Process for the preparation of a GLP-1 receptor agonist

Abstract

Disclosed herein is a process for the preparation of a GLP-1 receptor agonist, the hemi-calcium salt of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (herein "GLP1RA ½ Ca2+") of Formula I.

Description

PROCESS FOR THE PREPARATION OF A GLP-1 RECEPTOR AGONISTTECHNICAL FIELD

[0001] Disclosed herein is a process for the preparation of a GLP-1 receptor agonist, the hemi-calcium salt of 3-[(LS',2 )-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S’)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fhioro-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 U2 Ca2+”).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. A useful salt of GLP1RA is the hemi-calcium salt, GLP1RA V2 Ca2+. with the structure as shown below:

[0003] GLP1RA was described and claimed in US 10,858,356. A process for the preparation of GLP1RA V2 Ca2+from isolated GLP1RA is described and claimed in WO 2024 / 137426.Alternative or improved method of preparing GLP1RA Vi Ca2+is needed.DESCRIPTION

[0004] Disclosed herein is a process for the synthesis of GLP1RA U2 Ca2+without first isolating GLP1RA. In one embodiment, the GLP1RA U2 Ca2+formed is a hydrate of GLP1RA U2 Ca2+.

[0005] In one embodiment, disclosed herein is a process for preparing the hemi-calcium salt of 3-[(l ,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fhioro-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- 1 -yl] -2-methylcy clopropy 1] -4H- 1 ,2,4-oxadiazol-5-one (GLP 1 RA 16 Ca2+) of Formula I:comprising contacting a reaction mixture product containing 3-[(lS.2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(45)-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 (GLP1RA) with a source of Ca2+in the presence of a suitable base.

[0006] In one embodiment, disclosed herein is a process for preparing a hemi-calcium salt of 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(45')-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 (GLP1RA 16 Ca2+) of Formula I:from 3-[(lS,2S)-l-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fhioro-3,5-dimethylphenyl)-3-[3-(4-fhioro-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 (GLP1RA), wherein the improvement comprises contacting a reaction mixture product containing GLP1RA with a source of Ca+2in the presence of a suitable base without first isolating GLP1RA.

[0007] In one embodiment, the reaction mixture product comprises GLP1RA in a first solvent.

[0008] In one embodiment, the first reaction mixture product solvent is tetrahydrofuran (THF), l,3-dimethyl-2-imidazolidinone (DMI), or dimethylacetamide (DMAc).

[0009] In one embodiment, there is a solvent exchange from the first reaction mixture product solvent to a second solvent prior to contacting the reaction mixture product with a source of Ca+2.

[0010] In one embodiment, the second reaction mixture product solvent is selected from methanol, aqueous ethanol, isopropanol, tetrahydrofuran, acetonitrile, dimethylformamide, ethyl acetate, toluene, dichloromethane, dimethyl sulfoxide, tert-butyl methyl ether, dimethyl acetamide, and 1,4-dioxane.

[0011] In one embodiment, the second reaction mixture product solvent is aqueous ethanol.

[0012] In one embodiment, the suitable base is selected from a metal hydroxide, a metal alkoxide, a metal carbonate, and a metal amide. In one embodiment, the suitable base is selected from sodium ethoxide, sodium tert-butoxide, potassium hydroxide, lithium hydroxide, sodium hydroxide, potassium ethoxide, potassium tert-butoxide, sodium / e / 7-amylate, sodium hydride, and sodium bis(trimethylsilyl)amide.

[0013] In one embodiment, the suitable base is a metal hydroxide.

[0014] In one embodiment, the metal hydroxide is selected from the group consisting of lithium hydroxide, potassium hydroxide, and sodium hydroxide.

[0015] In one embodiment, the base is sodium hydroxide.

[0016] In one embodiment, the source of Ca2+is a water-soluble calcium salt.

[0017] In one embodiment, the source of Ca2+is a calcium salt selected from calcium acetate, calcium acetate hemihydrate, calcium acetate monohydrate, calcium acetate dihydrate, calcium citrate, calcium lactate, calcium gluconate, calcium chloride, calcium sulfate, calcium nitrate, calcium iodide, and tricalcium phosphate.

