Processes for the preparation of an intermediate for a GLP-1 receptor agonist
Optimized synthetic steps for preparing Intermediate (i) enhance efficiency and yield by minimizing isolation steps and solvent use, addressing inefficiencies in existing methods.
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- ELI LILLY & CO
- Filing Date
- 2026-01-15
- Publication Date
- 2026-07-23
AI Technical Summary
Existing processes for the preparation of Intermediate (i), a key component in the synthesis of GLP-1 receptor agonists, are inefficient and require multiple isolation steps, leading to reduced yields and increased costs.
A series of optimized synthetic steps involving controlled crystallization, solvent exchanges, and direct reaction mixture processing are employed to streamline the preparation of Intermediate (i), eliminating intermediate isolation and reducing cycle times and solvent use.
The improved process achieves higher yields and faster processing times, resulting in more efficient production of Intermediate (i) with reduced solvent and waste disposal costs.
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Abstract
Description
PROCESSES FOR THE PREPARATION OF AN INTERMEDIATE FOR A GLP-1 RECEPTOR AGONISTTECHNICAL FIELD
[0001] Disclosed herein are processes for the preparation of ( )- l-(4-fluoro-l -methyl- 1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-l,3-dihydro-2H-imidazol-2-one, an intermediate useful for the preparation of 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2-oxoimidazol-l-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l-yl]-2-methylcyclopropyl]-4H-l,2,4-oxadiazol-5-one, a GLP-1 receptor agonist.BACKGROUND
[0002] The compound, 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-l-methylindazol-5-yl)-2-oxoimidazol-l-yl]-4-methyl-6.7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-l-yl]-2-methylcyclopropyl]-4H- 1,2,4-oxadiazol-5-one (herein, “GLP1RA”), is a GLP-1 receptor agonist of the following structure:
[0003] Processes for the preparation of GLP1RA are described in US 10,858,356 and WO 2024 / 137426. GLP1RA may be prepared under amide coupling conditions between an appropriate amine (i) and carboxylic acid (ii) as described in Scheme 1:Scheme 1
[0004] Certain processes for the preparation of the amine coupling partner (i) (hereinafter, “Intermediate (i)”), (S)-l-(4-fhioro-l-methyl-lH-indazol-5-yl)-3-(2-(4-fhioro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-l,3-dihydro-2H-imidazol-2-one, are known. There is a need for alternative or improved processes for the preparation of Intermediate (i).DESCRIPTION
[0005] Intermediate (i) may be prepared in a multistep synthesis as illustrated in Scheme 2 below, beginning with tert-butyl (5)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (a).Scheme 2
[0006] In one embodiment, disclosed herein is a method for the isolation of tert-butyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (b):wherein the method comprises effecting crystallization of formula (b) from a reaction mixture containing the compound of formula (b) in a solvent by the slow addition of water at T > 30°C.
[0007] In one embodiment is the isolation method for the compound of formula (b), wherein the compound of formula (b) is recovered in >90% yield.
[0008] In one embodiment is the isolation method for the compound of formula (b), wherein the compound of formula (b) is recovered in >95% yield.
[0009] In one embodiment is the isolation method for the compound of formula (b), wherein the solvent is l-methyl-2-pyrrolidinone, N,N-dimethylacetamide, or l,3-dimethyl-2-imidazolidinone.
[0010] In one embodiment is the isolation method for the compound of formula (b). wherein the solvent is l,3-dimethyl-2-imidazolidinone.
[0011] In one embodiment is the isolation method for the compound of formula (b), wherein the reaction mixture solution is heated to T > 30 °C prior to the addition of water.
[0012] In one embodiment is the isolation method for the compound of formula (b), wherein the reaction mixture solution is heated to T = 30 - 40 °C.
[0013] In one embodiment is the isolation method for the compound of formula (b), wherein the reaction mixture solution is heated to T = 35 °C.
[0014] In one embodiment is the isolation method for the compound of formula (b), wherein the water is added over more than 2 hours.
[0015] In one embodiment is the isolation method for the compound of formula (b), wherein the water was added over at least 5 hours.
[0016] In one embodiment is the isolation method for the compound of formula (b), wherein the water is added over between 5 to 6 hours.
[0017] In one embodiment is the isolation method for the compound of formula (b), wherein the water is added over 5.5 hours.
[0018] In one embodiment is the isolation method for the compound of formula (b), wherein the ratio of watersolvent (v:v) is about 12-17 vols water to about 4-6 vols DMI. In one embodiment, the ratio is about 12.7-16.2 vols water to about 4.62-5.88 vols DMI. In one embodiment, the preferred ratio of watersolvent (v:v) is about 14.5:5.5.
[0019] In one embodiment is the isolation method for the compound of formula (b), wherein the compound of formula (b) is isolated by filtration.
[0020] In one embodiment is the isolation method for the compound of formula (b), wherein the crystallized compound of formula (b) has improved filtration efficiency. In one embodiment, the crystallized compound of formula (b) filters at least 20 times faster. In one embodiment, the crystallized compound of formula (b) filters 40 times faster. In one embodiment, at 10 psi pressure, a comparable amount of slurry from the instant process filters in < 1 minute vs. about 35 minutes for the process of WO 2024 / 137426.
[0021] In one embodiment disclosed herein is a method for the isolation of tert-butyl (5)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro- lH-imidazol-l-yl)-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (c):wherein the method comprises crystallizing the compound of formula (c) from a reaction mixture product containing the compound of formula (c) in 2-methyltetrahydrofuran by the addition of n-heptane.
[0022] In one embodiment is the isolation method for the compound of formula (c), wherein the compound of formula (c) is recovered in >80% yield.
[0023] In one embodiment is the isolation method for the compound of formula (c), wherein the compound of formula (c) is recovered in at least 90% yield.
[0024] In one embodiment is the isolation method for the compound of formula (c), wherein the reaction mixture is heated to a temperature of at least 50 °C prior to the addition of n- heptane.
[0025] In one embodiment is the isolation method for the compound of formula (c), wherein the reaction mixture is heated to a temperature of 55 - 65 °C.
[0026] In one embodiment is the isolation method for the compound of formula (c), wherein the w-heptane is added over at least 7 hours.
[0027] In one embodiment is the isolation method for the compound of formula (c), wherein the / / -heptane is added over 7.5 hours.
[0028] In one embodiment is the isolation method for the compound of formula (c), wherein the final ratio of 2-methyltetrahydrofuran to / / -heptane is about 3-5 volumes to about 7-9 volumes. In one embodiment, the final ratio is about 4 volumes of 2-methyltetrahydrofuran to about 8 volumes of zt-heptane.
[0029] In one embodiment is the isolation method for the compound of formula (c), further comprising isolating the compound of formula (c) by filtration.
[0030] In one embodiment is the isolation method for the compound of formula (c), wherein the isolated compound of formula (c) is suitable for use in subsequent synthetic steps without recrystallization.
[0031] In one embodiment is the isolation method for the compound of formula (c), wherein the isolated compound of formula (c) is a free-flowing material and suitable for use in subsequent synthetic steps without milling.
