Methods for preparing aminopyrimidine compounds

Abstract

To provide methods for preparing aminopyrimidine compounds.SOLUTION: Provided herein are improved methods for preparing aminopyrimidine compounds of Formula (I). The disclosed methods advantageously proceed through a β-diketoester intermediate of Formula (A) and avoid a direct link between a pyrimidine moiety and a phenyl moiety. The disclosed methods significantly increase the yield of the target compounds and simplify the synthetic route.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119 to U.S. Provisional Application No. 62 / 858,050, filed June 6, 2019, which is incorporated by reference in its entirety for all purposes.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT N / A

[0003] Reference for sequence list etc. N / A [Background technology]

[0004] Adenosine is a purine nucleoside compound that contains a complex of adenine and a ribose sugar molecule (ribofuranose). Adenosine occurs naturally in mammals and plays an important role in several biochemical processes, including energy transfer (as adenosine triphosphate and adenosine monophosphate) and signal transduction (as cyclic adenosine monophosphate). Adenosine also functions in processes related to vasodilation, including vasodilation in the heart, and as a neuromodulator (e.g., thought to be involved in promoting sleep). These In addition to its involvement in biochemical processes, adenosine is used to treat, e.g., supraventricular tachycardia. As described in detail herein, tumors are used as therapeutic antiarrhythmic agents for It evades the host response by inhibiting immune function and promoting tolerance, and adenosine It has been shown that the immune system plays an important role in mediating tumor evasion. A is expressed in a subset of immune cells and endothelial cells 2A RS and A 2B Adenosine signaling via RS Neural signaling has been shown to play an important role in protecting tissues during inflammatory responses. Therefore, under certain conditions, adenosine protects tumors from immune destruction ( For example, Fishman, P, et al. (2009) Handb Exp Phar (see macol 193:399-441).

[0005] Adenosine receptors are purinergic G proteins that have adenosine as their endogenous ligand. The four types of adenosine receptors in humans are A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30 2A , A 2B The regulation of A1 is known to be involved in the treatment of, for example, neuropathy, asthma, and heart failure. It has been proposed for the management and treatment of total and renal failure. 2A Antagonists include, for example, It has been proposed for the management and treatment of pulmonary tuberculosis. 2B Regulation of the pulmonary endothelial cell Modulation of A3 has been proposed for the management and treatment of diseases such as asthma and chronic obstructive pulmonary disease. It has been proposed for the management and treatment of glaucoma, cancer, and stroke.

[0006] Historically, adenosine receptor modulators have been nonselective. However, recent studies have shown that In the study, adenosine A 2A Receptor (A 2A R) or adenosine A 2B Receptor (A 2B R) as a singular These studies have identified useful adenosine modulators that can be targeted specifically. The compound containing the aminopyrimidine moiety described in WO2018 / 136700 is Included.

[0007] Despite these advances, the compounds of WO2018 / 136700 are still in the process of being prepared. The described synthetic process hampers large scale production and commercial availability of the compounds. The chemical conversion involves lower yields, which hampers availability.

[0008] Therefore, the art is in need of improved methods for preparing aminopyrimidine compounds. There is a need to provide a method for detecting and preventing atherosclerosis. The present disclosure addresses this need and provides related advantages as well. do. Summary of the Invention

[0009] In some embodiments, provided herein is a compound represented by formula (I): [ka] (In the formula, R 1a , R 1b , R 2a , R 2b , R 3 and X is as described herein. A method for preparing a) A compound of formula (A) [ka] (In the formula, R 4 is selected from the group consisting of C1-C8 alkyl and C3-C8 cycloalkyl. Each of these is optionally selected from 1 to 6 elements independently selected from the group consisting of F and Cl. (optionally substituted) is contacted with a guanidine reagent and a solvent system containing at least one halogenated alcohol. Contacting the compound of formula (B) [ka] to obtain; and b) substituting the hydroxyl group of formula (B) to form a compound of formula (I); A method of preparation is disclosed, comprising:

[0010] In some embodiments, the compound of formula (I) is a compound of formula (Ia) [ka] It is.

