Processes and intermediates for preparing pyrimidine aminopyrazole compounds

Abstract

This disclosure relates to N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 The present invention relates to a method for making 5-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine and intermediates thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 427,303, filed November 22, 2022, which is incorporated by reference in its entirety.

[0002] The present disclosure relates to methods of making pyrimidine aminopyrazole compounds and intermediates thereof, which are inhibitors of LRRK2 kinase and find use in treating LRRK2-mediated diseases such as Parkinson's disease. DETAILED DESCRIPTION OF THE INVENTION

[0003] Leucine-rich repeat kinase 2 (LRRK2) is a complex signaling protein that is an important therapeutic target, particularly in Parkinson's disease (PD). Combined genetic and biochemical evidence implicates specific kinase function in the pathogenesis of neurodegenerative disorders (Christensen, KV (2017) Progress in medicinal chemistry 56:37-80; Fuji, RNet al (2015) Science Translational Medicine 7(273):273ra15; Taymans, JMet al (2016) Current Neuropharmacology 14(3):214-225). Kinase inhibitors are being investigated to treat Alzheimer's disease, Parkinson's disease, ALS, and other diseases (Estrada, AA et al (2015) J. Med. Chem. 58(17):6733-6746, Estrada, AA et al (2013) J. Med. Chem. 57:921-936, Chen, H. et al (2012) J. Med. Chem. 55:5536-5545, Estrada, AA et al (2015) J. Med. Chem. 58:6733-6746, Chan, BK et al (2013) ACS Med. Chem. Lett. 4:85-90, WO2017218843, US 8354420, US 8569281, US 8791130, US 8796296, US 8802674, US 8809331, US 8815882, US 9145402, US 9212173, US 9212186, US 9932325, US 10590114, US 11111235, and WO 2012 / 062783).

[0004] The present disclosure provides an LRRK2 inhibitor, N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4The present invention relates to a method for making 5-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine and intermediates thereof, the inhibitors also referred to herein as compounds of Formula I, having the following structure: [ka] It has.

[0005] In one embodiment, there is provided a method for preparing Compound I or a salt thereof, comprising: [ka] a) contacting compound II with a compound of formula B and a base to provide a compound of formula C [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 are independently H, cyano, halo, methyl, or NO2; and b) reacting a compound of formula C under conditions sufficient to provide compound I contacting with ethylamine; The method includes:

[0006] In some embodiments, the compound of formula B is compound B-1. [ka] The compound of formula C is compound C-1 [ka]

[0007] In some embodiments, B-1 is provided with a regioisomeric purity of 90% or greater. In other embodiments, B-1 is provided with a regioisomeric purity of 95% or greater. In some embodiments, B-1 is provided with a regioisomeric purity of 96% or greater. In other embodiments, B-1 is provided with a regioisomeric purity of 97% or greater. In still other embodiments, B-1 is provided with a regioisomeric purity of 98% or greater. In some embodiments, compound B-1 is provided with a regioisomeric purity of 99% or greater. Regioisomers of B-1 have the following structures: [ka] This means that the compound has the formula:

[0008] In some embodiments, C-1 is provided with a regioisomeric purity of 96% or greater. In other embodiments, C-1 is provided with a regioisomeric purity of 97% or greater. In yet other embodiments, C-1 is provided with a regioisomeric purity of 98% or greater. In some embodiments, compound C-1 is provided with a regioisomeric purity of 99% or greater. Regioisomers of C-1 have the following structures: [ka] This means that the compound has the formula:

[0009] In some embodiments, the base is 2,6-lutidine or 2,4,6-collidine. In some embodiments, the reaction is carried out in NMP or DMSO. In other embodiments, the reaction is carried out in DMF or DMAc.

[0010] In some embodiments, compound II is contacted with compound B-1 at a temperature of about 60°C to about 70°C.

[0011] In some embodiments, Formula C is contacted with ethylamine in an aprotic polar solvent. In other embodiments, the solvent is THF. In yet other embodiments, the solvent is DMF, DMAc, NMP, and DMSO. In another embodiment, the solvent is NMP.

[0012] In one embodiment, compound B-1 is a) contacting compound D-1 with compound D-2 and a base under conditions sufficient to provide compound B-1; and [ka] b) optionally crystallizing compound B-1 from heptane, isopropanol, or an isopropanol / water mixture; It is prepared by

[0013] In some embodiments, compound B-1 is crystallized from heptane. In some such embodiments, compound B-1 is crystallized from heptane with a regioisomeric purity of 99% or greater. In other embodiments, compound B-1 is crystallized from isopropanol. In some embodiments, compound B-1 is crystallized from isopropanol with a regioisomeric purity of 99% or greater. In some such embodiments, compound B-1 is crystallized from an isopropanol / water mixture with a regioisomeric purity of 99% or greater. In certain embodiments, the isopropanol / water mixture contains at least 50%, 60%, 70%, 80%, or 90% isopropanol by volume.

[0014] In some such embodiments, the base is an inorganic base. In some such embodiments, the inorganic base is KCO or NaOH. In other embodiments, the base is an organic amine base. In some such embodiments, the organic amine base is TEA or DIPEA. In some embodiments, the reaction is carried out at a temperature of about 30° C. or less. In other embodiments, the reaction is carried out at 20° C. or less.

[0015] In one embodiment, compound D-1 is prepared in situ by contacting compound E-1 with POCl3 under conditions sufficient to provide compound D-1. [ka]

[0016] In some embodiments, compound E-1 is contacted with POCl 3 and diisopropylethylamine.

