Processes for making modulators of cystic fibrosis transmembrane conductance regulator

0001This application claims priority from <patcit id="pcit0001" dnum="EP17382829A" dnum-type="L"><text>European Provisional Application No. 17382829.4, filed December 1, 2017</text></patcit>.

0002The disclosure relates to processes for preparing compounds useful for treating a cystic fibrosis transmembrane conductance regulator (CFTR) mediated disease such as cystic fibrosis.

0003Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 30,000 children and adults in the United States and approximately 30,000 children and adults in Europe. Despite progress in the treatment of CF, there is no cure.

0004CF is caused by mutations in the CFTR gene that encodes an epithelial chloride ion channel responsible for aiding in the regulation of salt and water absorption and secretion in various tissues. Small molecule drugs, known as potentiators, that increase the probability of CFTR channel opening represent one potential therapeutic strategy to treat CF.

0005Specifically, CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelia cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.

0006The gene encoding CFTR has been identified and sequenced (See <nplcit id="ncit0001" npl-type="s"><text>Gregory, R. J. et al. (1990) Nature 347:382-386</text></nplcit>; <nplcit id="ncit0002" npl-type="s"><text>Rich, D. P. et al. (1990) Nature 347:358-362</text></nplcit>), (<nplcit id="ncit0003" npl-type="s"><text>Riordan, J. R. et al. (1989) Science 245: 1066-1073</text></nplcit>). A defect in this gene causes mutations in CFTR resulting in CF, the most common fatal genetic disease in humans. CF affects approximately one in every 2,500 infants in the United States. Within the general United States population, up to 10 million people carry a single copy of the defective gene without apparent ill effects. In contrast, individuals with two copies of the CF associated gene suffer from the debilitating and fatal effects of CF, including chronic lung disease.

0007In patients with CF, mutations in CFTR endogenously expressed in respiratory epithelia leads to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death. In addition, the majority of males with CF are infertile and fertility is decreased among females with CF. In contrast to the severe effects of two copies of the CF associated gene, individuals with a single copy of the CF associated gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea - perhaps explaining the relatively high frequency of the CF gene within the population.

0008Sequence analysis of the CFTR gene of CF chromosomes has revealed a variety of disease-causing mutations (<nplcit id="ncit0004" npl-type="s"><text>Cutting, G. R. et al. (1990) Nature 346:366-369</text></nplcit>; <nplcit id="ncit0005" npl-type="s"><text>Dean, M. et al. (1990) Cell 61:863:870</text></nplcit>; and <nplcit id="ncit0006" npl-type="s"><text>Kerem, B-S. et al. (1989) Science 245:1073-1080</text></nplcit>; <nplcit id="ncit0007" npl-type="s"><text>Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451</text></nplcit>). To date, greater than 1000 disease-causing mutations in the CF gene have been identified (http://www.genet.sickkids.on.ca/cftr/app). The most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence and is commonly referred to as ΔF508-CFTR. This mutation occurs in approximately 70% of the cases of CF.

0009The deletion of residue 508 in ΔF508-CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the endoplasmic recticulum and traffic to the plasma membrane. As a result, the number of channels present in the membrane is far fewer than observed in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion transport across epithelia, leading to defective ion and fluid transport. (<nplcit id="ncit0008" npl-type="s"><text>Quinton, P. M. (1990), FASEB J. 4: 2709-2727</text></nplcit>). Studies have shown, however, that the reduced numbers of ΔF508-CFTR in the membrane are functional, albeit less than wild-type CFTR. (<nplcit id="ncit0009" npl-type="s"><text>Dalemans et al. (1991), Nature Lond. 354: 526-528</text></nplcit>; Denning et al., supra; <nplcit id="ncit0010" npl-type="s"><text>Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50</text></nplcit>). In addition to ΔF508-CFTR, other disease-causing mutations in CFTR that result in defective trafficking, synthesis, and/or channel gating could be up- or down-regulated to alter anion secretion and modify disease progression and/or severity.

0010There is a need for processes for the preparation of compounds that modulate CFTR activity and possess favorable absorption, distribution, metabolism, and/or excretion (ADME) properties. Ivacaftor, known by the chemical name <i>N-</i>(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide and the brand name Kalydeco^®, is a CFTR potentiator and is approved by the United States Food and Drug Administration (U.S. FDA) for the treatment of CF. Ivacaftor is also one of the active pharmaceutical ingredients of Symdeko^®, which was approved by the U.S. FDA in February 2018 for treating patients with certain CFTR mutations. Ivacaftor is also one of the components of triple combination approaches for CF currently being tested in Phase III clinical trials (ivacaftor/tezacaftor/VX-659 and ivacaftor/tezacaftor/VX-445). Despite the beneficial activities of ivacaftor, there is a continuing need for modulators of CFTR activity and compositions thereof, which can be used to modulate the activity of the CFTR in the cell membrane of a mammal.

0011A deuterated form of ivacaftor, known by the chemical name N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide, also acts as a CFTR potentiator. This deuterated derivative of ivacaftor metabolizes more slowly than ivacaftor, which results in a slower drug clearance from the body. This slower metabolism allows less frequent or lower dosing of the drug.

0012There is a need for efficient processes for the synthesis of compounds useful as CFTR modulators that deliver these compounds in for example, higher yield, higher selectivity, or with higher purity relative to known processes. Accordingly, this disclosure provides processes for the synthesis of ivacaftor and pharmaceutically acceptable salts thereof. An alternative process for preparing ivacaftor is disclosed in <patcit id="pcit0002" dnum="WO2010108162A"><text>PCT Publication No. WO 2010/108162</text></patcit>. The preparation of compound 11A is also disclosed in <patcit id="pcit0003" dnum="US2010184739A"><text>US 2010/184739</text></patcit>.

0013The invention provides a process for preparing Compound <b>11A:</b><chemistry id="chem0001" num="0001"><img file="EP3717455B1_D0001.tif" /></chemistry> comprising converting Compound <b>12:</b><chemistry id="chem0002" num="0002"><img file="EP3717455B1_D0002.tif" /></chemistry><ul id="ul0001" list-style="none" compact="compact"><li>into Compound <b>11A</b> in the presence of NaNO₃ and AlCl₃,</li><li>wherein the methyl (Me) of the -OCO₂Me of Compound <b>12</b> is optionally replaced by a group selected from aliphatic, heteroaliphatic, aryl, and heteroaryl,</li><li>wherein "aliphatic" means a straight-chain or branched, substituted, or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule, and includes haloaliphatic groups; and wherein "heteroaliphatic" means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, that is substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and includes heterocyclic groups which are non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members is an independently selected heteroatom.</li></ul>

0014In some embodiments, the conversion is performed in the presence of a solvent.

0015In some embodiments, the solvent is CH₂Cl₂.

0016In some embodiments, the process of the invention further comprises the preparation of a compound having the structure: <chemistry id="chem0003" num="0003"><img file="EP3717455B1_D0003.tif" /></chemistry>

0017The process of the invention may be useful in the preparation of ivacaftor (compound <b>1</b>). An example of a process for the preparation of ivacaftor (compound <b>1</b>): <chemistry id="chem0004" num="0004"><img file="EP3717455B1_D0004.tif" /></chemistry> comprises: <ol id="ol0001"><li>(a) reacting compound <b>3:</b><chemistry id="chem0005" num="0005"><img file="EP3717455B1_D0005.tif" /></chemistry> with compound <b>4:</b><chemistry id="chem0006" num="0006"><img file="EP3717455B1_D0006.tif" /></chemistry> in the presence of T3P^® and pyridine using 2-methyl tetrahydrofuran as the solvent to form compound <b>5</b><chemistry id="chem0007" num="0007"><img file="EP3717455B1_D0007.tif" /></chemistry> and</li><li>(b) reacting compound <b>5</b> with NaOMe/MeOH in 2-methyl tetrahydrofuran to form ivacaftor (compound <b>1</b>).</li></ol>

I. DEFINITIONS

0018The term "CFTR" as used herein means cystic fibrosis transmembrane conductance regulator or a mutation thereof capable of regulator activity.

0019The term "CFTR potentiator" as used herein refers to a compound that increases the channel activity of CFTR protein located at the cell surface, resulting in enhanced ion transport.

0020Compounds described herein may be optionally substituted with one or more substituents, as illustrated generally above, or as exemplified by particular classes, subclasses, and species of the disclosure. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.

0021Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds.

0022The term "compound," when referring to a compound of this disclosure, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this disclosure will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound. However, as set forth above the relative amount of such isotopologues <i>in toto</i> will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues <i>in toto</i> will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

0023The term "isotopologue" refers to a species in which the chemical structure differs from a specific compound of this disclosure only in the isotopic composition thereof. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C or ¹⁴C, are within the scope of this disclosure.

0024The term "stable," as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.

0025The term "stable compounds," as used herein, refers to compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compounds for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents).

0026Throughout the disclosure, wherever "methyl" (Me) is referenced in a structure containing a carbomethoxy carbonate (i.e., -OCO₂Me), it may be replaced with groups selected from "aliphatic," "heteroaliphatic," "heterocyclic," "haloaliphatic," "aryl," and "heteroaryl."

0027The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain (i.e., unbranched) or branched, substituted, or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle", "cycloaliphatic", or "cycloalkyl"), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain one to twenty aliphatic carbon atoms. In some embodiments, aliphatic groups contain one to ten aliphatic carbon atoms. In other embodiments, aliphatic groups contain one to eight aliphatic carbon atoms. In still other embodiments, aliphatic groups contain one to six aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain one to four aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C_3-8 hydrocarbon or bicyclic or tricyclic C_8-14 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has three to seven members. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. Suitable cycloaliphatic groups include cycloalkyl, bicyclic cycloalkyl (e.g., decalin), bridged bicycloalkyl such as norbornyl or [2.2.2]bicyclo-octyl, or bridged tricyclic such as adamantyl.

0028The term "heteroaliphatic," as used herein, means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocycle," "heterocyclyl," "heterocycloaliphatic," or "heterocyclic" groups.

0029The term "heterocycle," "heterocyclyl," "heterocycloaliphatic," or "heterocyclic" as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members is an independently selected heteroatom. In some embodiments, the "heterocycle," "heterocyclyl," "heterocycloaliphatic," or "heterocyclic" group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains three to seven ring members.

0030The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl)).

0031The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

0032The term "alkoxy," or "thioalkyl," as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen ("alkoxy") or sulfur ("thioalkyl") atom.

