EP4731209A1 - Processes for preparing soluble guanylate cyclase stimulators - Google Patents

Processes for preparing soluble guanylate cyclase stimulators

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Publication number
EP4731209A1
EP4731209A1 EP24832716.5A EP24832716A EP4731209A1 EP 4731209 A1 EP4731209 A1 EP 4731209A1 EP 24832716 A EP24832716 A EP 24832716A EP 4731209 A1 EP4731209 A1 EP 4731209A1
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EP
European Patent Office
Prior art keywords
compound
formula
copper
salt
dihydrooxazole
Prior art date
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Pending
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EP24832716.5A
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German (de)
French (fr)
Inventor
Andrew J. Neel
Jamie Marie MCCABE DUNN
Jennifer V. Obligacion
Gregorio J. ESTRADA
Lu Wang
Matthew S. Winston
Tao Liang
Artis Klapars
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Merck Sharp and Dohme LLC
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Merck Sharp and Dohme LLC
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Publication of EP4731209A1 publication Critical patent/EP4731209A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/16—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of hydrazones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C07C251/74—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/78—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C07C251/80—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates a processes for preparing a compound of Formula I or a pharmaceutically acceptable salt thereof, which are useful for the treatment of cardiovascular disease, endothelial dysfunction, diastolic dysfunction, atherosclerosis, hypertension, heart failure, pulmonary hypertension (WHO groups I, II, III, IV), angina pectoris, thrombosis, restenosis, myocardial infarction, stroke, cardiac insufficiency, fibrosis, pulmonary hypertonia, erectile dysfunction, asthma, chronic kidney disease, diabetes, cirrhosis of the liver, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome, acute lung injury, pulmonary fibrosis, cystic fibrosis, or interstitial lung disease. The invention also relates to intermediates used in the processes for preparing the compound of Formula I.

Description

25722 PROCESSES FOR PREPARING SOLUBLE GUANYLATE CYCLASE STIMULATORS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/510,222, filed June 26, 2023. FIELD OF THE INVENTION [0002] The invention relates to processes for preparing soluble guanylate cyclase stimulator compounds useful for the treatment of treating diseases or disorders which are associated with a disturbed cyclic guanosine monophosphate (cGMP) balance. More specifically, the invention relates to processes for preparing and intermediates used in the processes for preparing (S)-3-(4- {4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid. BACKGROUND OF THE INVENTION [0003] Cyclic GMP (cGMP) is an important intracellular messenger which triggers a multitude of different effects via the modulation of cGMP-dependent protein kinases, phosphodiesterases and ion channels. Examples are the relaxation of smooth muscles, the inhibition of thrombocyte activation and the inhibition of the proliferation of smooth-muscle cells and of leukocyte adhesion. cGMP is produced by particulate and soluble guanylate cyclases as a response to a number of extracellular and intracellular stimuli. In the case of the particulate guanylate cyclases, stimulation is essentially effected by peptidic messengers, such as the atrial natriuretic peptide or the cerebral natriuretic peptide. The soluble guanylate cyclases ("sGC"), which are cytosolic heterodimeric heme proteins, in contrast, are essentially regulated by a family of low-molecular- weight factors which are formed enzymatically. The most important stimulant is nitrogen monoxide ("NO") or a closely related species. The function of other factors such as carbon monoxide or the hydroxyl radical is still largely unclear. The binding of NO to the heme with formation of a penta-coordinate heme-nitrosyl complex is proposed as the mechanism of the activation by