Method for preparing aminopyrimidine compounds

Abstract

Provided herein is an improved method for preparing aminopyrimidine compounds of formula (I). The disclosed method advantageously proceeds through a β-diketoester intermediate of formula (A) and avoids direct connection of pyrimidine to the phenyl moiety. The disclosed method significantly increases the yield of the desired compound and simplifies the synthetic route.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 858,050, filed on June 6, 2019, which is incorporated herein by reference in its entirety for all purposes.

[0003] STATEMENT AS TO RIGHTS TO INVENTS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0004] not applicable

[0005] Reference to a "Sequence Listing", table or computer program listing appendix submitted on a compact disc

[0006] not applicable Background of the Invention

[0008] Adenosine is a purine nucleoside compound that contains a complex of adenine and a ribose molecule (furanose). Adenosine is naturally present in mammals and plays an important role in several biochemical processes, including energy transfer (such as adenosine triphosphate and adenosine monophosphate) and signal transduction (such as cyclic adenosine monophosphate). Adenosine also plays a role in processes related to vasodilation (including cardiac vasodilation) and acts as a neuromodulator (for example, it is believed to be involved in promoting sleep). In addition to participating in these biochemical processes, adenosine is also used as a therapeutic antiarrhythmic agent to treat, for example, supraventricular tachycardia. As further discussed herein, tumors evade host responses by suppressing immune function and promoting tolerance, and adenosine has been shown to play an important role in mediating tumor escape from the immune system. Adenosine is expressed on various immune cell subsets and endothelial cells through the A 2A R and A 2B Adenosine signaling by R has been established to have an important role in protecting tissues during inflammatory responses. Thus, in certain instances, adenosine protects tumors from immune destruction (e.g., see Fishman, P et al., (2009) Handb Exp Pharmacol 193:399-441).

[0009] Adenosine receptors are a class of purinergic G protein-coupled receptors that use adenosine as an endogenous ligand. The four types of adenosine receptors in humans are called A1, A 2A , A 2B Modulation of A1 has been suggested to manage and treat, for example, neurological disorders, asthma, and heart and kidney failure; A 2A Antagonists are used to manage and treat, for example, Parkinson's disease; modulation of A 2BUseful in the management and treatment of, for example, chronic lung disease, including asthma; and modulation of A3 has been suggested for the management and treatment of, for example, asthma and chronic obstructive pulmonary disease, glaucoma, cancer, and stroke.

[0010] Historically, modulators of adenosine receptors have been non-selective. However, recent work has identified modulators that specifically target adenosine A 2A Receptor (A 2A R) or adenosine A 2B Receptor (A 2B R) useful adenosine modulators. This work includes compounds described in WO2018 / 136700, which include an aminopyrimidine moiety.

[0011] Despite these advances, the synthetic methods described for preparing the compounds of WO2018 / 136700 include chemical transformations with relatively low yields, which hinder large-scale production and impede the commercial availability of the compounds.

[0012] Therefore, there is a need in the art to provide improved methods for preparing aminopyrimidine compounds. The present disclosure satisfies this need and also provides related advantages. Summary of the invention

[0013] In some aspects, provided herein are methods of preparing compounds represented by formula (I):

[0014]

[0015] Where R 1a , R 1b , R 2a , R 2b , R 3 and X as described in this article,

[0016] The method comprises:

[0017] a) making a compound of formula (A):

[0018]

[0019] contacting with a guanidine reagent and a solvent system comprising at least one halogenated alcohol to obtain a compound of formula (B)

[0020]

[0021] Where R 4 is selected from the group consisting of C1-C8 alkyl and C3-C8 cycloalkyl, each of which is optionally substituted with 1 to 6 members independently selected from the group consisting of F and Cl; and

[0022] b) replacing the hydroxyl group of formula (B) to form a compound of formula (I).

[0023] In some embodiments, the compound of formula (I) is a compound of formula (Ia)

[0024]

[0025] In some aspects, provided herein are methods for preparing compounds of formula (II)

[0026]

[0027] Where R 1a , R 1b , R 2a , R 2b , R 3 As stated in this article,

[0028] The method comprises:

[0029] a') preparing a compound of formula (I) according to the method described herein;

[0030] b') converting the compound of formula (I) into a compound of formula (C);

[0031]

[0032] as well as

[0033] c') combining the compound of formula (C) with an azide compound of formula (D),

[0034]

[0035] To produce the compound of formula (II).

[0036] In some embodiments, the methods described herein can be used to prepare compounds of formula (IIa)

[0037] BRIEF DESCRIPTION OF THE DRAWINGS

[0038] not applicable DETAILED DESCRIPTION

[0039] I. Overview

[0040] The present disclosure provides an improved process for preparing aminopyrimidine compounds of formula (I). In particular, the process described herein uses guanidine and a compound of formula (A) having a β-diketoester to provide a compound of formula (B). The present invention advantageously improves the yield of preparing the compound of formula (B). Subsequent conversion of the alcohol of formula (B) can be used to prepare the compound of formula (I).

