Preparation method and intermediate of pyrimidine aminopyrazole compound

Abstract

The present disclosure relates to a process for the preparation of 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 and intermediates thereof, and to a process for the preparation of N < 2 >-(3-(2-(2H-1, 2, 3-triazol-2-yl) propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N < 4 >-

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit under 35 USC §119(e) of U.S. Provisional Application No. 63 / 427,303, filed on November 22, 2022, which is incorporated by reference in its entirety. Technical Field

[0003] The present disclosure relates to methods for preparing pyrimidine aminopyrazole compounds and intermediates thereof. The compounds are inhibitors of LRRK2 kinase and can be used to treat LRRK2-mediated diseases, such as Parkinson's disease.

[0004] describe

[0005] Leucine-rich repeat kinase 2 (LRRK2) is a complex signaling protein that is a key therapeutic target, particularly for Parkinson's disease (PD). Combined genetic and biochemical evidence suggests that kinases play a role in the pathogenesis of neurodegenerative disorders (Christensen, KV (2017) Progress in medicinalchemistry 56:37-80; Fuji, RN et al. (2015) Science Translational Medicine 7(273):273ra15; Taymans, JM et al. (2016) Current Neuropharmacology 14(3):214-225). Kinase inhibitors are being studied for the treatment of 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; US8791130; US 8796296; US 8802674; US 8809331; US ​​8815882; US 9145402; US 9212173; US 9212186; US 9932325, US 10590114, US 11111235 and WO 2012 / 062783.

[0006] The present disclosure relates to the preparation of LRRK2 inhibitor N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine and intermediates thereof, said inhibitors are also referred to herein as compounds of formula I and have the following structure:

[0007] (I).

[0008] In one aspect, a method for preparing Compound I or a salt thereof is provided.

[0009] (I)

[0010] The method comprises:

[0011] a) contacting compound II with a compound of formula B and a base to produce a compound of formula C

[0012]

[0013] where R 1 、R 2 、R 3 、R 4 and R 5 are independently H, cyano, halo, methyl or NO2;

[0014] as well as

[0015] b) contacting a compound of formula C with ethylamine under conditions sufficient to produce compound I.

[0016] In some embodiments, the compound of formula B is compound B-1

[0017] (B-1),

[0018] And the compound of formula C is compound C-1

[0019] (C-1).

[0020] In some embodiments, B-1 is provided at 90% or greater regioisomer purity. In other embodiments, B-1 is provided at 95% or greater regioisomer purity. In some embodiments, B-1 is provided at 96% or greater regioisomer purity. In other embodiments, B-1 is provided at 97% or greater regioisomer purity. In other embodiments, B-1 is provided at 98% or greater regioisomer purity. In some embodiments, compound B-1 is provided at 99% or greater regioisomer purity. By regioisomer of B-1 is meant a compound having the following structure:

[0021] .

[0022] In some embodiments, C-1 is provided at 96% or greater regioisomeric purity. In other embodiments, C-1 is provided at 97% or greater regioisomeric purity. In other embodiments, C-1 is provided at 98% or greater regioisomeric purity. In some embodiments, compound C-1 is produced at 99% or greater regioisomeric purity. A regioisomer of C-1 is defined as a compound having the structure:

[0023] .

[0024] 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.

[0025] In some embodiments, Compound II is contacted with Compound Bl at a temperature of about 60°C to about 70°C.

[0026] In some embodiments, Formula C is contacted with ethylamine in a polar aprotic solvent. In other embodiments, the solvent is THF. In other embodiments, the solvent is DMF, DMAc, NMP, and DMSO. In another embodiment, the solvent is NMP.

[0027] In one aspect, compound B-1 is prepared by:

[0028] a) contacting compound D-1 with compound D-2 and a base under conditions sufficient to produce compound B-1; and

[0029]

[0030] b) Optionally, compound B-1 is crystallized from heptane, isopropanol or an isopropanol / water mixture.

[0031] In some embodiments, Compound B-1 is crystallized from heptane. In some such embodiments, Compound B-1 is crystallized from heptane with 99% or greater regional isomer purity. In other embodiments, Compound B-1 is crystallized from isopropyl alcohol. In some embodiments, Compound B-1 is crystallized from isopropyl alcohol with 99% or greater regional isomer purity. In some such embodiments, Compound B-1 is crystallized from isopropyl alcohol / water mixture with 99% or greater regional isomer purity. In certain embodiments, the isopropyl alcohol / water mixture contains at least 50 volume %, 60 volume %, 70 volume %, 80 volume % or 90 volume % of isopropyl alcohol.