NO. The associated release of the histidine which is bound in the basal state to the iron converts the enzyme into the active conformation. [0004] Active soluble guanylate cyclases are each composed of an α and a β subunit. Several subunit subtypes have been described which differ from one another with respect to sequence, tissue-specific distribution and expression in different development stages. The subtypes α1 and β 1 are mainly expressed in brain and lung, while β 2 is found in particular in liver and kidney. The subtype α 2 was shown to be present in human fetal brain. The subunits referred to as α 3 and β 3 were isolated from human brain and are homologous to α 1 and β 1 . More recent works indicate an α 2i subunit which contains an insert in the catalytic domain. All subunits show great homologies in the region of the catalytic domain. The enzymes presumably contain one heme per heterodimer, which is bound via β 1 -Cys-78 and/or β 1 -His-105 and is part of the regulatory center. [0005] Under pathologic conditions, the formation of guanylate-cyclase-activating factors can be reduced, or their degradation may be promoted owing to the increased occurrence of free radicals. The resulting reduced activation of the sGC leads, via a weakening of the respective cGMP-mediated cellular response, for example to an increase of the blood pressure, to platelet activation or to increased cell proliferation and cell adhesion. As a consequence, formation of endothelial dysfunction, atherosclerosis, hypertension, stable or unstable angina pectoris, thrombosis, myocardial infarction, strokes or erectile dysfunction results. Pharmacological stimulation of sGC offers a possibility to normalize cGMP production and therefore may make possible the treatment and/or prevention of such disorders. [0006] For the pharmacological stimulation of the sGC, use has been made of compounds whose activity is based on an intermediate NO release, for example organic nitrates. The drawback of this treatment is the development of tolerance and a reduction of activity, and the higher dosage which is required because of this. [0007] International Patent Application WO 2017/112617 describes a class of soluble guanylate cyclate inhibitors. Among the compounds disclosed in WO ‘617 include (S)-3-(4-{4-Amino-2-[6- chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid: referred to as Compound 1). Methods of making and using Compound 1 are disclosed in WO ‘617. [0008] Development of efficient and low-cost processes to prepare soluble guanylate cyclase stimulators would be desired to supply individuals in need of treatment with such compounds. [0009] The methods disclosed in this application are also applicable in formulating crystalline forms of (S)-3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5- methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid, including such forms as disclosed in PROCESSES FOR PREPARING CRYSTALLINE SOLUBLE GUANYLATE CYCLASE STIMULATORS, US Application No.63/510,231, which is hereby incorporated by reference. SUMMARY OF THE INVENTION [0010] The invention is directed to processes and intermediates for preparing Compound 1, also referred to as the compound of Formula I.: . processes for preparation of Compound 1, or pharmaceutically acceptable salts thereof. [0012] Embodiments, sub-embodiments and features of the invention are either further described herein or will be apparent from the ensuing description, examples and appended claims. DETAILED DESCRIPTION OF THE INVENTION Definitions [0013] The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. [0014] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention 25722 which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. In some embodiments, pharmaceutically acceptable salts are ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion- exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidinyl, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidinyl, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. [0015] The term “patient” refers to a mammalian patient, including a human, canine, feline, bovine, or porcine patient, preferably a human patient, receiving or about to receive