[0032] In one embodiment disclosed herein is a method for the preparation of a reaction mixture product containing tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro- IH-imidazol- l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (c):from / -butyl (5)-3-amino-2-(4-fluoro-3.5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (a)wherein the method comprises contacting a first reaction mixture product containing r -butyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (b):with a suitable acid without first isolating the compound of formula (b).
[0033] In one embodiment is the method for the preparation of a reaction mixture product containing a compound of formula (c), wherein the first reaction mixture product comprises the compound of formula (b) in a suitable solvent.
[0034] In one embodiment is the method for the preparation of a reaction mixture product containing a compound of formula (c), wherein the first reaction mixture product solvent is 2-methyltetrahydrofuran.
[0035] In one embodiment is the method for the preparation of a reaction mixture product containing a compound of formula (c), wherein the acid is methanesulfonic acid.
[0036] In one embodiment is the method for the preparation of tert-butyl (5)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (c):from tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (a)wherein the method comprises contacting a first reaction mixture product containing tert-butyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (b):with a suitable acid without first isolating the compound of formula (b).
[0037] In one embodiment is a method for the preparation of a compound of formula (c), further comprising isolating the compound of formula (c) by the addition of -heptane.
[0038] In one embodiment is a process for the preparation of Intermediate (i):comprising:a) partitioning a reaction mixture product containing zc / 7-butyl (5)-3-(3-(4-fluoro-l-methyl-lH-indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (d):between 4: 1 ethyl acetate: methylcyclohexane (v:v) and aqueous ammonium chloride at a temperature > 40 °C; andb) washing the organic phase with aqueous acetic acid.
[0039] In one embodiment is a process for preparing a compound of formula (i). wherein the partitioning is performed at 40 - 50 °C.
[0040] In one embodiment is a process for preparing a compound of formula (i), wherein the aqueous acetic acid is 3% aqueous acetic acid.
[0041] In one embodiment is a process for preparing a compound of formula (i), wherein the compound of formula (d) remains in solution during partitioning of the reaction mixture.
[0042] In one embodiment is a process for preparing a compound of formula (i) comprising: a) partitioning a reaction mixture product containing the compound of formula (d) between 4: 1 ethyl acetate: methylcyclohexane (v:v) and aqueous ammonium chloride at a temperature > 40 °C; b) washing the organic phase with aqueous acetic acid; and c) performing a solvent exchange with acetonitrile.
[0043] In one embodiment is a process for preparing a compound of formula (i) comprising: a) partitioning a reaction mixture product containing the compound of formula (d) between 4: 1 ethyl acetate: methylcyclohexane (v:v) and aqueous ammonium chloride at a temperature > 40°C; b) washing the organic phase with aqueous acetic acid; c) performing a solvent exchange with acetonitrile to form a second solution containing the compound of formula (d); and d) reacting the acetonitrile solution with methanesulfonic acid.
[0044] In one embodiment is a process for preparing a compound of formula (i) comprising: a) partitioning a reaction mixture product containing the compound of formula (d) between 4: 1 ethyl acetate: methylcyclohexane (v:v) and aqueous ammonium chloride at a temperature > 40 °C; b) washing the organic phase with aqueous acetic acid; c) performing a solvent exchange with acetonitrile to form a second solution containing the compound of formula (d); d) reacting the acetonitrile solution with methanesulfonic acid to provide Intermediate (i); and e) isolating Intermediate (i).
[0045] In one embodiment is a process for the preparation of Intermediate (i):comprising the steps of:a) reacting a first reaction mixture product containing / -butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (c):with 5-bromo-4-fluoro-l -methyl- IH-indazole in the presence of a source of Cu(I) to provide a second reaction mixture product containing a compound of formula (d):b) reacting the second reaction mixture product with a suitable acid.
[0046] In one embodiment is a process for the preparation of Intermediate (i), wherein the first reaction mixture product comprises the compound of formula (c) in a suitable solvent.
[0047] In one embodiment is a process for the preparation of Intermediate (i), wherein the first reaction mixture solvent is selected from l-methyl-2-pyrrolidinone (NMP), N,N-dimethylacetamide (DMAc), and l,3-dimethyl-2-imidazolidinone (DMI).
[0048] In one embodiment is a process for the preparation of Intermediate (i), wherein the first reaction mixture solvent is DMI.
[0049] In one embodiment is a process for the preparation of Intermediate (i), wherein the source of Cu(I) is a Cu(I) halide.
[0050] In one embodiment is a process for the preparation of Intermediate (i), wherein the source of Cu(I) is Cu(I) chloride.
[0051] In one embodiment is a process for the preparation of Intermediate (i), wherein the first reaction mixture product is partitioned between 3:1 ethyl acetate: methylcyclohexane (v:v) and aqueous ammonium chloride at a temperature > 45 °C.
[0052] In one embodiment is a process for the preparation of Intermediate (i), wherein the first reaction mixture product solvent is exchanged for acetonitrile to provide a second reaction mixture product prior to reacting the compound of formula (d) with a suitable acid.
[0053] In one embodiment is a process for the preparation of Intermediate (i), wherein the second reaction mixture product is reacted with a suitable acid.
[0054] In one embodiment is a process for the preparation of Intermediate (i), wherein the second reaction mixture product is reacted with methanesulfonic acid.
[0055] In one embodiment is a process for the preparation of Intermediate (i), wherein Intermediate (i) is isolated.
[0056] In one embodiment is a multistep process for the preparation of Intermediate (i):beginning with / -butyl (5)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)- 4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (b):wherein the process comprises avoiding the isolation of terr-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (c):[00571 The skilled person will appreciate that the processes described herein may be combined as necessary or desired to provide Intermediate (i) or any one of compounds (b), (c), or (d). In one embodiment is a multistep process for preparing Intermediate (i), comprising the use of at least one of the processes described herein.In one embodiment is a multistep process for preparing Intermediate (i) comprising the steps of:a) providing a reaction mixture product containing the compound of formula (b) in a solvent, wherein the compound of formula (b) is optionally crystallized from said reaction mixture product by the slow addition of water at T > 30 °C to provide the isolated compound of formula (b);b) reacting either a reaction mixture product containing the compound of formula (b) or the isolated compound of formula (b) in a solvent with a suitable acid to provide a reaction mixture product containing the compound of formula (c) in a solvent, wherein the reaction mixture product containing the compound of formula (c) is prepared by extraction of the reaction mixture with 2-methyltetrahydrofuran;c) optionally crystallizing the compound of formula (c) from a reaction mixture product containing the compound of formula (c) in 2-methyltetrahydrofuran at T > 50 °C by the addition of n-heptane to provide the isolated compound of formula (c);d) reacting either the reaction mixture product containing the compound of formula (c) in a solvent or the isolated compound of formula (c) in a solvent with 5-bromo-4-fluoro-l-methy 1- 1 H- indazole in the presence of a source of Cu(I) to provide a reaction mixture product containing the compound of formula (d), wherein said reaction mixture product is prepared by partitioning the reaction mixture at T > 40 °C with 4: 1 ethyl acetate: methylcyclohexane (v:v) and aqueous ammonium chloride and the resultant organic phase washed with aqueous acetic acid;e) reacting the reaction mixture product containing the compound of formula (d) in a solvent with a suitable acid to provide a reaction mixture product containing Intermediate (i); and f) isolating Intermediate (i).
