanically stirred flask and use 2-propanol (466 mL) to complete the transfer. Cool the solution with ice water to below 5°C, add sodium hydroxide solution (5 moles/L in water, 240 mL, 1.18 moles) in five portions, and then heat the mixture to 20°C. After 6 hours, transfer the mixture to a separatory funnel filled with toluene (500 mL) and water (100 mL). Swirl the mixture, allow the layers to separate, and remove the bottom layer. Add water (250 mL), swirl the mixture and allow it to settle, and then remove the bottom layer. Add saturated aqueous NaCl, stir the mixture and allow to separate, and remove the bottom layer. Dry the solution over sodium sulfate, filter, and concentrate the solution by rotary evaporation. Dry the residue in vacuo to yield the title compound as a syrup (270.7 g, 99% yield over 2 steps), which by 1H-NMR appears to contain 8.7% w/w toluene. 1H-NMR (400 MHz, CDCl3) δ 7.45-7.23 (m, 10H), 3.82 (brd, J = 13.6 Hz, 2H), 3.59 (brd, J = 13.6 Hz, 2H), 3.10 (br, 1H), 2.79 (brd, J = 12.8 Hz, 2.7), 0 (t, J = 4.4 Hz, 1H), 2.48-2.40 (m, 2H). ES-MS m/z 254 (M+H).

[0048] Method B (one pot procedure from (R)-(-)-epi-chlorohydrin): To a vessel, add dibenzylamine (152 kg, 770 moles) and 2-propanol (121 kg) and stir the mixture at 10-20oC. Slowly add (R)-(-)-epichlorohydrin (105 kg, 1135 moles) and stir the mixture at 10-20oC until the reaction reaches <1% epichlorohydrin remaining. Slowly add 20% w/w sodium hydroxide in water (183 kg, 915 moles NaOH) and stir the mixture at 20-25oC. Add another portion of 20% w/w sodium hydroxide in water (20 kg, 100 moles NaOH) and stir the mixture at 20-25°C until <0.5% intermediate remains. Separate the layers and concentrate the organic layer under reduced pressure to approximately 200 L remaining volume. Add EtOAc (688 kg), concentrate the mixture again under reduced pressure to approximately 200 L remaining volume, then add EtOAc (683 kg) and water (460 kg). Stir the mixture, then stand, and separate the aqueous layer. Add another portion of water (461 kg) to the organic layer. Stir the mixture, then settle, and separate the aqueous layer. Add another portion of water (451 kg) to the organic layer. Stir the mixture, then settle, and separate the aqueous layer. Concentrate the organic layer under reduced pressure to approximately 130 L remaining, then add tert-butanol (595 kg). Concentrate the mixture under reduced pressure to approximately 130 L remaining. Dilute the solution with tert-butanol (167 kg) to yield a solution of the title compound (373.4 kg of solution, 50.8 wt %, 189.7 kg of title compound, 749 moles, 97% yield). The HPLC retention time for the title compound is 14.0 min [HPLC: Waters XBridge C18 (4.6 × 150 mm, 3.5 μm), 35°C, 1.2 mL/min, 215 nm detection, gradient: 5-95% B in 16 min, retain for 18 min, 5% B in 18.1 min; Solvent A = 10 mM ammonium formate, pH 9.0, in purified water, Solvent B = ACN].Preparation 3(S)-N,N-dibenzyl-1-(oxetan-2-yl) methanamine