medical treatment. [0016] The term "treat" or "treatment" means to administer an agent, such as a composition containing any of the compounds described herein, internally or externally to a subject or patient having one or more disease symptoms, or being suspected of having a disease, for which the agent has therapeutic activity. Typically, the agent is administered in an amount effective to alleviate one or more disease symptoms in the treated subject or population, whether by inducing the regression of or inhibiting, delaying or slowing the progression of such symptom(s) by any clinically measurable degree. The amount of an agent that is effective to alleviate any particular disease symptom may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the drug to elicit a desired response in the subject. Whether a disease symptom has been alleviated can be assessed by any clinical measurement typically used by physicians or other skilled healthcare providers to assess the severity or progression status of that symptom. The term further includes a postponement of development of the symptoms associated with a disorder and/or a reduction in the severity of the symptoms of such disorder. The terms further include ameliorating existing uncontrolled or unwanted symptoms, preventing additional symptoms, and ameliorating or preventing the underlying causes of such symptoms. Thus, the terms denote that a beneficial result has been conferred on a mammalian subject with a disorder, disease or symptom, or with the potential to develop such a disorder, disease or symptom. Processes and Intermediates for Preparing Compound 1 [0017] In one embodiment, the invention relates to a process for preparing a compound of Formula I according to the following scheme: . of Formula I
a pharmaceutically acceptable salt thereof, acceptable salt thereof with a compound of Formula (III) acceptable salt thereof. [0019] In another embodiment, the invention also relates to processes for preparing a compound of Formula (III) or a pharmaceutically acceptable salt thereof, comprising contacting a compound of Formula (IV) salt. [0020] In particular embodiments, the ammonium salt is selected from the group consisting of ammonium trifluoromethanesulfonate, ammonium benzenesulfonate, ammonium diphenyl phosphate, ammonium camphor sufonate, ammonium bromide, ammonium iodide, ammonium chloride, ammonium perchlorate, ammonium triflamide, ammonium pentafluorophosphate. In certain embodiments, the ammonium salt is ammonium trifluoromethanesulfonate. [0021] In another embodiment, the invention also relates to processes for preparing a compound of Formula (IV) or a pharmaceutically acceptable salt thereof, comprising contacting a compound of Formula (V) acceptable salt thereof, with a copper salt and a ligand. the copper salt is selected from the group consisting of copper (I) chloride, copper (I) iodide and copper (I) bromide. In certain embodiments, the copper salt is copper (I) chloride. [0023] In particular embodiments, the ligand is selected from the group consisting of quinolin- 8-ol, dimethylglycine, proline, picolinic acid, N1,N1,N2,N2-tetramethylethane-1,2-diamine, N1,N2- dimethylethane-1,2-diamine, cyclohexane-1,2-diamine, 2,2'-bipyridine, 1,10-phenanthroline, (2E,4E)-N2,N4-dimethylpentane-2,4-diimine, picolinamide, N,N-diethyl-2-hydroxybenzamide, 2,2':6',2''-terpyridine, thiophene-2-carboxylic acid, and 1,3-di(pyridin-2-yl)propane-1,2-dione. In certain embodiments, the ligand is 1,10-phenanthroline. [0024] In another embodiment, the invention also relates to processes for preparing a compound of Formula (V) or a pharmaceutically salt thereof, comprising contacting a compound of Formula (VI) O OEt of K2CO3, K3PO4, K2HPO4, KOtBu, LiOtBu, NaOEt. In certain embodiments, the base is K2CO3. [0026] In another embodiment, the invention also relates to processes for preparing a compound of Formula (II) acceptable salt thereof, comprising contacting a compound of Formula (VIII) the hydroxide is selected from the group consisting of LiOH, NaOH, KOH, and NH4OH. In certain embodiments, the hydroxide is LiOH. [0028] In another embodiment, the invention also relates to processes for preparing a