[0058] The term "reaction mixture product” means the compound specified as formed in any suitable synthetic step without isolation, including the entire reaction mixture after a synthetic step has been completed or terminated, an extract containing the reaction mixture product after partitioning the reaction mixture between an organic and aqueous phase, and a solution or suspension of the reaction mixture product prepared from the residue remaining after concentration of the reaction mixture or extract containing the reaction mixture product. The skilled person will appreciate that a synthetic step may be completed either by termination of the reaction upon consumption of one or more of the reactants or by addition of an agent to quench the synthetic step.
[0059] Unless otherwise defined in the specification, certain abbreviations are defined as follows:ACN acetonitrileAq or aq. aqueousDM Ac N,N-dimethylacetamideDMI 1 ,3-dimethyl-2-imidazolidinoneEtOAc ethyl acetateEtOH ethanolH hour(s)IP Ac isopropyl acetate2-MeTHF 2-methyltetrahydrofuranNMP l-methyl-2-pyrrolidinoneT temperatureTHF tetrahydrofuranTOF-MS time of flight mass spectrometervol or v volume(s)v / v volume / volume
[0060] Step A of Scheme 2 is the preparation of r -butyl (5)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (b) by the reaction of tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4.6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (a) with N-(2,2-dimethoxyethyl)-lH-imidazole-l -carboxamide as described in Scheme 3:Scheme 3
[0061] Conditions for this reaction are described in WO 2024 / 137426. After quenching this reaction by the addition of water and seeding with crystals of compound (b), the method of isolation of compound (b) disclosed herein comprises effecting crystallization of compound (b) from this quenched reaction mixture by the slow addition of additional water at an elevatedtemperature relative to the prior art method of isolation. The reaction mixture comprises compound (b) in a suitable solvent, such as l-methyl-2-pyrrolidinone, N,N-dimethylacetamide, or l,3-dimethyl-2-imidazolidinone. Prior to the addition of sufficient additional water to effect crystallization of compound (b), the quenched reaction mixture is heated to T > 30 °C. In one embodiment, the quenched reaction mixture is heated to T = 30 - 40 °C. In another embodiment, the quenched reaction mixture is heated to T = 35 °C.
[0062] After heating, additional water sufficient to effect crystallization of compound (b) is added over more than 2 hours with stirring while maintaining the temperature at 23-47 °C. In one embodiment the temperature is maintained at 30 - 40 °C. In one embodiment, the additional water is added over at least 5 hours. In one embodiment, the additional water is added over between 5 to 6 hours. In another embodiment, the additional water is added over 5.5 hours. In one embodiment, the amount of water that is added over 5.5 h to crystallize the product is 9 - 13 vols.
[0063] In one embodiment, the amount of water that is added over 5.5 h to crystallize the product is 9.6-12.4 vols at 23-47 °C.
[0064] After stirring, the suspension is cooled to 15-25 °C and compound (b) isolated, preferably by filtration. This method of isolation provides compound (b) in higher yield with improved filterability properties relative to known methods. In one embodiment, at 10 psi pressure, the slurry from the instant process filters in < 1 minute.
[0065] Step B of Scheme 2 is the preparation of tert-butyl (S)-2-(4-fhioro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5 -carboxylate (c) from tert-butyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (b) as illustrated in Scheme 4:Scheme 4
[0066] Conditions for this reaction are described in WO 2024 / 137426.
[0067] Here, after isolation of the reaction mixture product containing the compound of formula (c) by concentration of the organic extract under reduced pressure, it is partitioned between 2-methyltetrahydrofuran and an aqueous phase, preferably aqueous NaCl. In one embodiment, about 7-10 vols of 2-MeTHF is added back. In one embodiment, the aqueous phase is aqueous NaCl. In one embodiment, the aqueous phase is 13 wt% - 18 wt% of aqueous NaCl. In one embodiment, the aqueous phase is 13% aqueous NaCl. In one embodiment, the amount of residual water at the end of the concentration / dilution cycle(s) is less than 0.5% w / w as measured using Karl Fischer titration test.
[0068] The organic phase is heated to at least T = 50 °C, preferably between 55 - 65 °C and is then seeded with crystalline compound of formula (c). After 0.5 - 2.5 h, more preferably, 1.5 h, at this temperature, the mixture is cooled to T < 60 °C, preferably between 50 - 60 °C and then n-heptane is added slowly over at least 7 h, preferably over 7.5 h, maintaining the temperature between 50 - 60 °C. After 5 additional hours, the mixture is cooled to T < 5 °C, preferably between -5 - 3 °C over 3 h and stirred at this temperature for 3 h. The compound of formula (c) is then isolated, preferably by filtration. This method of isolation provides the compound of formula (c) in higher yield relative to known methods. It also provides a material suitable for use in subsequent synthetic steps without requiring a recrystallization step. The advantages of eliminating a product recrystallization step include greater efficiency due to higher overall yields, reduced cycle times, and additional economic advantages due to reduced solvent and waste disposal costs.
[0069] The preparation of Zrj / 7- butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (c) from (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (a) is described in WO 2024 / 137426 as a two-step procedure requiring the isolation of the intermediate / -butyl (5)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (b). Disclosed herein is an improved process for the preparation of the compound of formula (c) from the compound of formula (a) without isolation of compound (b) as illustrated in Scheme 5:Scheme 5UNISOLATED REACTION MIXTURE PRODUCT
[0070] In the instant process for the preparation of the compound of formula (c), amine (a) is reacted with (N-(2,2-dimethoxyethyl)-lH-imidazole-l-carboxamide (Step A) in a suitable solvent, such as l-methyl-2-pyrrolidinone, N,N-dimethylacetamide, or l,3-dimethyl-2-imidazolidinone, to provide a reaction mixture product containing the compound of formula (b) essentially as described in WO 2024 / 137426. A solvent exchange is then performed by methods well known to the skilled artisan to provide a reaction mixture product containing the compound of formula (b) as a suspension in a second solvent, such as 2-methyltetrahydrofuran. This suspension is then reacted with a suitable acid, such as methanesulfonic acid, to provide a reaction mixture product containing a compound of formula (c) and its deprotected form, (S)-2-(4-fluoro-3.5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6.7-tetrahydro-5H-pyrazolo[4,3-c]pyridine, of formula (c’):This reaction mixture product is then reacted with di- / e / 7-butyl dicarbonate to provide a reaction mixture product containing a compound of formula (c). The compound of formula (c) may then be isolated by the addition of / / -heptane as previously described. The process described herein provides the compound of formula (c) in higher yield from the compound of formula (a) (68%) relative to previous methods (62%). Further, the advantages of eliminating an isolation step include greater efficiency due to reduced cycle times, and additional economic advantages due to reduced solvent and waste disposal costs.