[0049] Method A: Equip a flask with mechanical stirring, a nitrogen source, a heating mantle, condenser, and thermocouple. Add trimethyl sulfoxonium iodide (66.5 g, 0.278 moles), followed by solid potassium t-butoxide (45.7 g, 0.371 moles) and t-butanol (500 mL) to the flask. Stir and heat the solution to 85°C and add a solution of (R)-N,N-dibenzyl-1-(oxiran-2-yl)methanamine (pure material from Preparation 2, Method A, 50.0 g, 0.186 moles) in t-butanol (250 mL) via pressure transfer. Heat the mixture at 80-85°C (gentle reflux) for 5 hours, then cool and remove the solids by filtration. Wash the solids with hexanes (200 mL) and combine the hexanes wash filtrate with the initial filtrate. Partially concentrate the product solution by rotary evaporation and transfer to a separatory funnel containing hexanes (500 mL) and water (200 mL). Shake the mixture, allow to stand, and drain the bottom layer; repeat this two more times. Wash the organic layer with saturated aqueous NaCl and dry over sodium sulfate. Remove the sodium sulfate by filtration and concentrate the solution by rotary evaporation to an oil. Purify the oil by silica gel chromatography using 15% EtOAc in hexanes to yield the title compound (23.4 g, 40%) as a yellow oil that appears to be ~85% pure by 1H NMR. 1H-NMR (400 MHz, CDCl3) δ 7.40¬7.22 (m, 10H), 5.03 (brpent, J = 5.8 Hz, 1H), 4.63 (td, J = 6.1, 8.0 Hz, 1H), 4.46 (td, J = 5.9, 9.1 Hz, 1H), 3.70 (br d, J = 13.7 Hz, 2H), 3.62 (brd, J = 13.7 Hz, 2H), 2.82 (dd, J = 6.1, 13.5 Hz, 1H), 2.71 (dd, J = 4.5, 13.5 Hz, 1H), 2.56 (m, 1H), 2.36 (m, 1H). ES-MS m/z 268 (M+H).

[0050] To assess the optical purity of the title compound, prepare the title compound as a racemic mixture essentially as described in Preparations 1 through 3 starting with racemic epichlorohydrin.

[0051] Analyze the racemic mixture by chiral HPLC (column: Chiral-cel OD-H 4.6 x 150 mm; flow rate 1 mL/min; detection at 254 nm; eluent: 2:98 EtOH/heptane (v/v) + 0.1% DMEA). Retention times for the individual enantiomers in the racemic sample using this method are 7.48 min and 8.59 min. Analysis of the optically pure material shows 96% ee (1.8% at 7.49 min and 86.0% at 8.61 min by UV peak area).

[0052] Method B: Add trimethyl sulfoxonium iodide (250 kg, 1136 moles) to a flask. Add potassium tert-butoxide (170.1 kg, 1516 moles), and tert-butanol (744 kg). Stir at 50-55°C for 2-3 hours, then at 65-75°C for 15-30 minutes, then heat to 75-80°C. Slowly add a solution of (R)-N,N-dibenzyl-1-(oxiran-2-yl)methanamine in tert-butanol (from Preparation 2, Method B, 372.2 kg of solution, 50.8 wt%, 189 kg, 749 moles). Heat the mixture to 80-90oC for 6-8 hours, then cool to 30-40oC and add EtOAc (534 kg). Filter the mixture and wash with EtOAc (51 + 54 + 60 + 59 + 60 + 60 +60 kg). Concentrate the mixture under reduced pressure to approximately 200-400 L remaining, then add EtOAc (858 kg) and concentrate again under reduced pressure to approximately 200-400 L remaining. Add EtOAc (861.5 kg) and water (570 kg) and adjust the temperature of the mixture to 20-30oC. Stir, then pour the mixture and separate the layers.

[0053] Purify the organic layer in portions. Add a portion of the organic layer to a flask (176 kg) and concentrate under reduced pressure to approximately 32 L remaining. Add a 4:1 v/v solution of heptane : EtOAc (25 kg), then silica gel (46 kg), and then heptane (107 kg) to the mixture. Stir the mixture for 2-3 hours at 20-30°C, then filter and rinse the silica gel with three portions (~60 kg each) of a 10:1 w/w solution of heptane : EtOAc, with 1.7 wt% triethylamine. Combine the filtrates and concentrate under reduced pressure to approximately 20 L remaining, then add heptane (11 kg). Chromatograph the heptane solution through a silica gel pad (60 kg) eluting with a 10:1 wt/wt mixture of heptane:EtOAc with 1.7 wt% triethylamine, combining the product-containing fractions for further processing. Process the remaining organic portions similarly and combine all chromatographed product fractions.