[0032] In some such embodiments, the base is an inorganic base. In some such embodiments, the inorganic base is K2CO3 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.

[0033] In one aspect, compound D-1 is prepared by reacting compound E-1 with POCl3

[0034] (E-1)

[0035] Prepared in situ by contacting under conditions sufficient to produce compound D-1.

[0036] In some embodiments, compound E-1 is contacted with POCl 3 and diisopropylethylamine.

[0037] In some embodiments, Compound 1 is obtained with a purity greater than 98%. In some embodiments, Compound 1 is obtained with a purity greater than 99%. In other embodiments, Compound 1 is obtained with a purity greater than 99.5%.

[0038] In one aspect, compound II is prepared by contacting compound III with compound IV and an acid.

[0039] (III) (IV).

[0040] In some embodiments, the acid is a strong acid. In other embodiments, the acid is MSA, BSA, PTSA, HBr, or TFA. In 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.

[0041] In some embodiments, Compound III is contacted with Compound IV at a temperature of about 50°C to about 60°C.

[0042] In another aspect, compound IV is prepared by:

[0043] a) contacting compound V with a compound of formula VI and a first base to produce a compound of formula VII

[0044] (V) (VI) (VII),

[0045] where R 6 is an alkyl group;

[0046] b) washing the compound of formula VII with an aqueous solution to remove N 1 -triazole regioisomers and obtaining a compound of formula VII with a regioisomeric purity of 95% or greater; and

[0047] c) contacting the compound of formula VII with a second base and CH3CN under conditions sufficient to produce compound IV.

[0048] In some embodiments, R 6 is methyl and the compound of formula VII is VII-1

[0049] (VII-1)

[0050] It has a regioisomeric purity of 95% or greater.

[0051] In some embodiments, the compound of Formula VII is obtained in a regioisomeric purity of 98% or greater.

[0052] 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 other embodiments, the acidic aqueous solution is an aqueous HCl solution.

[0053] 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, CH3CN, NMP, DMF, or DMAc.

[0054] In some embodiments, the second base is n-BuLi, KOt-Bu, LiHMDS, LDA, NaOt-Bu, or KOt-pentyl. In other embodiments, the second base is n-BuLi. In other embodiments, the second base is LiHMDS.

[0055] In some embodiments, Compound IV is obtained in a purity of at least 99% or greater.

[0056] In another aspect, compound IV is prepared by:

[0057] a) making a compound of formula VIII

[0058] (VIII)

[0059] contacting with a compound of formula VI and a first base to produce a compound of formula IX

[0060]

[0061] where R 6 is an alkyl group and R 7 and R 8 are independently Br or trimethylsilyl (TMS);

[0062] b) Make R 7 and R 8 The compound of formula IX, wherein at least one of the compounds is Br, is contacted with H2 or HCO2H and a hydrogenation catalyst;

[0063] and / or make R 7 and R 8 contacting the compound of Formula IX wherein at least one of the compounds is TMS with a base;

[0064] To produce the compound of formula VII

[0065] (VII); and

[0066] c) contacting the compound of formula VII with a second base and CH3CN under conditions sufficient to produce compound IV.

[0067] In some embodiments, R 6 is CH3 and R 7 For Br.

[0068] In some embodiments, the hydrogenation catalyst is a Pd catalyst.

[0069] In some embodiments, the first base is an inorganic base. In some such embodiments, the first base is K2CO3.

[0070] In some embodiments, the second base is n-BuLi, KOt-Bu, LiHMDS, LDA, NaOt-Bu, or KOt-pentyl. In some embodiments, the second base is n-BuLi, KOt-Bu, LiHMDS, or KOt-pentyl. In some such embodiments, the second base is n-BuLi. In other embodiments, the second base is LiHMDS.

[0071] In one aspect, a compound of formula IX is provided

[0072] (IX)

[0073] or a salt thereof, wherein:

[0074] R 6 is an alkyl group and R 7 and R 8 are independently Br or trimethylsilyl (TMS).

[0075] In one aspect, the following compounds are provided:

[0076] (IX-1), (IX-2) or (IX-3).