compound of Formula (VIII) or a pharmaceutically acceptable salt thereof, comprising contacting a compound of Formula (IX) or lithium 2,2,4,4,5,5-hexamethyl-1,3,2-dioxaborolan-2-uide. [0029] In particular embodiments, the compound of Formula (IX) is treated with trimethylboroxine in the presence of a copper salt, a ligand, an alkoxide and an alcohol. A ligand refers to an organic molecule attached to a transition metal ion through coordination bonding used to modulate reactivity and/or selectivity of the desired chemical transformation. In certain embodiments, the copper salt is selected from the group consisting of copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) pentafluorophosphate tetraacetonitrile complex, copper (I) thiophene-2-carboxylate, copper (I) trifluoromethanesulfonate. In specific embodiments, the copper salt is copper (I) chloride. In some embodiments, the alkoxide is selected from the group consisting of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert- amylate, sodium tert-amylate, potassium tert-amylate. In particular embodiments, the alkoxide is potassium tert-amylate. In certain embodiments, the alcohol is selected from the group consisting of tert-butanol and tert-amyl alcohol. In specific embodiments, the alcohol is tert-amyl alcohol. In particular embodiments, the ligand is a Pymox or Quinox ligand of formulas A and B , wherein R1, R2, R3, and R4 or heteroaryl, and R6, R7, and R8 are independently alkyl, cycloalkyl, aryl or heteroaryl. In some embodiments, the ligand is 25722 selected from the group consisting of (4R,5S)-4,5-diphenyl-2-(quinolin-2-yl)-4,5- dihydrooxazole, (R)-4-(naphthalen-1-yl)-2-(quinolin-2-yl)-4,5-dihydrooxazole, (4R,5S)-2-(6- methoxyquinolin-2-yl)-4,5-diphenyl-4,5-dihydrooxazole, (4R,5S)-2-(6-methylpyridin-2-yl)-4,5- diphenyl-4,5-dihydrooxazole, (R)-2-(6-methylpyridin-2-yl)-4-(naphthalen-1-yl)-4,5- dihydrooxazole, and (R)-4-(2-(tert-butyl)phenyl)-2-(quinolin-2-yl)-4,5-dihydrooxazole. In certain embodiments. the ligand is (4R,5S)-4,5-diphenyl-2-(quinolin-2-yl)-4,5-dihydrooxazole or (4R,5S)-2-(6-methoxyquinolin-2-yl)-4,5-diphenyl-4,5-dihydrooxazole. [0030] In particular embodiments, the compound of Formula (IX) is treated with lithium 2,2,4,4,5,5-hexamethyl-1,3,2-dioxaborolan-2-uide in the presence of a copper salt and a ligand. In certain embodiments, the copper salt is selected from the group consisting of copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) pentafluorophosphate tetraacetonitrile complex, copper (I) thiophene-2-carboxylate, copper (I) trifluoromethanesulfonate. In specific embodiments, the copper salt is copper (I) chloride. In particular embodiments, the ligand is selected from the group consisting of (4R,5S)-4,5-diphenyl-2-(quinolin-2-yl)-4,5- dihydrooxazole, (R)-4-(naphthalen-1-yl)-2-(quinolin-2-yl)-4,5-dihydrooxazole, (4R,5S)-2-(6- methoxyquinolin-2-yl)-4,5-diphenyl-4,5-dihydrooxazole, (4R,5S)-2-(6-methylpyridin-2-yl)-4,5- diphenyl-4,5-dihydrooxazole, (R)-2-(6-methylpyridin-2-yl)-4-(naphthalen-1-yl)-4,5- dihydrooxazole, and (R)-4-(2-(tert-butyl)phenyl)-2-(quinolin-2-yl)-4,5-dihydrooxazole. In certain embodiments, the ligand is (4R,5S)-4,5-diphenyl-2-(quinolin-2-yl)-4,5-dihydrooxazole or (4R,5S)-2-(6-methoxyquinolin-2-yl)-4,5-diphenyl-4,5-dihydrooxazole. [0031] In another embodiment, the invention also relates to processes for preparing a compound of Formula (VIII’) salt thereof, comprising contacting a compound of Formula (IX) methyl source. 25722 [0032] In particular embodiments, the organometallic methyl source is selected from the group consisting of methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide, dimethyl zinc, trimethyl aluminum. [0033] In another embodiment, the invention also relates to processes for preparing a compound of Formula (IX), or a pharmaceutically acceptable salt thereof, comprising contacting a compound of Formula (X) in methanol. the invention also relates to processes for preparing a compound of Formula (X) or a pharmaceutically acceptable salt thereof, comprising contacting a compound of formula (XI) [0035] In particular embodiments, the compound of Formula (XI) is treated with malononitrile in the presence of an amine