[0041] The methods described herein are specifically useful for preparing 3-[2-amino-6-(1-{[6-(2-hydroxypropan-2-yl)pyridin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile, but it will be appreciated that the synthetic methods disclosed herein can be used to improve the efficiency and synthetic yields of a wide variety of compounds.

[0042] II. Definitions

[0043] As used herein, the term "contacting" refers to the process of bringing at least two different substances into contact so that they can react. However, it should be understood that the resulting reaction product can be produced directly from the reaction between the added reagents or from an intermediate of one or more added reagents that can be produced in the reaction mixture.

[0044] As used herein, unless otherwise stated, the term "alkyl" by itself or as part of another substituent means a straight or branched hydrocarbon group. Alkyl substituents and other hydrocarbon substituents may contain a numerical designator indicating the number of carbon atoms in the substituent (i.e., C1-C8 means 1 to 8 carbons), but such designators may be omitted. Unless otherwise specified, the alkyl group of the present invention contains 1 to 12 carbon atoms. For example, the alkyl group may contain 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0045] "Alkoxy" refers to an alkyl group with an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. As with alkyl, alkoxy groups can have any suitable number of carbon atoms, for example, C 1-6 Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like. Alkoxy groups may be further substituted with various substituents described herein. Alkoxy groups may be substituted or unsubstituted.

[0046] "Halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.

[0047] As used herein, the term "protecting group" refers to a portion formed to render a functional moiety non-reactive. The protecting group can be removed to restore the functional moiety to its original state. Various protecting groups and protecting agents (including nitrogen protecting groups) are well known to those of ordinary skill in the art and include Protective Groups in Organic Synthesis, 4th edition, TW Greene and PGM Wuts, John Wiley & Sons, New York, 2006 (which is incorporated herein by reference in its entirety) disclosed compounds.

[0048] As used herein, the term "basic" is an adjective that refers to a chemical substance that is a base. A basic additive refers to an additive that is a base. Basic reaction conditions refer to reaction conditions that include a pH value above 7.

[0049] III. Implementation of the Present Disclosure

[0050] A. Preparation of compounds of formula (I)

[0051] The inventors of the present disclosure have found that combining a compound of formula (A) with a guanidine reagent in a solvent system comprising a halogenated alcohol advantageously and effectively provides a compound of formula (B) in high yield. Without being bound by any particular theory, it is believed that the electron-withdrawing properties of the halogen group in the halogenated alcohol solvent system favor the condensation reaction rather than the replacement reaction product, thereby obtaining the compound of formula (B).

[0052] Thus, in one aspect, provided herein is a method for preparing a compound represented by formula (I):

[0053]

[0054] in

[0055] R 1a and R 1b Independently selected from the group consisting of: H, C 1-8 Alkyl, C 1-8 Alkoxy and halogen;

[0056] R 2a and R 2b independently selected from the group consisting of: H, CN, and halo;

[0057] R 3 Selected from the group consisting of: H, C 1-8 Alkyl and halogen;

[0058] X is a leaving group selected from the group consisting of halogen and O-sulfonate,

[0059] The method comprises:

[0060] a) making a compound of formula (A):

[0061]

[0062] Where R 4 Selected from the group consisting of C1-C8 alkyl and C3-C8 cycloalkyl, each of which is optionally substituted with 1 to 6 members independently selected from the group consisting of F and Cl;

[0063] contacting with a guanidine reagent and a solvent system comprising at least one halogenated alcohol to obtain a compound of formula (B)

[0064]

[0065] as well as

[0066] b) replacing the hydroxyl group of formula (B) to form a compound of formula (I).

[0067] In some embodiments of the above methods, the compound of formula (I) is a compound of formula (Ia)

[0068]

[0069] In the embodiment wherein the compound of formula (Ia) is prepared, step a) comprises

[0070] The compound of formula (Aa)

[0071]

[0072] contacting with a guanidine reagent and a solvent system comprising at least one halogenated alcohol to obtain a compound of formula (Ba)

[0073]

[0074] Where R 4 As defined herein for Formula B.

[0075] The formula disclosed herein has a substituent R 1a , R 1b , R 2a , R 2b and R 3 The phenyl ring of may be any of the above substituents. In some embodiments, the phenyl ring having the substituent R 1a , R 1b , R 2a , R 2b and R 3 The phenyl ring of includes no more than three non-hydrogen moieties. 1a In some embodiments, R 2ais CN. In some embodiments, R 1b and R 2b Both are H. In some embodiments, R 1a is methyl, R 2a is CN, and R 1b , R 2b and R 3 Each is H.

[0076] In some embodiments, R 4 is selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl and 2,2,2-trifluoroethyl. 4 It is ethyl.

[0077] Regarding step a), guanidine reagent is important for preparing the desired product. There are many commercially available guanidine reagent sources that can be used in the present disclosure. In some embodiments, guanidine reagent is selected from the group consisting of: guanidine, guanidine hydrochloride, guanidine carbonate, guanidine hydrobromide, guanidine nitrate, guanidine hydroiodide, guanidine acetate, guanidine sulfate, guanidine bisulfate, guanidine thiocyanate, guanidine sulfamate, guanidine phosphate and 4-benzenesulfonate. In some embodiments, guanidine is guanidine carbonate. In some embodiments, guanidine reagent is guanidine hydrochloride.