[0077] In one aspect, a compound of formula B is provided:

[0078] (B),

[0079] or a salt thereof, wherein:

[0080] X is chlorine or

[0081] ;and

[0082] R 1 、R 2 、R 3 、R 4 and R 5 are independently H, cyano, halo, methyl or NO2,

[0083] The restriction is

[0084] a) When X is Cl and R 1 、R 2 、R 3 and R 5 When H, R 4 Not NO2 or H;

[0085] b) When X is Cl and R 1 and R 2 When it is CH3, R 4 is not a cyano group; and

[0086] c) When X is Cl, then R 3 Not NO2.

[0087] In one embodiment, the following compounds are provided:

[0088] B-1

[0089] or a salt thereof. In another embodiment, compound B-1 is provided.

[0090] In one embodiment, the following compounds are provided:

[0091] C-1.

[0092] definition

[0093] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0094] A dash ("-") not between two letters or symbols is used to indicate the point of attachment of a substituent. Dashes preceding or ending a chemical group are for convenience; a chemical group can be described with or without one or more dashes without losing its general meaning. A wavy or dashed line drawn through a structure indicates the designated point of attachment of a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply any directionality or stereochemistry.

[0095] References herein to "about" values ​​or parameters include and describe embodiments for the values ​​or parameters themselves. In certain embodiments, the term "about" includes ± 10% of the amount shown. In other embodiments, the term "about" includes ± 5% of the amount shown. In certain other embodiments, the term "about" includes ± 1% of the amount shown. Additionally, the term "about X" includes a description of "X."

[0096] As used herein, the term "alkyl" refers to a group having one to twelve carbon atoms (C1-C 12), wherein the alkyl group is optionally substituted independently with one or more of the following substituents. In another embodiment, the alkyl group 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, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(CH3)C H2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (pentyl, 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 (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 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.

[0097] 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 on the spot according to conventional methods for preparing acid addition salts from alkaline compounds. Acid addition salts can be prepared from inorganic or organic acids. Inorganic acids that can generate salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids that can generate salts 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, etc. 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.

[0098] Any compound or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compound. These forms of the compound may also be referred to as "isotopically enriched analogs." An isotopically labeled compound has a structure depicted herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, 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, for example, compounds into which radioactive isotopes such as 3H, 13C, and 14C are incorporated. Such isotopically labeled compounds are 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 radiotherapy of patients.

[0099] The terms "reaction conditions" and "sufficient reaction conditions" refer to the physical and / or environmental conditions under which a chemical reaction is carried out. Examples of reaction conditions include, but are not limited to, one or more of the following: temperature of reaction, solvent, pH, pressure, reaction time, molar ratio of reactants, presence of base or acid, one or more protecting groups, or catalyst, radiation, etc. Reaction conditions can be named according to the specific chemical reaction employing the conditions, such as coupling conditions, hydrogenation conditions, acylation conditions, reduction conditions, etc. The reaction conditions for most reactions are generally known to those skilled in the art or are easily obtained from the literature. Exemplary reaction conditions sufficient for the chemical transformations provided herein can be found in the full text, particularly in the examples below. It is also contemplated that reaction conditions may include reagents other than those listed in the specific reactions.

[0100] The term "contacting" or "contact" refers to the process of bringing at least two different substances into contact so that they can interact with each other, such as in a non-covalent or covalent binding interaction or binding reaction. However, it should be understood that the resulting complex or reaction product can be produced directly from the interaction or reaction between the added reagents, or from one or more added reagents or moieties of an intermediate that can be produced in the contact mixture.

[0101] abbreviation

[0102]

[0103]

[0104] Craftsmanship

[0105] The starting materials and reagents used to prepare the compounds of the present disclosure are generally available from commercial sources or are readily prepared using methods well known to those skilled in the art (e.g., by the methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, Vols. 1-19, Wiley, NY (eds. 1967-1999); or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database).

[0106] The following illustrative Schemes 1-4 are directed to certain chemical reactions, processes, methods, and certain reagents and novel intermediates used to synthesize compounds of the present disclosure.

[0107] In Scheme 1, routes A and B to compound I are depicted. Route B was found to overcome the yield and purity deficiencies of route A. The reaction of A-1 with amine II requires higher temperatures, resulting in increased by-product formation, and multiple recrystallizations are required to purify compound I, providing compound I in low to moderate yields, typically 45% on a manufacturing scale. In contrast, compound I can be prepared from amine II via route B with an overall yield exceeding 60% on a manufacturing scale, with single crystal purity typically reaching 100% (no impurities detected).