[0071] Steps C and D of Scheme 2 are the preparation of (S)-l-(4-fluoro-l-methyl-lH-indazol-5-yl)-3-(2-(4-tluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-l,3-dihydro-2H-imidazol-2-one (i) from fe -butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (c) as illustrated in Scheme 6:
[0072] Disclosed herein is a process for the preparation of (S)-l-(4-fluoro-l-methyl-lH-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-l,3-dihydro-2H-imidazol-2-one of formula (i), comprising partitioning a reaction mixture product containing tert-butyl (S)-3-(3-(4-fluoro-l-methyl-lH-indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (d) between 4:1 ethyl acetate: methylcyclohexane (v:v) and aqueous ammonium chloride at a temperature > 40 °C, preferably 40-50 °C and then washing the organic phase with aqueous acetic acid, preferably 3% acetic acid. The resulting reaction mixture product containing the compound of formula (d) may then be subjected to a solvent exchange by methods well known to the skilled artisan to provide a second solution containing the compound of formula (d) in a second solvent, such as acetonitrile. This second solution containing the compound of formula (d) may then be treated with a suitable acid,such as methanesulfonic acid, to provide the compound of formula (i). The skilled artisan will appreciate the operational efficiencies gained by avoiding the difficult processing associated with precipitation of product during extraction.
[0073] Steps B, C, and D of Scheme 2 represent a 3-step process for the preparation of Intermediate (i) from rert-butyl (5)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (b) whereby the intermediate z -butyl (5)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro- IH-imidazol- l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (c) is isolated prior to coupling with 5-bromo-4-fluoro- 1 -methyl- 1 / / -indazole in the presence of a source of Cu(I) to provide r -butyl (S)-3-(3-(4-fluoro-l-methyl-lH-indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (d) followed by an acid mediated deprotection. Disclosed herein is an improved process for the preparation of Intermediate (i) from the compound of formula (b) without isolation of compound (c) as illustrated in Scheme 7:
[0074] Either isolated / -butyl (S)-3-(3-(2.2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (b) or areaction mixture product containing the compound of formula (b) in a solvent, such as DMI, is reacted with a suitable acid, such as methanesulfonic acid, to provide a reaction mixture product containing fert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (c) essentially as described in WO 2024 / 137426. This reaction mixture product is then reacted with 5-bromo-4-fhioro-1 -methyl- I / / -indazole in the presence of a source of Cu(I), such as CuCl, to provide a reaction mixture product containing the compound of formula (d). A solvent exchange is performed by methods well known to the skilled artisan to provide a solution of the compound of formula (d) in acetonitrile. This solution is treated with a suitable acid, such as methanesulfonic acid, to provide Intermediate (i) which is isolated by standard techniques. The process described in WO 2024 / 137426 beginning from isolated compound of formula (b) provides Intermediate (i) in from 61-67%. The process disclosed herein eliminates the isolation of the compound of formula (c) and provides Intermediate (i) in 83.3%. Additionally, the instant process has the advantages of eliminating an isolation step include greater efficiency due to reduced cycle times, and additional economic advantages due to reduced solvent and waste disposal costs.Example 1Isolation of tert-butyl (5)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3.5-dimethylphenyl)-4- methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylatea) Preparationtert-Butyl (5)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (580.0 kg, 1.5489 kmol) in DMI (1160 L) was added to the solution of (N-(2,2-dimethoxyethyl)-lH-imidazole-l-carboxamide at 5-15 °C, rinsing in with DMI (435 L). The combined mixture was stirred at 5-15 °C for > 0.5 h. Solid potassium tert-butoxide (870 kg, 7.7533 kmol) was added in 8 portions over 8 h, maintaining 5-15 °C. The charging box was rinsed with DMI (145 L). The internal temperature was set to 10-20 °C, andthe mixture stirred for 6-12 h, resulting in > 98% conversion. The reaction mixture was quenched by the addition of water (1160 L) maintaining 10-20 °C.b) IsolationThe reaction mixture was transferred, rinsing the line with DMI (290 L). The contents were heated to 30-40 °C. Next, water (870 L) was added over 0.5 h. The mixture was seeded by the addition of z -butyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (5.8 kg). The mixture was stirred for 0.5 h. Water (6380 L) was added over 5.5 h while maintaining 30-40 °C. After an additional 1 h at 30-40°C, the slurry was cooled to 15-25 °C over 2 h. The slurry was stirred at 15 °C to 25 °C for 0.5 h before it was filtered. The resulting wet cake was washed with water (2 x 2900 L) and dried at 55-65 °C, to give the title compound as a solid (755.7 kg, 96.5%). m.p.202.79 °C - 206.06 °C; IR (cm1): 3270.1, 2977.3, 2937.6, 1682.2, 1667.0, 1563.0, 1498.9, 1429.0, 1412.0, 1392.8, 1362.4, 1334.8, 1267.1, 1258.0, 1242.0, 1203.8, 1175.7, 1161.1, 1140.6, 1120.4, 1078.0, 1063.5, 1051.9, 1039.0, 693.03270.1, 2977.3, 2937.6, 1682.2, 1667.0, 1563.0, 1498.9, 1429.0, 1412.0, 1392.8, 1362.4, 1334.8, 1267.1, 1258.0, 1242.0, 1203.8, 1175.7, 1161.1, 1140.6, 1120.4, 1078.0, 1063.5, 1051.9, 1039.0, 693.0; 'H NMR (DMSO-d6) 88.07 (s, 1H), 7.20 (d. J = 6.4 Hz, 2H), 6.41 (t, J = 5.8 Hz, 1H), 5.09 (d, J = 32.6 Hz, 1H). 