0033The terms "haloaliphatic" and "haloalkoxy" means aliphatic or alkoxy, as the case may be, substituted with one or more halo atoms. The term "halogen" or "halo" means F, Cl, Br, or I. Examples of haloaliphatic include -CHF₂, -CH₂F, -CF₃, - CF₂-, or perhaloalkyl, such as -CF₂CF₃.

0034The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term "aryl" also refers to heteroaryl ring systems as defined herein below.

0035The term "heteroaryl", used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members.

0036An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents.

0037An aliphatic or heteroaliphatic group or a non-aromatic heterocyclic ring may contain one or more substituents.

0038The term "alcoholic solvent" as used herein represents a solvent that is an alcohol (e.g., methanol, ethanol).

0039The term "aprotic solvent" as used herein describes a solvent that lacks the ability to donate or exchange a proton.

0040The term "coupling reaction" as used herein describes the reaction of a carboxylic acid and an amine to form an amide bond.

0041The term "reducing agent" as used herein describes a compound that donates an electron to another species.

0042The term "alkoxyformylating" as used herein describes the protection of an alcohol with a -C(O)OR group to form a carbonate.

0043The term "halogenating agent" as used herein describes a reagent that replaces one or more C-H bonds with a corresponding number of C-X bonds, wherein X is a halogen.

0044Examples of useful protecting groups for carboxylic acids are substituted alkyl esters such as 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, pivaloyloxymethyl, phenylacetoxymethyl, triisopropropylsysilylmethyl, cyanomethyl, acetol, phenacyl, substituted phenacyl esters, 2,2,2- trichloroethyl, 2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, t-butyl, 3-methyl-3-pentyl, dicyclopropylmethyl, cyclopentyl, cyclohexyl, allyl, methallyl, cinnamyl, phenyl, silyl esters, benzyl and substituted benzyl esters, and 2,6-dialkylphenyl esters such as pentafluorophenyl and 2,6-dialkylpyhenyl. Other useful protecting groups for carboxylic acids are methyl or ethyl esters.

0045Methods of adding (a process generally referred to as "protection") and removing (a process generally referred to as "deprotection") such amine and carboxylic acid protecting groups are well-known in the art and available, for example in <nplcit id="ncit0011" npl-type="s"><text>P. J. Kocienski, Protecting Groups, Thieme, 1994</text></nplcit> and in <nplcit id="ncit0012" npl-type="b"><text>Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley &amp; Sons, New York, 1999</text></nplcit>).

0046Examples of suitable solvents that may be used in this disclosure are, but not limited to, water, methanol (MeOH), methylene chloride (CH₂Cl₂), acetonitrile, <i>N,N-</i>dimethylformamide (DMF), methyl acetate (MeOAc), ethyl acetate (EtOAc), isopropyl acetate (IPAc), <i>tert</i>-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), <i>tert</i>-butanol, diethyl ether (Et₂O), methyl <i>tert</i>-butyl ether (MTBE), 1,4-dioxane, and <i>N</i>-methyl pyrrolidone (NMP).

0047Examples of suitable coupling agents that may be used in this disclosure are, but not limited to, 1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (EDCI), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 1-hydroxybenzotriazole (HOBT), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU), 2-chloro-1,3-dimethyl-2-imidazolium tetrafluoroborate, 1-H-benzotriazolium-1-[bis(dimethylamino)methylene]-5-chlorohexafluorophosphate (HCTU), 2-chloro-4,6-dimethoxy-1,3,5-triazine, and 2-propane phosphonic anhydride (T3P^®).

0048Examples of suitable bases that may be used in this disclosure are, but not limited to, potassium carbonate (K₂CO₃), <i>N</i>-methylmorpholine (NMM), triethylamine (Et₃N; TEA), diisopropylethyl amine (<i>i</i>-Pr₂EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), and sodium methoxide (NaOMe; NaOCH₃).

0049Unless otherwise stated, structures depicted herein are also meant to include all isomeric forms of the structure, e.g., geometric (or conformational), such as (<i>Z</i>) and (<i>E</i>) double bond isomers and (Z) and (E) conformational isomers. Therefore, geometric or conformational mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure. A compound of Formula <b>9</b> may exist as a tautomer: <chemistry id="chem0008" num="0008"><img file="EP3717455B1_D0008.tif" /></chemistry>

0050"D" and "d" both refer to deuterium. "Stereoisomer" refers to both enantiomers and diastereomers. "Tert" and "t-" each refer to tertiary.

0051"Substituted with deuterium" or "deuteration" refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms. "Deuterated" refers to a compound that has undergone substitution with deuterium.

0052The disclosure also provides processes for preparing salts of the compounds of the disclosure.

0053A salt of a compound of this disclosure is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxylic acid or phenolic functional group. According to another embodiment, the compound is a pharmaceutically acceptable salt.

0054The term "pharmaceutically acceptable," as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

0055Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as paratoluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and preferably those formed with organic acids such as maleic acid.

0056It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. Thus, a preparation of ivacaftor will inherently contain small amounts of deuterated isotopologues. The concentration of naturally abundant stable hydrogen and carbon isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this disclosure. See, for instance, <nplcit id="ncit0013" npl-type="s"><text>Wada, E et al., Seikagaku, 1994, 66:15</text></nplcit>; <nplcit id="ncit0014" npl-type="s"><text>Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725</text></nplcit>.

0057In the compounds of this disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Also unless otherwise stated, when a position is designated specifically as "D" or "deuterium," the position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 45% incorporation of deuterium).

0058The percentage of isotopic enrichment for each designated deuterium is at least 90%.

0059The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. In other embodiments, a compound of this disclosure has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

0060The percentage of isotopic enrichment for each designated deuterium can be at least 90%.

0061The invention is defined by the claims and relates to a process for preparing Compound 11A. Compound 11A and the process of the invention may be useful for the synthesis of ivacaftor or pharmaceutically acceptable salts of ivacaftor. Ivacaftor or pharmaceutically acceptable salts of ivacaftor may be for use as potentiators of CFTR.

0062The disclosure describes a process for preparing ivacaftor (compound <b>1</b>): <chemistry id="chem0009" num="0009"><img file="EP3717455B1_D0009.tif" /></chemistry> comprising converting compound <b>5:</b><chemistry id="chem0010" num="0010"><img file="EP3717455B1_D0010.tif" /></chemistry> into ivacaftor (compound <b>1</b>).

0063In some embodiments, the conversion of compound <b>5</b> into compound <b>1</b> is performed in the presence of a base and an alcoholic solvent.

0064In some embodiments, the base is selected from NaOH, KOH, and NaOMe.

0065In some embodiments, the base is NaOMe.

0066In some embodiments, the alcoholic solvent is methanol.

0067In some embodiments, the conversion is performed in the presence of an aprotic solvent.

0068In some embodiments, the aprotic solvent is 2-methyl tetrahydrofuran.

0069The disclosure further describes a process for the preparation of compound <b>5:</b><chemistry id="chem0011" num="0011"><img file="EP3717455B1_D0011.tif" /></chemistry> comprising reacting compound <b>3:</b><chemistry id="chem0012" num="0012"><img file="EP3717455B1_D0012.tif" /></chemistry> with compound <b>4:</b><chemistry id="chem0013" num="0013"><img file="EP3717455B1_D0013.tif" /></chemistry> to form compound <b>5.</b>

0070In some embodiments, the reaction of compound <b>3</b> with compound <b>4</b> is performed in the presence of a coupling agent.

0071In some embodiments, the coupling agent is selected from 2-chloro-1,3-dimethyl-2-imidazolium tetrafluoroborate, HBTU, HCTU, 2-chloro-4,6-dimethoxy-1,3,5-triazine, HATU, HOBT/EDC, and T3P^®.

0072In some embodiments, the coupling agent is T3P^®.

0073In some embodiments, the coupling reaction is performed in the presence of a base.

0074In some embodiments, the base is selected from K₂CO₃, Et₃N, NMM, pyridine, and DIPEA.

0075In some embodiments, the base is pyridine.

0076In some embodiments, the coupling reaction is performed in the presence of a solvent.

0077In some embodiments, the solvent is 2-methyl tetrahydrofuran.

0078The disclosure further describes a process for the preparation of compound <b>3:</b><chemistry id="chem0014" num="0014"><img file="EP3717455B1_D0014.tif" /></chemistry> comprising converting compound <b>10:</b><chemistry id="chem0015" num="0015"><img file="EP3717455B1_D0015.tif" /></chemistry> into compound <b>3.</b>

0079In some embodiment, the conversion of compound <b>10</b> into compound <b>3</b> is performed in the presence of a base.

0080In some embodiments, the base is selected from NaOH, KOH, and NaOMe.

0081In some embodiments, the base is NaOMe.

0082In some embodiments, the conversion is performed in the presence of an acid.

0083In some embodiments, the acid is HCl.

0084The disclosure further describes a process for the preparation of compound <b>4:</b><chemistry id="chem0016" num="0016"><img file="EP3717455B1_D0016.tif" /></chemistry> comprising converting compound <b>11A:</b><chemistry id="chem0017" num="0017"><img file="EP3717455B1_D0017.tif" /></chemistry> into compound <b>4.</b>

0085In some embodiments, the conversion of compound <b>11A</b> into compound <b>4</b> is performed in the presence of a reducing agent.

0086In some embodiments, the reducing agent is H₂.

0087In some embodiments, the reaction is performed in the presence of a transition-metal catalyst.

0088In some embodiments, the transition-metal catalyst is a platinum catalyst.

0089In some embodiments, the transition-metal catalyst is a palladium catalyst.

0090In some embodiments, the palladium catalyst is palladium on carbon.

0091In some embodiments, the reaction is performed in the presence of a solvent.

0092In some embodiments, the solvent is an alcohol.

0093In some embodiments, the alcohol is methanol.

0094The invention, which is defined by the claims, provides a process for the preparation of compound <b>11A:</b><chemistry id="chem0018" num="0018"><img file="EP3717455B1_D0018.tif" /></chemistry> comprising converting compound <b>12:</b><chemistry id="chem0019" num="0019"><img file="EP3717455B1_D0019.tif" /></chemistry> into compound <b>11A.</b>

0095The conversion of compound <b>12</b> into compound <b>11A</b> is performed in the presence of one or more acids or salts, wherein the one or more acids or salts is NaNO₃ and AlCl₃.

0096In some embodiments, the conversion is performed in the presence of a solvent.

0097In some embodiments, the solvent is CH₂Cl₂.