[0108] Solution 1

[0109]

[0110] As shown in Scheme 2, in addition to B-1, other intermediates 2-3 can also be used, wherein R 1 、R 2 、R 3 、R 4 and R 5 are independently H, cyano, halide, methyl, or NO2. These intermediates can be prepared by coupling phenol 2-1 with dichloride 2-2 in the presence of a base. A convenient in situ preparation of dichloride 2-2 has also been developed, wherein 2,4-dihydroxy-5-(trifluoromethyl)pyrimidine is treated with POCl3 and an amine base, thereby avoiding the need to isolate compound 2-2, which has a pungent odor and is a strong tear-inducing agent.

[0111] When 2-1 is 4-chlorophenol, a mixture of regioisomers favoring 2-chloro-4-(4-chloro-phenoxy)-5-(trifluoromethyl)pyrimidine (compound of Formula 2-3) is formed. It was unexpectedly discovered that simple crystallization using heptane can completely remove unwanted regioisomer byproducts, such as undesirable regioisomers, thereby isolating B-1 in high purity on a manufacturing scale (see Examples 4 and 5a). This regioselective crystallization was also observed using isopropanol or a mixture of isopropanol and water (see Examples 5b-c). In many other solvents, compound B-1 is generally highly soluble, or the selective solubility favoring B-1 crystallization is less important.

[0112] Option 2

[0113]

[0114] Scheme 3 illustrates the formation of amine II from ketone IV. The use of di-Boc compound III (Pathway B) was found to be superior to the hygroscopic and less stable hydrazine salt 3-1 (Pathway A). Compound III can be prepared by reacting 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 protection of III can be removed in a one-pot process in the presence of acid, followed by condensation with ketone IV and subsequent cyclization to afford aminopyrazole II.

[0115] Option 3

[0116]

[0117] Ketone IV can be prepared as shown in Schemes 4 and 5. Triazole 4-1 is coupled with bromide 4-2 in the presence of a base to give N 2 -triazole 4-3 and a large amount of N 1 -triazole regioisomer 4-4. Surprisingly, it was discovered that the unwanted regioisomer 4-4 could be removed by washing with water to afford 4-3 with a regioisomeric purity exceeding 95%. Treatment of 4-3 with base and acetonitrile afforded ketone IV.

[0118] Option 4

[0119]

[0120] Ketone IV can also be prepared as shown in Scheme 5. A compound of formula VIII can be coupled with a compound of formula VI in the presence of a base, wherein R 6 is an alkyl group and R 7 and R 8 R is independently Br or trimethylsilyl (TMS). Intermediate IX does not need to be isolated and can be treated with appropriate reagents and conditions to remove R 7 and R 8 The ester VII also does not need to be isolated and can be treated with a base and acetonitrile to provide the ketone IV.

[0121] Option 5

[0122] Example

[0123] The compounds were characterized and their structures confirmed by NMR. Samples for NMR analysis were prepared by completely dissolving an appropriate amount of material in a deuterated solvent (CDCl3). Spectra were recorded at 400 MHz using a Bruker 400 MHz NMR spectrometer at room temperature. 1 H NMR spectrum.

[0124] Example 1. 2-Cyclopropyl-5-[1-methyl-1-(triazol-2-yl)ethyl]pyrazol-3-amine

[0125]

[0126] A reactor was charged with ketone IV (1.0 equiv., 45 kg scale), diBoc III (1.5 equiv.), and ethanol (10 vol). The reaction mixture was cooled to 0°C, and concentrated HSO (1.8 equiv.) was then added to the reactor while maintaining the internal temperature below 10°C. The reaction mixture was stirred at 55°C for 32 hours. The reaction mixture was cooled to 0°C, and 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 NHOH 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 twice under reduced pressure with i-PrOH (2 to 3 vol). The mixture was heated to 45°C and n-heptane (2 vol) was added over 30 minutes. The mixture was cooled to 20°C over 1 hour, and the slurry was stirred at 20°C for 2 hours. The slurry was filtered, the filter cake washed with n-heptane (3 vol), and the solid dried to afford aminopyrazole II in 70% yield and 99.4% a / a. 1 H 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).