[0054] Concentrate the product fractions under reduced pressure to approximately 200 L remaining. Add EtOH (470 kg) to the mixture and concentrate under reduced pressure to approximately 200 L remaining. Dilute the mixture with EtOH (297 kg) to yield a solution of the title compound (407.8 kg solution, 18.7 wt %, 76.3 kg title compound, 285 moles, 38% yield). HPLC retention time for the title compound is 9.8 minutes [HPLC: Agilent Zorbax Bonus RP (4.6 x 150 mm, 3.5 μ), 35°C, 1.2 mL/minute, 215 nm detection, gradient: 5-50% B in 15 minutes, to 95% B in 20 minutes, retain for 22 minutes, 5% B in 22.1 minutes; Solvent A = 0.05% TFA in purified water, Solvent B = 0.05% TFA in ACN]. Preparation 4(S)-Oxetan-2-yl methanamine hydrochloride

[0055] In a pressure bottle, dissolve (S)-N,N-dibenzyl-1-(oxetan-2-yl)methanamine (pure material from Preparation 3, Method A, 46.0 g, 172 mmol) in EtOH (460 mL) and add aqueous HCl (5 M, 31 mL, 155 mmol). Add palladium on carbon (60 wt% water, 5% Pd loading on a dry basis, 9.2 g) and stir the mixture at room temperature under 40 psig of hydrogen for 20 h. Remove the catalyst by filtration through Celite and remove the solvent by rotary evaporation. The residue is a colorless oil, which crystallizes on standing to provide the title compound (20.8 g, 98%). 1H-NMR (400 MHz, DMSO-d6) δ 7.98 (br, 3H), 4.90 (m, 1H), 4.52 (ddd, J = 5.9, 7.2, 8.6 Hz, 1H), 4.46 (td, J = 6.2, 9.0 Hz, 1H), 3.05 (dd, J = 6.4, 13 .5 Hz, 1H), 2.98 (dd, J = 4.3, 13.5 Hz, 1H), 2.66 (m, 1H), 2.52 (m, 1H). Preparation 5(S)-Oxetan-2-yl methanamine

[0056] Add the EtOH solution of (S)-N,N-dibenzyl-1-(oxetan-2-yl)methanamine from Preparation 3, Method B to a vessel (203.6 kg solution, 18.7 wt %, 38.1 kg starting material, 142 moles). Add activated carbon (3.9 kg) to the solution and rinse with EtOH (5 kg). Stir the mixture for 4-6 hours, then filter and rinse with EtOH (38 + 39 + 38 kg). Concentrate the solution to approximately 152 L remaining (187.6 kg solution, 19.9 wt %, 37.3 kg starting material, 140 moles), then add acetic acid (10 kg) and rinse with EtOH (2 kg). Add palladium on carbon (50 wt% water, 10 wt% palladium charge on a dry basis, 1.87 kg) to the mixture and rinse with EtOH (3 x 5 kg). Subject the mixture to 0.3-0.5 MPa hydrogen pressure and heat to 40-50°C. After 5-6 hours, add another portion of palladium on carbon (1.87 kg) to the reaction mixture and rinse with EtOH (5 + 10 + 6 kg). Resubmit the reaction mixture to 0.3-0.5 MPa hydrogen at 40-50°C. After 5-6 hours, add another portion of palladium on carbon (1.87 kg), rinse with EtOH (10 + 10 + 11 kg), and resubmit the reaction mixture to 0.3-0.5 MPa hydrogen at 40-50°C. After 5-6 hours, add another portion of palladium on carbon (1.87 kg), rinse with EtOH (10 + 5 + 6 kg), and resubject the reaction mixture to 0.3-0.5 MPa of hydrogen at 40-50°C. After 5-6 hours, add another portion of palladium on carbon (0.38 kg), rinse with EtOH (6 + 7 + 5 kg), and resubject the reaction mixture to 0.3-0.5 MPa of hydrogen at 40-50°C. After 5-6 hours, cool the reaction mixture to 15-25°C, filter through diatomite (7 kg), and rinse with EtOH (40 + 48 kg). The title compound is obtained as an EtOH solution (381 kg solution, 2.8 wt%, 10.75 kg title compound, 123 moles, 87% yield). Retention time for the title compound is 6.6 minutes [GC: DB-624, 30 m x 0.32 mm ID x 1.8 μm, FID detection at 280°C, constitution flow (N2) 30 mL/min, H2 flow 40 mL/min, air flow 400 mL/min, 60°C for 1 minute, ramp from 30°C/min to 130°C, hold for 6 minutes, ramp from 30°C/min to 240°C, hold for 22 minutes. Injector temperature 240°C, split ratio 10:1].Preparation methyl 6(S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate

[0057] Dissolve (S)-oxetan-2-yl methanamine hydrochloride (20.8 g, 168 mmol) in DMF (150 mL) and add methyl 3-fluoro-4-nitrobenzoate (30.0 g, 151 mmol), followed by triethylamine (45.7 g, 452 mmol). Stir the mixture for 20 h at room temperature. Pour the mixture into a separatory funnel and add MTBE (400 mL) and water (400 mL). Stir the mixture, allow to settle, and remove the bottom layer. Wash the organic layer sequentially with water, saturated aqueous NaCl, and then dry over sodium sulfate. After filtration, concentrate the solution by rotary evaporation and chromatography on silica gel (1.5 kg) using EtOAc/isohexanes (gradient elution, 0 to 40% (v/v) EtOAc to isohexanes). Combine the product-rich fractions and concentrate by rotary evaporation to afford the product as a yellow solid (33.3 g, 125 mmol, 83% yield). Chiral HPLC analysis indicates that the product had 94.2% ee (r.e. = 97.1 : 2.9).

[0058] Chiral HPLC conditions: 3:7 (v/v) EtOH/heptane with 0.1% (w/w) DMEA, Chiralpak AD-H, 4.6 x 150 mm, 1 mL/min, 254 nm, S-enantiomer = 7.93 min, R-enantiomer = 9.50 min. 1H-NMR (400 MHz, CDCl3) δ 8.37 (br, 1H), 8.25 (d, J = 9.0 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 7.28 (dd, J = 1.8, 8.8 Hz, 1H), 5.17 (m, 1H), 4.76 (ddd, J = 6.1, 7.6, 8.4 Hz, 1H), 4.64 (td, J = 6.0, 9.2 Hz, 1H), 3.95 (s, 3H), 3.64 (t, J = 4.9 Hz, 2H), 2.79 (m, 1H), 2.62 (m, 1H), ES-MS m/z 267 (M+H).Preparation 7(S)-4-Nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid

[0059] Add an EtOH solution of (S)-oxetan-2-yl methanamine (from Preparation 5, 6.9 kg corrected assay, 79 moles) to 3-fluoro-4-nitrobenzoic acid (15.3 kg, 83 moles, 1.05 equivalents). Add triethylamine (26 kg, 257 moles, 3.1 equivalents) slowly, rinse with EtOH (3 kg), and heat the mixture to 110-120oC in a sealed vessel until 3-fluoro-4-nitrobenzoic acid is <2% remaining. Cool the mixture, transfer to a drum, and rinse with EtOH (15 kg). In a similar manner, process a total of 20.7 kg of pure (S)-oxetan-2-yl methanamine (238 moles) and 45.6 kg of 3-fluoro-4-nitrobenzoic acid (246 moles) in three batches. Concentrate the combined EtOH solutions of the title compound to approximately 100 L, then add EtOH (71 kg) and concentrate again to approximately 100 L. Cool the mixture to 5-15°C and slowly add 15% w/w citric acid in water (287 kg). Stir for 1-2 hours, then filter the mixture and rinse with water (88 + 86 kg). Stir the wet filter cake in EtOH (113 kg) and heat the mixture to 40-50°C. After 4-6 hours, cool the mixture to 5-15oC, stir for 2-4 hours, then filter and wash the cake with EtOH (28 kg). Dry the wet cake to obtain the title compound as an orange solid (34.6 kg, 32.4 kg corrected assay, 137 moles, 58% yield). 1H NMR (400 MHz, DMSO) δ 13.50 (s, 1H), 8.33 (t, J = 5.8 Hz, 1H), 8.16 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 1.7 Hz, 1H), 7.16 (dd, J = 8.9, 1.7 Hz, 1H), 5, 00 (m, 1H), 4.60 - 4.38 (m, 2H), 3.74 - 3.58 (m, 2H), 2.71 - 2.50 (m, 2H). HPLC retention time for the title compound is 12.5 minutes [HPLC: Agilent Zorbax Bonus RP (4.6 x 150 mm, 3.5 μm), 35°C, 1.2 mL/minute, 237 nm detection, gradient: 5¬95% B in 20 minutes, 5% B in 20.1 minutes; Solvent A = 0.05% TFA in purified water, Solvent B = 0.05% TFA in ACN]. Preparation 8 (S)-4-Amino-3-((oxetan-2-ylmethyl)amino)benzoic acid