[0078] As mentioned above, the solvent system comprising at least one halogenated alcohol in step a) guides the favorable reaction product toward the condensation product of formula (B). In some embodiments, the solvent system comprising at least one halogenated alcohol is selected from 2,2,2-trifluoroethanol, 2-fluoroethanol and 2-chloroethanol. In some embodiments, the solvent system comprising at least one halogenated alcohol is only 2,2,2-trifluoroethanol. In some embodiments, the solvent system comprising at least one halogenated alcohol is a combination of 2,2,2-trifluoroethanol and an alcohol selected from the group consisting of: methanol, ethanol, propanol, 2-fluoroethanol, 2-chloroethanol, 2-methoxyethanol and 2-(methanesulfonyl) ethane-1-ol.

[0079] In some embodiments, the conversion of step a) further comprises a base. Suitable bases include NaH, NaOH, KOH, LiOH, Ca(OH)2, NaO-C 1-8 Alkyl and KO-C 1-8 alkyl.

[0080] The conversion of step a) can be completed at various temperatures. Typically, step a) is heated to provide a high desired conversion level. In some embodiments, step a) is implemented under reflux. In some embodiments, step a) is implemented at a temperature higher than 70° C. In some embodiments, the conversion of step a) is implemented at a temperature of about 75-105° C. In some embodiments, the conversion of step a) is implemented at a temperature of about 100° C.

[0081] The period of the reaction of step a) will depend on many factors, including the specific reagents used and the temperature. In some embodiments, the reaction of step a) is incubated for about 2, 4, 6, 8, 10, 12, 14, 16 or 18 or more hours. In some embodiments, the reaction of step a) is incubated for about 6 hours. In some embodiments, the reaction of step a) is incubated for about 14 hours.

[0082] The yield of the desired product of the conversion of step a) varies according to the precise reaction conditions utilized. In some embodiments, the yield of formula (B) in the conversion of step a) exceeds 60%. In some embodiments, the yield of formula (B) in the conversion of step a) is at least 65%. In some embodiments, the yield of formula (B) in the conversion of step a) is at least 70%. In some embodiments, the yield of formula (B) in the conversion of step a) is at least 75%. In some embodiments, the yield of formula (B) in the conversion of step a) is at least 80%.

[0083] The conversion described in step a) generally involves the formation of a small amount of by-products. The small amount of by-products formed are the conversion of the compound of formula (A) into the compound of formula (i)

[0084]

[0085] In some embodiments, the byproduct form is a compound of formula (ia):

[0086]

[0087] In some embodiments, the methods described herein further comprise grinding the byproduct of formula (i) or (ia) with an organic solvent. Organic solvents that can be used for grinding the undesirable byproducts include, but are not limited to, ethanol, methanol, acetonitrile, dichloromethane, ethyl acetate, and methyl tert-butyl ether (MTBE). In some embodiments, the organic solvent used is MTBE or dichloromethane.

[0088] Those skilled in the art will recognize that the amount of the by product formed will depend on the reaction conditions used.Usually, the amount of the by product formed is usually no more than 20% of the total amount of the formula (A) converted from the starting material.In some embodiments, the by product formed is no more than 15% of the total amount of the formula (A) converted from the starting material.In some embodiments, the by product formed is no more than 10% of the total amount of the formula (A) converted from the starting material.In some embodiments, the by product formed is no more than 5% of the total amount of the formula (A) converted from the starting material.

[0089] The modification or replacement of the hydroxyl group of formula (B) in step b) can be achieved using many different reagents. In some embodiments, the hydroxyl group is modified by a sulfonation process, which provides a compound of formula (I) wherein X is a sulfonate of a hydroxyl group. In some embodiments, step b) comprises a halogenation process wherein the hydroxyl group of formula (B) is replaced by a halogen.

[0090] Sulfonation can be achieved using sulfonating agents known in the art. This includes, but is not limited to, methanesulfonyl chloride, trifluoromethanesulfonic anhydride, and 4-toluenesulfonyl chloride.

[0091] Halogenation can be achieved using known halogenating agents in the art. This includes, but is not limited to, POCl3, PSCl3, SOCl2, (COCl)2, PCl5, PBr3, N-chlorosuccinimide (NCS) and N-bromosuccinimide (NBS). In some embodiments, the halogenating agent is POCl3.

[0092] In some embodiments, the molar ratio of the halogenating agent or sulfonating agent to the compound of formula (B) or formula (Ba) is controlled. In some embodiments, the molar ratio of the halogenating agent or sulfonating agent to the compound of formula (B) is about 1:1 to about 3:1, or about 1.2:1 to about 1.8:1.

[0093] Typically, the solvent system used in step b) is a polar aprotic organic solvent. Suitable polar aprotic organic solvents include (but are not limited to) acetonitrile, DMF, DMSO, NMP, and combinations thereof. In some embodiments, the polar aprotic organic solvent is acetonitrile.