4.33 (t, J = 5.3 Hz, 1H), 4.19 (d, J = 35.5 Hz, OH), 3.26 (s, 6H), 3.17 (s, 3H), 3.10 (Broad) 2.73 - 2.52 (m, 2H), 2.25 (d, J = 2.1 Hz, 6H), 1.44 (s, 9H), 1.21 (d, J = 6.2 Hz, 3H);13C NMR (DMSO-ck) 8 158.32 (d, J = 242.4 Hz), 155.68, 154.08, 146.29, 134.75 (d, J = 3.4 Hz), 132.63, 124.86 (d, J = 19.3 Hz), 124.59 (d, J = 5.1 Hz), 114.69, 102.84, 79.38, 53.69, 44.98 (Broad), 41.39, 36.97 (Broad), 28.57, 24.26, 18.86, 14.77 (d, J = 3.6 Hz);19F NMR (DMSO-d6) 8 -123.68. HRMS m / z. calculated: 506.2773; found: 506.3059 (M+H); Enantiomer 0.00%; Chiral purity: 100.00% by HPLC.Example 2Isolation of n?rz-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH- imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylatea) Preparation of Reaction Mixture ProductA vessel was charged with THF (7050 L) and tert-butyl (5)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (705 kg, 1.3944 kmol). Methanesulfonic acid (147.5 kg, 1.5349 mol) was added into the mixture at 15-45 °C. The mixture, with 0.14-0.26% water content as determined by Karl Fischer titration, was heated to 40-50 °C and stirred for 10 h where HPLC showed a mixture of the title compound and the deprotected title compound. The reaction mixture was cooled to 0-10 °C, quenched with aqueous K3PO4 (296.0 kg, dissolved in 2820 L water) while maintaining 0-10 °C, then warmed to 15-25 °C, and assayed the organic phase. Di-terf-butyl dicarbonate (137.9 kg, 0.6319 kmol, based on the amount of deprotected intermediate according to HPLC result) was added at 15-25 °C then stirred for > 11 h until the area% of the deprotected title compound dropped to < 1.0 area%. The aqueous phase was separated, and the organic phase was concentrated in vacuo to 2470 L.b) Isolation2-MeTHF (5993 L) and 13% aqueous NaCl (2225 L) were added to the organic phase. The organic phase was separated and concentrated in vacuo to 3875 L. Next, 3878 L 2-MeTHF was added and concentrated in vacuo to 3875 L. Again 3878 L 2-MeTHF was added and concentrated in vacuo to 3525 L. The mixture was heated to 55-65 °C, seeded with the title compound (7.1 kg) and held at this temperature for 1.5 h, cooled to 50-60 °C and ^-heptane (5640 L) was added over 7.5 h and maintained at 50-60 °C another 5 h. Then, the mixture was cooled to -5-3 °C over 3 h, stirred for 5 h, filtered, then the resulting wet cake was washed with cold (-5 °C to 3 °C) 2-MeTHF / w-heptane (810.5 L / 1304 L). The resulting material was dried at 50-60 °C to give the title compound (554 kg, 90.0%). m.p. 209.51 °C - 210.49 °C; IR (cm1): 3192.8, 3106.3, 2981.8, 1696.6, 1657.2, 1601.3, 1500.4, 1491.8. 1478.2, 1398.3. 1362.8, 1319.3.1265.4, 1255.1, 1217.7, 1206.2, 1153.2, 1112.3, 1059.7, 879.1, 780.7, 774.0; ‘H NMR (-d6) 810.35 (s, 1H), 7.09 (d, J = 6.3 Hz, 2H), 6.60 (t, J = 2.7 Hz, 1H), 6.56 (t, J = 2.5 Hz, 1H), 5.06 (s, 1H), 4.22 (s, 1H), 3.11 (s, 1H), 2.85 - 2.55 (m, 2H), 2.20 (d, J = 2.1 Hz, 6H), 1.44 (s, 9H), 1.14 (d, J = 6.9 Hz, 3H).13C NMR (DMSO-d6) 8 158.55 (d, J = 243.2 Hz), 154.00, 153.18, 146.91, 134.13 (d, J = 3.4 Hz), 130.27, 125.17 (d, J = 19.2 Hz). 124.27 (d, J = 5.3 Hz), 116.63, 112.84, 111.31, 79.68, 44.50 (Broad), 37.40 (Broad), 28.53, 24.15, 19.21, 14.79 (d, J = 3.5 Hz);19F NMR (DMSO-de) 8 -122.61; HRMS m / z calculated: 442.2249; found: 442.2351 (M+H);Enantiomer 0.00%; Chiral purity: 100.00% by HPLC.Example 3tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-iH-imidazol-l- yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (c)
[0075] fert-Butyl (5)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (10.036 g, 25.051 mmol) in DMI (29.9 mL) was added to the solution of (N-(2,2-dimethoxyethyl)-lH-imidazole-l-carboxamide at 5-10 °C, rinsing in with DMI (11.8 mL). Solid potassium / ert-butoxide (15.385 g, 135.74 mmol) was added while maintaining 0-10 °C. The internal temperature was set to 5-10 °C, and the mixture stirred for 19 h, resulting in > 99% conversion. The reaction mixture was quenched by the addition of water (15.1 mL) over 1 h. Next, 2-MeTHF (250 mL) and saturated aqueous NaCl solution (20 mL) were added, and the mixture heated to 50 °C. The phases were separated. The organic phase at 50 °C was washed with a mixture of water (40 mL) and saturated aqueous NaCl solution (20 mL), followed by a mixture of water (50 mL) and saturated aqueous NaCl solution (20 mL). The organic phase was cooled to 20-30 °C and washed with a mixture of 0.5 N aq HC1 (50 mL) and saturated aqueous NaCl solution (20 mL). The organic phase was distilled in vacuo to 73 mL, before 2-MeTHF (100 mL) was added back. The mixture was distilled in vacuo to 90 mL,resulting in a slurry. Additional 2-MeTHF (100 mL) was added, and the mixture concentrated to 83 mL, resulting in a thick slurry. Additional 2-MeTHF (48 mL) was added back.
[0076] Methane sulfonic acid (2.502 g, 26.04 mmol) was added to this slurry at 15-25 °C. The resulting solution was heated to 40-50 °C and stirred for 15 h where HPLC showed a mixture of the title compound and the deprotected title compound. The reaction mixture was cooled to 0-10 °C, quenched with aqueous K3PO4 (5.263 g, dissolved in 48.869 mL water) while maintaining 0-20 °C, then warmed to 15-25 °C, and assayed the organic phase. Di-r -butyl dicarbonate (3.206 g, 14.69 mol, based on the amount of deprotected intermediate according to HPLC result) was added at 15-25 °C then stirred for > 2 h until the area% of the deprotected title compound dropped to < 1.0 area%. The aqueous phase was separated. Saturated aqueous NaCl solution (50 mL) was added, and the organic phase was separated and concentrated in vacuo to 57 mL. 2-MeTHF (100 mL) was added and concentrated in vacuo to 43 mL. Again 2-MeTHF (100 mL) was added and concentrated in vacuo to 63 mL. This reaction mixture product was seeded with the title compound (96 mg) at 20-25 °C, and 77-heptane (154 mL) was added over 3 h and maintained at 20-25 °C another 12 h. The mixture was filtered, and the resulting wet cake was washed with 2-MeTHF / / ?- heptane (5 mL / 15 mL). The resulting material was dried at 40-50 °C to give the title compound (8.06 g, 67.9% yield from rert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate). m.p.171.46 °C - 176.86 °C; IR (cm1): 2970.6, 1687.4, 1603.8, 1494.6, 1476.8, 1463.8, 1410.7, 1382.0, 1365.4, 1328.2, 1321.9, 1294.5, 1244.3, 1208.3, 1183.0, 1158.7, 1114.1, 1054.6;JH NMR (DMSO-d6) 5 10.35 (t, J = 2.3 Hz, 1H), 7.09 (d, J = 6.3 Hz, 2H), 6.60 (t, J = 2.7 Hz, 1H), 6.56 (t, J = 2.6 Hz, 1H), 5.09 - 5.04 (m, 1H), 4.24 - 4.19 (m, 1H), 3.13 - 3.08 (m, 1H), 2.76 - 2.56 (m, 2H), 2.20 (d, J = 2.1 Hz. 6H), 1.44 (s, 9H), 1.14 (d, J = 6.7 Hz. 3H);13C NMR (DMSO-d6) 8 158.55 (d, J = 243.1 Hz), 154.00, 153.18, 146.92, 134.13 (d, J = 3.3 Hz), 130.27, 125.17 (d, J = 19.4 Hz), 124.27 (d, J = 5.1 Hz), 112.84, 111.31, 79.68, 44.48 (Broad), 37.89 (Broad), 28.54, 24.15, 19.20. 