[0011] In some embodiments, provided herein is a compound of formula (II): [ka] (In the formula, R 1a , R 1b , R 2a , R 2b , R 3 are as described herein) A method for preparing a') preparing a compound of formula (I) according to the methods described herein; b') reacting the compound of formula (I) with a compound of formula (C) [ka] Converting into; and c') reacting the compound of formula (C) with an azide compound of formula (D) [ka] to form a compound of formula (II); A method of preparation is disclosed comprising:

[0012] In some embodiments, the methods described herein comprise the step of: [ka] It is useful for the manufacture of [Brief description of the drawings]

[0013] N / A DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] 1. Overview The present disclosure provides improved methods for preparing aminopyrimidine compounds of formula (I). The method described herein provides a compound of formula (A) having a guanidine and a β-diketo ester. to provide a compound of formula (B). This conversion is useful for preparing a compound of formula (B). Subsequent conversion of the alcohol of formula (B) can be used to obtain the alcohol of formula (I ) can be prepared.

[0015] The methods described herein include the steps of: lopan-2-yl)pyridin-2-yl]methyl}-1H-1,2,3-triazole- Particularly useful in the preparation of 4-yl)pyrimidin-4-yl]-2-methylbenzonitrile However, the synthetic methods disclosed herein improve the efficiency and synthetic yield of many compounds. It is understood that the present invention can be used for

[0016] II. Definition As used herein, the term "contacting" refers to making something capable of reacting. However, the resulting reaction The product may be one or more species that may form directly from the reaction between the added reagents or in the reaction mixture. It should be understood that the reaction may be produced from an intermediate derived from an added reagent.

[0017] As used herein, the term "alkyl" by itself or as part of another substituent. By alkoxy is meant, unless otherwise specified, a straight or branched chain hydrocarbon radical. C11, C12, and other hydrocarbon substituents are designated by a number indicating the number of carbon atoms in the substituent. (i.e. C1-C8 means 1-8 carbons), but such designations Unless otherwise specified, the alkyl groups of the present invention are 1 to 12 carbon atoms. For example, the alkyl group may have 1-2, 1-3, 1-4, 1-5, or 1- 6 pieces, 1~7 pieces, 1~8 pieces, 1~9 pieces, 1~10 pieces, 1~11 pieces, 1~12 pieces, 2~3 pieces , 2~4 pieces, 2~5 pieces, 2~6 pieces, 3~4 pieces, 3~5 pieces, 3~6 pieces, 4~5 pieces, 4~6 pieces , 5-6 carbon atoms. Examples of alkyl groups are methyl, ethyl, n -propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n -pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0018] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment: As for the alkyl group, the alkoxy group is C 1~6 Any suitable The alkoxy group may have, for example, methoxy, ethoxy, propoxy, oxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy Examples of alkoxy groups include oxy, tert-butoxy, pentoxy, and hexoxy. The alkoxy group may be further substituted with various substituents as described in It may be substituted or unsubstituted.

[0019] "Halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine.

[0020] As used herein, the term "protecting group" refers to a group formed to render a functional moiety unreactive. A protecting group can be removed to restore a functional moiety to its original state. A variety of protecting groups and protecting reagents, including nitrogen protecting groups, are well known to those of skill in the art and include, for example, Pro Tective Groups in Organic Synthesis,4th edition,TW Greene and PGMWuts,John Contains compounds listed in Wiley & Sons, New York, 2006. No. 6,399,413, which is incorporated herein by reference in its entirety.

[0021] As used herein, the term "basic" is an adjective that refers to a chemical that is a base. A basic additive refers to an additive that is a base. Basic reaction conditions are a pH greater than 7. Refers to reaction conditions including values.

[0022] III. EMBODIMENTS OF THE DISCLOSURE A. Preparation of Compounds of Formula (I) The inventors of the present disclosure have discovered that a compound of formula (A) can be prepared in a solvent system containing a halogenated alcohol. can be conveniently and efficiently combined with a guanidine reagent to give compounds of formula (B) in high yields. Without being bound to any particular theory, it has been found that the halogenated alko The electron-withdrawing nature of the halo group in the alcohol solvent system favors condensation reactions over alternative reaction products. It is believed to be advantageous to produce a compound of formula (B).