catalyst. In certain embodiments, the amine catalyst is 6- aminohexanoic acid. EXAMPLES [0036] The meanings of the abbreviations in Examples and Specification are shown below. Rb flask = round-bottomed flask Meldrum’s acid = 2,2-dimethyl-1,3-dioxane-4,6-dione °C = degrees Celsius FIG (or FIG. or Fig. or Fig or fig. or fig) means Figure (or figure) and refers to the corresponding figure 6 N HCl = 6 normal hydrochloric acid 1H NMR = proton nuclear magnetic resonance 13C NMR = carbon-13 nuclear magnetic resonance DMSO-d6 = per-deuterated dimethyl sulfoxide MHz = megahertz THF = tetrahydrofuran 25722 LiBr = lithium bromide Ot = tert-butoxide N2 = nitrogen EA = ethyl acetate MeOH = methanol H3PO4 = phosphoric acid V = volumes KF = Karl Fischer (i.e water content determined by Karl Fischer titration) TMSCl = trimethylsilyl chloride HOAc = acetic acid IY = isolated yield CDCl3 = deuterated chloroform (R,S)-(4,5-diphenyl)-6-MeO-Quinox = (4R,5S)-2-(6-methoxyquinolin-2-yl)-4,5-diphenyl-4,5- dihydrooxazole CuCl = copper (I) chloride Me = methyl LiOH = lithium hydroxide 2-MeTHF = 2-methyltetrahydrofuran MeOH-d4 = deuterated methanol P(OEt)3 = triethyl phosphite Rpm = revolutions per minute Nm = nanometers LED = light emitting diode W = watt SCCM = standard cubic centimeters per minute PSIG = pounds per square inch gauge MSA = methanesulfonic acid NMP = N-methyl-2-pyrrolidone NaHCO3 = sodium hydrogen carbonate or sodium bicarbonate EOR = end of reaction MTBE = methyl tert-butyl ether IPA = isopropyl alcohol or isopropanol mL/min = milliliters per minute MeCN = acetonitrile 25722 Wt% = weight percent HOTf = trifluoromethanesulfonic acid HMDS = hexamethyldisilazane KOH = potassium hydroxide NaCl = sodium chloride NH3 = ammonia 19F NMR = fluorine 19 nuclear magnetic resonance K2CO3 = potassium carbonate EXAMPLE 1 [0037] Bisnitrile acid amine salt (II) (8.0 g, 17.18 mmol, 1 eq) was partitioned between MTBE (32 mL) and 2 N aq. HCl (20 mL, 2.33 eq). The aqueous layer was discarded and the organic phase was washed with H2O (2 x 8 mL) and then the solvent was switched into 2-propanol (final volume = 60 mL) in vacuo. Amidine MSA salt (II) (8.25 g, 18.90 mmol, 1.1 eq) was then charged, followed by K2CO3 (3.56 g, 25.77 mmol, 1.5 eq). The reaction mixture was stirred for 36-48 h at 75 – 80 °C. The mixture was then diluted with H2O (20 mL) and cooled to 20 °C. The pH of the mixture was adjusted to 6.0 – 6.1 using 2 N HCl (13.7 mL, 1.6 eq). The resulting homogeneous mixture was seeded with crystalline (III) and aged at 20 °C for 4 h, at which point the slurry was warmed to 35 °C and 0.6 N HCl (16 mL, 0.56 eq) was charged over 4 h. Upon completion of the addition, the mixture was slowly cooled to 20 °C over 4 h and then aged at 20 °C for 12 h. The solids were filtered and then washed with 45:55 IPA:H2O (2 x 25 mL), and dried in a vacuum oven at 55 °C for 24 h. The product (III) was obtained (8.37 g, 13.74 mmol, 80 % yield) as a white solid. EXAMPLE 2 25722 [0038] To an autoclave was charged anisole (12.78 L), indazole ester (IV) (2.13 kg, 5.64 mol), and hexamethyldisilazane (4.55 kg, 28.2 mol). The mixture was cooled to 0-5 oC and the vessel was placed under slight positive pressure with no N2 sweeping. A solution of H2O (203.21 g, 11.27 mol) in sulfolane (6.39 L) was added while keeping at < 10 oC in order to minimize NH3 gas escaping. The resulting mixture was cooled to -10 oC, then TfOH (1.692 kg, 11.27 mol) was slowly added at < 22 oC. The vessel was sealed and the mixture was heated at 120-130 °C for 24 h. The upper vessel was kept warm so that solid ammonium triflate did not deposit there. [0039] After cooling the mixture to rt, the batch (biphasic) was further cooled to 0-10 oC.2.4 equiv 1N KOH (13.53 L, 14.207 kg, 13.53 mol) was slowly added at < 25 oC. After agitating for 30 min, and letting settle at rt, the bottom aqueous layer was removed (pH~14). The organic layer was washed with 18% brine (10.5 L). The aqueous layer was removed (pH ~12). To the organic phase was added ¼ (101 mL, 149 g) of 1.1 equiv methanesulfonic acid (402 mL, 595 g, 6.20 mol), then seeded with 0.2 wt% amidine MSA type A (8.5 g). The rest of MSA (447 g, 302 mL) was then slowly added over 