14.79 (d, J = 3.6 Hz);19F NMR (DMSO-d6) 8 -122.61; HRMS m / z calculated: 442.2249; found: 442.2354 (M+H). Enantiomer 0.00%; Chiral purity: 100.00% by HPLC.Example 4(S)-l-(4-Fhioro-l-methyl-lH-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl- 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-l,3-dihydro-2H-imidazol-2-one (i)a) CouplingA vessel was charged with l,3-dimethyl-2-imidazolidinone (DMI, 122 L), tert-butyl (5)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (41.4 kg, 93.76 mol), 5-bromo-4-fluoro-l-methyl-l / / -indazole (25.3 kg, 110.46 mol), and powdered potassium carbonate (19.5 kg, 141.10 mmol). Next, copper (I) chloride (1.85 kg, 18.69 mol) and 50 wt% trans-N T-dimethylcyclohexane-l,2-diamine (12.00 kg, 42.18 mol) in DMI were added. The materials were rinsed in with DMI (58 L). The reactor was degassed with a series of vacuum and N2 purge cycles until the % O2 was acceptable. The mixture was heated to 100 °C over 3 h and held for 15 h. The reaction mixture was cooled to 40-60 °C. Assay showed completion of the reaction.b) Partitioning of Reaction Mixture ProductThe mixture was transferred to another reactor, rinsing with DMI (10 L). To the mixture was added EtOAc (251 L), methylcyclohexane (86 L), and 12.1% aqueous ammonium chloride (258.2 kg). The temperature was adjusted to 40-50 °C. The mixture was stirred and allowed to settle, and the aqueous phase was separated from organic phase. The organic phase was washed at 40-50 °C with another portion of 12.1% aqueous ammonium chloride (257 kg) and 3% aqueous acetic acid (166 kg) sequentially. The mixture was washed at 40-50°C with 5% aq sodium bicarbonate (250 kg) and water (170 kg) sequentially.c) Solvent ExchangeThe final organic phase was vacuum distilled at jacket temperature of <58 °C down to 125 L. ACN (213 L) was added, and the mixture was again vacuum distilled down to 125 L. ACN (212 L) was added, and the mixture was again vacuum distilled down to 125 L. ACN (295 L) was added, and the mixture was assayed, showing acceptable levels of water and ethyl acetate.d) Acid Mediated DeprotectionTo a vessel containing the ACN solution of tert-butyl (S)-3-(3-(4-fluoro-l-methyl-lH-indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate was added methanesulfonic acid (17.05 kg, 177.4 mol) while maintaining 20-30 °C. The charging device, pump, and spray ball were rinsed with ACN (31 L) and added to the reactor. The reaction mixture was heated to 50-60 °C and was held at 50-60 °C for 1-3 h. After which, assay by HPLC showed complete consumption of the intermediate fert-butyl (S)-3-(3-(4-fhioro-l-methyl-lH-indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2.4.6.7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate. Cooled to 17-27 °C, the contents were transferred to another reactor by rinsing with ACN (23 L). Added IN aqueous sodium hydroxide (133.0 kg, 126.58 mol) over 1-4.5 h at 17-27 °C. Added seeds (0.50 kg, 1 wt%), resulting in the seeds persisting. The slurry was stirred for 0.5-2.0 h. Added 1% aqueous sodium hydroxide (282 kg, 70.32 mol) over 1-4 h to the slurry at 17-27 °C. The slurry was stirred for 16-24 h and filtered in 2 drops. Each wet cake was rinsed with 1:1 ACN / water (52 kg) and water (105 kg) sequentially. The combined wet cake (57.35 kg) was conditioned under vacuum and further dried at 60-70 °C in vacuo with N2 purge, to give the title compound as a solid (38.53 kg, 83.2%). m.p. 240.75 °C - 241.46 °C; FTIR (cm’1): 3278.1, 1705.7, 1528.2, 1493.3, 1465.9, 1430.2, 1257.1, 1214.7, 1126.5, 798.2, 668.3;1H NMR (DMSO-d6) 58.30 (d, J = 0.9 Hz, 1H), 7.62 (dd, J = 8.9, 1.0 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.14 (d, J = 6.3 Hz, 2H), 7.02 (d, J = 3.1 Hz, 1H), 6.85 (s, 1H), 4.11 (s, 3H), 3.89 (q, J = 6.5 Hz, 1H), 3.24 - 3.13 (m, 1H), 2.91 - 2.76 (m, 1H), 2.73 - 2.55 (m, 2H), 2.32 (s, 1H), 2.24 (d, J = 2.1 Hz, 6H), 1.14 (d, J = 6.6 Hz, 3H);nC NMR (DMSO-d6) 5 158.38 (d, J = 242.8 Hz), 151.56, 149.51 (d, J = 256.5 Hz), 148.34, 141.76 (d, J = 9.2 Hz), 134.35, 129.71, 129.17, 126.73, 125.23 (d, J = 19.5 Hz), 123.84, 119.23, 115.20, 114.98 (d, J = 10.2 Hz), 114.00 (d, J = 21.1 Hz), 113.69, 107.20 (d, J = 4.4 Hz). 46.87, 42.50, 36.34, 24.93, 20.25. 14.78 (d, J = 3.5 Hz);19F NMR (DMSO) 8 -123.12, -126.62 (d, J = 7.0 Hz); HRMS m / z calculated: 490.2161; found: 490.2366 (M+H); Chiral purity (by HPLC) 100.00%.Example 5Alternate Synthesis of (5)-l-(4-Fluoro-l-methyl-lH-indazol-5-yl)-3-(2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-l,3-dihydro-2H- imidazol-2-onea) / crt-Buty I (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro- 1H- imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate
[0077] A vessel was charged with THF (504 mL) and te -butyl (5)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (50.03 g, 97.96 mmol). Methanesulfonic acid (10.39 g, 108.1 mmol) was added into the mixture at 15-45 °C. The mixture was heated to 40-50 °C and stirred for 8 h where HPLC showed a mixture of the title compound and the deprotected title compound. The reaction mixture was cooled to 0-10 °C, quenched with aqueous K3PO4 (21.52 g, dissolved in 200.4 mL water) while maintaining 0-10 °C, then warmed to 15-25 °C, and assayed the organic phase. Di-fert-butyl dicarbonate (9.31 g, 42.64 mmol, based on the amount of deprotected intermediate according to HPLC result) was added at 15-25 °C then stirred for 5 h until the area% of the deprotected title compound dropped to < 1.0 area%. The aqueous phase was separated, and the organic phase was concentrated in vacuo to 150 mL. Added 2-MeTHF (432 mL) and 13.1% aqueous NaCl (158 mL). Separated the organic phase and concentrated in vacuo to 268 mL. Added 275 mL 2-MeTHF was added and concentrated in vacuo to 272 mL. Again 275 mL 2-MeTHF was added and concentrated in vacuo to 198 mL. DMI (152 mL) wasadded, and the mixture atmospherically distilled until the distillate slowed, resulting in a concentrate that contained 6.3 wt% 2-MeTHF. This concentrate was used as is in the next step.b) fe -Butyl (5)-3-(3-(4-fluoro-l-methyl-lH-indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol- l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridine-5-carboxylate