[0127] 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

[0128]

[0129] A reactor was charged with aminopyrazole II (1.0 equiv., 40 kg scale), chloropyrimidine B-1 (1.1 equiv.), and NMP (3 vol). 2,6-Lutidine (1.1 equiv.) was added to the reactor, and the reaction mixture was stirred at 67°C for 48 hours. The reaction mixture was cooled to 27°C, and then MTBE (10 vol) and 0.25 N aqueous HCl (10 vol) were added to the reactor. The organic layer was washed with 0.25 N aqueous HCl (5 vol) and water (5 vol). The organic layer was concentrated to 3 vol, and i-PrOH (3 vol) was added to the reactor. The mixture was concentrated to 4 vol, and i-PrOH (3 vol) was added to the reactor. 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 vol), and the solid was dried to afford 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).

[0130] 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

[0131]

[0132] A reactor was charged with C-1 (1.0 equiv., 60 kg scale) and THF (3 vol). A 70 wt.% aqueous ethylamine solution (6.0 equiv.) was charged to the reactor, and the reaction mixture was stirred at 25°C for 24 hours. The reaction mixture was concentrated under reduced pressure to 1.5 vol, and MTBE (10 vol) was charged to the reactor. The organic layer was washed twice with a 3 wt.% aqueous NaOH solution (5 vol) and twice with water (5 vol). The organic layer was concentrated under reduced pressure to 3 vol, and MTBE (5 vol) was charged to the reactor. The mixture was heated to 50°C, and then n-heptane (2 vol) was charged to the reactor. The mixture was slowly cooled to -5°C over 6 hours and stirred at -5°C for 2 hours. The slurry was filtered, the filter cake was washed with a cold 1:3 v / v mixture of MTBE:n-heptane (4 vol), and the solid was dried to obtain 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).

[0133] Example 4. 2-Chloro-4-(4-chloro-phenoxy)-5-(trifluoromethyl)pyrimidine

[0134]

[0135] A reactor was charged with 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.0 equiv., 110 kg scale), potassium carbonate (1.1 equiv.), and acetone (8 volumes). The reaction mixture was cooled to 0°C, and then a solution of 4-chlorophenol (1.0 equiv.) in acetone (1 volume) was charged to the reactor while maintaining the internal temperature below 10°C. The reaction mixture was stirred at 5°C for 40 hours to obtain a mixture of B-1 and its regioisomers. The reaction mixture was filtered and the filter cake was washed twice with acetone (2 volumes). The filtrate was concentrated to 3 volumes under reduced pressure. n-heptane (5 volumes) was charged to the reactor, and the mixture was concentrated to 3 volumes under reduced pressure. n-heptane (10 volumes) was charged to the reactor, and the mixture was concentrated to 6 volumes under reduced pressure. The concentrated mixture was stirred at 60°C for 2 hours, then cooled to 0°C over 6 hours. The slurry was stirred at 0°C for 3 hours. The slurry was filtered (to remove unwanted regioisomers) and the filter cake was charged back into the reactor along with n-heptane (2 volumes). The slurry was agitated 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 afford 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).

[0136] Example 5. 2-Chloro-4-(4-chloro-phenoxy)-5-(trifluoromethyl)

[0137]

[0138] A reactor was charged with 2,4-dihydroxy-5-(trifluoromethyl)pyrimidine (1.0 equiv., 30 kg scale) and acetonitrile (3 vol). The reaction mixture was brought to 20°C, and POCl (3.0 equiv.) was then added to the reactor while maintaining the internal temperature between 20°C and 30°C. The reaction mixture was heated to 55°C, and DIPEA (3.0 equiv.) was then added to the reactor over 6 hours. Following the addition, the reaction mixture was stirred at 55°C for 40 hours. The reaction mixture was brought to 20°C and then charged to another reactor containing n-heptane (10 vol) and water (10 vol). The aqueous layer was separated and extracted twice with n-heptane (5 vol). The combined organic layers were washed once with water (5 vol). Charcoal (5 wt.%) was added to the combined organic layers 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 2,4-dichloro-5-(trifluoromethyl)pyrimidine (69% assay yield, 97.5% a / a) in n-heptane was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H).