[0017] In some embodiments, Compound I is obtained with a purity of greater than 98%. In some embodiments, Compound I is obtained with a purity of greater than 99%. In other embodiments, Compound I is obtained with a purity of greater than 99.5%.

[0018] In one embodiment, compound II is prepared by contacting compound III with compound IV and an acid. [ka]

[0019] In some embodiments, the acid is a strong acid. In other embodiments, the acid is MSA, BSA, PTSA, HBr, or TFA. In still other embodiments, the acid is H2SO4 or HCl in an alcoholic solvent. In some such embodiments, the alcoholic solvent is i-PrOH or MeOH. In other embodiments, the alcoholic solvent is EtOH.

[0020] In some embodiments, compound III is contacted with compound IV at a temperature of about 50°C to about 60°C.

[0021] In another embodiment, compound IV is a) contacting compound V with a compound of formula VI and a first base to provide a compound of formula VII [ka] (In the formula, R 6is alkyl), b) Washing the compound of formula VII with an aqueous solution to form N 1 - removing the triazole regioisomer to obtain a compound of formula VII with a regioisomeric purity of 95% or more; and c) contacting the compound of formula VII with a second base and CHCN under conditions sufficient to provide compound IV; It is prepared by

[0022] In some embodiments, R 6 is methyl, and the compound of formula VII is VII-1 having a regioisomeric purity of 95% or more. [ka] is.

[0023] In some embodiments, the compound of formula VII is obtained with 98% or greater regioisomeric purity.

[0024] In some embodiments, the compound of Formula VII is washed at least twice with an aqueous solution. In some embodiments, the aqueous solution is water. In other embodiments, the aqueous solution is an acidic aqueous solution. In yet other embodiments, the acidic aqueous solution is an HCl aqueous solution.

[0025] In some embodiments, the first base is an inorganic base. In some embodiments, the base is an alkoxide base. In some such embodiments, the first base is NaOt-Bu. In some embodiments, the solvent is THF, CHCN, NMP, DMF, or DMAc.

[0026] In some embodiments, the second base is n-BuLi, KOt-Bu, LiHMDS, LDA, NaOt-Bu, or KOt-amyl. In other embodiments, the second base is n-BuLi. In yet other embodiments, the second base is LiHMDS.

[0027] In some embodiments, compound IV is obtained with a purity of at least 99% or greater.

[0028] In another embodiment, compound IV is a) a compound of formula VIII [ka] with a compound of formula VI and a first base to provide a compound of formula IX [ka] (In the formula, R 6 is alkyl, and R 7 and R 8 are independently Br or trimethylsilyl (TMS), b)R 7 and R 8 is Br, contacting a compound of formula IX with H or HCOH and a hydrogenation catalyst to and / or R 7 and R 8 is TMS, contacting the compound of formula IX with a base to providing a compound of formula VII [ka] and c) contacting the compound of formula VII with a second base and CHCN under conditions sufficient to provide compound IV; It is prepared by

[0029] In some embodiments, R 6 is CH3 and R 7 is Br.

[0030] In some embodiments, the hydrogenation catalyst is a Pd catalyst.

[0031] In some embodiments, the first base is an inorganic base. In some such embodiments, the first base is K2CO3.

[0032] In some embodiments, the second base is n-BuLi, KOt-Bu, LiHMDS, LDA, NaOt-Bu, or KOt-Amyl. In some embodiments, the second base is n-BuLi, KOt-Bu, LiHMDS, or KOt-Amyl. In some such embodiments, the second base is n-BuLi. In yet other embodiments, the second base is LiHMDS.

[0033] In one aspect, a compound of formula IX [ka] or a salt thereof, wherein: R 6 is alkyl, and R 7 and R 8 are independently Br or trimethylsilyl (TMS).

[0034] In one aspect, [ka] A compound is provided wherein:

[0035] In one aspect, a compound of formula B: [ka] or a salt thereof, wherein: X is chloro or [ka] and R 1 , R 2 , R 3 , R 4 , and R 5 are independently H, cyano, halo, methyl, or NO2, however, a) X is Cl and R 1 , R 2 , R3 , and R 5 If is H, then R 4 is not NO2 or H, b) X is Cl and R 1 and R 2 If is CH3, R 4 is not cyano, and c) When X is Cl, R 3 is not NO2.

[0036] In one embodiment, [ka] or a salt thereof. In another embodiment, a compound is provided which is B-1.

[0037] In one embodiment, [ka] A compound is provided wherein:

[0038] definition As used herein, the following words, phrases and symbols are generally intended to have the meanings set forth below, unless otherwise indicated by the context in which they are used.

[0039] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment of a substituent. Dashes preceding or following a chemical group are for convenience; chemical groups may be represented with or without one or more dashes without losing their ordinary meaning. Wavy or dashed lines drawn in a structure indicate a particular point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which chemical groups are written or named.

[0040] Reference herein to a value or parameter by "about" includes and describes embodiments directed to that value or parameter. In certain embodiments, the term "about" includes ±10% of the indicated amount. In other embodiments, the term "about" includes ±5% of the indicated amount. In certain other embodiments, the term "about" includes ±1% of the indicated amount. Additionally, the term "about X" includes the description of "X."

[0041] As used herein, the term "alkyl" refers to an alkyl group having 1 to 12 carbon atoms (C1-C 12)), where the alkyl radical is optionally substituted independently with one or more substituents described below. In another embodiment, the alkyl radical is one to eight carbon atoms (C1-C8), or one to six carbon atoms (C1-C6). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH2CH(CH3)2 ...butyl (s-Bu, s-butyl, -CH2CH(CH3)2), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH2CH(CH3)2), 2-butyl ( -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (amyl, n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl- 1-Butyl (-CH2CH2CH(CH3)2), 2-Methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-Hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-Hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-Hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-Methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-Methyl-2-pentyl (-CH(CH3)CH (CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), 1-heptyl, and 1-octyl.