1 h. During MSA addition, the temperature was controlled at < 25 oC. The resulting slurry, after aging at 22 oC for 15 h, was filtered, then displacement washed with 2 x 3 vol 2-MeTHF (2 x 6.4 L), and vacuum dried under N2 at < 30 °C for 24 h. The product (III) was obtained (4.62 kg, 10.58 mol, 93 % yield) as an off-white to light beige solid. EXAMPLE 3-4 wt% in MeCN), 2-(3,3,4,4,4-pentafluorobutyl)hydrazin-1-ium (VII) (1.7) methanesulfonate (7.60 g, 22.26 mmol), potassium carbonate solution (6.19 g, 6.78 mmol, 15 wt% in water) were mixed together. The mixture was stirred for 20 h before potassium carbonate solution (3.68 g, 12.14 mmol, 46 wt% in water) was charged. The aqueous layer was discarded and the organic layer (V) was charged with acetonitrile (26.0 ml), potassium carbonate (5.59 g, 40.5 mmol), 1,10-phenanthroline (0.073 g, 0.405 mmol), and copper(I) chloride (0.020 g, 0.202 mmol). Air was purged with N2 three times and the mixture was stirred for 22 h at 70 °C. The mixture was then cooled down to 35 °C for 2 25722 hours and water (25 mL) was charged. The aqueous layer was discarded and the organic layer was charged with acetonitrile (1.5 mL). The stream was cooled down to 7 °C, seeded with crystalline (IV) and aged for 4 h, at which point water (40 mL) was charged over 6 h. The mixture was aged for additional 2 h, then the solids were filtered and washed with 1.5:1 Water:MeCN (2 x 20 mL), and dried in a vacuum oven at 30 °C for 24 h. The product (IV) was obtained (6.66 g, 19.97 mmol, 89 % yield) as a white solid. EXAMPLE 5 to 0 °C.1 M LiOH (170 mL, 3 eq) was then added slowly, maintaining the internal temperature below 5 °C. The resulting biphasic mixture was stirred at 0 °C for 3 hours.3 M HCl (33 mL, 1.75 eq) was then charged slowly to tune the pH between 9.0 and 9.5. While cold, the biphasic mixture was allowed to settle, and the organic phase discarded. The aqueous phase was then transferred to a separate flask along with 2-MeTHF (180 mL, 7.2 V).3 M HCl (1.5 eq) was then charged to a final aqueous pH of 2. The aqueous phase was discarded, and the organic phase (II) washed with 13% brine (35 mL). EXAMPLE 6 (125 mL, 5 V). CuCl (784 mg, 0.10 eq) was then added, and the mixture stirred under N2 at room temperature for 3 hours. A separate round bottom flask was purged 3x with N2/vacuum cycles. Toluene (275 mL, 11 V), Trimethylboroxine (50 wt% in THF, 66.5 mL, 3 eq) and tert-amyl alcohol (17.5 mL, 2 eq) were added to the flask. Potassium tert-pentoxide (25 wt% in toluene, 89 mL, 2 eq) was then added slowly over the course of 30 minutes. The resulting heterogeneous mixture was stirred at room temperature for 1 hour. Bisnitrile SM (IX) (25.0 g) was added to the boroxine mixture. The Cu-Quinox catalyst mixture was then transferred to the reaction vessel. The reaction mixture was heated to 75 °C and stirred under N2 for 40 hours. The reaction mixture was cooled to 40 °C.3 M HCl (175 mL, 7 V) was added, and the biphasic mixture stirred at 40 25722 °C for 3 hours. The aqueous phase was then discarded. The organic phase (VIII) was washed with 13% brine (125 mL, 5 V) and the aqueous phase discarded. EXAMPLE 7 was dissolved in 2-Me-THF was - bromide (3 M in THF, 1.2 eq, 5.41 mol, 1.8 kg) was charged dropwise over 2 h. The mixture was stirred at -60 °C for 1 h, at which point AcOH (3.5 eq, 15.82 mol, 0.95 kg) in 2-Me-THF (0.9 L) was added over 1 h at -60 °C. The mixture was warmed to 5 °C and water (9.0 L) was added over 1 h. The aqueous phase was discarded. The organic phase containing (VIII) (9.6 wt%, 4.59 mol, 1.507 kg, 95.6 % yield) was further processed according to the procedure from Example 5. EXAMPLE 8 by MeOH (9V, 2000 mL). The reaction was cooled to 15 oC. Malononitrile (159 g, 1494 mmol, 1.7 eq) and 6-aminohexanoic acid (5.76 g, 43.9 mmol, 0.05 eq) were charged at 15 oC, then the reaction was aged for 26 h. TMSCl (47.7 g, 439 mmol, 0.5 eq) was charged and the reaction was aged at 15 oC for another 14 h. Then the reaction was cooled to 5 oC. A mixture of H2O and HOAc (3:1, 1.6L) was charged over 4 h. After 17 h, the mixture was filtered and washed with MeOH/H2O to afford the product (IX) as a white solid (229.8 g, 733 mmol, 83%).