0098The disclosure further describes a process for the preparation of compound <b>12:</b><chemistry id="chem0020" num="0020"><img file="EP3717455B1_D0020.tif" /></chemistry> comprising converting compound <b>13:</b><chemistry id="chem0021" num="0021"><img file="EP3717455B1_D0021.tif" /></chemistry> into compound <b>12.</b>

0099In some embodiments, the conversion of compound <b>13</b> into compound <b>12</b> is performed with an alkoxyformylating agent.

0100In some embodiments, the alkoxyformylating agent is methyl chloroformate.

0101In some embodiments, the conversion is performed in the presence of a base.

0102In some embodiments, the base is an organic base.

0103In some embodiments, the organic base is Et₃N.

0104In some embodiments, the conversion is performed in the presence of a solvent.

0105In some embodiments, the solvent is CH₂Cl₂.

0106A listing of exemplary embodiments includes: <ol id="ol0002"><li>1. A process for preparing Compound <b>11A:</b><chemistry id="chem0022" num="0022"><img file="EP3717455B1_D0022.tif" /></chemistry> comprising converting Compound <b>12</b><chemistry id="chem0023" num="0023"><img file="EP3717455B1_D0023.tif" /></chemistry> into compound <b>11A</b> in the presence of NaNO₃ and AlCl₃, <ul id="ul0002" list-style="none" compact="compact"><li>wherein the methyl (Me) of the -OCO₂Me of Compound <b>12</b> is optionally replaced by a group selected from aliphatic, heteroaliphatic, aryl, and heteroaryl,</li><li>wherein "aliphatic" means a straight-chain or branched, substituted, or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule, and includes haloaliphatic groups; and wherein "heteroaliphatic" means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, that is substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and includes heterocyclic groups which are non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members is an independently selected heteroatom.</li></ul></li><li>2. The process of embodiment 1, wherein the conversion is performed in the presence of a solvent.</li><li>3. The process of embodiment 2, wherein the solvent is CH₂Cl₂.</li><li>4. The process of embodiment 1, wherein compound <b>12</b> is produced by converting compound <b>13:</b><chemistry id="chem0024" num="0024"><img file="EP3717455B1_D0024.tif" /></chemistry> into compound <b>12.</b></li><li>5. The process of embodiment 4, wherein the conversion of compound <b>13</b> into compound <b>12</b> is performed with an alkoxyformylating agent.</li><li>6. The process of embodiment 5, wherein the alkoxyformylating agent is methyl chloroformate.</li><li>7. The process of embodiment 4, wherein the conversion is performed in the presence of a base.</li><li>8. The process of embodiment 7, wherein the base is an organic base.</li><li>9. The process of embodiment 8, wherein the organic base is DIPEA.</li><li>10. The process of embodiment 4, wherein the conversion is performed in the presence of a catalyst.</li><li>11. The process of embodiment 10, wherein the catalyst is 4-dimethylaminopyridine.</li><li>12. The process of embodiment 4, wherein the conversion is performed in the presence of a solvent.</li><li>13. The process of embodiment 12, wherein the solvent is CH₂Cl₂.</li></ol>

II. GENERAL SYNTHESIS

0107Compound <b>1</b> can be synthesized according to Scheme 1. <chemistry id="chem0025" num="0025"><img file="EP3717455B1_D0025.tif" /></chemistry>

0108In some embodiments, the disclosure is directed to a process comprising one or more of the following steps: <ol id="ol0003" compact="compact"><li>a. Reacting compound <b>13</b> with an alkoxyformylating agent;</li><li>b. Reacting compound <b>12</b> with a nitrating agent;</li><li>c. Reacting compound <b>11A</b> with a reducing agent;</li><li>d. Reacting compound <b>4</b> with compound <b>3;</b></li><li>e. Reacting compound <b>5</b> with a base.</li></ol>

0109Compound <b>3</b> can be prepared as disclosed in <patcit id="pcit0004" dnum="WO2010108162A"><text>PCT Publication No. WO 2010/108162</text></patcit>.

0110Compound <b>2</b> can be synthesized according to Scheme 2. <chemistry id="chem0026" num="0026"><img file="EP3717455B1_D0026.tif" /></chemistry>

0111In one embodiment, the disclosure is directed to a process comprising one or more of the following steps: <ol id="ol0004" compact="compact"><li>a. Reacting compound <b>14</b> with a source of deuterium;</li><li>b. Reacting compound <b>19</b> with a source of -C(CD₃)₃;</li><li>c. Reacting compound <b>18</b> with a brominating agent;</li><li>d. Reacting compound <b>17</b> with an alkoxyformylating agent;</li><li>e. Reacting compound <b>16</b> with a nitrating agent;</li><li>f. Reacting compound <b>15</b> with a reducing agent;</li><li>g. Reacting compound <b>7</b> with compound <b>3;</b> and</li><li>h. Reacting compound <b>8</b> with a base.</li></ol>

0112Compound <b>3</b> can be prepared as disclosed in PCT Publication No. WO 2010/108162.

0113Compound <b>2</b> can be prepared wherein each D in the CD₃ group has an isotopic enrichment of at least 90%.

0114Compound <b>2</b> may also be prepared as outlined in Scheme 3. <chemistry id="chem0027" num="0027"><img file="EP3717455B1_D0027.tif" /></chemistry>

0115In one embodiment, the disclosure is directed to a process comprising one or more of the following steps: <ol id="ol0005" compact="compact"><li>a. Reacting compound <b>26</b> with a metal to effect metal/halogen exchange, then reacting the product with an appropriate electrophile;</li><li>b. Subjecting compound <b>25</b> to esterification reaction conditions;</li><li>c. Reacting compound <b>24</b> with a protecting agent;</li><li>d. Reacting compound <b>23</b> with a source of -C(CD₃)₃;</li><li>e. Reacting compound <b>22</b> with an alkoxyformylating agent;</li><li>f. Reacting compound <b>21</b> with a nitrating agent;</li><li>g. Reacting compound <b>20</b> with a reducing agent.</li><li>h. Reacting compound <b>7</b> with compound <b>3;</b> and</li><li>i. Reacting compound <b>8</b> with a base.</li></ol>

0116Compound <b>3</b> can be prepared as disclosed in <patcit id="pcit0005" dnum="WO2010108162A"><text>PCT Publication No. WO 2010/108162</text></patcit>.

0117Compound <b>2</b> can be prepared wherein each D in the CD₃ group has an isotopic enrichment of at least 90%.

0118The synthesis of compounds <b>1</b> and <b>2</b> may be readily achieved by synthetic chemists of ordinary skill by reference to the General Synthesis and Examples disclosed herein.

0119In order that the disclosure described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner.

III.

EXAMPLES

Example 1:

<i>Synthesis of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (1)</i>

0120The overall scheme of the synthesis of compound 1 is shown below (which incorporates the process of the invention). <chemistry id="chem0028" num="0028"><img file="EP3717455B1_D0028.tif" /></chemistry>

0121Compounds <b>12, 4, 5,</b> and <b>1,</b> can be prepared as disclosed in <patcit id="pcit0006" dnum="WO2010108162A"><text>PCT Publication No. WO 2010/108162</text></patcit>.

0122The investigation of a procedure to synthesize compound <b>11A</b> is shown below.

<i>Investigation of Nitration Reaction Conditions</i> -

<b>Nitration Reaction of Compound</b> 12 <b>with H₂SO₄ and NaNO₃ or KNO₃ to form 2,4-di-tert-butyl-5-nitrophenyl methyl carbonate</b> (11A)

0123<tables id="tabl0001" num="0001"><table frame="bottom"><title><b>Table 1</b></title><tgroup cols="7" colsep="0"><colspec colnum="1" colname="col1" colwidth="29mm" align="center" /><colspec colnum="2" colname="col2" colwidth="29mm" align="center" /><colspec colnum="3" colname="col3" colwidth="29mm" align="center" /><colspec colnum="4" colname="col4" colwidth="41mm" align="center" /><colspec colnum="5" colname="col5" colwidth="56mm" align="center" /><colspec colnum="6" colname="col6" colwidth="29mm" align="center" /><colspec colnum="7" colname="col7" colwidth="31mm" align="center" /><thead><row valign="top"><entry namest="col1" nameend="col7"><chemistry id="chem0029" num="0029"><img file="EP3717455B1_D0029.tif" /></chemistry></entry></row><row><entry>entry</entry><entry>-NO₂ source</entry><entry>acid</entry><entry>purity at end of reaction¹ (% <b>11A</b>)</entry><entry>nitration ratio of <b>11A: 11B : 11C</b> (unpurified)</entry><entry>isolated yield (%)</entry><entry>isolated purity (%)</entry></row></thead><tbody><row rowsep="0"><entry>1</entry><entry>HNO₃</entry><entry>H₂SO₄</entry><entry>21</entry><entry>47 : 39 : 14</entry><entry>37</entry><entry>73</entry></row><row rowsep="0"><entry>2</entry><entry>HNO₃</entry><entry>H₂SO₄</entry><entry>17</entry><entry>41 : 41 : 17</entry><entry>--</entry><entry>--</entry></row><row rowsep="0"><entry>3</entry><entry>KNO₃</entry><entry>H₂SO₄</entry><entry>18</entry><entry>43 : 40 : 17</entry><entry>--</entry><entry>--</entry></row><row><entry>4</entry><entry>KNO₃</entry><entry>H₂SO₄</entry><entry>17</entry><entry>41 : 43 : 16</entry><entry>--</entry><entry>--</entry></row></tbody></tgroup><tgroup cols="7" rowsep="0"><colspec colnum="1" colname="col1" colwidth="29mm" align="justify" /><colspec colnum="2" colname="col2" colwidth="29mm" /><colspec colnum="3" colname="col3" colwidth="29mm" /><colspec colnum="4" colname="col4" colwidth="41mm" /><colspec colnum="5" colname="col5" colwidth="56mm" /><colspec colnum="6" colname="col6" colwidth="29mm" /><colspec colnum="7" colname="col7" colwidth="31mm" /><tbody><row><entry namest="col1" nameend="col7">¹ HPLC purity of <b>11A</b> in the reaction mixture once the reaction is completed, prior to any workup or isolation step.</entry></row></tbody></tgroup></table></tables>

<i>Procedure for nitration reaction (Table 1, entry 1)</i>

0124100 ml of 96% sulfuric acid were charged in reactor 1 and cooled to 0 °C 50 g of 2,4-di-tert-butylphenyl methyl carbonate (<b>12</b>) were added over the sulfuric acid maintaining the temperature below 10 °C. Then the reactor was cooled to -5 °C. To another reactor (reactor 2) 50 ml of 96% sulfuric acid and 14.4 ml of 65% nitric acid were charged, and the resulting mixture was cooled to -5 °C. The contents of reactor 2 were added into reactor 1 maintaining the temperature below 0 °C. The mixture was stirred at 0/-5 °C for 4 hours. The crude of reaction reaction was quenched by adding it slowly over a mixture formed by 200 ml of DCM and 353 ml of water at 0 °C. Then the mixture was heated to 20 °C and stirred for 1 hour. The phases were separated and the aqueous phase was washed with 100 ml of DCM. The combined organic phases were washed with 123 ml of water first and then with 160 ml of a 13% sodium chloride solution in water. The resulting organic solution was then concentrated under vacuum to 55 ml to obtain an oil that precipitated. The solid was dissolved with 155 ml of methanol at 65 °C. The solution was distilled at atmospheric pressure until 155 ml. 20 ml of methanol were added and the solution was cooled to 25/30 °C in 2 hours and stirred at this temperature for 1 hour. The solids were filtered and washed with 11.5 ml of methanol to yield 24.06 g of 2,4-di-tert-butyl-5-nitrophenyl methyl carbonate <b>(11A)</b> as wet solid with a 10.6% of methanol. Yield: 37% HPLC purity: 73%.