[0023] Thus, in one aspect, there is provided herein a compound of formula (I): [ka] (In the formula, R 1a and R 1b , H, C 1~8 Alkyl, C 1~8 alkoxy, and halogen; independently selected; R 2a and R 2bis independently selected from the group consisting of H, CN, and halo; R 3 , H, C 1~8 selected from the group consisting of alkyl, and halogen; X is a leaving group selected from the group consisting of halogens and O-sulfonates. A method for preparing a) A compound of formula (A) [ka] (In the formula, R 4 is selected from the group consisting of C1-C8 alkyl and C3-C8 cycloalkyl. Each of these is optionally selected from 1 to 6 elements independently selected from the group consisting of F and Cl. (optionally substituted) is contacted with a guanidine reagent and a solvent system containing at least one halogenated alcohol. Contacting the compound of formula (B) [ka] to obtain; and b) substituting the hydroxyl group of formula (B) to form a compound of formula (I); A method of preparation is disclosed, comprising:

[0024] In some embodiments of the above method, the compound of formula (I) is a compound of formula (Ia) [ka] It is.

[0025] In some embodiments in which a compound of formula (Ia) is prepared, step a) comprises: Compound of formula (Aa) [ka] is contacted with a guanidine reagent and a solvent system containing at least one halogenated alcohol. Contacting the compound of formula (Ba) [ka] (In the formula, R 4 is as defined herein for formula B. This includes obtaining

[0026] The substituent R of the formula disclosed herein 1a , R 1b , R 2a , R 2b , and R 3 The phenyl ring having , can be any of the substituents described above. In some embodiments, the substituent R 1a , R 1b , R 2a , R 2b , and R 3 A phenyl ring having the formula: contains up to three non-hydrogen moieties. In some embodiments, R 1a is methyl. In some embodiments, R 2a is CN In some embodiments, R 1b and R 2b are both H. In some embodiments, R 1a is methyl, R 2a is CN and R 1b , R 2b , and R 3 are H, respectively.

[0027] In some embodiments, R 4 is methyl, ethyl, isopropyl, tert-butyl and 2,2,2-trifluoroethyl. So, R 4 is ethyl.

[0028] Regarding step a), the guanidine reagent is central to the preparation of the desired product. There are many commercial sources of guanidine reagents that are useful in the present disclosure. In embodiments, the guanidine reagent is guanidine, guanidine HCl, guanidine carbonate, Guanidine HBr, Guanidine Nitrate, Guanidine HI, Guanidine Acetate, Guanidine Sulfate, guanidine hydrogen sulfate, guanidine thiocyanate, guanidine sulfamate salt, guanidine phosphate, and guanidine 4-benzenesulfonate. In some embodiments, the guanidine is guanidine carbonate. In an embodiment, the guanidine reagent is guanidine HCl.

[0029] As mentioned above, in step a) the reaction mixture contains at least one halogenated alcohol. The solvent system drives the preferred reaction products towards the condensation product of formula (B). In one embodiment, the solvent system containing at least one halogenated alcohol is 2,2,2-triphenylphosphine. 2-fluoroethanol, 2-fluoroethanol, and 2-chloroethanol. In some embodiments, the solvent system comprising at least one halogenated alcohol comprises In some embodiments, at least 1 The solvent system containing the halogenated alcohols is 2,2,2-trifluoroethanol and methyl Methanol, ethanol, propanol, 2-fluoroethanol, 2-chloroethanol , 2-methoxyethanol, and 2-(methanesulfonyl)ethan-1-ol in combination with an alcohol selected from the group.

[0030] In some embodiments, the conversion in step a) further comprises a base. Suitable bases include is NaH, NaOH, KOH, LiOH, Ca(OH)2, NaO-C 1~8 Alkyl, and KO-C 1~8 Examples of such alkyl groups include alkyl.

[0031] The conversion of step a) can be completed at a variety of different temperatures. Step a) is heated to obtain a high level of the desired conversion. In some embodiments, step a) is carried out at reflux. In some embodiments, step a) is carried out at above 70° C. In some embodiments, the conversion in step a) is carried out at a temperature of about 75 to 105 In some embodiments, the converting in step a) is carried out at a temperature of about 100° C. It is held.