Claims
25722 WHAT IS CLAIMED 1. A method for preparing a compound of Formula I contacting a compound of Formula (II) acceptable salt thereof with a compound of Formula (III) acceptable salt thereof. 2. A method for preparing a compound of Formula (III) acceptable salt thereof, comprising contacting a compound of Formula (IV)
25722 O OEt a pharmaceutically acceptable salt thereof, with an ammonium salt. 2 wherein the ammonium salt is selected from the group consisting of ammonium trifluoromethanesulfonate, ammonium benenesulfonate, ammonium diphenyl phosphate, ammonium camphor sufonate, ammonium bromide, ammonium iodide, ammonium chloride, ammonium perchlorate, ammonium triflamide, amonium pentafluorophosphate.
4. The method of claim 2 wherein the ammonium salt is ammonium trifluoromethanesulfonate.
5. A method for preparing a compound of Formula (IV) or a pharmaceutically acceptable salt thereof, comprising contacting a compound of Formula (V) salt thereof, with a copper salt and a ligand.
6. The method of claim 5 wherein the copper salt is selected from the group consisting of copper (I) chloride, copper (I) iodide and copper (I) bromide.
7. The method of claim 6 wherein the copper salt is copper (I) chloride.
8. The method of claim 5 wherein the ligand is selected from the group consisting of quinolin-8-ol, dimethylglycine, proline, picolinic acid, N1,N1,N2,N2-tetramethylethane-1,2- diamine, N1,N2-dimethylethane-1,2-diamine, cyclohexane-1,2-diamine, 2,2'-bipyridine, 1,10- phenanthroline, (2E,4E)-N2,N4-dimethylpentane-2,4-diimine, picolinamide, N,N-diethyl-2- hydroxybenzamide, 2,2':6',2''-terpyridine, thiophene-2-carboxylic acid, and 1,3-di(pyridin-2- yl)propane-1,2-dione. 25722
9. The method of claim 8 wherein the ligand is 1,10-phenanthroline.
10. A method for preparing a compound of Formula (V) or a pharmaceutically salt thereof, comprising contacting a compound of Formula (VI) acceptable salt thereof, with a compound of Formula (VII) salt thereof, in the presence of a base.
11. The method of claim 10, wherein the base is selected from the group consisting of K2CO3, K3PO4, K2HPO4, KotBu, LiOtBu, and NaOEt.
12. The method of claim 11, wherein the base is of K2CO3.
13. A method for preparing a compound of Formula (II) acceptable salt thereof, comprising contacting a compound of Formula (VIII) salt thereof, with a hydroxide.
14. The method of claim 13, wherein the hydroxide is selected from the group consisting of LiOH, NaOH, KOH, and NH4OH. 25722
15. The method of claim 14, wherein the hydroxide is LiOH.
16. A method for preparing a compound of Formula (VIII) or a pharmaceutically acceptable salt thereof, comprising contacting a compound of Formula (IX) salt thereof, with trimethylboroxine or lithium 2,2,4,4,5,5- 2-uide.
17. The method of claim 16, wherein the compound of Formula (IX) is treated with trimethylboroxine in the presence of a copper salt, a ligand, an alkoxide and an alcohol.
18. The method of claim 17, wherein the copper salt is selected from the group consisting of copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) pentafluorophosphate tetraacetonitrile complex, copper (I) thiophene-2-carboxylate, and copper (I) trifluoromethanesulfonate.
19. The method of claim 18 wherein the copper salt is copper (I) chloride.
20. The method of claim 17 wherein the alkoxide is selected from the group consisting of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-amylate, sodium tert-amylate, and potassium tert-amylate.
21. The method of claim 20 wherein the alkoxide is potassium tert-amylate.
22. The method of claim 17 wherein the alcohol is selected from the group consisting of tert- butanol and tert-amyl alcohol.