[0018] In one embodiment, the source of Ca2+is selected from calcium acetate, calcium acetate hemihydrate, calcium acetate monohydrate, and calcium acetate dihydrate.

[0019] In one embodiment, the source of Ca2+is calcium acetate.

[0020] In one embodiment, the source of Ca2+is calcium acetate monohydrate.

[0021] In one embodiment, Ca2+is calcium acetate dihydrate.

[0022] In one embodiment, the base is sodium hydroxide, the second reaction mixture product solvent is aqueous ethanol, and the source of Ca2+is calcium acetate.

[0023] Unless otherwise defined in the specification, certain abbreviations are defined as follows:Ca2+calcium ionCOMU l-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morphoIino- carbenium hexafluorophosphateDIPEA N,N-diisopropylethylamineDMAc dimethylacetamideDMI 1 ,3-dimethyl-2-imidazolidinoneESI electrospray ionizationEtOAc ethyl acetateEtOH ethanolh hour(s)min minute(s)N2 nitrogen gasNMR nuclear magnetic resonanceHATU l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium-3- oxide hexafluorophosphateTHF tetrahydrofuranTOF-MS time of flight mass spectrometerWt or wt weight

[0024] Disclosed herein is a process for the preparation of GLP1RAl / i Ca2+of Formula I comprising reacting a reaction mixture product containing GLP1RA with a source of Ca2+in the presence of a suitable base as illustrated in Scheme 1:Scheme 1

[0025] The compound of Formula I may be referred to as either 3-((lS.2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((1S')-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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-lH-indol-l-yl)-2-methylcyclopropyl)-5-oxo-l,2,4-oxadiazol-4-ide hemi-calcium or hemi-calcium salt 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. Each name refers to the compound of Formula I and is encompassed by the term “GLP1RA Vi Ca2+”.

[0026] The term "reaction mixture product” means GLP1RA as formed in any suitable synthetic step without isolation, including the entire reaction mixture after a synthetic step has beencompleted 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.

[0027] Reaction mixture products containing GLP1RA include those resulting from any synthetic pathway resulting in the preparation of GLP1RA. A non-limiting example is a reaction mixture product prepared under standard peptide coupling conditions of carboxylic acid (i) and amine (ii) as illustrated in the following Scheme 2:Scheme 2GLP1RA REACTION MIXTURE PRODUCTsuch as those described and exemplified in US 10,858,356 and WO 2024 / 137426.

[0028] The reaction mixture product may comprise GLP1RA in a solvent (“first reaction mixture solvent”). This first reaction mixture solvent means the original reaction solvent, such as THF, DMI, or DMAc, or an extraction solvent used when the original reaction mixture is partitioned between organic and aqueous phases, such as ethyl acetate. If necessary or desired, this first reaction mixture solvent may be exchanged with a solvent suitable for formation and isolation of GLP1RA Vi Ca2+, including methanol, aqueous ethanol, isopropanol, tetrahydrofuran, acetonitrile, dimethylformamide, ethyl acetate, toluene, dichloromethane, dimethyl sulfoxide, rert-butyl methyl ether, dimethyl acetamide, and 1,4-dioxane (“second reaction mixture solvent”). In one embodiment, the second reaction mixture solvent is an aqueous ethanol. Inone embodiment, the aqueous ethanol comprises ethanol and water at a ratio in the range of about 1.8:1 to about 3.4:1 before seeding. In one embodiment, the volume ratio of ethanol to water is about 2.8:1 before seeding. In one embodiment, the volume ratio of ethanol to water is in the range of about 1:1.9 to about 1:2.3 at the end of seeding. In one embodiment, the volume ratio of ethanol to water is about 1:2.1 at the end of seeding.

[0029] A solvent exchange may be performed by methods well known to the skilled artisan, including serial concentration and dilution cycles of the reaction mixture or reaction mixture extract to replace a first solvent with a second solvent. When the first reaction mixture solvent is substantially or completely removed by evaporation or distillation, the remaining residue may be dissolved or suspended in a second reaction mixture solvent to provide a reaction mixture product suitable for use in the disclosed process.