<i>Investigation of Nitration Reaction Conditions</i> -

<b>Nitration Reaction of Compound 12 with Trimethylsilylchloride, AlCl₃, and KNO₃ to form 2,4-di-tert-butyl-5-nitrophenyl methyl carbonate</b> (11A)

0125<tables id="tabl0002" num="0002"><table frame="bottom"><title><b>Table 2</b></title><tgroup cols="7" colsep="0"><colspec colnum="1" colname="col1" colwidth="29mm" align="center" /><colspec colnum="2" colname="col2" colwidth="29mm" align="center" /><colspec colnum="3" colname="col3" colwidth="29mm" align="center" /><colspec colnum="4" colname="col4" colwidth="29mm" align="center" /><colspec colnum="5" colname="col5" colwidth="29mm" align="center" /><colspec colnum="6" colname="col6" colwidth="41mm" align="center" /><colspec colnum="7" colname="col7" colwidth="57mm" align="center" /><thead><row valign="top"><entry namest="col1" nameend="col7"><chemistry id="chem0030" num="0030"><img file="EP3717455B1_D0030.tif" /></chemistry></entry></row><row><entry>entry</entry><entry>KNO₃ (equiv)</entry><entry>TMSCI (equiv)</entry><entry>AlCl₃ (equiv)</entry><entry>T (°C)</entry><entry>purity at end of reaction¹ (% <b>11A)</b></entry><entry>nitration ratio of <b>11A : 11B : 11C</b> (unpurified)</entry></row></thead><tbody><row rowsep="0"><entry>1</entry><entry>1.5</entry><entry>2.0</entry><entry>3.0</entry><entry>0</entry><entry>55</entry><entry>85 : 5 : 10</entry></row><row rowsep="0"><entry>2</entry><entry>1.5</entry><entry>2.0</entry><entry>3.0</entry><entry>0</entry><entry>43</entry><entry>82 : 4 : 14</entry></row><row rowsep="0"><entry>3</entry><entry>1.5</entry><entry>2.0</entry><entry>3.0</entry><entry>0</entry><entry>57</entry><entry>89 : 6 : 4</entry></row><row rowsep="0"><entry>4</entry><entry>1.1</entry><entry>2.5</entry><entry>3.3</entry><entry>0</entry><entry>47</entry><entry>87 : 9 : 4</entry></row><row rowsep="0"><entry>5</entry><entry>1.1</entry><entry>2.5</entry><entry>3.3</entry><entry>20</entry><entry>42</entry><entry>64 : 30 : 6</entry></row><row rowsep="0"><entry>6</entry><entry>1.1</entry><entry>2.5</entry><entry>4.5</entry><entry>20</entry><entry>36</entry><entry>88 : 0 : 12</entry></row><row rowsep="0"><entry>7</entry><entry>1.2</entry><entry>2.0</entry><entry>3.0</entry><entry>0</entry><entry>46</entry><entry>66 : 34 : 0</entry></row><row rowsep="0"><entry>8</entry><entry>1.5</entry><entry>2.0</entry><entry>3.0</entry><entry>-15</entry><entry>53</entry><entry>91 : 6 : 3</entry></row><row><entry>9</entry><entry>1.5</entry><entry>2.0</entry><entry>3.0²</entry><entry>-15</entry><entry>21</entry><entry>48 : 46 : 6</entry></row></tbody></tgroup><tgroup cols="7" rowsep="0"><colspec colnum="1" colname="col1" colwidth="29mm" align="justify" /><colspec colnum="2" colname="col2" colwidth="29mm" /><colspec colnum="3" colname="col3" colwidth="29mm" /><colspec colnum="4" colname="col4" colwidth="29mm" /><colspec colnum="5" colname="col5" colwidth="29mm" /><colspec colnum="6" colname="col6" colwidth="41mm" /><colspec colnum="7" colname="col7" colwidth="57mm" /><tbody><row><entry namest="col1" nameend="col7">¹ HPLC purity of <b>11A</b> in the reaction mixture once the reaction is completed, prior to any workup or isolation step.</entry></row></tbody></tgroup></table></tables>

<i>Procedure for nitration reaction (Table 2, entry 1)</i>

01261.15 g of potassium nitrate and 14.6 ml of dichloromethane were charged into a reactor. The suspension was cooled to 0 °C. 1.95 ml of chloromethylsilane were added at 0 °C and then 2.0 g of 2,4-di-tert-butylphenyl methyl carbonate <b>(12)</b> and 2 ml of dichloromethane. 3.03 g of aluminum trichloride were added slowly at 0 °C and the mixture was stirred then at this temperature for 20 hours. The reaction was then quenched by adding 20 ml of water maintaining the temperature below 30 °C 15 ml of dichloromethane were charged and the mixture was heated to 25 °C. The two phases were separated and the aqueous phase was washed with 20 ml of dichloromethane. The combined organic phases were washed with 20 ml of water two times and the resulting organic phase was concentrated to dryness to yield 2.044 g (87.4%) of 2,4-di-tert-butyl-5-nitrophenyl methyl carbonate <b>(11A).</b> HPLC purity: 55%.

<i>Investigation of Nitration Reaction Conditions</i> - <i>Nitration Reaction of Compound 12 with AlCl₃</i>/

<b>NaNO₃ to form 2,4-di-tert-butyl-5-nitrophenyl methyl carbonate</b> (11A)

0127<tables id="tabl0003" num="0003"><table frame="bottom"><title><b>Table 3</b></title><tgroup cols="8" colsep="0"><colspec colnum="1" colname="col1" colwidth="25mm" align="center" /><colspec colnum="2" colname="col2" colwidth="27mm" align="center" /><colspec colnum="3" colname="col3" colwidth="25mm" align="center" /><colspec colnum="4" colname="col4" colwidth="25mm" align="center" /><colspec colnum="5" colname="col5" colwidth="34mm" align="center" /><colspec colnum="6" colname="col6" colwidth="50mm" align="center" /><colspec colnum="7" colname="col7" colwidth="29mm" align="center" /><colspec colnum="8" colname="col8" colwidth="30mm" align="center" /><thead><row valign="top"><entry namest="col1" nameend="col8"><chemistry id="chem0031" num="0031"><img file="EP3717455B1_D0031.tif" /></chemistry></entry></row><row><entry>entry</entry><entry>NaNO₃ (equiv)</entry><entry>AlCl₃ (equiv)</entry><entry>T (°C)</entry><entry>purity at end of reaction¹ (% <b>11A)</b></entry><entry>nitration ratio of <b>11A</b> : <b>11B</b> : <b>11C</b> (unpurified)</entry><entry>isolated yield (%)</entry><entry>isolated purity (%)</entry></row></thead><tbody><row rowsep="0"><entry>1</entry><entry>1.2</entry><entry>3.0</entry><entry>-15</entry><entry>88</entry><entry>96 : 3 : 1</entry><entry>87</entry><entry>99.3</entry></row><row><entry>2</entry><entry>1.2</entry><entry>3.0</entry><entry>-15</entry><entry>89</entry><entry>96 : 3 : 1</entry><entry>87</entry><entry>99.6</entry></row></tbody></tgroup><tgroup cols="8" rowsep="0"><colspec colnum="1" colname="col1" colwidth="25mm" align="justify" /><colspec colnum="2" colname="col2" colwidth="27mm" /><colspec colnum="3" colname="col3" colwidth="25mm" /><colspec colnum="4" colname="col4" colwidth="25mm" /><colspec colnum="5" colname="col5" colwidth="34mm" /><colspec colnum="6" colname="col6" colwidth="50mm" /><colspec colnum="7" colname="col7" colwidth="29mm" /><colspec colnum="8" colname="col8" colwidth="30mm" /><tbody><row><entry namest="col1" nameend="col8">¹ HPLC purity of <b>11A</b> in the reaction mixture once the reaction is completed, prior to any workup or isolation step.</entry></row></tbody></tgroup></table></tables>

<i>Procedure for nitration reaction (Table 3, entry 2)</i>

0128143.75 g of aluminum trichloride and 789 ml of methylene chloride were charged to a 1 liter reactor. The mixture was cooled to 0 °C and 36.65 g of sodium nitrate were added. The crude of reaction was stirred at 0 °C for 3 hours. Then the reactor was cooled to -20 °C and 95 g of 2,4-di-tert-butylphenyl methyl carbonate <b>(12)</b> dissolved in 76 ml of methylene chloride were added while maintaining the temperature at -15 °C. The mixture was then stirred for twenty hours at -15 °C. In another reactor 665 ml of 2M hydrochloric acid were charged and cooled to 3 °C, then the crude of reaction was quenched slowly over the hydrochloric solution at 10 °C. The mixture was heated to 20 °C and stirred for 1 hour at this temperature before separating both layers. The aqueous phase was washed with 190 ml of methylene chloride that were combined with the initial organic phase. The two combined organic phases were washed three times with 510 ml of sodium chloride solution containing 475 ml of water and 95 g of sodium chloride each. The resulting organic phase was concentrated under vacuum to 190 ml and then 618 ml of methanol were added. The mixture was concentrated again to a final volume of 570 ml and heated to 64 °C. 190 ml of methanol are added to the mixture while maintaining 64 °C to obtain complete dissolution of the solids. Then the mixture was cooled to 55 °C and maintained at this temperature for 1 hour. Later it was cooled to 2 °C in 2 hours and stirred at this temperature for 2 additional hours before filtering the solid. The wet cake was washed twice with 47.5 ml of cold methanol and the wet solids were dried at 45 °C under vacuum to yield 96.15 g (86.5%) of 2,4-di-tert-butyl-5-nitrophenyl methyl carbonate <b>(11A).</b> HPLC purity: 99.6%

<i>Synthesis of 2,4-di-tert-butyl-5-nitrophenyl methyl carbonate (11A)</i>

0129<chemistry id="chem0032" num="0032"><img file="EP3717455B1_D0032.tif" /></chemistry>

0130Methylene chloride (3091 L) was charged into a reactor and cooled to -5 - 5 °C, then aluminum trichloride (564 kg) and sodium nitrate (144 kg) were added. The mixture was stirred at -1 - 5 °C for not less than 3 hours and then further cooled to -20 - - 12 °C. A solution of 2,4-di-tert-butylphenyl methyl carbonate (373 kg) in methylene chloride (300 L) was added while maintaining the temperature at -20 - -12 °C. After the addition, the mixture was maintained at -21 - -15 °C. The completeness of the reaction was measured by HPLC with in-process control sample taken after 2 hours. The reaction was considered complete when the peak area of 2,4-di-tert-butylphenyl methyl carbonate was less than 4.5%.