[0060] To a flask, add (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid (3.55 kg, 13.9 moles) and THF (35 L). Add palladium on carbon (50 wt% water, 10 wt% palladium charge on a dry basis, 356 g). Subject the reaction mixture to hydrogen pressure (0.3 MPa) at 35°C until the reaction is complete. Filter the reaction mixture through Celite to remove the catalyst, then concentrate to approximately 7 L remaining. Add back 17 L of EtOAc and concentrate again to approximately 7 L remaining. Add back another 17 L of EtOAc and concentrate to approximately 7 L remaining. Filter and rinse with EtOAc. Dry the wet cake under vacuum at 45-50°C to obtain the title compound as a brown solid (2.89 kg, 12.6 moles, 91% yield). HPLC retention time for the title compound is 6.2 minutes [HPLC: Waters XBridge C18 (4.6 x 150 mm, 3.5 μm), 35°C, 1.2 mL/minute, 237 nm detection, gradient: 5-95% B in 20 minutes, 5% B in 20.1 minutes; Solvent A = 0.05% TFA in purified water, Solvent B = 0.05% TFA in ACN]. Preparation 9(S)-4-(2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluoro-5-methylphenyl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoic acid

[0061] To a vessel add 2-[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridyl]-2-fluoro-5-methylphenyl]acetic acid (4.75 kg, 13.6 moles) (Preparations 9a through 9f below) and THF (25 kg). Add 1,1-carbonyl diimidazole (2.6 kg, 17.7 moles, 1.3 equivalents) and rinse with THF (4 kg). Heat the mixture to 35-40°C for 0.5-1 h, then add (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid (2.8 kg, 14.3 moles, 1.05 equivalents) and rinse with THF (4.2 kg). Stir the mixture at 35-40°C until the reaction is complete, then cool to 20-30°C and add 5% citric acid in water (18.5 kg). Add EtOAc (22 kg), stir the mixture, then allow it to settle and separate the layers. Add another portion of 5% citric acid in water (18.5 kg) to the organic layer. Stir, then settle and separate the layers. Add water (23.9 kg) to the organic layer. Stir, then settle and separate the layers. Add THF (32.8 + 26 kg), then add Si-Thiol scavenger (0.5 kg) and stir the mixture for 6-8 hours. Filter the scavenger and rinse with THF (11 kg). Concentrate the mixture to approximately 10-15 L remaining, then add EtOAc (21 kg). Repeat this twice with two 20 kg portions of EtOAc. Reconcentrate the mixture to approximately 10-15 L remaining, then add EtOAc (20 kg). Concentrate the mixture a third time to approximately 10-15 L remaining, then add EtOAc (20 kg). Filter, then rinse the wet cake with EtOAc (13 kg). Dry the wet cake under vacuum at 30-40°C to obtain the title compound as an off-white solid (4.35 kg, 8.2 moles, 60% yield). HPLC retention time for the title compound is 16.0 minutes. [HPLC: Waters XBridge C18 (4.6 x 150 mm, 3.5 μm), 35oC, 1.2 mL/min, detection at 230 nm, gradient: 5-40% B in 7 min, to 95% B in 19 min, hold to 21 min, to 5% B in 21.1 min; Solvent A = 0.05% TFA in purified water, Solvent B = 0.05% TFA in ACN].