[0032] The reaction time of step a) depends on many factors, such as the specific reagents used as well as the temperature. In some embodiments, the reaction of step a) may be carried out in a reaction mixture of about 2, 4, 6, 8 Incubate for 10, 12, 14, 16, or 18 hours or longer. In some embodiments, the reaction in step a) is incubated for about 6 hours. In this embodiment, the reaction in step a) is incubated for about 14 hours.

[0033] The yield of the desired product for the conversion of step a) depends on the exact reaction conditions employed. In some embodiments, the formula (B) in the conversion of step a) may vary. The yield is greater than 60%. In some embodiments, in the conversion of step a), In some embodiments, the yield of the compound in the conversion of step a) is at least 65%. The yield of formula (B) obtained by the reaction is at least 70%. The yield of the compound of formula (B) in the conversion is at least 75%. The yield of formula (B) in the conversion of top a) is at least 80%.

[0034] The conversion described in step a) is often accompanied by the formation of small amounts of by-products. The by-product of the reaction of the compound of formula (A) is the compound of formula (i) [ka] This is a conversion to.

[0035] In some embodiments, the by-product form is a compound of formula (ia) [ka] It is.

[0036] In some embodiments, the methods described herein include a process for the preparation of a compound according to formula (i) or (ii) using an organic solvent. further comprising triturating the by-products of (ia). Organic solvents useful for trituration of include, but are not limited to, ethanol. , methanol, acetonitrile, dichloromethane, ethyl acetate, and methyl tert-butyl ether. In some embodiments, the organic solvent used is methyl ethyl ether (MTBE). is MTBE or dichloromethane.

[0037] One skilled in the art will recognize that the amount of by-products formed will depend on the reaction conditions used. Typically, the amount of by-product formed is usually determined by the amount of the compound of formula (A In some embodiments, the by-products formed do not exceed 20% of the total amount of the starting No more than 15% of the total amount of formula (A) converted from the substance. The amount of by-products formed does not exceed 10% of the total amount of formula (A) converted from the starting material. In some embodiments, the by-product formed is the sum of the compounds of formula (A) converted from the starting material. Not to exceed 5% of the amount.

[0038] The modification or substitution of the hydroxyl group of formula (B) in step b) can be carried out using a number of different reagents. In some embodiments, the hydroxyl can be achieved by using a hydroxyl group. The sulfonation process gives the compound of formula (I), which is a sulfonate ester of the hydroxyl group. In some embodiments, step b) is modified by the addition of a hydroxyl group of formula (B). This includes halogenation processes in which is substituted with halogen.

[0039] Sulfonation can be accomplished using sulfonating agents known in the art. This includes, but is not limited to, methanesulfonyl chloride, trifluoromethane sulfonic anhydride, and 4-toluenesulfonyl chloride.

[0040] Halogenation can be accomplished using halogenating agents known in the art. This includes, but is not limited to, POCl3, PSCl3, SOCl2, (COCl)2 , PCl5, PBr3, N-chlorosuccinimide (NCS), and N-bromosuccinimide In some embodiments, the halogenating agent is POCl3. .

[0041] In some embodiments, a halogenating agent or a compound of formula (B) or formula (Ba) In some embodiments, the molar ratio of the halogenating agent or sulfonating agent is controlled. The molar ratio of the sulfonating agent to the compound of formula (B) is from about 1:1 to about 3:1, or about 1.2:1. ~About 1.8:1.

[0042] 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 the present invention, the polar aprotic organic solvent is acetonitrile.

[0043] In some embodiments, the conversion in step b) further comprises a base additive. Additives include trimethylamine, diisopropylethylamine, dimethylaniline, Benzyltrimethylammonium chloride and benzyltriethylammonium chloride In some embodiments, the base additive is benzyltriethylammonium. It is mucloride.