[0094] In some embodiments, the conversion of step b) further comprises a base additive. Suitable base additives include trimethylamine, diisopropylethylamine, dimethylaniline, benzyltrimethylammonium chloride and benzyltriethylammonium chloride. In some embodiments, the base additive is benzyltriethylammonium chloride.

[0095] The conversion of step b) can be completed at various temperatures. The preferred temperature will depend on the desired chemical conversion and the reagents used. Those skilled in the art will be able to determine the appropriate temperature based on the selected reagents. In some embodiments, step b) is implemented at an elevated temperature. In some embodiments, step b) is implemented at a temperature of about 60-90° C. In some embodiments, step b) is implemented at a temperature of about 67-83° C. In some embodiments, step b) is implemented at a temperature of about 70° C. In some embodiments, step b) is implemented at a temperature of about 80° C.

[0096] B. Preparation of compounds of formula (II)

[0097] In some aspects, the compound of formula (I) can be used to prepare the compound of formula (II)

[0098]

[0099] in

[0100] R 1a and R 1b Independently selected from the group consisting of: H, C 1-8 Alkyl, C 1-8 Alkoxy and halogen;

[0101] R 2a and R 2b independently selected from the group consisting of: H, CN, and halo;

[0102] R 3 Selected from the group consisting of: H, C 1-8 Alkyl and halogen.

[0103] In such embodiments, the method comprises:

[0104] a') preparing the compound of formula (I) by: making a compound of formula (A)

[0105]

[0106] Contact with a guanidine reagent to obtain a compound of formula (B)

[0107] Where R 4 selected from the group consisting of: C1-C8 alkyl and C3-C8 cycloalkyl, each of which is optionally substituted independently by 1 to 6 members; and replacing the hydroxyl group of formula (B) to form a compound of formula (I), as described above;

[0108] b') converting the compound of formula (I) into a compound of formula (C);

[0109]

[0110] as well as

[0111] c') combining the compound of formula (C) with an azide compound of formula (D),

[0112]

[0113] To produce the compound of formula (II).

[0114] In some embodiments, in the above method, the compound of formula (II) is a compound of formula (IIa)

[0115]

[0116] In the embodiment wherein the compound of formula (IIa) is prepared, in step a') the compound of formula (Ia) is prepared; and step b') the compound of formula (Ia) is converted to a compound of formula (Ca)

[0117] and

[0118] Step c) comprises combining a compound of formula (Ca) with an azide compound of formula (D) to produce a compound of formula (IIa).

[0119] After preparing the compound of formula (I) as described herein, the X position of the compound of formula (I) is replaced with an acetylene group, and the above step b'). This can be carried out using any known method in the art, such as the method described in WO2018 / 136700. In some embodiments, step b') includes the following sub-steps:

[0120] b'-1) contacting a compound of formula (I) with a silyl protected acetylene and a palladium catalyst and a copper co-catalyst to produce an intermediate of formula (C'):

[0121]

[0122] Where R 5 is a silyl protecting group; and

[0123] b'-2) contacting the compound of formula (C') with a desilylation agent to produce the compound of formula (C).

[0124] Various palladium and copper catalysts can be used in the transformation. In some embodiments, the palladium catalyst is Pd(PPh3)2Cl2. In some embodiments, the copper co-catalyst is CuI.

[0125] The conversion in step b'-1) may also include a base. In some embodiments, the base is an amine base. Many different amine bases are suitable for this conversion and include (but are not limited to) triethylamine or N,N-diisopropylethylamine.

[0126] Many different organic solvents can be used to carry out the conversion of step b'-1). Suitable organic solvents include tetrahydrofuran, acetonitrile, dichloromethane, ethyl acetate and methyl tert-butyl ether (MTBE).

[0127] The conversion of step b'-1) can be carried out at various temperatures. In some embodiments, the conversion of step b'-1 is carried out at a temperature of about 20-90°C. In some embodiments, the conversion of step b'-1 is carried out at a temperature of about 30-75°C. In some embodiments, the conversion of step b'-1 is carried out at a temperature of about 40-60°C. In some embodiments, the conversion of step b'-1 is carried out at a temperature of about 50°C.

[0128] Typically, the conversion of step b'-1) is carried out over the course of several hours, but longer reaction times are also encompassed. In some embodiments, the reaction is incubated for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 or more hours. In some embodiments, the reaction is incubated for about 3 hours. In some embodiments, the reaction is incubated for about 5 hours. In some embodiments, the reaction is incubated for about 7 hours.

[0129] The silyl protected acetylene used in step b'-1) may include many silyl protecting groups known in the art. Suitable groups include, but are not limited to, triisopropylsilyl, trimethylsilyl, tert-hexyldimethylsilyl, benzyldimethylsilyl, biphenyldiisopropylsilyl, and tris(biphenyl-4-yl)silyl. In some embodiments, the silyl protecting group is triisopropylsilyl.