0131In another reactor 2N hydrochloric acid solution was prepared (526 kg of concentrated HCl in 1864 L of water) and cooled to 0±5 °C. The reaction mixture was then added slowly to the hydrochloric solution at not more than 20 °C to quench the reaction. The mixture temperature was heated to 15 - 21 °C and stirred for 1 hour before separating both layers. The aqueous phase was washed with methylene chloride (745 L, 2.0 vol) at 15 to 21 °C. The combined organic phase was washed three times with 16.7% sodium chloride aqueous solution (prepared by the dissolution of NaCl (298 kg) in water (1491 L) at 15 to 21 °C). The resulting organic phase was then concentrated to 746 L at not more than 45 °C, and methanol (3169 L) was added. The resulting mixture was concentrated to 2237 L at not more than 65 °C and then additional methanol (373 L) was added. The mixture was concentrated again to 2237 L at not more than 65 °C and then heated to reflux (~ 65 °C) to dissolve any solids present. If any solids were still present, methanol (373 L) was added while maintaining the temperature at reflux. This procedure was repeated until all solids were dissolved. At this point the solution was cooled to 45 - 55 °C until crystallization was observed and maintained at this temperature for 1 hour. The resulting slurry was cooled at -5 - 5 °C in 2-5 hours and stirred at this temperature for one additional hour before filtration. The filter cake was washed twice with cold methanol (298 L).

0132The crude product (402 kg), methylene chloride (804 L) and methanol (804 L) were charged into a reactor. The mixture was heated to 40 - 45 °C until all solids completely dissolved. The solution was treated with activated carbon for not less than 1 hour at 40 - 45 °C. After the filtration, methanol (804 L) was added. The solution was concentrated to 804 L under vacuum at not more than 45 °C. Methanol (804 L) was added and the resulting slurry was concentrated to 804 L under vacuum at not more than 45 °C. Methanol (804 L) was added again. The slurry was cooled at -10 - 0 °C in 2-5 hours and then stirred at this temperature for minimum 3 hours before filtration. The filter cake was washed twice with cold methanol (402 L).

0133The wet cake was dried at not more than 50 °C under vacuum until residual methanol and methylene chloride contents were less than 5000 ppm. A light yellow solid, 2,4-di-<i>tert</i>-butyl-5-nitrophenyl methyl carbonate <b>(11A),</b> was obtained (364.9 kg, 99.9% purity measured by HPLC analysis) with 83.6% yield.

Reference Example 2

:

<i>N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (2)</i>

0134The overall scheme of the synthesis of compound <b>2</b> is shown below, followed by the procedure for the synthesis of each intermediate. <chemistry id="chem0033" num="0033"><img file="EP3717455B1_D0033.tif" /></chemistry>

<i>Procedure for the synthesis of 4-(tert-butyl)phen-2, 6-d2-ol-d (19)</i>

0135<chemistry id="chem0034" num="0034"><img file="EP3717455B1_D0034.tif" /></chemistry>

0136To a 5 L round bottom flask equipped with overhead stirrer was charged 4-<i>tert</i>-butylphenol (<b>14,</b> 503.2 g), K₂CO₃ (46.3 g), D₂O (1949 g, 1761 mL, 3.5 vol), and MeOD (409 g, 503 mL, 1.0 vol). The mixture was heated to reflux under a nitrogen atmosphere. The reaction mixture was aged at reflux for 16 hours. The reaction mixture was cooled to room temperature and sampled for conversion (%D incorporation). The reaction was cooled to 5 °C and 35% DCl solution (90 g, 71.2 mL) was added. The reaction mixture was aged at 5 °C for 2 hours. The resultant slurry was filtered and the cake washed with D₂O (836 g, 755 mL, 1.5 vol). This process was repeated until the target %D incorporation is met (normally two exchanges required). The wet cake is dried in a vacuum oven with a nitrogen bleed at 40 °C until a constant weight is obtained. Yield of 4-(tert-butyl)phen-2,6-d2-ol-d (<b>19</b>) is 506 g of a white solid (98%) with a purity of 99.6% and %D incorporation of 99.3%.

<i>Procedure for the synthesis of 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phen-6-d-ol-d and 4-(tert-butyl)-2,6-bis(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenol-d (18)</i>

0137<chemistry id="chem0035" num="0035"><img file="EP3717455B1_D0035.tif" /></chemistry>

01384-(tert-butyl)phen-2,6-d2-ol-d (<b>19</b>) (101.8 g, 0.66 mol, 1.0 equiv.) was dissolved in CH₂Cl₂ (400 mL) in a 2 L reactor. <i>tert</i>-Butanol-<i>d₁₀</i> (43.0 g, 0.51 mol, 0.77 equiv.) was dissolved in CH₂Cl₂ (100 mL) in a 250 mL flask. The solution of <i>tert-</i>butanol-<i>d₁₀</i> was charged to the 2 L reactor at room temperature. The reaction mixture was cooled to -5 °C. D₂SO₄ (51.1 g, 0.51 mol, 0.77 equiv.) was charged dropwise <i>via</i> an addition funnel while maintaining a temperature range of -4 to -2 °C. The reaction mixture was stirred at -2 °C for 3-4 hours. Upon complete conversion the reaction was quenched by adding water (28 mL) and warmed to 18-20 °C. The bottom aqueous layer was drained and discarded. The CH₂Cl₂ layer was treated with sat. aq. NaHCO₃ solution (approximately 200 mL), adjusting the pH to 6-8. NaCl (sat.) solution (400 mL) was charged to the mixture. The resulting solution was stirred for 5 min, and settled for 5 min. The lower CH₂Cl₂ layer was drained into a 1 L flask. The aqueous layer was discarded. The CH₂Cl₂ solution was concentrated to minimal volume and <i>n</i>-heptane (200 mL) was charged. The solution was concentrated to minimal volume and <i>n</i>-heptane charged to a final volume of 800 mL. 0.5 N NaOH solution 600 mL (6 vol) was charged to the reactor and the resulting mixture was stirred for 5 min, and settled for at least 5 min. The aqueous layer was drained and discarded. 1.0 N NaOH solution 300 mL (3 vol) was charged to the reactor and the resulting mixture was stirred for 5 min, and settled for at least 5 min. The aqueous layer was drained and discarded. 1.0 N NaOH solution 300 mL (3 vol) was charged to the reactor and the resulting mixture was stirred for 5 min, and settled for at least 5 min. The aqueous layer was drained and discarded. The remaining <i>n</i>-heptane solution was concentrated to dryness to afford the desired product, 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phen-6-d-ol-d (<b>18</b>) as a clear oil, 104.5 g, which was carried forward into the next step without further purification.

<i>Procedure for the synthesis of 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenol (17)</i>

0139<chemistry id="chem0036" num="0036"><img file="EP3717455B1_D0036.tif" /></chemistry>

01404-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phen-6-d-ol-d (<b>18</b>) (100 g, 0.462 mol, 1.0 equiv.) was dissolved in CH₂Cl₂ (800 mL, 7 vol) in a 2 L reactor and the solution was stirred. The batch was cooled down to 0 ± 3 °C. To the batch was charged portion-wise <i>N</i>-bromosuccinimide (84.4 g, 0.462 mol, 1.0 equiv) over 30 min. The batch was stirred at 0 ± 2 °C for at least 30 minutes. The batch was then heated to 20 ± 2 °C over a period of 2 hours, and stirred at 20 ± 2 °C for at least 12 hours. Upon complete conversion, sat. aq. NaHCOs solution (500 mL, 5 vol) was charged and the batch stirred for at least 10 minutes. The agitation was stopped to allow the phases to separate for at least 5 minutes and the CH₂Cl₂ layer was drained, followed by removal of the aqueous layer. The CH₂Cl₂layer was charged back to the vessel. To the batch was charged sat. aq. NaHCO₃ bicarbonate solution (500 mL, 5 vol), and the batch was stirred for at least 10 minutes. The agitation was stopped to allow the phases to separate for at least 5 minutes and the CH₂Cl₂ layer was drained, followed by removal of the aqueous layer. The CH₂Cl₂ layer was charged back to the vessel and diluted with an additional CH₂Cl₂ (300 mL, 3 vol). The batch was distilled (removal of 300 ml) and checked by KF to achieve dryness. The resulting clear yellow solution of <b>17</b> was carried forward into the next step without further purification.