[0042] The term "salt" includes, for example, salts with inorganic acids and salts with organic acids. Salts can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid or a reagent that generates an acid in situ, according to conventional procedures for preparing acid addition salts from basic compounds. Acid addition salts can be prepared from inorganic or organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, and the like. Examples of organic acid addition salts include salts of propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, ethanesulfonic acid, salicylic acid, and the like.

[0043] Any compound or structure given herein is intended to represent not only unlabeled forms of the compound, but also isotopically labeled forms. Such compound forms may also be referred to as "isotopically enriched analogs." Isotopically labeled compounds have the structures depicted herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P,35 S, 18 F, 36 Cl, 123 I and 125 I. Various isotopically labeled compounds of the present disclosure are those into which radioactive isotopes such as H, C, and C are incorporated. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiation treatment of patients.

[0044] The terms "reaction conditions" and "sufficient reaction conditions" are intended to refer to the physical and / or environmental conditions under which a chemical reaction proceeds. Examples of reaction conditions include, but are not limited to, one or more of the following: reaction temperature, solvent, pH, pressure, reaction time, molar ratio of reactants, the presence of a base or acid, one or more protecting groups, or a catalyst, educt, etc. Reaction conditions may be named after the particular chemical reaction in which they are employed, e.g., coupling conditions, hydrogenation conditions, acylation conditions, reduction conditions, etc. Reaction conditions for most reactions are generally known to those of skill in the art or can be readily obtained from the literature. Exemplary reaction conditions sufficient to carry out the chemical transformations provided herein can be found throughout, and particularly in the Examples below. It is also contemplated that reaction conditions may include reagents other than those listed for a particular reaction.

[0045] The terms "contact" or "contacting" refer to the process of bringing at least two different species into contact so that they can interact with each other, for example, in a non-covalent or covalent interaction or reaction. However, it should be understood that the resulting complex or reaction product can result directly from an interaction or reaction between the added reagents, or from an intermediate derived from one or more of the added reagents or moieties, which may result in the contacting mixture.

[0046] Abbreviation [Table 1-1] [Table 1-2]

[0047] process The starting materials and reagents for preparing the compounds of the present disclosure are generally commercially available or readily prepared using methods well known to those of ordinary skill in the art (e.g., generally prepared by the methods described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, NY (1967-1999 ed.), or Beilstein's Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including appendices (also available via the Beilstein online database)).

[0048] The following illustrative Schemes 1-4 are directed to certain chemical reactions, processes, methodologies, as well as certain reagents and novel intermediates for synthesizing compounds of the present disclosure.

[0049] Scheme 1 depicts Routes A and B to Compound I. Route B was found to overcome the deficiencies of Route A in terms of yield and purity. The reaction of A-1 with amine II requires higher temperatures, resulting in increased formation of by-products and requiring multiple recrystallizations to purify Compound I, which provides Compound I in low to moderate yields (typically 45% yield) on a preparative scale. In contrast, Compound I can be prepared from amine II using Route B on a preparative scale in over 60% overall yield, with purity typically 100% (no detectable impurities) after a single crystallization. [ka]

[0050] As shown in Scheme 2, other intermediates 2-3 can be used in addition to B-1 (where R 1 , R 2 , R 3 , R 4 , and R 5 are independently H, cyano, halo, methyl, or NO. These intermediates can be prepared by coupling phenols 2-1 with dichlorides 2-2 in the presence of base. A convenient in situ method for the preparation of dichlorides 2-2 has also been developed, where 2,4-dihydroxy-5-(trifluoromethyl)pyrimidine is treated with POCl and an amine base, avoiding the need to isolate compound 2-2, a pungent odor and potent lachrymator.

[0051] When 2-1 is 4-chlorophenol, a mixture of regioisomers is formed, with the compound of formula 2-3, 2-chloro-4-(4-chloro-phenoxy)-5-(trifluoromethyl)pyrimidine, predominating. Surprisingly, it was discovered that simple crystallization using heptane to isolate B-1 in high purity on a preparative scale can completely remove by-products, such as the undesired regioisomer (see Examples 4 and 5a). This regioselective crystallization was also observed in isopropyl alcohol or a mixture of isopropyl alcohol and water (see Examples 5b-c). Many other solvents typically either had high solubility for compound B-1 or did not exhibit the same degree of selective solubility in favor of crystallization of B-1. [ka]

[0052] Scheme 3 shows the formation of amine II from ketone IV. The use of di-Boc compound III (Route B) was found to be superior to the use of the hygroscopic and less stable hydrazine salt 3-1 (Route A). Compound III can be prepared from the reaction of di-tert-butyl azodicarboxylate with cyclopropylmagnesium bromide or cyclopropanecarboxylic acid (e.g., in the presence of cerium trichloride, tetrabutylammonium chloride, cesium carbonate, and a 455 nm LED). Boc deprotection of III, followed by condensation with ketone IV, and subsequent cyclization can be carried out in the presence of acid as a single-pot process to afford aminopyrazole II. [ka]

[0053] Ketone IV can be prepared as shown in Schemes 4 and 5. N-methyl-4-bromide 4-2 can be obtained by coupling triazole 4-1 with bromide 4-2 in the presence of base. 2 -triazole 4-3 contains significant amounts of N 1 -triazole regioisomer 4-4. Surprisingly, it was discovered that the undesired regioisomer 4-4 could be removed by aqueous washing to afford 4-3 in greater than 95% regioisomeric purity. Treatment of 4-3 with base and acetonitrile affords ketone IV. [ka]