[0139] Example 5a. 4-Chlorophenol Coupling and Heptane Crystallization

[0140] The reactor was charged with a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.0 equiv., 37 kg scale) in n-heptane. The reaction mixture was cooled to 5°C. A solution of KCO (1.1 equiv.) and 4-chlorophenol (1.0 equiv.) in water (5 vol) was charged to the reactor while maintaining the internal temperature between 0°C and 10°C. The reaction mixture was stirred at 5°C for 39 hours. A solution of KCO (0.1 equiv.) and 4-chlorophenol (0.1 equiv.) in water (1 vol) was charged to the reactor while maintaining the internal temperature between 0°C and 10°C. The reaction mixture was stirred at 5°C for 16 hours. The reaction mixture was brought to 20°C, and n-heptane (5 vol) was then charged to the reactor. The reaction mixture was stirred for 30 minutes, after which the organic layer was separated 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 was washed with cold n-heptane (2 volumes), and the solid was dried to obtain B-1 in 75% yield and 99.9% a / a. 1H NMR (400MHz, CDCl3) δ 8.72 (d, J = 0.9 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.17 - 7.11 (m,2H).

[0141] Example 5b. 4-Chlorophenol Coupling and Heptane Crystallization 4-Chlorophenol Coupling and IPA / Water Crystallization

[0142] The reactor was charged with a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.0 equiv., scale factor, 50 g scale) and 4-chlorophenol (1.1 equiv.) in n-heptane. The reaction mixture was cooled to 5°C. A solution of KCO (1.1 equiv.) in water (5 vol) was charged to the reactor while maintaining the internal temperature between 0°C and 10°C. The reaction mixture was stirred at 5°C for 24 hours. The reaction mixture was then brought to 30°C and n-heptane (4 vol) was added to the reactor. The resulting solution was stirred for an additional 40 hours. The organic layer was separated and washed twice with water (5 vol) until the pH reached 7. The organic layer was concentrated under reduced pressure to 3 vol. The slurry was brought to 6 vol with isopropanol and heated to 30°C. Water (2 vol) was added and the resulting slurry was stirred for 30 minutes, cooled to 0°C over 3 hours, and stirred for an additional two hours. 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 afford 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).

[0143] Example 5c. 4-Chlorophenol Coupling and Heptane Crystallization 4-Chlorophenol Coupling and IPA Crystallization

[0144] A reactor was charged with a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.0 equiv., scale factor, 35 g scale) and 4-chlorophenol (1.1 equiv.) in n-heptane. The reaction mixture was brought to 22°C. A solution of KCO (1.1 equiv.) in water (5 vol) was added to the reactor while maintaining the internal temperature between 20°C and 30°C. The reaction mixture was stirred at 30°C for 45 hours. The organic layer was separated 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 five hours and then held for three hours. The slurry was filtered, the filter cake washed with cold isopropanol (2 vol), and the solid dried to yield DN11247 in 68% yield and 99.9% a / a. 1 H NMR (400 MHz, CDCl3) δ8.72 (d, J = 0.9 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.17 - 7.11 (m, 2H).

[0145] Example 6. Methyl 2-methyl-2-(triazol-2-yl)propionate

[0146]

[0147] The reactor was charged with 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 charged 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 charged 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 yield a mixture of triazole regioisomers 4-3 and 4-4. Water (10 vol) was charged 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 aqueous HCl (3 vol) to remove the unwanted regioisomer. The combined organic layers were washed with 5 wt.% aqueous NaHCO (3 vol) and water (3 vol). The combined organic layers were concentrated under reduced pressure to 2 volumes and MTBE (4 volumes) were charged to the reactor. The mixture was concentrated under reduced pressure to 2 volumes and MTBE (4 volumes) were charged to the reactor. The mixture was concentrated under reduced pressure to 2 volumes and MTBE (4 volumes) were charged to the reactor to give N as a solution in MTBE. 2-triazole 4-3 (32% assay yield, 84.9% a / a), exchanged into THF or used directly to prepare ketone IV. 1 H NMR (400 MHz, CDCl3) δ 7.64 (s, 2H), 3.69 (s, 3H), 1.95 (s, 6H).

[0148] Example 7a. 4-Methyl-3-oxo-4-(triazol-2-yl)pentanenitrile

[0149]

[0150] The reactor was charged with CHCN (2.1 equiv.) and THF (10 vol). The reaction mixture was cooled to -75°C, and then 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 to 5 with 3 M aqueous HCl. The aqueous layer was separated and extracted twice with EtOAc (5 vol). The combined organic layers were washed with saturated aqueous NaCl (5 vol) and concentrated under reduced pressure to 1.5 vol. The mixture was concentrated four times with MTBE (3 vol) to 3 vol. The slurry was agitated 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 afford ketone IV in 60% yield and 100% a / a. 1 H NMR (400 MHz, CDCl3) δ7.74 (s, 2H), 3.10 (s, 2H), 1.88 (s, 6H).