[0044] The conversion of step b) can be completed at a variety of different temperatures. The preferred temperatures are The degree of specificity of the reaction will depend on the chemical transformation desired and the reagents used. In some embodiments, the appropriate temperature may be determined based on the Step b) is carried out at an elevated temperature. In some embodiments, step b) is carried out at a temperature of about 60-90° C. In some embodiments, step b) is carried out at a temperature of about 67-83° C. In some embodiments, step b) is carried out at a temperature of about 70° C. In an embodiment, step b) is carried out at a temperature of about 80°C.

[0045] B. Preparation of Compounds of Formula (II) In some embodiments, a compound of formula (I) is used in the preparation of a compound of formula (II). can [ka] (In the formula, R 1a and R 1b , H, C 1~8 Alkyl, C 1~8 alkoxy, and halogen; independently selected; R 2a and R 2b is independently selected from the group consisting of H, CN, and halo; R 3 , H, C 1~8 alkyl, and halogen).

[0046] In such an embodiment, the method comprises: a') A compound of formula (A) [ka] (In the formula, 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 elements. with a guanidine reagent to obtain a compound of formula (B), and then reacting the compound of formula (B) as described above. Compounds of formula (I) are prepared by displacing the hydroxy group to form compounds of formula (I). To manufacture; b') reacting the compound of formula (I) with a compound of formula (C) [ka] Converting into; and c') reacting the compound of formula (C) with an azide compound of formula (D) [ka] to form a compound of formula (II); Includes.

[0047] In some embodiments of the above-described methods, the compound of formula (II) is represented by the formula (IIa): compound [ka] It is.

[0048] In the embodiment in which a compound of formula (IIa) is prepared, a compound of formula (la) is prepared by reacting ) and step b') converting a compound of formula (la) into a compound of formula (Ca) [ka] step c) is a step of combining a compound of formula (Ca) with an azide compound of formula (D) Producing a compound of formula (IIa):

[0049] After the compound of formula (I) described herein is prepared, the X position of the compound of formula (I) may be acetylated. This is substituted with an aryl group (step b') above). This can be done using any method known in the art, such as those described in In some embodiments, step b') comprises the following sub-steps: b'-l) Compounds of formula (I) are reacted with silyl-protected acetonitriles in the presence of a palladium catalyst and a copper cocatalyst. with ethylene to produce an intermediate of formula (C'): [ka] (In the formula, R 5 is a silyl protecting group); and b'-2) contacting a compound of formula (C') with a desilylation reagent to produce a compound of formula (C); To accomplish.

[0050] A variety of palladium and copper catalysts can be utilized in the transformations described. In some embodiments, the palladium catalyst is Pd(PPh3)2Cl2. In an embodiment, the copper promoter is CuI.

[0051] The conversion in step b'-1) may also include a base. In some embodiments, the base is an amine base. A number of different amine bases are suitable for this transformation, including Examples of suitable amines include, but are not limited to, triethylamine or N,N-diisopropylethylamine. Examples include:

[0052] A number of different organic solvents can be used to carry out the conversion of step b'-1). Suitable organic solvents include tetrahydrofuran, acetonitrile, dichloromethane, Examples of ethyl acetate include methyl tert-butyl ether (MTBE).

[0053] The conversion of step b'-1) can be carried out at a variety of different temperatures. In some embodiments, the conversion of step b'-1 is carried out at a temperature of about 20 to 90° C. In some embodiments, the conversion of step b'-1 is carried out at a temperature of about 30 to 75° C. In some embodiments, the conversion of step b'-1 is carried out at a temperature of about 40-60° C. In one embodiment, the conversion of step b'-1 is carried out at a temperature of about 50°C.

[0054] Typically, the conversion in step b'-1) takes place over a period of several hours, although longer reaction times may be used. In some embodiments, the reaction may be performed within about 1, 2, 3, 4, 5, 6, 7, 8 Incubate for 9, 10, 11, or 12 hours or more. In embodiments, the reaction is incubated for about 3 hours. The reaction is incubated for about 5 hours. In some embodiments, the reaction is incubated for about 7 hours. It will be.