[0054] Ketone IV can also be prepared as shown in Scheme 5. Compounds of formula VIII can be coupled with compounds of formula VI (where R 6 is alkyl, and R 7 and R 8 are independently Br or trimethylsilyl (TMS). Intermediate IX does not need to be isolated and can be treated with appropriate reagents and conditions to give R 7 and R 8Removal of the group gives VII. Ester VII also does not need to be isolated and can be treated with base and acetonitrile to give ketone IV. [ka] [Example]

[0055] Characterization and structural confirmation of the compounds were carried out by NMR. Samples for NMR analysis were prepared by completely dissolving an appropriate amount of material in a deuterated solvent (CDCl3). 1 1 H NMR spectra were recorded at 400 MHz at room temperature on a Bruker 400 MHz NMR spectrometer.

[0056] Example 1. 2-Cyclopropyl-5-[1-methyl-1-(triazol-2-yl)ethyl]pyrazol-3-amine [ka] To a reactor was added ketone IV (1.0 equiv., 45 kg scale), di-Boc III (1.5 equiv.), and ethanol (10 vol.). After the reaction mixture was cooled to 0°C, concentrated H2SO4 (1.8 equiv.) was added to the reactor while maintaining the internal temperature below 10°C. The reaction mixture was stirred at 55°C for 32 h. After the reaction mixture was cooled to 0°C, water (4 vol.) was added to the reactor while maintaining the internal temperature below 10°C. The pH of the reaction mixture was adjusted to pH 9 with 28 wt% aqueous NH4OH while maintaining the internal temperature below 10°C. The mixture was extracted twice with iPAc (10 vol. and 5 vol.), and the combined organic layers were concentrated under reduced pressure twice, successively with i-PrOH (2–3 vol.). The mixture was heated to 45°C, and n-heptane (2 vol.) was added over 30 min. The mixture was cooled to 20° C. over 1 h and the slurry was stirred for 2 h at 20° C. The slurry was filtered, the filter cake was washed with n-heptane (3 volumes) and the solid was dried to give aminopyrazole II in 70% yield and 99.4% a / a. 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 2H), 5.01 (s, 1H), 3.71 (s, 2H), 3.12 - 3.06 (m, 1H), 2.02 (s, 7H), 1.16 - 1.06 (m, 1H), 1.02 - 0.96 (m, 2H).

[0057] Example 2. N-[1-cyclopropyl-3-[1-methyl-1-(2H-1,2,3-triazol-2-yl)ethyl]-1H-pyrazol-5-yl]-4-(4-chlorophenoxy)-5-trifluoromethyl-2-pyrimidinamine [ka] A reaction vessel was charged with aminopyrazole II (1.0 equiv., 40 kg scale), chloropyrimidine B-1 (1.1 equiv.), and NMP (3 volumes). 2,6-Lutidine (1.1 equiv.) was added to the reaction vessel, and the reaction mixture was stirred at 67°C for 48 hours. After the reaction mixture was cooled to 27°C, MTBE (10 volumes) and 0.25 N aqueous HCl (10 volumes) were added to the reaction vessel. The organic layer was washed with 0.25 N aqueous HCl (5 volumes) and water (5 volumes). The organic layer was concentrated to 3 volumes, and i-PrOH (3 volumes) was added to the reaction vessel. The mixture was concentrated to 4 volumes, and i-PrOH (3 volumes) was added to the reaction vessel. The mixture was heated to 50°C and stirred for 3 hours. The mixture was slowly cooled to 20°C over 3 hours and stirred at 20°C for 1 hour. The slurry was filtered, the filter cake was washed with cold i-PrOH (3 volumes), and the solid was dried to give C-1 in 74% yield and 99.9% a / a. 1 H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.60 (s, 2H), 7.37 (d, J = 8.9 Hz, 2H), 7.10 (d, J = 8.9 Hz, 2H), 5.74 (s, 1H), 3.16 (m, 1H), 1.93 (s, 6H), 1.16 - 1.03 (m, 4H).

[0058] Example 3. N2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine [ka] C-1 (1.0 equiv., 60 kg scale) and THF (3 vol.) were added to a reactor. 70 wt. % aqueous ethylamine solution (6.0 equiv.) was added to the reactor, and the reaction mixture was stirred at 25°C for 24 h. The reaction mixture was concentrated to 1.5 vol. under reduced pressure, and MTBE (10 vol.) was added to the reactor. The organic layer was washed three times with 3 wt. % aqueous NaOH solution (5 vol.) and twice with water (5 vol.). The organic layer was concentrated to 3 vol. under reduced pressure, and MTBE (5 vol.) was added to the reactor. The mixture was heated to 50°C, and then n-heptane (2 vol.) was added to the reactor. The mixture was slowly cooled to -5°C over 6 h and stirred at -5°C for 2 h. The slurry was filtered, and the filter cake was washed with a cold 1:3 v / v MTBE:n-heptane mixture (4 vol.). The solid was dried to give product I in 84% yield and 100% a / a. 1 H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.61 (s, 2H), 7.33 (s, 1H), 6.11 (s, 1H), 5.18 (s, 1H), 3.41 (qd, J = 7.2, 5.2 Hz, 2H), 3.23 (tt, J = 6.9, 3.6 Hz, 1H), 2.09 (s, 6H), 1.31 - 1.16 (m, 5H), 1.16 - 1.08 (m, 2H).