[0130] The conversion of step b'-2) comprises the use of a desilylation agent to remove the silyl protecting group. Many different methods and conditions for removing the silyl protecting group are known in the art and can be used in the methods disclosed herein. In some embodiments, the desilylation agent used is selected from the group consisting of: tetra-N-butylammonium fluoride (TBAF), tetrabutylammonium hydroxide, sodium tetrachloroauric acid (III) and acetyl chloride. In one embodiment, step b'-2 comprises tetrabutylammonium hydroxide (TBAH) (20 mol%) and K2HPO4 buffer. In one embodiment, step b'-2 comprises tetrabutylammonium hydroxide (20 mol%) and acetic acid buffer.

[0131] Returning to step c') in the method for preparing the compound of formula II, this step uses click chemistry to connect the azide of formula (D) and the alkynyl of formula (C) to form a tetrazole moiety. Click chemistry is a method that is fully described and understood, and those skilled in the art can easily identify suitable conditions for implementing this reaction. In some embodiments, the reaction of step c') includes a copper catalyst. Various copper catalysts can be used for this conversion and include CuSO4, CuI, CuBr, copper (II) trifluoromethanesulfonate and copper (II) acetate. In some embodiments, the copper catalyst is CuSO4.

[0132] Azide compounds of formula (D) can be prepared, for example, as described in WO2018 / 136700.

[0133] C. Preparation of Compounds of Formula (A)

[0134] In some aspects, provided herein are methods for preparing compounds having formula (A):

[0135]

[0136] in

[0137] R 1a and R 1b Independently selected from the group consisting of: H, C 1-8 Alkyl, C 1-8 Alkoxy and halogen;

[0138] R 2a and R 2b are independently selected from the group consisting of: H, CN, and halo; and

[0139] R 3 Selected from the group consisting of: H, C 1-8 Alkyl and halogen.

[0140] Formula (A) can be prepared from known starting materials. For example, in some embodiments, the compound of formula (A) is prepared by

[0141] i) making a compound of formula (a)

[0142]

[0143] Contact with a halogenating agent to prepare a compound of formula (b)

[0144]

[0145] in

[0146] Y is halogen;

[0147] R 1a and R 1b Independently selected from the group consisting of: H, C 1-8 Alkyl, C 1-8 Alkoxy and halogen;

[0148] R 2a and R 2b are independently selected from the group consisting of: H, CN, and halo; and

[0149] R 3 Selected from the group consisting of: H, C 1-8 Alkyl and halogen;

[0150] ii) combining the compound of formula (b) with the compound of formula (c) in the presence of a base

[0151]

[0152] To form a compound of formula (A)

[0153]

[0154] Where R 4 Selected from the group consisting of C1-C8 alkyl and C3-C8 cycloalkyl, each of which is optionally substituted with 1 to 6 members independently selected from the group consisting of F and Cl.

[0155] Halogenation can be achieved using known halogenating agents in the art. This includes, but is not limited to, POCl3, PSCl3, SOCl2, (COCl)2, PCl5, PBr3, N-chlorosuccinimide (NCS) and N-bromosuccinimide (NBS). In some embodiments, the halogenating agent is (COCl)2.

[0156] Regarding step ii), the compound of formula (c) can also be provided in the form of a salt, which also includes a cation. Suitable cations include (but are not limited to) K + 、Na + and Li + .

[0157] Many bases can be used in step ii). Typically, an amine base is used. Many different amine bases are suitable for this transformation and include (but are not limited to) pyridine, triethylamine or N,N-diisopropylethylamine.

[0158] In some embodiments, the conversion in step ii) comprises a metal catalyst. In some embodiments, the metal catalyst is MgCl2.

[0159] In some embodiments, the conversion of step ii) comprises cooling the reaction to less than 20° C. before combining formula (b) and formula (c). In some embodiments, the conversion of step ii) comprises cooling the reaction to less than 15° C. before combining formula (b) and formula (c). In some embodiments, the conversion of step ii) comprises cooling the reaction to less than 10° C. before combining formula (b) and formula (c).

[0160] D. Preparation of compounds of formula (a')

[0161] In some aspects, the present invention also provides a method for preparing a compound having formula (a'):

[0162]

[0163] in

[0164] R 1b Independently selected from the group consisting of: H, C 1-8 Alkyl, C 1-8 Alkoxy and halogen;

[0165] R 2bare independently selected from the group consisting of: H, CN, and halo; and

[0166] R 3 Selected from the group consisting of: H, C 1-8 Alkyl and halogen.

[0167] In some embodiments, compounds having formula (a') can be prepared, for example, by:

[0168] i) making a compound of formula (a'y)

[0169]

[0170] Contact with a cyaniding agent to prepare a compound of formula (a'x)

[0171]

[0172] in

[0173] R 1b Independently selected from the group consisting of: H, C 1-8 Alkyl, C 1-8 Alkoxy and halogen;

[0174] R 2b are independently selected from the group consisting of: H, CN, and halo; and

[0175] R 3 Selected from the group consisting of: H, C 1-8 Alkyl and halogen; and

[0176] ii) contacting the compound of formula (a'y) with a Grignard reagent and CO2 to obtain the compound of formula (a'x).