23. The method of claim 17 wherein the alcohol is tert-amyl alcohol.
24. The method of claim 17 wherein the ligand is selected from the group consisting of (4R,5S)-4,5-diphenyl-2-(quinolin-2-yl)-4,5-dihydrooxazole, (R)-4-(naphthalen-1-yl)-2-(quinolin- 25722 2-yl)-4,5-dihydrooxazole, (4R,5S)-2-(6-methoxyquinolin-2-yl)-4,5-diphenyl-4,5-dihydrooxazole, (4R,5S)-2-(6-methylpyridin-2-yl)-4,5-diphenyl-4,5-dihydrooxazole, (R)-2-(6-methylpyridin-2- yl)-4-(naphthalen-1-yl)-4,5-dihydrooxazole, and (R)-4-(2-(tert-butyl)phenyl)-2-(quinolin-2-yl)- 4,5-dihydrooxazole.
25. The method of claim 24 wherein the ligand is (4R,5S)-4,5-diphenyl-2-(quinolin-2-yl)-4,5- dihydrooxazole or (4R,5S)-2-(6-methoxyquinolin-2-yl)-4,5-diphenyl-4,5-dihydrooxazole.
26. The method of claim 16, wherein the compound of Formula (IX) is treated with lithium 2,2,4,4,5,5-hexamethyl-1,3,2-dioxaborolan-2-uide in the presence of a copper salt and a ligand.
27. The method of claim 26, wherein the copper salt is selected from the group consisting of copper (I) chloride, copper (I) bromide, copper (I) iodide, tetrakis(acetonitrile)copper (I) hexafluorophosphate, copper (I) thiophene-2-carboxylate, and copper (I) trifluoromethanesulfonate.
28. The method of claim 27 wherein the copper salt is copper (I) chloride.
29. The method of claim 26 wherein the ligand is selected from the group consisting of (4R,5S)-4,5-diphenyl-2-(quinolin-2-yl)-4,5-dihydrooxazole, (R)-4-(naphthalen-1-yl)-2-(quinolin- 2-yl)-4,5-dihydrooxazole, (4R,5S)-2-(6-methoxyquinolin-2-yl)-4,5-diphenyl-4,5-dihydrooxazole, (4R,5S)-2-(6-methylpyridin-2-yl)-4,5-diphenyl-4,5-dihydrooxazole, (R)-2-(6-methylpyridin-2- yl)-4-(naphthalen-1-yl)-4,5-dihydrooxazole, and (R)-4-(2-(tert-butyl)phenyl)-2-(quinolin-2-yl)- 4,5-dihydrooxazole.
30. The method of claim 29 wherein the ligand is (4R,5S)-2-(6-methylpyridin-2-yl)-4,5- diphenyl-4,5-dihydrooxazole.
31. A method for preparing a compound of Formula (VIII’) salt thereof, comprising contacting a compound of Formula 25722 (IX) salt thereof, with an organometallic methyl source.
32. The method of claim 31 wherein the organometallic methyl source is selected from the group consisting of methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide, dimethyl zinc, and trimethyl aluminum.
33. A method for preparing a compound of Formula (IX), or a pharmaceutically acceptable salt thereof, comprising contacting a compound of Formula (X) salt thereof, with trimethylsilyl chloride in methanol.
34. A method for preparing a compound of Formula (X) or a pharmaceutically acceptable salt thereof, comprising contacting a compound of formula (XI) acceptable salt thereof, with malononitrile.
35. The method of claim 34 wherein said treatment of the compound of formula (XI) with malononitrile is performed in the presence of an amine catalyst.
36. The method of claim 35, wherein said amine catalyst is 6-aminohexanoic acid.
37. A compound of Formula (I).
38. A compound of Formula (II).
39. A compound of Formula (III).
40. A compound of Formula (IV).
41. A compound of Formula (V).
42. A compound of Formula (VII).
43. A compound of Formula (VII’).
44. A compound of Formula (IX).
45. A compound of Formula (X).
46. A compound of Formula (XI).
EP24832716.5A 2023-06-26 2024-06-20 Processes for preparing soluble guanylate cyclase stimulators Pending EP4731209A1 (en)

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KR20140019004A (en) * 2010-05-27 2014-02-13 머크 샤프 앤드 돔 코포레이션 Soluble guanylate cyclase activators
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