[0059] Example 4. 2-chloro-4-(4-chloro-phenoxy)-5-(trifluoromethyl)pyrimidine [ka] To a reactor was added 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.0 equiv., 110 kg scale), potassium carbonate (1.1 equiv.), and acetone (8 volumes). After cooling the reaction mixture to 0°C, a solution of 4-chlorophenol (1.0 equiv.) in acetone (1 volume) was added to the reactor while maintaining the internal temperature below 10°C. The reaction mixture was stirred at 5°C for 40 hours to give a mixture of B-1 along with its regioisomers. The reaction mixture was filtered, and the filter cake was washed twice with acetone (2 volumes). The filtrate was concentrated under reduced pressure to 3 volumes. n-Heptane (5 volumes) was added to the reactor, and the mixture was concentrated under reduced pressure to 3 volumes. n-Heptane (10 volumes) was added to the reactor, and the mixture was concentrated under reduced pressure to 6 volumes. The concentrated mixture was stirred at 60°C for 2 hours and then cooled to 0°C over 6 hours. The slurry was stirred at 0°C for 3 hours. The slurry was filtered (to remove the undesired regioisomer) and the filter cake was returned to the reactor with n-heptane (2 volumes). The slurry was stirred at 0° C. for 1 hour. The slurry was filtered, the filter cake was washed with cold n-heptane (0.5 volumes), and the solid was dried to give B-1 in 58% yield and 100% a / a. 1 H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 0.9 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.17 - 7.11 (m, 2H).

[0060] Example 5. 2-chloro-4-(4-chloro-phenoxy)-5-(trifluoromethyl) [ka] 2,4-Dihydroxy-5-(trifluoromethyl)pyrimidine (1.0 equiv., 30 kg scale) and acetonitrile (3 vol.) were added to a reactor. After adjusting the reaction mixture to 20°C, POCl3 (3.0 equiv.) was added to the reactor while maintaining the internal temperature between 20 and 30°C. The reaction mixture was heated to 55°C, and DIPEA (3.0 equiv.) was added to the reactor over 6 hours. After the addition, the reaction mixture was stirred at 55°C for 40 hours. After adjusting the reaction mixture to 20°C, it was added to another reactor containing n-heptane (10 vol.) and water (10 vol.). The aqueous layer was isolated and extracted twice with n-heptane (5 vol.). The combined organic layer was washed once with water (5 vol.). Charcoal (5 wt.%) was added to the combined organic layer and stirred at 25°C for 2 hours. The slurry was filtered, and the filter cake was washed with n-heptane (1 vol.). The filtrate, containing an n-heptane solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (assay yield 69%, 97.5% a / a), was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H).

[0061] Example 5a. 4-Chlorophenol Coupling and Heptane Crystallization A solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.0 equiv., 37 kg scale) in n-heptane was added to the reactor. The reaction mixture was cooled to 5°C. A solution of K2CO3 (1.1 equiv.) and 4-chlorophenol (1.0 equiv.) in water (5 vol.) was added to the reactor while maintaining the internal temperature between 0 and 10°C. The reaction mixture was stirred at 5°C for 39 hours. A solution of K2CO3 (0.1 equiv.) and 4-chlorophenol (0.1 equiv.) in water (1 vol.) was added to the reactor while maintaining the internal temperature between 0 and 10°C. The reaction mixture was stirred at 5°C for 16 hours. After adjusting the reaction mixture to 20°C, n-heptane (5 vol.) was added to the reactor. After stirring the reaction mixture for 30 minutes, the organic layer was isolated and washed with water (5 vol.) until the pH reached 7. The organic layer was concentrated under reduced pressure to 6 vol. The slurry was heated to 80° C. for 2 hours, then adjusted to 60° C. and stirred for 2 hours. The slurry was cooled to 0° C. over 6 hours and stirred for 3 hours. The slurry was filtered, the filter cake washed with cold n-heptane (2 volumes), and the solid dried to give B-1 in 75% yield and 99.9% a / a. 1 H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 0.9 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.17 - 7.11 (m, 2H).

[0062] Example 5b. 4-Chlorophenol Coupling and Heptane Crystallization 4-Chlorophenol Coupling and IPA / Water Crystallization A solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.0 equiv., scaling factor, 50 g scale) in n-heptane and 4-chlorophenol (1.1 equiv.) were added to the reactor. The reaction mixture was cooled to 5°C. A solution of K2CO3 (1.1 equiv.) in water (5 vol.) was added to the reactor while maintaining the internal temperature between 0 and 10°C. The reaction mixture was stirred at 5°C for 24 h. The reaction mixture was then adjusted to 30°C, and n-heptane (4 vol.) was added to the reactor. The resulting solution was stirred for an additional 40 h. The organic layer was isolated and washed twice with water (5 vol.) until pH 7. The organic layer was concentrated under reduced pressure to 3 vol. The slurry was adjusted to 6 vol. with isopropanol and heated to 30°C. Water (2 vol.) was added, and the resulting slurry was stirred for 30 min, cooled to 0°C over 3 h, and stirred for an additional 2 h. The slurry was filtered and the wet cake was combined with isopropanol (3 volumes) and the temperature was adjusted to 30° C. Water (1 volume) was added at 30° C. and the slurry was cooled to 0° C. over 3 hours and stirred for an additional 2 hours. The slurry was filtered, the filter cake was washed with cold n-heptane (0.5 volumes) and the solid was dried to give B-1 in 78% yield and 99.6% a / a. 1 H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 0.9 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.17 - 7.11 (m, 2H).