[0177] Cyanidation can be achieved using known cyaniding agents in the art. This includes, but is not limited to, copper-mediated cyaniding agents such as CuCN or K3Fe(CN)6. In one embodiment, cyanidation is performed using CuCN in the presence of NaNO2 and HCl.

[0178] Regarding step ii), the Grignard reagent generally has the general formula R-Mg-X, wherein X is a halogen and R is an organic carbon group. Examples of Grignard reagents include, but are not limited to, methylmagnesium chloride, phenylmagnesium bromide, and isopropylmagnesium chloride. In one embodiment, step ii) is implemented using iPrMgCl in the presence of LiCl, THF, and CO2.

[0179] Example

[0180] Example 1: Trifluoroethanol-assisted condensation of β-keto esters to provide hydroxypyrimidines (and chloropyrimidines).

[0181]

[0182] Step 1: Add 12M HCl to the (水溶液) 3-bromo-2-methylaniline (18.6 g, 100 mmol) was added dropwise to a mixture of 4-nitropropene (26 mL) and water (26 mL) to form a fine white suspension. The mixture was cooled to 0 ° C, and a solution of sodium nitrite (7.31 g, 106 mmol) in water (15.1 mL) was added dropwise. The mixture was stirred at 0 ° C for 30 minutes. Sodium bicarbonate (17.8 g, 212 mmol) was added to the homogeneous mixture at 0 ° C to avoid excessive gas evolution. The aqueous phase of the brown suspension was found to have a pH of about 7. This suspension was maintained at 0 ° C.

[0183] In a separate flask, copper cyanide (9.85 g, 110 mmol), potassium cyanide (13.0 g, 200 mmol) and water (31 mL) were heated to 60 ° C to form a homogeneous solution. At 60 ° C, the above suspension was added dropwise to this stirred solution to avoid excess gas evolution. After addition, the mixture was stirred at 100 ° C for 30 minutes. The mixture was cooled, MTBE (200 mL) was added, the mixture was stirred, and filtered to remove any solids, washed with MTBE. The organic phase was dried over Na2SO4 and concentrated. The resulting crude product was purified by vacuum distillation to obtain the desired product (13.6 g, 69%) as a light orange solid.

[0184] Step 2: In a two-liter two-necked flask, aryl bromide (101.9 g, 520 mmol, 1.0 eq) was dissolved in THF (520 mL) under N2 atmosphere, and the mixture was cooled in an ice-water bath. iPrMgCl·LiCl (400 mL, 1.3 M in THF, 520 mmol, 1.0 eq) was added via cannula. When the addition was complete, the ice bath was removed. After 4 hours, the flask was cooled in an ice-water bath and dry ice (about 230 g, 5.2 mol, 10 eq) was added portionwise to prevent overheating or excessive bubbling (Note: CO2 gas can be bubbled through the solution instead of solid dry ice). When the bubbling of the addition was complete, the mixture was diluted with MTBE (500 mL) and 2M HCl (250 mL). The layers were separated, and the aqueous layer was washed with additional MTBE (500 mL). The organic layer was extracted with 10% NaOH (190 mL x 2), and the combined aqueous layers were cooled in an ice-water bath and acidified with concentrated HCl until a white precipitate formed. The precipitate was isolated by filtration and washed with water, then dried in a vacuum oven at 80°C overnight to give benzoic acid (64.1 g, 76% yield) as a white solid.

[0185] Step 3: benzoic acid (50g, 311mmol, 1.0 equivalent) is suspended in CH2Cl2, and oxalyl chloride (40mL, 466mmol, 1.5 equivalent) is added, followed by DMF (about 30 drops). Gas emission is observed immediately, and the reaction flask is opened to the atmosphere under the positive pressure of N2. As determined by LCMS and visual inspection (starting material is completely dissolved), after the initial acid is completely consumed, the reaction mixture is concentrated. Excess oxalyl chloride is removed by azeotropic distillation with toluene to obtain the corresponding acyl chloride in a light brown-brown solid.

[0186] In a separate two-necked flask equipped with an overhead stirrer, ethyl malonate potassium salt (66.1 g, 388 mmol, 1.25 eq.), triethylamine (108 mL, 777 mmol, 2.5 eq.) and MeCN (777 mL) were cooled in a salt / ice-brine bath. Solid MgCl2 (74 g, 777 mmol, 2.5 eq.) was added and the resulting suspension was stirred vigorously at about -10 °C. After 1 hour, the solid acyl chloride was added at a rate that ensured dissolution in the concentrated suspension. The suspension quickly became homogeneous and the stirring rate was reduced to avoid splashing. The ice bath was removed. As determined by TLC analysis, after complete consumption of the starting material, the reaction mixture was cooled in an ice-water bath, 2M HCl (971 mL, 1.9 mol, 6.25 eq.) was added, and the ice bath was removed. After 30 minutes, the layers were separated and the aqueous layer was extracted with MTBE. The combined organic layers were washed with saturated NaHCO 3 and brine, dried over sodium sulfate, filtered and concentrated to give the keto-ester as a light brown-brown solid (67 g, 93% yield).