[0030] The reaction mixture product containing GLP1RA is contacted with a source of Ca2+in the presence of a suitable base. The source of Ca2+is preferably a water-soluble calcium salt. Suitable Ca2+salts include calcium acetate, calcium acetate hemihydrate, calcium acetate monohydrate, calcium acetate dihydrate, calcium citrate, calcium lactate, calcium gluconate, calcium chloride, calcium sulfate, calcium nitrate, calcium iodide, and tricalcium phosphate. Preferred Ca2+salts are calcium acetate and its hemi-, mono- and dihydrates.

[0031] Suitable bases include sodium ethoxide, sodium te -butoxide, potassium hydroxide, lithium hydroxide, sodium hydroxide, potassium ethoxide, potassium te -butoxide, sodium tertamylate, sodium hydride, or sodium bis(trimethylsilyl)amide. Preferred bases include metal hydroxides, such as lithium hydroxide, potassium hydroxide, and sodium hydroxide. The use of sodium hydroxide is especially preferred. In one embodiment, the above process is carried out at a temperature of about 0 °C to about 150 °C. In one embodiment, the above process is carried out at a temperature of about 0 °C to about 50 °C. In one embodiment, the above process is carried out at a temperature of about 15 °C to about 50 °C.

[0032] The disclosed process provides GLP1RA Pi Ca2+without the need of first isolating GLP1RA as required by the process described in WO 2014 / 137426. The elimination of this isolation step results in the preparation of GLP1RA Vi Ca2+in an 84.7% yield from a reaction mixture product containing GLP1RA. Further, the skilled artisan will appreciate that the advantages of eliminating an isolation step also include greater efficiency due to reduced cycle times and additional economic advantages due to reduced solvent and waste disposal costs.Example 13-((15,2S)-l-(5-((5)-2,2-Dimethyltetrahydro-2H-pyran-4-yl)-2-((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- 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-lH-indol-l-yl)-2- methylcyclopropyl)-5-oxo- 1 ,2,4-oxadiazol-4-ide hemi-calcium

[0033] To a reaction vessel containing DMI (14.7 mL) was added 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-l-((lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl)-17 / -indole-2-carboxylic acid (6.00 g, 14.6 mmol) and HATU (6.09 g, 16.0 mmol). The solids were suspended in the solvent under an atmosphere of N2, with overhead agitation. To the vessel was added THF (30.1 mL). To the Stirling suspension was then added DIPEA (5.64 g, 43.6 mmol) via syringe, while maintaining the temperature below 30 °C. To the mixture was added solid (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 (7.00 g, 14.3 mmol). The mixture was then heated while stirring to 35 °C and this temperature was maintained for 30 h. EtOAc (77.7 mL) was added to dilute the reaction mixture, followed by a 1.5 wt% aqueous solution of Na2SOr (36.4 mL).

[0034] The resulting biphasic mixture was stirred for at least 45 min, after which the layers were separated. The organic layer was returned to the flask and 15 wt% aqueous NaiCCE solution (60.2 mL) was added. The resulting biphasic mixture was stirred for at least 45 min, after which the layers were separated. The same wash process with 5 wt% aqueous NazSCL solution (60.2mL) was repeated three times, and the organic layer was concentrated under reduced pressure at <55 °C. 3A EtOH (70 mL) was added, and the resulting mixture was concentrated under reduced pressure at <55 °C again. 3A EtOH (42 mL) was added to the distillation vessel followed by 18 wt% NaOH (aq.) (3.95 g, 17.8 mmol) and water (8.75 mL) to give a clear solution. To the solution was added a solution of calcium acetate (0.52 equivalent) in water (9.60 mL) via syringe pump over 1 h.