[0063] Example 5c. 4-Chlorophenol Coupling and Heptane Crystallization 4-Chlorophenol Coupling and IPA Crystallization A solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.0 equiv., scaling factor, 35 g scale) in n-heptane and 4-chlorophenol (1.1 equiv.) were added to the reactor. The reaction mixture was adjusted to 22°C. A solution of K2CO3 (1.1 equiv.) in water (5 vol.) was added to the reactor while maintaining the internal temperature between 20 and 30°C. The reaction mixture was stirred at 30°C for 45 hours. The organic layer was isolated and washed twice with water (5 vol.). Isopropanol (3 vol.) was added, and the temperature was adjusted to 50°C. The resulting solution was cooled to 0°C over 5 hours and then held for 3 hours. The slurry was filtered, the filter cake was washed with cold isopropanol (2 vol.), and the solid was dried to give DN11247 in 68% yield and 99.9% a / a. 1 H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 0.9 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.17 - 7.11 (m, 2H).

[0064] Example 6. Methyl 2-methyl-2-(triazol-2-yl)propanoate [ka] To the reactor was added NaOt-Bu (1.1 equiv.) and NMP (5 vol.). The reaction mixture was cooled to 5°C, and 2H-1,2,3-triazole 4-1 (1.0 equiv., 100 kg scale) was added to the reactor while maintaining the internal temperature below 10°C. The reaction mixture was heated to 55°C, and methyl 2-bromoisobutyrate 4-2 (1.1 equiv.) was added to the reactor while maintaining the internal temperature below 60°C. The reaction mixture was stirred at 55°C for 18 hours and then cooled to 5°C to give a mixture of triazole regioisomers 4-3 and 4-4. Water (10 vol.) was added to the reactor while maintaining the internal temperature below 10°C. The mixture was extracted twice with MTBE (10 vol.), and the combined organic layers were washed twice with 2.5 M aq. HCl (3 vol.) to remove the undesired regioisomer. The combined organic layers were washed with 5 wt% aq. NaHCO3 (3 volumes) and water (3 volumes). The combined organic layers were concentrated under reduced pressure to 2 volumes and MTBE (4 volumes) was added to the reactor. The mixture was concentrated under reduced pressure to 2 volumes and MTBE (4 volumes) was added to the reactor. The mixture was concentrated under reduced pressure to 2 volumes and MTBE (4 volumes) was added to the reactor and N 2 -Triazole 4-3 (assay yield 32%, 84.9% a / a) was obtained as a solution in MTBE, which was either transferred to THF or used directly in the preparation of ketone IV. 1 H NMR (400 MHz, CDCl3) δ 7.64 (s, 2H), 3.69 (s, 3H), 1.95 (s, 6H).

[0065] Example 7a. 4-Methyl-3-oxo-4-(triazol-2-yl)pentanenitrile [ka] To the reactor was added CH3CN (2.1 equiv) and THF (10 vol). After the reaction mixture was cooled to -75°C, a 2.5 M solution of n-butyllithium in hexane (2.0 equiv) was added to the reactor while maintaining the internal temperature below -70°C. The reaction mixture was stirred at -75°C for 1 hour. A solution of 4-3 (1.0 equiv, 113 kg scale) in THF (4 vol) was added to the reactor while maintaining the internal temperature below -70°C. The reaction mixture was stirred at -75°C for 2.5 hours. Water (5 vol) was added to the reactor while maintaining the internal temperature below 5°C, and the reaction mixture was warmed to 5°C. The pH of the mixture was adjusted to 3-5 with 3 M aqueous HCl. The aqueous layer was isolated and extracted twice with EtOAc (5 vol). The combined organic layers were washed with saturated aqueous NaCl (5 vol) and concentrated to 1.5 vol under reduced pressure. The mixture was concentrated to 3 volumes successively four times with MTBE (3 volumes). The slurry was stirred for 2 hours at 20° C. The slurry was filtered, the filter cake was washed with MTBE (1 volume), and the solid was dried to give ketone IV in 60% yield and 100% a / a. 1 H NMR (400 MHz, CDCl3) δ 7.74 (s, 2H), 3.10 (s, 2H), 1.88 (s, 6H).

[0066] Example 7b. 4-Methyl-3-oxo-4-(triazol-2-yl)pentanenitrile [ka] To a reactor was added 4-3 (1.0 equiv., 10 g scale), CHCN (2.1 equiv.), and THF (3 vol.). After cooling the reaction mixture to -10 °C, a 1.0 M solution of KOt-Bu in THF (2.0 equiv.) was added to the reactor while maintaining the internal temperature below 0 °C. The reaction mixture was stirred at -10 °C for 12 h. Water (5 vol.) was added to the reactor while maintaining the internal temperature below 5 °C, and the reaction mixture was warmed to 5 °C. The pH of the mixture was adjusted to 3-5 with 3 M aqueous HCl. The aqueous layer was isolated and extracted twice with EtOAc (5 vol.). The combined organic layers were washed with saturated aqueous NaCl (5 vol.) and concentrated to 1.5 vol. under reduced pressure. The mixture was concentrated to 3 vol. four times successively using MTBE (3 vol.). The slurry was stirred at 20 °C for 2 h. The slurry was filtered, the filter cake washed with MTBE (1 vol) and the solid dried to give ketone IV in 86% yield and 100% a / a. 1 H NMR (400 MHz, CDCl3) δ 7.74 (s, 2H), 3.10 (s, 2H), 1.88 (s, 6H).