<i>Procedure for the synthesis of 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (16)</i>

0141<chemistry id="chem0037" num="0037"><img file="EP3717455B1_D0037.tif" /></chemistry>

0142To a clean reactor was charged the CH₂Cl₂ solution of 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phen-6-d-ol-d (<b>17</b>) (136 g, 0.462 mol, 1.0 equiv.) followed by additional CH₂Cl₂ (130 mL, 1 vol), and this solution was stirred. To the batch was charged 4-(dimethylamino)pyridine (2.8 g, 0.023 mol, 0.05 equiv) and triethylamine (70.1 g, 0.693 mol, 1.5 equiv). The batch was cooled to 0 ± 3 °C. To the batch was charged dropwise methyl chloroformate (48.0 g, 0.508 mol, 1.1 equiv) over 40 minutes while maintaining a batch temperature ≤ 5 °C. The batch was stirred at 3 ± 2 °C for at least 30 minutes, and then warmed to 20 ± 2 °C over a period of 1 hour. Upon complete conversion, 1 N HCl (400 mL, 3 vol) was charged. The batch was stirred for at least 10 minutes, and then the layers were allowed to separate for at least 5 minutes. The lower organic layer was drained followed by the aqueous layer (1^st aqueous layer). The organic layer was charged back to the reactor, along with 1 N HCl solution (400 mL, 3 vol). The batch was stirred for at least 10 minutes, and then the layers were allowed to separate for at least 5 minutes. The lower organic layer was drained. The 1^st aqueous layer was charged to the reactor, along with CH₂Cl₂ (300 mL, 2.2 vol). The batch was stirred for at least 10 minutes, and then the layers were allowed to separate for at least 5 minutes. The lower organic layer was drained and combined with the 1^st organic layer, followed by removal of the aqueous layer. Charge the vessel with the contents of both organic layers. The reactor was charged with water (500 mL, 3.7 vol). The batch was stirred for at least 10 minutes, and then the layers were allowed to separate for at least 5 minutes. The lower organic layer was drained, followed by the aqueous layer. The organic layer was charged back to the reactor, along CH₂Cl₂ (400 mL, 3 vol). The batch was distilled to remove 800 ml and checked by KF to ensure dryness. The resulting clear yellow solution of <b>16</b> was telescoped into the next step without further purification.

<i>Procedure for the synthesis of 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-3-nitrophenyl methyl carbonate (15)</i>

0143<chemistry id="chem0038" num="0038"><img file="EP3717455B1_D0038.tif" /></chemistry>

0144To a reactor was charged 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (<b>16</b>) and then the solution was cooled to 0 °C. Sulfuric acid (4.9 equiv) and nitric acid (100%, 2.0 equiv) was charged while maintaining a temperature of not more than 5 °C. The reaction was stirred at 0 °C for 2 hours until complete conversion. The reaction was then quenched with water (8.8 vol) and diluted with CH₂Cl₂ (1.7 vol). The layers were separated and the upper aqueous layer was extracted with CH₂Cl₂ (2.8 vol). After separating the layers, the organic layers were combined, returned to the reactor, and washed with sodium bicarbonate (7.4% w/w, 6.8 vol). After separating the layers, the organic layer was returned to the reactor and washed with sodium chloride (23% w/w, 3.8 vol). After separating the layers, the organic layer was returned to the reactor and concentrated to minimal volume. Methanol (1.2 vol) was charged, followed by concentration to minimal volume. Methanol (1.2 vol) was charged, followed by concentration to minimal volume. Methanol (1.7 vol) was charged, and the slurry was heated to reflux for 30 min and then cooled slowly over 4 hours to 5 °C. The solid product (<b>15</b>) was filtered and the cake washed with cold methanol (1.0 vol). The solid 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-3-nitrophenyl methyl carbonate (<b>15</b>) was dried under vacuum at 40 - 50 °C to yield an off-white solid, 99.9% purity and 99% D incorporation.

<i>Procedure for the synthesis of 5-amino-4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (7)</i>

0145<chemistry id="chem0039" num="0039"><img file="EP3717455B1_D0039.tif" /></chemistry>

0146Charge 5 wt% (50 - 65 wt% wet, JM Type 37) of 5% Pd/C to a reactor. Charge (4.0 vol) Methanol. Close the system. Purge with N_{2 (g)} at 2.0 Bar. Activate with H_{2 (g)} at 2.0 Bar. Charge the vessel to 2.0 Bar with H_{2 (g)} at25°C +/- 5°C. Stir for not less than 2 hours while maintaining a temperature of 25°C +/- 5°C. Vent and purge with N_{2 (g)} at 2.0 Bar. Charge compound <b>15</b> (1.0 eq) to a reactor, together with Na₂HPO₄ (2.3 eq). Charge (11.0 vol) Methanol. Close the system. Purge with N_{2 (g)} at 2.0 Bar. Activate with H_{2 (g)} at 2.0 Bar. Charge the vessel to 2.0 Bar with H_{2 (g)} at25°C +/- 5°C. Stir for about 24 hours while maintaining a reaction temperature of 25°C +/- 5°C. Upon complete conversion, dilute reaction mixture by adding 7.7 vol of MeOH. Heat reaction mixture to 35.0°C +/- 5°C. Filter off catalyst and Na₂HPO₄. Wash the reactor and filter cake with Methanol (4.0 vol), and filter, combining with the initial filtrate. Check Pd content and if needed perform resin treatment (resin treatment is: Charge SPM-32 resin (5 wt%). Stir the resin treated solution for not less than 3 hours at 35.0°C +/- 5°C. Filter off resin. Wash the reactor and filter cake with Methanol (2.0 vol), and filter, combining with the initial filtrate). Charge Norit CASP active carbon (3 wt%,). Stir for not less than 3 hours at 35.0°C +/- 5°C. Filter off active carbon. Wash the reactor and filter cake with Methanol (2.0 vol), and filter, combining with the initial filtrate. Distill under vacuum at not more than 50°C to 8.0 vol. Charge water (2.0 vol) while maintaining a temperature of 45°C +/- 5°C. Cool the resultant slurry to 0°C +/- 5°C over 2 hours. Hold and stir the slurry at 0°C +/- 5°C for not less than 1 hour. Filter and wash the cake with 2.0 volumes Methanol / Water (8:2) at 0°C +/- 5°C. Dry <i>5-amino-4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1, 1, 3, 3, 3-d6)phenyl methyl carbonate (7)</i> under vacuum at not more than 40°C to give a yield of a white solid, >99.5% purity.

<i>Procedure for the synthesis of 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate (8)</i>

0147<chemistry id="chem0040" num="0040"><img file="EP3717455B1_D0040.tif" /></chemistry>

0148The procedure for the conversion of compound <b>7</b> into compound <b>8</b> may be performed according to the analogous procedure for compound <b>5.</b>

<i>Procedure for the synthesis of N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (2)</i>

0149<chemistry id="chem0041" num="0041"><img file="EP3717455B1_D0041.tif" /></chemistry>

0150The procedure for the conversion of compound <b>8</b> into compound <b>2</b> may be performed according to the analogous procedure for the synthesis of compound <b>1.</b>

Reference Example 3:

<i>Synthesis of 5-amino-4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (7)</i>

0151An alternative overall scheme of the synthesis of compound <b>7</b> is shown below, followed by the procedure for the synthesis of each synthetic intermediate. <chemistry id="chem0042" num="0042"><img file="EP3717455B1_D0042.tif" /></chemistry>

<i>Procedure for the synthesis of 4-(tert-butyl)phen-2, 6-d2-ol-d (19)</i>

0152<chemistry id="chem0043" num="0043"><img file="EP3717455B1_D0043.tif" /></chemistry>

0153To a clean and dry 500-mL reactor was charged 4-<i>tert</i>-butylphenol (<b>14</b>) (24.6 g, 0.162 mmol, 1.00 equiv), CH₂Cl₂ (64 mL, 2.6 vol), and heptane (64 mL, 2.6 vol), and this mixture was warmed to 25 °C and stirred until all solids dissolved. To this solution was charged deuterium chloride (35% w/w in deuterium oxide, 25 mL, 1.0 vol), and this mixture was agitated for at least 3.5 hours. The agitation was stopped and the phases were allowed to separate, and then the aqueous layer (bottom) was drained from the reactor. To the reactor was charged deuterium chloride (35% w/w in deuterium oxide, 25 mL, 1.0 vol), and this mixture was agitated for at least 3.5 hours. The agitation was stopped and the phases were allowed to separate, and then the aqueous layer (bottom) was drained from the reactor. To the reactor was charged deuterium chloride (35% w/w in deuterium oxide, 25 mL, 1.0 vol), and this mixture was agitated for at least 3.5 hours. The agitation was stopped and the phases were allowed to separate, and then the aqueous layer (bottom) was drained from the reactor. The resulting solution was sampled and confirmed to be at least 99% of the desired deuterium incorporation product 4-(tert-butyl)phen-2,6-d2-ol-d (<b>19</b>) relative to starting material 4-<i>tert</i>-butylphenol. The solution in the reactor was carried on to the next step described below.

<i>Procedure for the synthesis of 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phen-6-d-ol (18)</i>

0154<chemistry id="chem0044" num="0044"><img file="EP3717455B1_D0044.tif" /></chemistry>

0155To the methylene chloride solution containing the reaction mixture of 4-(tert-butyl)phen-2,6-d2-ol-d (<b>19</b>) was charged CH₂Cl₂ (125 mL, 5 vol). Approximately 125 mL of the reaction solution was distilled from the reactor using a distillation head and heating the reactor to 60 °C. To the reactor was charged CH₂Cl₂ (125 mL, 5 vol). Approximately 100 mL of the reaction solution was then distilled from the reactor, and at this time the solution was sampled to confirm water content (KF) was less than 300 ppm and determine the CH₂Cl₂ and heptane content. After measuring the batch volume, CH₂Cl₂ (8 mL, 0.24 vol) was charged to adjust the total CH₂Cl₂ content to 3 vol and heptane (68 mL, 2.8 vol) was charged to adjust the heptane content to 4.5 vol. To the solution was charged <i>tert</i>-butyl acetate-<i>d₉</i> (30.2 g, 1.46 equiv), and the resulting solution was cooled to 0 °C. To the solution was charged sulfuric acid-<i>d₂</i> (8.12 g, 0.49 equiv) over at least 15 min, and the solution was agitated for 2 hours while maintaining the temperature at 0-5 °C. After this time, the temperature was set to ramp up to 20 °C over two hours and the solution was agitated for another 14 hours. The solution was sampled to confirm 4-<i>tert</i>-butylphenol (<b>14</b>) or 4-(tert-butyl)phen-2,6-d2-ol-d (<b>19</b>) were present at less than 3%. To the reactor was charged CH₂Cl₂ (58 mL, 2.4 vol) and heptane (90 mL, 3.7 vol), and the solution was cooled to 0-5 °C before charging water (125 mL, 5 vol). The mixture was agitated for 15 min before agitation was stopped and the phases were allowed to separate. After the aqueous phase (bottom) was drained from the reactor, 0.5 N aqueous NaOH (125 mL, 5 vol) was charged and the temperature was adjusted to 20 °C. The mixture was agitated for 20 min before agitation was stopped and the phases were allowed to separate. The organic phase (top) was sampled to confirm <i>4-tert-</i>butylphenol (<b>14</b>) or 4-(tert-butyl)phen-2,6-d2-ol-d (<b>18</b>) were present at less than 0.5%. The aqueous phase (bottom) was drained from the reactor. The solution in the reactor was carried on to the next step described below.