[0062] 2-[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridyl]-2-fluoro-5-methylphenyl] acetic acid, one of the starting materials in Preparation 9 above can be prepared according to the preparations below: Preparation 9a(4-bromo-2-fluoro-5-methylphenyl)methanol

[0063] To a flask add: 4-bromo-2-fluoro-5-methyl benzoic acid (100 g, 421 mmol), THF (200 mL), and borane (dimethyl sulfide complex, 2 moles/L solution in THF, 210 mL, 10 mmol). Stir the mixture at room temperature overnight. Quench the reaction mixture with HCl (1.0 N aqueous solution, 50 mL) and filter the mixture. Concentrate the filtrate in vacuo and partition the residue between EtOAc (400 mL) and water (400 mL). Wash the organics with saturated aqueous NaCl (400 mL), dry over Na2SO4, filter, and concentrate to yield the title compound as a solid (93.5 g, 99%), 1H-NMR (400 MHz, CDCl3) δ 7.29 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 9.1 Hz, 1H), 4.69 (s, 2H), 2.38 (s, 3H). Preparation 9b2-(4-Bromo-2-fluoro-5-methylphenyl)acetonitrile

[0064] Dissolve (4-bromo-2-fluoro-5-methylphenyl)methanol (92 g, 420 mmol) in DCM (500 mL) and add triethylamine (120 mL, 861 mmol). Cool the mixture to -15 °C and add a solution of methanesulfonyl chloride (40 mL, 517 mmol) in DCM (30 mL) dropwise to the reaction mixture. Stir the mixture for 30 min at room temperature. Partition the reaction mixture between DCM (500 mL) and water (500 mL). Wash the organics with saturated aqueous NaCl (500 mL), dry over sodium sulfate, filter, and concentrate. Dissolve the residue in DMF (400 mL) and cool the mixture with an ice bath. Add NaCN (21.0 g, 429 mmol) in one portion to the reaction mixture and stir at room temperature overnight. Partition the mixture between EtOAc (400 mL) and water (500 mL). Wash the organics with saturated aqueous NaCl (500 mL), dry over sodium sulfate, filter, and concentrate. Purify the residue by chromatography on silica gel using a gradient of 10 to 30% EtOAc in hexanes to yield the title compound (47.0 g, 48%) as an oil. Preparation 9c2-(4-Bromo-2-fluoro-5-methylphenyl)methyl acetate

[0065] To a flask add: 2-(4-bromo-2-fluoro-5-methylphenyl)acetonitrile (1.20 g, 5.10 mmol), EtOH (5 mL), water (3 mL), and potassium hydroxide (0.90 g, 16 mmol). Heat the mixture at 90°C overnight. Cool the mixture with an ice bath and acidify with 1.0 M HCl to pH 4-5, then partition the mixture between EtOAc (30 mL) and water (30 mL). Wash the organics with saturated aqueous NaCl (30 mL), dry over sodium sulfate, filter, and concentrate to yield 2-(4-bromo-2-fluoro-5-methylphenyl)acetic acid as a solid. Dissolve this in DCM (10 mL), then add DMF (0.05 mL, 0.6 mmol) and oxalyl chloride (0.5 mL, 6 mmol) at room temperature. Stir the mixture at room temperature for 30 min, then add MeOH (2 mL, 49.4 mmol) dropwise. After 30 min, remove the solvent in vacuo and partition the residue between EtOAc (40 mL) and 5% NaHCO 3 (30 mL). Wash the organics with saturated aqueous NaCl (40 mL), dry over sodium sulfate, filter, and concentrate to yield the title compound as an oil (1.1 g, 80%). ES/MS m/z (79Br, 81Br) 278.280 (M+NH 4 + ). Preparation 9d2-[2-fluoro-4-(6-hydroxy-2-pyridyl)-5-methyl phenyl] methyl acetate