[0187] Step 4: A round-bottom flask was charged with 42.0 g (181.8 mmol) of β-keto-ester, 32.7 g (181.8 mmol) of guanidine carbonate and 227 mL of trifluoroethanol. The suspension was heated to reflux under N2 for 16 h.

[0188] Workup: The reaction was cooled to room temperature and the solvent was evaporated under reduced pressure to give a viscus red oil. The oil was redissolved in 250 mL of H2O and the aqueous solution was extracted with dichloromethane (2 x 250 mL). The reaction mixture was then eluted with 1.0 M HCl (水溶液) The aqueous phase was acidified to pH about 2-3. The precipitated product was collected by filtration, washed thoroughly with H2O and dried in a vacuum oven at 70°C. Yield 30.81 g (75%), purity >99%.

[0189] Step 5: A round-bottom flask was charged with 50.0 g (221.2 mmol) of the pyrimidinone from step 4 and 100.8 g (442.2 mmol) of benzyltriethylammonium chloride. The mixture was suspended in 442.2 mL of anhydrous acetonitrile and 31.0 mL (331.8 mmol) of POCl3 was added. The suspension thus obtained was then heated to reflux under N2 for 4 h.

[0190] Workup: The reaction was cooled to room temperature and about 200 g of crushed ice was added. The mixture was then stirred for 30 min, followed by dropwise addition of ice-cold 15% NH4OH aqueous solution to about pH 10-11. (Note: Slow addition of cold NH4OH is recommended to avoid sudden exotherm due to quenching of excess POCl3). The suspension was then stirred at room temperature for another 1.5 h. The precipitated product was collected by filtration, washed thoroughly with H2O and dried in a vacuum oven at 70°C. Yield 48.2 g (89%), purity>99%.

[0191] HPLC conditions

[0192] HPLC: Agilent 1100

[0193] Column: YMC-HPLC column; 250x 4.6; S-5μm, 20nm; AQ20S05-2546WT; No.0425058945

[0194] Solvent: H2O / MeCN with 0.1% HCO2H

[0195] Flow rate: 0.8 mL / min

[0196] Column temperature: 30°C

[0197] method:

[0198]

[0199] Example 2: Comparative pyrimidine coupling

[0200] A synthetic route to prepare 3-[2-amino-6-(1-{[6-(2-hydroxypropan-2-yl)pyridin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile utilizing boronate ester benzonitrile to link the phenyl and pyrimidine rings is shown below and is also provided in WO2018 / 136700.

[0201]

[0202] The following scheme shows the synthetic route for preparing the boronate benzonitrile used in the above process and the subsequent reaction with pyrimidine to form the compound of formula (I). Significantly, the desired linkage between pyrimidine and phenyl provides less than 50% yield.

[0203]

[0204] The following scheme shows a synthetic route for the preparation of compounds of formula (I) utilizing the conversion of a β-diketoester to a pyrimidine using guanidine. The route afforded a 75% yield.

[0205]

[0206] Specific embodiments of the present invention are described herein, including the best mode known to the inventors for implementing the present invention. After reading the foregoing description, variations of the disclosed embodiments will become apparent to practitioners in the art, and it is expected that those skilled in the art may appropriately adopt such variations. Therefore, it is expected that the present invention can be practiced in a manner different from that specifically described herein, and the present invention includes all modifications and equivalents of the subject matter described in the appended claims as permitted by applicable law. In addition, unless otherwise specified herein or the context is otherwise clearly contradictory, any combination of the above elements in all possible variations thereof is encompassed in the present invention.

[0207] All publications, patent applications, accession numbers, and other references cited in this specification are herein incorporated by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. A method for preparing a compound represented by formula (I), in R 1a and R 1b Independently selected from the group consisting of: H and C 1-8 Alkyl; R 2a and R 2b independently selected from the group consisting of: H and CN; R 3 It is H; X is a halogen, The method comprises: a) making a compound of formula (A): Where R 4 is selected from C1-C8 alkyl, optionally substituted with 1 to 6 members independently selected from the group consisting of F and Cl; contacting with a guanidine reagent and a solvent system comprising at least one halogenated alcohol to obtain a compound of formula (B) wherein the solvent system comprising at least one halogenated alcohol is only 2,2,2-trifluoroethanol, and b) replacing the hydroxyl group of formula (B) to form a compound of formula (I).

2. The process according to claim 1, wherein step b) is a halogenation process which provides a compound of formula (I) wherein X is a halogen.

3. The method of claim 2, wherein the halogenation process uses a halogenating agent selected from the group consisting of POCl3, PSCl3, SOCl2, (COCl)2, PCl5, PBr3, N-chlorosuccinimide (NCS) and N-bromosuccinimide (NBS).

4. The method of claim 1, wherein the guanidine reagent is selected from the group consisting of guanidine, guanidine hydrochloride, guanidine carbonate, guanidine hydrobromide, guanidine nitrate, guanidine hydroiodide, guanidine acetate, guanidine sulfate, guanidine bisulfate, guanidine thiocyanate, guanidine sulfamate, guanidine phosphate and guanidine 4-benzenesulfonate.