[0151] Example 7b. 4-Methyl-3-oxo-4-(triazol-2-yl)pentanenitrile

[0152]

[0153] A reactor was charged with 4-3 (1.0 equiv., 10 g scale), CH3CN (2.1 equiv.), and THF (3 vol). The reaction mixture was cooled to -10°C, and then a 1.0 M solution of KOt-Bu in THF (2.0 equiv.) was charged to the reactor while maintaining the internal temperature below 0°C. The reaction mixture was stirred at -10°C for 12 hours. Water (5 vol) was charged 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 to 5 with 3 M aqueous HCl. The aqueous layer was separated and extracted twice with EtOAc (5 vol). The combined organic layers were washed with saturated aqueous NaCl (5 vol) and concentrated under reduced pressure to 1.5 vol. The mixture was concentrated four times with MTBE (3 vol) to 3 vol. The slurry was stirred at 20°C for 2 hours. The slurry was filtered, the filter cake washed with MTBE (1 vol), and the solid dried to afford 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).

[0154] Example 7c. 4-Methyl-3-oxo-4-(triazol-2-yl)pentanenitrile

[0155]

[0156] A reactor was charged with a solution of 4-3 (1.0 equiv., scale factor, 37 kg scale) in THF (6 vol). 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 hours. 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 separated and extracted with MTBE (5 vol). The combined organic layers were washed with 10 wt% aqueous NaCl (5 vol) and concentrated under reduced pressure to 1.5 vol. The mixture was concentrated twice with MTBE (3 vol) to 1.5 vol. MTBE (1 vol) was added and the temperature was adjusted to 50°C. The resulting solution was cooled to 5°C over two hours and then held for three hours. The slurry was filtered, the filter cake washed with cold MTBE (1 volume), and the solid dried to afford IV in 83% yield and 99.9% a / a. 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 2H), 3.10 (s, 2H), 1.88 (s, 6H).

[0157] Example 8. 4-Methyl-3-oxo-4-(triazol-2-yl)valeronitrile

[0158]

[0159] A reactor was charged with dibromotriazole 5-1 (1.0 equiv., 24 kg scale), potassium carbonate (1.0 equiv.), and NMP (5 vol). Methyl 2-bromoisobutyrate (1.3 equiv.) was charged to the reactor while maintaining the internal temperature below 20°C. The reaction mixture was stirred at 35°C for 24 hours. The reaction mixture was cooled to 10°C, and then 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 to 2 vol under reduced pressure. MeOH (2 vol) was charged to the reactor, and the mixture was concentrated to 2 vol under reduced pressure. MeOH (6 vol) and water (0.7 vol) were charged to the reactor to obtain the methyl ester 5-2 as a solution in MeOH and water (90% assay yield, 86.3% a / a), which was used directly to prepare 4-3. 1 HNMR (400 MHz, CDCl3) δ 3.70 (s, 3H), 1.91 (s, 6H).

[0160] A reactor was charged with a solution of 5-2 (1.0 equiv., 15 kg scale) 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 to 1.5 mPa with H2 and stirred at 55°C for 10 hours. The reaction mixture was filtered and the filter cake was washed with MeOH (2 vol). The filtrate was concentrated under reduced pressure to 1 vol. MTBE (10 vol) and 8 wt.% aqueous NaHCO3 (8 vol) were charged to the reactor. The organic layer was separated and washed with water (5 vol). The combined aqueous layers were extracted with MTBE (5 vol) and the combined organic layers were concentrated under reduced pressure to 1 vol. THF (3 vol) was charged to the reactor and the mixture was concentrated under reduced pressure to 1 vol. THF (3 vol) was charged to the reactor and the mixture was concentrated under reduced pressure to 1 vol. The reactor was charged with THE (1.5 vol) to afford 4-3 as a solution in THF (97% assay yield, 98.4% a / a), which was used directly to prepare IV.1 H NMR (400 MHz, CDCl3) δ7.64 (s, 2H), 3.69 (s, 3H), 1.95 (s, 6H).