[0078] The / e / v-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (5.034 g, 11.40 mmol) in DMI from the previous step was combined with 5-bromo-4-fluoro- 1 -methyl- \H-indazole (26.18 g, 114.28 mmol), and powdered potassium carbonate (20.61 g, 149.11 mmol). The vessel was fitted with a mechanical stirrer, heating mantle, and thermocouple, and N2 inlet. The mixture was vigorously bubbled with N2 for 0.5 h, before rraw.v- A’-dimethylcyclohexane-1,2-diamine (6.43 g, 43.62 mmol) was added. The mixture was bubbled with N2 for another 0.3 h before copper (I) chloride (1.949 g. 19.69 mmol) was added, rinsing in with DMI (13.5 mL). The mixture was bubbled with N2 for 0.5 h and then heated to 100 °C and held for 15 h. After this time, the mixture was cooled to < 50 °C and assayed, showing completion of the reaction. To the mixture was added EtOAc (250 mL), methylcyclohexane (80 mL), and 12% aqueous ammonium chloride (250 mL). The mixture was stirred, heated to > 45 °C and allowed to settle, and the aqueous phase was separated from organic phase. The organic phase was washed with another portion of 12% aqueous ammonium chloride (250 mL) and 3 wt% aqueous acetic acid (165 mL) sequentially at > 45 °C. The organic phase was then washed with 5% aqueous sodium bicarbonate (250 mL) and water (165 mL) sequentially at > 45 °C. The final organic phase was vacuum distilled at 40 °C down to 126 mL. ACN (205 mL) was added, and the mixture was vacuum distilled down to 144 mL. ACN (205 mL) was added, and the mixture was vacuum distilled down to 155 mL. ACN (330 mL) was added, and the mixture was vacuum distilleddown to 124 mL. After the distillations, ACN (318 mL) was added to the resulting mixture. This solution was used as is in the subsequent reaction.c) DeprotectionThe vessel containing the ACN solution of rert-butyl (5)-3-(3-(4-fluoro-l-methyl-lH-indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate from the previous step was fitted with a mechanical stirrer, heating mantle, thermocouple, and N2 inlet. Methanesulfonic acid (17.76 g, 184.8 mmol) was added at 21 °C. After the addition, the reaction mixture was heated at 30 °C / h from 21 °C to 55 °C and was held at 55 °C for another 2 h. After which, assay by HPLC showed complete consumption of the intermediate te -butyl (S)-3-(3-(4-fluoro-l-methyl-l / / -indazol-5-yl)-2-oxo-2,3-dihydro- IH-imidazol- l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate. Cooled to 24 °C, then added IN aqueous sodium hydroxide (128.28 g, 130.9 mmol) over 1 h. Next, seeds of the title compound (454 mg, 1 wt%) were added, resulting in the seeds persisting. In a separate container, IN aqueous sodium hydroxide (72.25 g, 73.71 mmol) was combined with water (205.5 g) and added to the slurry at 21 °C over 2 h. The slurry was stirred for 20 h and filtered. The wet cake was rinsed with 1:1 ACN / water (90 mL) and water (225 mL) sequentially. The wet cake was dried under vacuum at 55 °C in vacuo with N2 purge for 16 h, to give the title compound (i) as a solid (40.62 g, 83.3%). m.p. 240.64 °C - 241.24 °C; FTIR (cm-1): 3278.0, 2960.3, 2941.1, 2923.8, 1705.8, 1598.2, 1528.2, 1493.5, 1466.0, 1430.1, 1394.4, 1369.7, 1357.7, 1257.0, 1238.7, 1214.8, 1189.3, 1126.5, 1105.5, 798.4, 774.5, 668.8;NMR (DMSO-d6) 5 8.30 (d, J = 0.9 Hz, 1H). 7.62 (dd, J = 8.9, 1.0 Hz. 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.14 (d, J = 6.3 Hz, 2H), 7.02 (d, J = 3.1 Hz, 1H), 6.85 (s, 1H), 4.11 (s, 3H), 3.89 (q, J = 6.5 Hz, 1H), 3.26 - 3.13 (m, 1H), 2.84 (m, 1H), 2.74 - 2.55 (m, 2H), 2.31 (s, 1H), 2.24 (d, J = 2.1 Hz, 6H), 1.14 (d, J = 6.5 Hz, 3H);13C NMR (DMSO-de) 8 158.38 (d. J = 242.8 Hz). 151.56, 149.51 (d, J = 256.4 Hz), 148.35, 141.76 (d, J = 9.2 Hz), 134.34, 129.71, 129.17, 126.73, 125.23 (d, J = 19.4 Hz), 123.83, 119.23, 115.20, 114.98 (d, J = 10.3 Hz), 114.00 (d, J = 21.1 Hz). 113.68, 107.20 (d, J = 4.4 Hz), 46.87, 42.50. 36.34, 24.93, 20.25, 14.78 (d, J = 3.5 Hz);19F NMR (DMSO-d6) 5 -123.12, -126.62 (d, J = 7.1 Hz); HRMS m / z calculated: 490.2161; found: 490.2400 (M+H); Chiral purity (by HPLC): 99.99%.
Claims
WE CLAIM:
1. A method for the isolation of terf-butyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3.5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (b):wherein the method comprises effecting crystallization of formula (b) from a reaction mixture containing compound of formula (b) in a solvent by the slow addition of water sufficient to effect crystallization at T > 30 °C.
2. The method of claim 1, wherein the compound of formula (b) is recovered in 90% yield.
3. The method of claim 1, wherein the compound of formula (b) is recovered in 95% yield.
4. The method of any one of claims 1 to 3, wherein the solvent is l-methyl-2-pyrrolidinone (NMP), N-butylpyrrolidinone (NBP). N,N-dimethylacetamide (DMAc), or 1,3-dimethyl-2-imidazolidinone (DMI).
5. The method of claim 4, wherein the solvent is l,3-dimethyl-2-imidazolidinone.
6. The method of any one of claims 1 to 5, wherein the reaction mixture solution is heated to T > 30 °C prior to the addition of water sufficient to effect crystallization.
7. The method of claim 6, wherein the reaction mixture solution is heated to T = 308. The method of claim 7, wherein the reaction mixture solution is heated to T = 35 °C.
9. The method of any one of claims 1 to 8. wherein the additional water sufficient to effect crystallization is added over more than 2 hours.
10. The method of claim 9, wherein the additional water sufficient to effect crystallization is added over at least 5 hours.
11. The method of claim 10, wherein the additional water sufficient to effect crystallization is added over between 5 to 6 hours.
12. The method of claim 11, wherein additional water sufficient to effect crystallization is added over 5.5 hours.
13. The method of any one of claims 1 to 13, wherein the temperature is maintained at T = 30 - 40 °C during the addition of the water sufficient to effect crystallization.