5. The method according to claim 1, wherein R 4 Selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl and 2,2,2-trifluoroethyl.

6. The method according to claim 1, wherein R 4 It is ethyl.

7. The method of claim 1, wherein the guanidine reagent is selected from the group consisting of guanidine hydrochloride and guanidine carbonate.

8. The method of claim 1, wherein the solvent system comprising at least one halogenated alcohol is a combination of 2,2,2-trifluoroethanol and an alcohol selected from the group consisting of methanol, ethanol, propanol, 2-fluoroethanol, 2-chloroethanol, 2-methoxyethanol and 2-(methanesulfonyl)ethan-1-ol.

9. The method according to claim 1, wherein step b) is carried out in a polar aprotic organic solvent.

10. The method of claim 9, wherein the polar aprotic organic solvent is selected from the group consisting of acetonitrile, DMF, DMSO, NMP, and combinations thereof.

11. The method of claim 9, wherein step b) is a halogenation process using POCl3 to provide a compound of formula (I) wherein X is Cl; the guanidine reagent is guanidine carbonate, and the polar aprotic organic solvent is acetonitrile.

12. The process according to any one of claims 1 to 11, wherein step b) is carried out at a temperature of about 67-83°C.

13. The process of claim 1, wherein the compound of formula (A), the guanidine reagent and the solvent system comprising 2,2,2-trifluoroethanol are heated to reflux temperature.

14. The method according to claim 1, wherein before step b), the compound of formula (B) is wet-milled with an organic solvent to remove the by-product of formula (i) 15. The method of claim 14, wherein the organic solvent is selected from the group consisting of ethanol, methanol, acetonitrile, dichloromethane, ethyl acetate and methyl tert-butyl ether.

16. The method according to claim 9, wherein step b) is performed using a base additive.

17. The method of claim 16, wherein the base additive is selected from the group consisting of trimethylamine, diisopropylethylamine, dimethylaniline, benzyltrimethylammonium chloride, and benzyltriethylammonium chloride.

18. The method of claim 16, wherein the base additive is benzyltriethylammonium chloride.

19. The method according to claim 1, wherein the compound of formula (A) is prepared by: i) making a compound of formula (a) Contact with a halogenating agent to prepare a compound of formula (b) in Y is halogen; R 1a and R 1b Independently selected from the group consisting of: H and C 1-8 Alkyl; R 2a and R 2b are independently selected from the group consisting of: H and CN; and R 3 It is H; ii) combining the compound of formula (b) with the compound of formula (c) in the presence of a base To form a compound of formula (A) Where R 4 is selected from C1-C8 alkyl, optionally substituted with 1 to 6 members independently selected from the group consisting of F and Cl.

20. The method according to claim 19, wherein the compound of formula (a) is a compound of formula (a'): in R 1b It is H; R 2b is H; and R 3 It's H.

21. A method for preparing a compound of formula (II), in R 1a and R 1b Independently selected from the group consisting of: H and C 1-8 alkyl; R 2a and R 2b independently selected from the group consisting of: H and CN; R 3 It is H; The method comprises: a') preparing a compound of formula (I) by a method according to any one of claims 1 to 20; b') converting the compound of formula (I) into a compound of formula (C); and c') combining the compound of formula (C) with an azide compound of formula (D), To produce the compound of formula (II).

22. The method according to claim 21, wherein step b') comprises b'-1) contacting the compound of formula (I) with silyl-protected acetylene, a palladium catalyst and a copper co-catalyst to produce an intermediate of formula (C'): Where R 5 is a silyl protecting group; and b'-2) contacting the compound of formula (C') with a desilylation agent to produce the compound of formula (C).

23. The method of claim 22, wherein the silyl protecting group is selected from the group consisting of triisopropylsilyl, trimethylsilyl, tert-hexyldimethylsilyl, benzyldimethylsilyl, biphenyldiisopropylsilyl, and tris(biphenyl-4-yl)silyl.

24. The method of claim 22, wherein the palladium catalyst is Pd(PPh3)2Cl2 and the copper co-catalyst is CuI.

25. The method according to any one of claims 22 to 24, wherein step b'-1) uses Sonogashira coupling conditions with an amine base.

26. The method of claim 25, wherein the amine base is triethylamine or N,N-diisopropylethylamine.

27. The method of claim 22, wherein the desilylation agent is selected from the group consisting of tetrabutylammonium fluoride (TBAF), tetrabutylammonium hydroxide, sodium tetrachloroaurate (III) and acetyl chloride.

28. The method of claim 21, wherein step c') further comprises a copper catalyst.

29. The method of claim 28, wherein the copper catalyst is selected from the group consisting of CuSO4, CuI, CuBr, copper (II) trifluoromethanesulfonate, and copper (II) acetate.

30. The method according to claim 21, wherein step b') comprises b'-1) making a compound of formula (Ia): Contact with triisopropylsilyl acetylene under Sonogashira coupling conditions to produce an intermediate of formula (Ca') as well as b'-2) contacting the compound of formula (Ca') with a desilylation agent to produce a compound of formula (Ca):

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