[0067] Example 7c. 4-Methyl-3-oxo-4-(triazol-2-yl)pentanenitrile [ka] A solution of 4-3 (1.0 equiv., scaling factor, 37 kg scale) in THF (6 vol.) was added to the reactor. Acetonitrile (2.8 equiv.) was added, and the resulting solution was cooled to -10 °C. A 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (2.5 equiv.) was added to the reactor while maintaining the internal temperature below 10 °C. The reaction was stirred at 20 °C for 2 h. The temperature was adjusted to 0 °C, and water (5 vol.) was added to the reactor while maintaining the internal temperature below 10 °C. The pH of the mixture was adjusted to 3-4 with 6 M aqueous HCl. The aqueous layer was isolated and extracted with MTBE (5 vol.). The combined organic layers were washed with 10 wt. % aqueous NaCl (5 vol.) and concentrated to 1.5 vol. under reduced pressure. The mixture was concentrated twice successively to 1.5 vol. using MTBE (3 vol.). MTBE (1 vol.) was added, and the temperature was adjusted to 50 °C. The resulting solution was cooled to 5° C. over 2 hours and then held for 3 hours. The slurry was filtered, the filter cake washed with cold MTBE (1 volume), and the solid dried to give ketone IV in 83% yield and 99.9% a / a. 1 H NMR (400 MHz, CDCl3) δ 7.74 (s, 2H), 3.10 (s, 2H), 1.88 (s, 6H).

[0068] Example 8. 4-methyl-3-oxo-4-(triazol-2-yl)pentanenitrile [ka] Dibromotriazole 5-1 (1.0 equiv., 24 kg scale), potassium carbonate (1.0 equiv.), and NMP (5 vol.) were added to a reactor. Methyl 2-bromoisobutyrate (1.3 equiv.) was added to the reactor while maintaining the internal temperature below 20°C. The reaction mixture was stirred at 35°C for 24 h. After the reaction mixture was cooled to 10°C, 3.2 wt.% aqueous HCl (15 vol.) was added while maintaining the internal temperature below 20°C. The mixture was extracted twice with MTBE (10 vol.), and the combined organic layers were washed with water (5 vol.). The combined organic layers were concentrated under reduced pressure to 2 vol. MeOH (2 vol.) was added to the reactor, and the mixture was concentrated under reduced pressure to 2 vol. MeOH (6 vol.) and water (0.7 vol.) were added to the reactor to give the methyl ester 5-2 (90% assay yield, 86.3% a / a) as a solution in MeOH and water, which was used directly in the preparation of 4-3. 1 H NMR (400 MHz, CDCl3) δ 3.70 (s, 3H), 1.91 (s, 6H).

[0069] A reactor was charged with 5-2 (1.0 equiv., 15 kg scale) as a solution in MeOH and water (7 vol.), 20 wt. % Pd(OH)2 / C (0.015 w / w, dry basis), and KOAc (3.0 equiv.). The mixture was pressurized with H2 to 1.5 mPa and stirred at 55 °C for 10 h. The reaction mixture was filtered, and the filter cake was washed with MeOH (2 vol.). The filtrate was concentrated to 1 vol. under reduced pressure. MTBE (10 vol.) and 8 wt. % aqueous NaHCO3 (8 vol.) were added to the reactor. The organic layer was isolated and washed with water (5 vol.). The combined aqueous layer was extracted with MTBE (5 vol.), and the combined organic layer was concentrated to 1 vol. under reduced pressure. THF (3 vol.) was added to the reactor, and the mixture was concentrated to 1 vol. under reduced pressure. THF (3 vol.) was added to the reactor, and the mixture was concentrated to 1 vol. under reduced pressure. THE (1.5 vol) was added to the reactor to give 4-3 (assay yield 97%, 98.4% a / a) as a solution in THF, which was used directly for the preparation of IV. 1 H NMR (400 MHz, CDCl3) δ 7.64 (s, 2H), 3.69 (s, 3H), 1.95 (s, 6H).

[0070] To the reactor was added CH3CN (2.1 equiv) and THF (10 vol). After the reaction mixture was cooled to -75°C, a 2.5 M solution of n-butyllithium in hexane (2.0 equiv) was added to the reactor while maintaining the internal temperature below -70°C. The reaction mixture was stirred at -75°C for 1 hour. A solution of 4-3 (1.0 equiv, 113 kg scale) in THF (4 vol) was added to the reactor while maintaining the internal temperature below -70°C. The reaction mixture was stirred at -75°C for 2.5 hours. Water (5 vol) was added to the reactor while maintaining the internal temperature below 5°C, and the reaction mixture was warmed to 5°C. The pH of the mixture was adjusted to 3-5 with 3 M aqueous HCl. The aqueous layer was isolated and extracted twice with EtOAc (5 vol). The combined organic layers were washed with saturated aqueous NaCl (5 vol) and concentrated to 1.5 vol under reduced pressure. The mixture was concentrated to 3 volumes successively four times with MTBE (3 volumes). The slurry was stirred for 2 hours at 20° C. The slurry was filtered, the filter cake was washed with MTBE (1 volume), and the solid was dried to give IV in 60% yield and 100% a / a. 1 H NMR (400 MHz, CDCl3) δ 7.74 (s, 2H), 3.10 (s, 2H), 1.88 (s, 6H).

Claims

1. Compound of Formula B: 【Chemistry 1】 or a salt thereof (wherein X is chloro or 【Chemistry 2】 and R １ , R ２ , R ３ , R ４ , and R ５ are independently H, cyano, halo, methyl, or NO ２ However, however, a) X is Cl and R １ , R ２ , R ３ , and R ５ is H, then R ４ No ２ Or not H, b) X is Cl and R １ and R ２ is CH ３ If R ４ is not cyano, and c) When X is Cl, R ３ No ２ isn't it). 【Request Item 2】 【Chemistry 3】 or a salt thereof. 【Request Item 3】 【Chemistry 4】 or a salt thereof.