[0161] The reactor was charged with CHCN (2.1 equiv.) and THF (10 vol). The reaction mixture was cooled to -75°C, and then 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 to 5 with 3 M aqueous HCl. The aqueous layer was separated and extracted twice with EtOAc (5 vol). The combined organic layers were washed with saturated aqueous NaCl (5 vol) and concentrated under reduced pressure to 1.5 vol. The mixture was concentrated four times with MTBE (3 vol) to 3 vol. The slurry was agitated 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 afford IV in 60% yield and 100% a / a. 1 H NMR (400 MHz, CDCl3) δ7.74 (s, 2H), 3.10 (s, 2H), 1.88 (s, 6H).

Claims

1. A compound of formula B: (B)， or a salt thereof, wherein: X is chlorine or ;and R 1 、R 2 、R 3 、R 4 and R 5 are independently H, cyano, halo, methyl or NO2, The restriction is a) When X is Cl and R 1 、R 2 、R 3 and R 5 When H, R 4 Not NO2 or H; b) When X is Cl and R 1 and R 2 When it is CH3, R 4 is not a cyano group; and c) When X is Cl, then R 3 Not NO2.

2. The compound according to claim 1, wherein the compound is B-1 or a salt thereof.

3. The compound according to claim 1, wherein the compound is C-1 or a salt thereof.

4. A method for preparing compound I or its salt (I) The method comprises: a) contacting compound II with a compound of formula B and a base to produce a compound of formula C where R 1 、R 2 、R 3 、R 4 and R 5 are independently H, cyano, halo, methyl or NO2; as well as b) contacting the compound of formula C with ethylamine; To produce compound I.

5. The method of claim 4, wherein the compound of formula B is compound B-1 (B-1)， And the compound of formula C is compound C-1 (C-1)。 6. The method of claim 5, wherein the compound C-1 is produced at a regioisomeric purity of 96% or greater, 97% or greater, 98% or greater, or 99% or greater.

7. The process 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 method of claim 5, wherein the compound B-1 is prepared by: a) contacting compound D-1 with compound D-2 and a base to produce said compound B-1; and b) optionally crystallizing the compound B-1 from heptane, isopropanol or an isopropanol / water mixture.

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

10. The method of claim 8, wherein the base is K2CO3 or NaOH.

11. The method of claim 10, wherein the base is K2CO3.

12. The method of claim 8, wherein the compound D-1 is prepared by contacting the compound E-1 with POCl3 Prepared on site to produce the compound D-1.

13. The method of claim 12, wherein the compound E-1 is contacted with POCl3 and diisopropylethylamine.

14. The method of claim 4, wherein the Compound 1 is obtained with a purity greater than 98% or greater than 99%.

15. The method of claim 14, wherein the compound 1 is obtained with a purity exceeding 99.5%.

16. The method of claim 4, wherein the compound II is prepared by contacting compound III with compound IV and an acid. (III) (IV)。 17. The method of claim 16, wherein the acid is H2SO4 or HCl in an alcohol solvent.

18. 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 method of claim 16, wherein the compound IV is prepared by: a) contacting compound V with a compound of formula VI and a first base to produce a compound of formula VII (V) (VI) (VII), where R 6 is an alkyl group; b) washing the compound of formula VII with an aqueous solution to remove N 1 -triazole regioisomers and obtaining said compound of formula VII with a regioisomeric purity of 95% or greater; and c) contacting said compound of formula VII with a second base and CH3CN under conditions sufficient to produce said compound IV.

20. The method of claim 19, wherein R 6 is methyl and the compound of formula VII is VII-1 (VII-1) It has a regioisomeric purity of 95% or greater.

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

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

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

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

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

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

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

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

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

30. The method of claim 16, wherein the compound IV is prepared by: a) making a compound of formula VIII (VIII) contacting with a compound of formula VI and a first base to produce a compound of formula IX where R 6 is an alkyl group and R 7 and R 8 are independently Br or trimethylsilyl (TMS); b) Make R 7 and R 8 The compound of formula IX when at least one of the is Br is contacted with H2 or HCO2H and a hydrogenation catalyst; and / or make R 7 and R 8 contacting the compound of Formula IX when at least one of the compounds is TMS with a base; To produce the compound of formula VII (VII); as well as c) contacting the compound of formula VII with a second base and CH3CN; To produce the compound IV.

31. The method of claim 30, wherein R 6 is CH3 and R 7 For Br.

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

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

34. The method of claim 33, wherein the first base is K2CO3.

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

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

37. A compound of formula IX (IX) or a salt thereof, wherein: R 6 is an alkyl group and R 7 and R 8 are independently Br or trimethylsilyl (TMS).

38. The compound of claim 37, which is or a salt thereof.

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