14. The method of any one of claims 1 to 13, wherein the compound of formula (b) is isolated by filtration.
15. The method of any one of claims 1 to 14, wherein the crystallized compound of formula (b) has improved filtration efficiency.
16. A method for the isolation of / ^ / 7-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro- IH-imidazol- l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (c):wherein the method comprises crystallizing the compound of formula (c) from a reaction mixture product containing the compound of formula (c) in 2-methyltetrahydrofuran by the addition of n-heptane.
17. The method of claim 16, wherein the compound of formula (c) is recovered in >80% yield.
18. The method of claim 17, wherein the compound of formula (c) is recovered in at least 90% yield.
19. The method of any one of claims 16 - 18, wherein the reaction mixture is heated to a temperature of at least 50 °C prior to the addition of / 7-heptane.
20. The method of claim 19, wherein the reaction mixture is heated to a temperature of 55 - 65 °C.
21. The method of any one of claims 16 -20, wherein the n-heptane is added over at least 7 hours.
22. The method of claim 21, wherein the n-heptane is added over 7.5 hours.
23. The method of any one of claims 16 - 22, wherein the final ratio of 2-methyltetrahydrofuran to / / -heptane is 3.1-4.9 volumes to 6.5-8.5 volumes.
24. The method of any one of claims 16 - 23, further comprising isolating the compound of formula (c) by filtration.
25. The method of any one of claims 16 - 24, wherein the isolated compound of formula (c) is suitable for use in subsequent synthetic steps without recrystallization.
26. The method of any one of claims 16 - 25, wherein the isolated compound of formula (c) is suitable for use in subsequent synthetic steps without milling.
27. The method of any one of claims 16 - 26, wherein the reaction mixture product containing the compound of formula (c) is prepared by contacting a reaction mixture product containing fert-butyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (b):in 2-methyltetrahydrofuran with a suitable acid.
28. A method for the preparation of tert-butyl (S)-2-(4-fluoro-3.5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro- IH-imidazol- l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine- 5-carboxylate of formula (c):from tert-butyl (S)-3-amino-2-(4-fluoro-3, 5-dimethylphenyl)-4-methyl-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (a)wherein the method comprises contacting a first reaction mixture product containing tertbutyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (b):with a suitable acid without first isolating the compound of formula (b).
29. The method of claim 28, wherein the first reaction mixture product comprises a suspension of the compound of formula (b) in 2-methyltetrahydrofuran.
30. The method of any one of claims 28 - 29, wherein the suitable acid is methanesulfonic acid.
31. The method of any one of claims 28 - 30, further comprising isolating the compound of formula (c) by the addition of n-heptane.
32. A process for the preparation of (S)-l-(4-fhioro-l-methyl-lH-indazol-5-yl)-3-(2- (4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-l,3-dihydro-2H-imidazol-2-one of formula (i):comprising:a) partitioning a reaction mixture product containing tert-butyl (S)-3-(3-(4-fluoro-l-methyl-lH-indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (d):between 4: 1 ethyl acetate: methylcyclohexane (v:v) and aqueous ammonium chloride at a temperature > 40°C; andb) washing the organic phase with aqueous acetic acid.
33. The process of claim 32, wherein the partitioning is performed at 40 - 50 °C.
34. The process of any one of claims 32 - 33, wherein the aqueous acetic acid is 3% aqueous acetic acid.
35. The process of any one of claims 32 to 34, wherein the compound of formula (d) remains in solution during partitioning of the reaction mixture.
36. The process of claim 35, further comprising performing a solvent exchange with acetonitrile.
37. The process of claim 36, further comprising reacting the acetonitrile solution with methanesulfonic acid to provide a compound of formula (i).
38. The process of claim 37, further comprising isolating the compound of formula (i).
39. A process for the preparation of (S)-l-(4-fhioro-l-methyl-lH-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-l,3-dihydro-2H-imidazol-2-one of formula (i):comprising the steps of:a) reacting a first reaction mixture product containing fert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (c):with 5-bromo-4-fluoro-l -methyl- IH-indazole in the presence of a source of Cu(I) to provide a second reaction mixture product containing a compound of formula (d):b) reacting the second reaction mixture product with a suitable acid.
40. The process of claim 39, where the first reaction mixture product comprises the compound of formula (c) in a suitable solvent.
41. The process of claim 40, where the solvent is selected from l-methyl-2-pyrrolidinone (NMP), N,N-dimethylacetamide (DMAc), and l,3-dimethyl-2-imidazolidinone (DMI).
42. The process of claim 41, where the solvent is DMI.
43. The process of any one of claims 39 to 42, where the source of Cu (I) is a Cu (I) halide.
44. The process of claim 43, where the source of Cu (I) is Cu (I) chloride.
45. The process of any one of claims 39 to 44, where the second reaction mixture product is partitioned between 3:1 ethyl acetate: methylcyclohexane (v:v) and aqueous ammonium chloride at a temperature > 45 °C.
46. The process of any one of claims 39 to 45, where the first reaction mixture product solvent is exchanged for acetonitrile prior to reacting the compound of formula (d) with a suitable acid.
47. The process of claim 46, where the acid is methanesulfonic acid.
48. The process of any one of claims 39 to 47, further comprising isolating the compound of formula (i).
49. A multistep process for the preparation of (S)- l-(4-fluoro- 1-methyl- lH-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin- 3-yl)-1.3-dihydro-2H-imidazol-2-one of formula (i):beginning with tert-butyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (b):wherein the process comprises avoiding the isolation of tert-butyl (5)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazoTl-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate of formula (c):
50. The process of any of the proceeding claims, wherein the process is used in the manufacture of Intermediate (i), having the following structure:
51. A multistep process for preparing Intermediate (i) comprising the steps of: a) providing a reaction mixture product containing the compound of formula (b) in a solvent, wherein the compound of formula (b) is optionally crystallized from said reactionmixture product by the slow addition of water at T > 30 °C to provide the isolated compound of formula (b);b) reacting either a reaction mixture product containing the compound of formula (b) or the isolated compound of formula (b) in a solvent with a suitable acid to provide a reaction mixture product containing the compound of formula (c) in a solvent, wherein the reaction mixture product containing the compound of formula (c) is prepared by extraction of the reaction mixture with 2-methyltetrahydrofuran;c) optionally crystallizing the compound of formula (c) from a reaction mixture product containing the compound of formula (c) in 2-methyltetrahydrofuran at T > 50°C by the addition of / / -heptane to provide the isolated compound of formula (c);d) reacting either the reaction mixture product containing the compound of formula (c) in a solvent or the isolated compound of formula (c) in a solvent with 5-bromo-4-fluoro-l-methy 1- 1 H- indazole in the presence of a source of Cu(I) to provide a reaction mixture product containing the compound of formula (d), wherein said reaction mixture product is prepared by partitioning the reaction mixture at T > 40 °C with 4: 1 ethyl acetate: methylcyclohexane (v:v) and aqueous ammonium chloride and the resultant organic phase washed with aqueous acetic acid;e) reacting the reaction mixture product containing the compound of formula (d) in a solvent with a suitable acid to provide a reaction mixture product containing Intermediate (i); andf) isolating Intermediate (i).