[0066] To a flask add 6-hydroxy pyridine-2-boronic acid ester pinacol (1.6 g, 6.9 mmol), 2-(4-bromo-2-fluoro-5-methylphenyl)methyl acetate (2.2 g, 8.4 mmol), THF (15 mL), water (1 mL), and potassium carbonate (2.0 g, 14 mmol). Purge the mixture with nitrogen for 10 minutes, then add Pd(dppf)Cl2 (0.26 g, 0.35 mmol) and heat at 75 °C for two hours. Partition the mixture between EtOAc (30 mL) and water (30 mL). Wash the organics with saturated aqueous NaCl (30 mL), dry over sodium sulfate, filter, and concentrate to yield the title compound (1.4 g, 74%) as a solid. ES/MS m/z 276 (M+H), 274 (MH). Preparation 9e2-[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridyl]-2-fluoro-5-methylphenyl] acetate

[0067] To a flask add methyl 2-[2-fluoro-4-(6-hydroxy-2-pyridyl)-5-methylphenyl] acetate (1.40 g, 5.09 mmol), 1,4-dioxane (35 mL), silver carbonate (1.7 g, 6.2 mmol), and 4-(bromomethyl)-3-fluorobenzonitrile (1.4 g, 6.2 mmol). Heat the mixture at 60 °C overnight. Filter the solid and concentrate the filtrate. Purify the residue by chromatography on silica gel using 12 to 55% EtOAc in hexanes to yield the title compound (1.60 g, 77%) as a solid. ES/MS m/z 409 (M+H), 407 (MH). Preparation 9f Acid 2-[4-[6-[(4-cyano-2-fluorophenyl) methoxy]-2-pyridyl]-2-fluoro-5-methyl phenyl] acetic

[0068] To a flask add 2-[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridyl]-2-fluoro-5-methylphenyl] methyl acetate (1.6 g, 3.9 mmol), ACN (20 mL), water (6 mL), and lithium hydroxide (0.45 g, 19 mmol). Heat the mixture at 45°C for two hours, cool the mixture with an ice bath, and acidify with 1.0 M HCl to pH = 4-5. Partition the mixture between EtOAc (50 mL) and water (50 mL). Wash the organics with saturated aqueous NaCl (50 mL), dry over sodium sulfate, filter, and concentrate to yield the title compound (1.55 g, 100%) as a solid. ES/MS m/z 395 (M+H). Preparation 102-[[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridyl]-2-fluoro-5-methylphenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]t-butyl ammonium benzimidazole-5-carboxylate

[0069] Mix (S)-4-(2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluoro-5-methylphenyl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoic acid (2.05 kg, 3.4 moles) and THF (19 kg), heat the mixture to 115-125°C in a sealed vessel until the reaction is complete, then rinse in a drum with THF (7 kg). Combine this reaction with another reaction run in a similar manner on a 2.05 kg scale. Recirculate the product solution through a new activated carbon cartridge filter for 4-6 hours, then rinse the filter with THF (8.4 kg). Concentrate the solution to the remaining 8-12 L, then add acetone (17 kg). Reconcentrate the solution to the remaining 8–12 L, then add acetone (18 kg). Concentrate the solution a third time to the remaining 8–12 L and add acetone (38 kg). Heat the mixture to 45–55°C and add purified water (1.7 kg). Prepare a solution of 2-methyl-2-propanamine (0.7 kg, 9.6 moles, 1.4 equivalents) in acetone (3.4 kg). Add 1/5 of the 2-methyl-2-propanamine solution to the product solution. Add seed crystals of the title compound (18.57 g) and stir the mixture for one to two hours, then add the remaining 2-methyl-2-propanamine solution slowly. Stir the mixture for one to two hours, then cool to 15–20°C slowly. Filter the solid and rinse with acetone (10 kg). Dry the solid under vacuum at 45-55°C to obtain the title compound as a white solid (3.48 kg, 5.1 moles, 75% yield). HPLC retention time for the title compound is 14.8 minutes. [[HPLC; Waters XBridge C18 (4.6 x 150 mm, 3.5 μm), 35°C, 1.2 mL/min, detection at 220 nm, gradient: 5-40% B in 6 minutes, to 95% B in 28 minutes, to 5% B in 28.1 minutes; Solvent A = 0.05% TFA in purified water; Solvent B = 0.05% TFA in ACN].