4. 1. A process for preparing Compound I or a salt thereof, comprising: 【Transformation 5】 a) contacting compound II with a compound of formula B and a base to provide a compound of formula C 【Transformation 6】 (In the formula, R １ , R ２ , R ３ , R ４ , and R ５ are independently H, cyano, halo, methyl, or NO ２ (which is and b) contacting the compound of formula C with ethylamine to provide compound I; The method comprising:

5. The compound of formula B is compound B-1 【Transformation 7】 and the compound of formula C is compound C-1 【Transformation 8】 The method of claim 4, wherein

6. 6. The method of claim 5, wherein the compound C-1 is provided with a regioisomeric purity of 96% or greater, 97% or greater, 98% or greater, or 99% or greater.

7. 6. The method of claim 5, wherein the base is 2,6-lutidine or 2,4,6-collidine, and the reaction is carried out in NMP or DMSO at a temperature of about 60°C to about 70°C.

8. The compound B-1 is a) contacting compound D-1 with compound D-2 and a base to provide compound B-1; and 【Chemistry 9】 b) optionally crystallizing said compound B-1 from heptane, isopropanol, or an isopropanol / water mixture; The method of claim 5, wherein the compound is prepared by

9. 9. The method of claim 8, wherein the compound B-1 is crystallized with a regioisomeric purity of 90% or greater, 95% or greater, or 99% or greater.

10. The base is K ２ CO ３ or NaOH.

11. The base is K ２ CO ３ The method of claim 10, wherein

12. Compound D-1 can be prepared by reacting compound E-1 with POCl to give compound D-1. ３ 9. The method of claim 8, wherein the compound is prepared in situ by contacting the compound with 【Chemistry 10】

13. The compound E-1 is POCl ３ and diisopropylethylamine.

14. 5. The method of claim 4, wherein the compound I is obtained with a purity of greater than 98% or greater than 99%.

15. 15. The method of claim 14, wherein the compound I is obtained with a purity of greater than 99.5%.

16. 5. The method of claim 4, wherein compound II is prepared by contacting compound III with compound IV and an acid. 【Chemistry 11】

17. The acid is H in an alcohol solvent. ２ SO ４ or HCl.

18. 17. The method of claim 16, wherein compound III is contacted with compound IV at a temperature of about 50°C to about 60°C.

19. The compound IV is a) contacting compound V with a compound of formula VI and a first base to provide a compound of formula VII 【Chemistry 12】 (In the formula, R ６ is alkyl), b) washing the compound of formula VII with an aqueous solution to form N １ - removing the triazole regioisomer to obtain the compound of formula VII with a regioisomeric purity of 95% or more; and c) reacting said compound of Formula VII with a second base and CH under conditions sufficient to provide said compound IV. ３ contacting with CN; 17. The method of claim 16, wherein the compound is prepared by:

20. R ６ is methyl, and the compound of formula VII is VII-1 having a regioisomeric purity of 95% or more. 【Chemistry 13】 20. The method of claim 19, wherein:

21. 21. The method of claim 19 or 20, wherein the compound of formula VII is obtained with a regioisomeric purity of 98% or greater.

22. 21. The method of claim 19 or 20, wherein the compound of formula VII is washed with an aqueous solution at least twice.

23. 23. The method of claim 22, wherein the aqueous solution is an acidic aqueous solution.

24. 24. The method of claim 23, wherein the aqueous solution is an aqueous HCl solution.

25. 20. The method of claim 19, wherein the first base is an alkoxide base.

26. 26. The method of claim 25, wherein the first base is NaOt-Bu.

27. 20. The method of claim 19, wherein the second base is n-BuLi, KOt-Bu, LiHMDS, LDA, NaOt-Bu, or Kot-Amyl.

28. 28. The method of claim 27, wherein the second base is n-BuLi or LiHMDS.

29. 20. The method of claim 19, wherein the compound IV is obtained with a purity of at least 99% or greater.

30. The compound IV is a) a compound of formula VIII 【Chemistry 14】 with a compound of formula VI and a first base to provide a compound of formula IX 【Chemistry 15】 (In the formula, R ６ is alkyl, and R ７ and R ８ are independently Br or trimethylsilyl (TMS), b) R ７ and R ８ is Br, the compound of formula IX can be reacted with H ２ or HCO ２ H and a hydrogenation catalyst, and / or R ７ and R ８ is TMS, contacting the compound of formula IX with a base to Providing a compound of formula VII 【Chemistry 16】 and c) reacting the compound of formula VII with a second base and CH to provide said compound IV. ３ contacting with CN; 17. The method of claim 16, wherein the compound is prepared by:

31. R ６ is CH ３ and R ７ 31. The method of claim 30, wherein is Br.

32. 32. The method of claim 30 or 31, wherein the hydrogenation catalyst is a Pd catalyst.

33. 32. The method of claim 30 or 31, wherein the first base is an inorganic base.

34. The first base is K ２ CO ３ 34. The method of claim 33, wherein:

35. 32. The method of claim 30 or 31, wherein the second base is n-BuLi, Kot-Bu, LiHMDS, LDA, NaOt-Bu, or Kot-Amyl.

36. 36. The method of claim 35, wherein the second base is n-BuLi or LiHMDS.

37. Compound of Formula IX 【Chemistry 17】 or a salt thereof (wherein R ６ is alkyl, and R ７ and R ８ are independently Br or trimethylsilyl (TMS). 【Request Item 38】 【Chemistry 18】 38. The compound of claim 37, which is: or a salt thereof.

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