[0035] When the liquid addition was complete, the tube used to add the liquid was rinsed with water (0.63 mL) and this was also added dropwise to the vessel. Dry seed (0.21 g) was then added and the suspension stirred for 10 h. Water (103 mL) was added over 9 h and the resulting suspension stirred for 23 h. The suspension was filtered and the wet cake washed with a premixed solution of 3A EtOH (21.7 mL) and water (38.5 mL). The wet cake was then washed twice with water (60.2 mL). The solids were dried in a vacuum oven at 55 °C with a N2 sweep for at least 20 h to give the title product as a free-flowing powder (10.92 g, 84.7%). TOF-MS (ESI) m / z 883.39 (M+2H-Ca).

Claims

WE CLAIM:

1. A process for the preparation of a GLP-1 receptor agonist, the hemi-calcium salt of 3-[(15,25)-l-[5-[(45)-2,2-dimethyloxan-4-yl]-2-[(45)-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 (herein “GLP1RA Vi Ca2+”) of Formula I:comprising contacting a reaction mixture product containing 3-[(15.25)-l-[5-[(45)-2,2-dimethyloxan-4-yl]-2-[(45')-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 (herein, "GLP1RA") with a source of Ca2+in the presence of a suitable base.

2. A process for the preparation of a GLP-1 receptor agonist, the hemi-calcium salt of 3-[(15,25)-l-[5-[(45)-2,2-dimethyloxan-4-yl]-2-[(45)-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 (herein “GLP1RA 1 / 2 Ca2+”) of Formula I:from GLP1RA, wherein the process comprises contacting a reaction mixture product containing GLP1RA with a source of Ca+2in the presence of a suitable base without first isolating GLP1RA.

3. The process of either of claims 1 or 2, where the reaction mixture product comprises GLP1RA in a first solvent.

4. The process of claim 3, further comprising a solvent exchange from the first solvent to a second solvent prior to contacting the reaction mixture product with a source of Ca+2.

5. The process of claim 4, where the second solvent is selected from the group consisting of methanol, aqueous ethanol, isopropanol, tetrahydrofuran, acetonitrile, dimethylformamide, ethyl acetate, toluene, dichloromethane, dimethyl sulfoxide, tert-butyl methyl ether, dimethyl acetamide, and 1,4-dioxane.

6. The process of claim 5, where the second solvent is aqueous ethanol.

7. The process of claim 6, wherein the aqueous ethanol comprises ethanol and water at a ratio in the range of about 1.8:1 to about 3.4:1 before seeding.

8. The process of claim 7, wherein the volume ratio of ethanol to water is about 2.8:1 before seeding.

9. The process of claim 6, wherein the volume ratio of ethanol to water is in the range of about 1:1.9 to about 1:2.3 at the end of seeding.

10. The process of claim 9, wherein the volume ratio of ethanol to water is about 1:2.1 at the end of seeding.

11. The process of any one of claims 1 to 10, where the suitable base is selected from the group consisting of sodium ethoxide, sodium fe -butoxide, potassium hydroxide, lithium hydroxide, sodium hydroxide, potassium ethoxide, potassium ze / 7-butoxide, sodium / erz-amylate, sodium hydride, and sodium bis(trimethylsilyl)amide.

12. The process of claim 11, where the base is selected from the group consisting of lithium hydroxide, potassium hydroxide, and sodium hydroxide.

13. The process of claim 12, where the base is sodium hydroxide.

14. The process of any one of claims 1 to 13, where the source of Ca2+is a water-soluble calcium salt.

15. The process of claim 14, where the calcium salt is selected from the group consisting of calcium acetate, calcium acetate hemihydrate, calcium acetate monohydrate, calcium acetate dihydrate, calcium citrate, calcium lactate, calcium gluconate, calcium chloride, calcium sulfate, calcium nitrate, calcium iodide, and tricalcium phosphate.

16. The process of claim 14, where the calcium salt is selected from the group consisting of calcium acetate, calcium acetate hemihydrate, calcium acetate monohydrate, and calcium acetate dihydrate.

17. The process of claim 14, where the calcium salt is calcium acetate.

18. The process of any one of claims 1 to 17, further comprising isolating GLP1RA 1 Ca2+.

19. The process of claim 18, wherein the isolated GLP1RA 16 Ca2is a hydrate of GLP1RA 16 Ca2+.

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