<i>Procedure for the synthesis of 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenol (17)</i>

0156<chemistry id="chem0045" num="0045"><img file="EP3717455B1_D0045.tif" /></chemistry>

0157After the agitated solution of the alkylation reaction to produce 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phen-6-d-ol-d (<b>18</b>) was brought to 0-5 °C, bromine (38.4 g, 1.45 equiv) was charged over at least 1 hour, maintaining the temperature below 5 °C. The solution was sampled to confirm 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phen-6-d-ol was present at less than 1%. To the solution was charged sodium metabisulfite (20% w/w aqueous solution, 147 g, 0.95 equiv) over at least 1 hour, maintaining the temperature below 10 °C. After adjusting the temperature to 20 °C, the mixture was agitated for another 1 hour. Agitation was stopped and the phases were allowed to separate. The aqueous phase (bottom) was drained from the reactor, and water (125 mL, 5 vol) was charged to the reactor. The mixture was agitated for 15 min before stopping agitation and allowing the phases to separate. The aqueous phase (bottom) was drained from the reactor. The solution of <b>17</b> in the reactor was carried on to the next step described below.

0158Surprisingly, this bromination reaction significantly improved the selectivity of the nitration reaction. Another unexpected advantage to this process was that bromination converted the mixture of compound <b>18</b> and 4-(tert-butyl)-2,6-bis(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenol to the same desired product <b>(17).</b> This significantly improved the overall yield.

<i>Procedure for the synthesis of 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (16)</i>

0159<chemistry id="chem0046" num="0046"><img file="EP3717455B1_D0046.tif" /></chemistry>

0160To the solution of the bromination reaction to produce 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenol <b>(17)</b> was charged CH₂Cl₂ (125 mL, 5 vol). Approximately 125 mL of the reaction solution was distilled from the reactor using a distillation head and heating the reactor to 60 °C. To the reactor was charge CH₂Cl₂ (125 mL, 5 vol). Approximately 125 mL of the reaction solution was distilled from the reactor. To the reactor was charged CH₂Cl₂ (125 mL, 5 vol). Approximately 125 mL of the reaction solution was then distilled from the reactor, and at this time the solution was sampled to confirm water content (KF) was less than 300 ppm and determine the CH₂Cl₂ and heptane content. After measuring the batch volume, CH₂Cl₂was charged to adjust the total CH₂Cl₂ content to 5.3 vol and heptane was charged to adjust the heptane content to 8 vol. To the solution was charged triethylamine (31.7 g, 1.91 equiv), and the solution was cooled to 0-5 °C. To the solution was charged methyl chloroformate (24.1 g, 1.56 equiv) over at least 1 hour, maintaining the temperature below 10 °C. The solution was agitated for 1 hour, and a sample of the solution was taken to confirm 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenol (<b>17</b><i>)</i> was present at less than 1%. To the solution was charged 1 N aqueous hydrochloric acid (125 mL, 0.76 equiv) over at least 30 min, maintaining the temperature below 10 °C. The temperature was then adjusted to 20 °C, and agitation was stopped and the phases were allowed to separate. After the aqueous phase (bottom) was drained from the reactor, water (125 mL, 5 vol) was charged to the reactor. The mixture was agitated for 15 min before agitation was stopped and the phases were allowed to separate. After the aqueous phase (bottom) was drained from the reactor, water (125 mL, 5 vol) was charged to the reactor. The mixture was agitated for 15 min before agitation was stopped and the phases were allowed to separate. The aqueous phase (bottom) was drained from the reactor. The solution of <b>16</b> in the reactor was carried on to the next step described below.

<i>Procedure for the synthesis of 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-3-nitrophenyl methyl carbonate (15)</i>

0161<chemistry id="chem0047" num="0047"><img file="EP3717455B1_D0047.tif" /></chemistry>

0162To the solution of the protection reaction to produce 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (<b>16</b>) was charged CH₂Cl₂ (125 mL, 5 vol). Approximately 125 mL of the reaction solution was distilled from the reactor using a distillation head and heating the reactor to 60 °C. To the reactor was charged CH₂Cl₂ chloride (125 mL, 5 vol). Approximately 125 mL of the reaction solution was distilled from the reactor. To the reactor was charged CH₂Cl₂ (125 mL, 5 vol). To the reactor was charged CH₂Cl₂ (125 mL, 5 vol). Approximately 125 mL of the reaction solution was distilled from the reactor. Approximately 125 mL of the reaction solution was then distilled from the reactor, and at this time the solution was sampled to confirm water content (KF) was less than 300 ppm and determine the CH₂Cl₂ and heptane content. After measuring the batch volume, CH₂Cl₂ was charged to adjust the total CH₂Cl₂ content to 6 vol and heptane was charged to adjust the heptane content to 9 vol. After cooling the solution to 0-5 °C, sulfuric acid (172 g, 10.3 equiv) was charged over at least 30 min, maintaining the temperature below 5 °C. To the mixture was charged nitric acid (70% w/w, 19.1 g, 1.31 equiv) over at least 30 min, maintaining the temperature below 10 °C. After agitating the mixture for 1 hour, a sample was taken and analyzed to confirm 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (<b>16</b>) was present at less than 1%. To the mixture was charged water (100 mL, 4 vol) over at least 1 hour, maintaining the temperature below 10 °C. Agitation was stopped and the phases were allowed to separate, and the aqueous phase (bottom) was drained from the reactor. After resuming agitation, sodium bicarbonate (8% w/w aqueous solution, 100 mL, 4 vol, 0.62 equiv) was charged over at least 10 min, maintaining the temperature below 10 °C. The temperature was adjusted to 20 °C, agitation was stopped, and the phases were allowed to separate. After draining the aqueous phase (bottom) from the reactor, water (100 mL, 4 vol) was charged to the reactor and the mixture was agitated for 15 min. Agitation was stopped, the phases were allowed to separate, and the aqueous phase (bottom) was drained from the reactor. To the mixture was charged water (100 mL, 4 vol), and this mixture was agitated for 15 min. Agitation was stopped, the phases were allowed to separate, and the aqueous phase (bottom) was drained from the reactor. After marking the solvent level on the reactor, a distillation head was attached and the temperature was set to 80 °C. To the solution was charged methanol (570 mL, 23 vol) while distilling at the same time, matching the addition rate to the distillation rate by keeping the solvent level at the mark. Distillation was continued until the batch volume was approximately 264 mL (11 vol) and approximately 1.10 kg of distillate had been removed. The mixture was sampled and analyzed to confirm heptane was present at less than 1% v/v. The temperature was adjusted to 0 °C over 4 hours. The mother liquor was sampled and analyzed to determine the concentration of 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-3-nitrophenyl methyl carbonate (<b>15</b>), and the mixture was filtered. To the reactor was charged methanol (51.1 mL, 2 vol), and this was agitated until the temperature reached 0-5 °C. This solution was used to wash the filter cake, and the filter cake was then dried by suction for at least 1 hour. The solid was then submitted to vacuum drying to produce 2-bromo-4-(tert-butyl)-6-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-3-nitrophenyl methyl carbonate (<b>15</b>) as 41.5 g of an off-white solid (98.4% pure w/w, 63% yield after purity correction).

<i>Procedure for the synthesis of 5-amino-4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (7)</i>

0163<chemistry id="chem0048" num="0048"><img file="EP3717455B1_D0048.tif" /></chemistry>

0164Charge 5 wt% (50 - 65 wt% wet, JM Type 37) of 5% Pd/C to a reactor. Charge (4.0 vol) Methanol. Close the system. Purge with N_{2 (g)} at 2.0 Bar. Activate with H_{2 (g)} at 2.0 Bar. Charge the vessel to 2.0 Bar with H_{2 (g)} at25°C +/- 5°C. Stir for not less than 2 hours while maintaining a temperature of 25°C +/- 5°C. Vent and purge with N_{2 (g)} at 2.0 Bar. Charge compound <b>15</b> (1.0 eq) to a reactor, together with Na₂HPO₄ (2.3 eq). Charge (11.0 vol) Methanol. Close the system. Purge with N_{2 (g)} at 2.0 Bar. Activate with H_{2 (g)} at 2.0 Bar. Charge the vessel to 2.0 Bar with H_{2 (g)} at25°C +/- 5°C. Stir for about 24 hours while maintaining a reaction temperature of 25°C +/- 5°C. Upon complete conversion, dilute reaction mixture by adding 7.7 vol of MeOH. Heat reaction mixture to 35.0°C +/- 5°C. Filter off catalyst and Na₂HPO₄. Wash the reactor and filter cake with Methanol (4.0 vol), and filter, combining with the initial filtrate. Check Pd content and if needed perform resin treatment (resin treatment is: Charge SPM-32 resin (5 wt%). Stir the resin treated solution for not less than 3 hours at 35.0°C +/- 5°C. Filter off resin. Wash the reactor and filter cake with Methanol (2.0 vol), and filter, combining with the initial filtrate). Charge Norit CASP active carbon (3 wt%,). Stir for not less than 3 hours at 35.0°C +/- 5°C. Filter off active carbon. Wash the reactor and filter cake with Methanol (2.0 vol), and filter, combining with the initial filtrate. Distill under vacuum at not more than 50°C to 8.0 vol. Charge water (2.0 vol) while maintaining a temperature of 45°C +/- 5°C. Cool the resultant slurry to 0°C +/- 5°C over 2 hours. Hold and stir the slurry at 0°C +/- 5°C for not less than 1 hour. Filter and wash the cake with 2.0 volumes Methanol / Water (8:2) at 0°C +/- 5°C. Dry <i>5-amino-4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1, 1, 3,3, 3-d6)phenyl methyl carbonate (7)</i> under vacuum at not more than 40°C to give a yield of a white solid, >99.5% purity.