[0070] A prepared sample of the title compound is characterized by an XRD pattern using CuKα radiation as having diffraction peaks (2-theta values) as described in Table 1 below, and in particular having peaks at 6.9 in combination with one or more of the peaks selected from the group consisting of 16.3 and 22.5; with a tolerance for the diffraction angles of 0.2 degrees. Table 1. X-ray diffraction peaks of sputtered 2-[[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridyl]-2-fluoro-5-methylphenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate t-butyl ammonium

Claims (19)

1. Process for preparing a compound of the formula: or a salt thereof, characterized by comprising the steps of: i. combining dibenzyl amine and a compound of the formula: then add a base to produce a compound of the formula: II. Take trimethyl sulfuxonium halide in the presence of a base and combine with a solution of the compound resulting from step (i) and heat above 40oC to produce a compound of the formula: III. deprotect the compound resulting from step (ii). 2. Process, according to claim 1, characterized in that the prepared compound is a compound of the formula: or its salt. 3. Process according to either of claims 1 or 2, characterized in that the trimethyl sulfuxonium halide is trimethyl sulfuxonium iodide. 4. Process according to any one of claims 1 to 3, characterized in that the base in step (ii) is selected from: potassium tert-butoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-amylate, lithium tert-amylate, sodium tert-amylate, lithium potassium hydride, sodium hydride, potassium hydride, lithium n-butyl in alcohol solvent, lithium hexamethyl disilazide, sodium hexamethyl disilazide, or potassium hexamethyl disilazide. 5. Process according to claim 4, characterized in that the base is potassium tert-butoxide. 6. Process according to any one of claims 1 to 5, characterized in that the solution in step (ii) comprises a solvent selected from: tert-butanol, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N-methyl-2-pyrrolidone, or tert-amyl alcohol. 7. Process according to claim 6, characterized in that the solvent is tert-butanol. 8. Process according to any one of claims 1 to 7, characterized in that step (ii) is carried out at a temperature greater than 70oC. 9. Process according to any one of claims 1 to 8, characterized in that step (iii) is carried out using a palladium catalyst. 10. Process according to claim 9, characterized in that the palladium catalyst is palladium on carbon. 11. Process according to any one of claims 1 to 10, characterized in that it further comprises the step of combining a base and a compound of the formula: where R is H or an acid protecting group, with a solution of a compound of the formula: to produce a compound of the formula: 12. Process according to claim 11, characterized in that R is H or C1-4 alkyl. 13. Process according to either of claims 11 or 12, characterized in that it further comprises the step of reducing the nitro group of the compound of formula: to produce a compound of the formula: 14. The process of claim 13, further comprising the steps of: a. performing an amide coupling reaction with a compound of the formula: and a compound of the formula: to produce a compound of the formula: or its salt;b. carry out a cyclization reaction on the compound resulting from step (a) to produce a compound of the formula: and optionally reacting to form a pharmaceutically acceptable salt thereof. 15. The process of claim 14, wherein R is an acid protecting group and the process further comprises the step of hydrolyzing the ester compound to produce the acid compound of the formula: and optionally reacting to form a pharmaceutically acceptable salt thereof. 16. Process according to either of claims 14 or 15, characterized in that the compound prepared is the tert-butyl amine salt of: 17. Compound, characterized by being of the formula: or its salt. 18. Compound, according to claim 17, characterized by being: or its salt. 19. Use of the compound according to either of claims 17 or 18, characterized in that it is in the preparation of a compound of the formula: or a pharmaceutically acceptable salt thereof.