<i>Procedure for the synthesis of 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate (8)</i>

0165<chemistry id="chem0049" num="0049"><img file="EP3717455B1_D0049.tif" /></chemistry>

0166The procedure for the conversion of compound <b>7</b> into compound <b>8</b> may be performed according to the analogous procedure for compound <b>5.</b>

<i>Procedure for the synthesis of N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (2)</i>

0167<chemistry id="chem0050" num="0050"><img file="EP3717455B1_D0050.tif" /></chemistry>

0168The procedure for the conversion of compound <b>8</b> into compound <b>2</b> may be performed according to the analogous procedure for the synthesis of compound <b>1.</b>

Example 4:

<i>Synthesis of 5-amino-4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (7)</i>

0169An alternative scheme of the synthesis of compound 7 is shown below, followed by the procedure for the synthesis of each synthetic intermediate. <chemistry id="chem0051" num="0051"><img file="EP3717455B1_D0051.tif" /></chemistry>

<i>Procedure for the synthesis of 5-(tert-butyl)-2-hydroxybenzoic acid (15)</i>

0170<chemistry id="chem0052" num="0052"><img file="EP3717455B1_D0052.tif" /></chemistry>

0171nBuLi 1.6 M in hexanes (3.49 g) was added to a round bottom flask equipped with a magnetic stirbar, a thermocouple, and a N₂ bubbler. The round bottom flask was cooled down to -20 °C and stirring started. A solution of 2-bromo-4-tert-butylphenol (<b>26</b>) (5.00 g) in MTBE (12.5 mL) was prepared, cooled to - 20 °C, and charged to the round bottom flask drop wise while maintaining the temperature at -20 °C +/- 5 °C. The reaction mixture was stirred at -20 °C +/- 5 °C for 15 min then allowed to warm up to 23 °C. The completeness of the lithiation was measured by ¹H NMR (200 µL reaction mixture diluted into 0.75 mL d4-MeOH) after 15 min at room temperature. The reaction was considered complete when less than 1% 2-bromo-4-tert-butylphenol was observed. The reaction mixture was cooled down to 0 °C, dry ice (solid CO₂) was added, and the reaction was stirred at room temperature for 45 min. Water (50.0 mL) was added to quench the reaction. The mixture was transferred into a separatory funnel, the phases were separated, and the organic phase was discarded. The aqueous phase was acidified to pH ~2 with 1 M HCl (15.0 mL), then extracted with MTBE (25.0 mL) three times. The combined organic extracts were concentrated under reduced pressure to yield 5-(tert-butyl)-2-hydroxybenzoic acid (<b>25</b>) as a yellow solid (2.25 g, 53.15% yield); ¹H NMR (400 MHz, d4-MeOH): 7.86 (1H, d, J = 2.6 Hz), 7.54 (1H, dd, J = 8.7, 2.6 Hz), 6.85 (1H, d, J = 2.7 Hz), 1.30 (9H, s).

<i>Procedure for the synthesis of methyl 5-(tert-butyl)-2-hydroxybenzoate (24)</i>

0172<chemistry id="chem0053" num="0053"><img file="EP3717455B1_D0053.tif" /></chemistry>

0173This reaction may be performed according to a procedure disclosed in <nplcit id="ncit0015" npl-type="s"><text>Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 21, p. 4752 - 4756</text></nplcit>.

<i>Procedure for the synthesis of methyl 2-((tert-butoxycarbonyl)oxy)-5-(tert-butyl)benzoate (23)</i>

0174<chemistry id="chem0054" num="0054"><img file="EP3717455B1_D0054.tif" /></chemistry>

0175Di-<i>tert</i>-butyl carbonate (230.55 g) and CH₂Cl₂ (400 mL) were charged to a 1 L reactor and the mixture was stirred until the solids dissolved completely. (Dimethylamino)pyridine (0.587 g) was charged to the stirring solution along with methyl 5-(<i>tert</i>-butyl)-2-hydroxybenzoate (<b>24</b>) (200 g). The reaction mixture was stirred at 15 - 30 °C and the completeness measured by HPLC (method) with sample aliquots after 60 m. The reaction was considered complete when the peak area of 5-tert-butyl-2-hydroxybenzoate (<b>24</b>) was less than 1%. A half-saturated solution of ammonium chloride was prepared in a separate flask by diluting saturated aqueous ammonium chloride solution (200 mL) with water (200 mL). The reaction mixture was twice washed with half saturated aqueous ammonium chloride solution (200 mL each wash). During each wash, the mixture was stirred for 15 minutes and held for 15 minutes. The organic solution was subsequently washed twice with water (100 mL each wash). During each wash, the mixture was stirred for 15 minutes and held for 15 minutes. The organic solution was transferred to a 1 L round bottom flask and concentrated below 35 °C and under vacuum to yield a white solid (275.51 g and 99.46 %purity as measured by HPLC analysis (method), a 93.0 %yield of methyl 2-((tert-butoxycarbonyl)oxy)-5-(<i>tert-</i>butyl)benzoate (<b>23</b>)). ¹H NMR (400 MHz, CDCl₃): 8.01 (m, 1H); 7.57 (m, 1H); 7.11 (m, 1H); 3.89 (s, 3H); 1.58 (s, 9H); 1.33 (s, 9H).

<i>Procedure for the synthesis of 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenol (22)</i>

0176<chemistry id="chem0055" num="0055"><img file="EP3717455B1_D0055.tif" /></chemistry>

0177THF (176 mL) was charged to a 500 mL jacketed reactor and cooled to 5 °C. To the stirring solvent and at 0 - 35 °C was slowly charged a solution of (methyl-d3)magnesium iodide (60.5 g) in dibutyl ether (145 mL). The resulting slurry was brought to and maintained at 20 - 30 °C while a solution of 2-((tert-butoxycarbonyl)oxy)-5-(<i>tert</i>-butyl)benzoate (<b>23</b>) (22 g) in THF (44 mL) was charged over 4 - 6 hours. The reaction mixture was stirred at 20 - 30 °C and the completeness measured by HPLC with sample aliquots after 60 m. The reaction was considered complete when the peak area of 2-((<i>tert</i>-butoxycarbonyl)oxy)-5-(<i>tert</i>-butyl)benzoate (<b>23</b>) was less than 1%. A second reactor was charged with 6N aqueous hydrochloric acid (110 mL) and the stirring solution was cooled to 0 - 10 °C. The reaction slurry was slowly transferred to the acid solution at 0 - 35 °C. The phases were stirred for 15 m and held for 15 m before being separated. The aqueous phase was extracted with dibutyl ether (132 mL). During the extraction the phases were stirred for 15 m and held for 15 m before being separated. The combined organic phases were washed sequentially with water (2 x 77 mL), 5% sodium thiosulfate aqueous solution (77 mL), and water (77 mL). During each wash, the mixture was stirred 15 minutes and held 15 minutes. The organic solution was transferred to a round bottom flask and concentrated below 80 °C and under vacuum to yield 4-(<i>tert</i>-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenol (<b>22</b>) as a crude oil (5.94 g and 83.8 % purity as measured by HPLC analysis with 99.3 %D9 isotopic purity by LC/MS analysis, a 84.9 %yield of methyl 4-(<i>tert</i>-butyl)-2-(2-(methyl-<i>d₃</i>)propan-2-yl-1,1,1,3,3,3-<i>d₆</i>)phenol (<b>23</b>)). ¹H NMR (400 MHz, CD₃OD): 7.22 (m, 1H); 7.00 (m, 1H); 6.65 (m, 1H); 1.26 (s, 9H).

0178The Grignard reaction of compound <b>23</b> led to some deuterium incorporation in compound <b>22</b>. To effect H/D exchange, the mixture was subjected to a series of HCl washes: <chemistry id="chem0056" num="0056"><img file="EP3717455B1_D0056.tif" /></chemistry>

<i>Procedure for H</i>/<i>D Exchange</i>

0179Charge the deuterated analogs of compound <b>22</b> (1.00 equiv) to a reactor. Charge DCM (5 vol). Set jacket to 20 °C. Agitate to dissolved solids. Charge 35% hydrochloric acid (5 vol). Agitate to mix the layers for not less than 6 hours. Stop agitation and let the layers settle at least 30 min. Drain the bottom layer (organic) from the reactor. Drain the aqueous layer from the reactor. Charge the organic portion back into the reactor. Repeat HCl wash sequence twice. Charge pre-mixed water (2.5 vol) and sat. aq. NaCl (2.5 vol). Agitate to mix the layers for 30 min. Stop agitation and let the layers settle at least 30 min. Drain the bottom layer (organic) from the reactor. Drain the aqueous from the reactor. Charge the organic portion back into the reactor. Charge water (5 vol). Agitate to mix the layers for 30 min. Stop agitation and let the layers settle at least 30 min. Drain the bottom layer (organic) from the reactor. Drain the aqueous from the reactor. Charge the organic portion back into the reactor. Distill the solvent under reduced pressure to minimal volume (a rotovap with 35 °C bath temperature was used). Charge DCM (5 vol). Distill the solvent under reduced pressure to minimal volume (a rotovap with 35 °C bath temperature was used). Charge DCM (5 vol). Sample the solution and measure water content by KF. Repeat until the water content is less than 300 ppm. <i>Note: This solution was used directly for the next reaction, so the final amount of DCM should be whatever is needed for the alkoxyformylation reaction of compound</i><b><i>22</i>.</b>

<i>Procedure for the synthesis of 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (21)</i>

0180<chemistry id="chem0057" num="0057"><img file="EP3717455B1_D0057.tif" /></chemistry>

0181The procedure for the conversion of compound <b>22</b> into compound <b>21</b> may be performed according to the analogous procedure for compound <b>12.</b>

<i>Procedure for the synthesis of 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-5-nitrophenyl methyl carbonate (20)</i>

0182<chemistry id="chem0058" num="0058"><img file="EP3717455B1_D0058.tif" /></chemistry>

0183The procedure for the conversion of compound <b>21</b> into compound <b>20</b> may be performed according to the analogous procedure for compound <b>11A.</b>

<i>Procedure for the synthesis of 5-amino-4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl methyl carbonate (7)</i>

0184<chemistry id="chem0059" num="0059"><img file="EP3717455B1_D0059.tif" /></chemistry>

0185The procedure for the conversion of compound <b>20</b> into compound <b>7</b> may be performed according to the analogous procedure for compound <b>4.</b>

<i>Procedure for the synthesis of 4-(tert-butyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate (8)</i>

0186<chemistry id="chem0060" num="0060"><img file="EP3717455B1_D0060.tif" /></chemistry>

0187The procedure for the conversion of compound <b>7</b> into compound <b>8</b> may be performed according to the analogous procedure for compound <b>5.</b>

<i>Procedure for the synthesis of N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (2)</i>

0188<chemistry id="chem0061" num="0061"><img file="EP3717455B1_D0061.tif" /></chemistry>

0189The procedure for the conversion of compound <b>8</b> into compound <b>2</b> may be performed according to the analogous procedure for the synthesis of compound <b>1.</b>