[0055] The silyl-protected acetylenes used in step b'-1) are known in the art. Suitable groups include, but are not limited to, a number of silyl protecting groups such as trimethylsilyl, tetra ... isopropylsilyl, trimethylsilyl, thexyldimethylsilyl, benzyldimethylsilyl silyl, biphenyldiisopropylsilyl, and tris(biphenyl-4-yl)silyl. In some embodiments, the silyl protecting group is triisopropylsilyl.

[0056] The conversion in step b'-2) involves removing the silyl protecting group using a desilylation reagent. Many different methods and conditions for removing silyl protecting groups are known in the art. can be used in the methods disclosed herein. The desilylation reagent used is tetra-N-butylammonium fluoride (TBAF), butylammonium hydroxide, sodium tetrachloroaurate(III), and chloride In one embodiment, step b'-2 is selected from the group consisting of tetrabutyl. The solution contains triethylammonium hydroxide (TBAH) (20 mol%) and K2HPO4 buffer. In one embodiment, step b'-2 comprises the step of reacting tetrabutylammonium hydroxide (20 molar equivalents) with tetrabutylammonium hydroxide (20 molar equivalents). % and acetate buffer.

[0057] Returning to step c') of the process for preparing the compound of formula II, this step is Using chemistry, an azide of formula (D) is coupled with an alkynyl group of formula (C) to form Click chemistry is well described and understood. This is a process in which the reaction is carried out in a desired manner, and one of ordinary skill in the art can readily identify suitable conditions for carrying out this reaction. In some embodiments, the reaction of step c') comprises a copper catalyst. CuSO4, CuI, CuBr, copper(II) triflate, and copper(II) acetate. A variety of copper catalysts can be used. In some embodiments, the copper catalyst is CuSO The answer is 4.

[0058] The azide compound of formula (D) can be prepared, for example, as described in WO2018 / 136700. It can be prepared as follows:

[0059] C. Preparation of Compounds of Formula (A) In some embodiments, methods for preparing compounds having the formula (A) are also provided. [ka] (In the formula, R 1a and R 1b , H, C 1~8 Alkyl, C 1~8 alkoxy, and halogen; independently selected; R 2a and R 2b is independently selected from the group consisting of H, CN, and halo; R 3 , H, C 1~8 alkyl, and halogen).

[0060] Formula (A) can be prepared from known starting materials. For example, in some embodiments So, the compound of formula (A) is i) A compound of formula (a) [ka] with a halogenating agent to prepare a compound of formula (b). [ka] (In the formula, Y is a halogen; R la and R lb , H, C 1~8 Alkyl, C 1~8 alkoxy, and halogen; independently selected; R 2a and R 2b is independently selected from the group consisting of H, CN, and halo; R 3 , H, C 1~8 selected from the group consisting of alkyl, and halogen; ii) reacting a compound of formula (b) with a compound of formula (c) in the presence of a base [ka] to form a compound of formula (A) [ka] (In the formula, R 4 is C 1~8 Alkyl and C 3~8 cycloalkyl, Each of these is optionally selected from 1 to 6 elements independently selected from the group consisting of F and Cl. may be substituted).

[0061] Halogenation can be accomplished using halogenating agents known in the art. This includes, but is not limited to, POCl3, PSCl3, SOCl2, (COCl)2 , PCl5, PBr3, N-chlorosuccinimide (NCS), and N-bromosuccinimide In some embodiments, the halogenating agent is (COCl)2. be.

[0062] Regarding step ii), the compound of formula (c) is provided in the form of a salt which also contains a cation. Suitable cations include, but are not limited to, K + , Na + , and Li + Examples include:

[0063] A number of bases can be used in step ii). Typically, an amine base is used. A number of different amine bases are suitable for this transformation, including but not limited to: However, pyridine, triethylamine, or N,N-diisopropyl ethyl amine are not Examples of suitable amines include amines.

[0064] In some embodiments, the conversion in step ii) comprises a metal catalyst. In an embodiment, the metal catalyst is MgCl2.

[0065] In some embodiments, the converting step ii) combines formula (b) with formula (c): In some embodiments, the reaction is cooled to less than 20° C. before the reaction is continued. The conversion of ii) can be carried out by cooling the reaction to less than 15°C before combining (b) and (c). In some embodiments, the conversion in step ii) comprises converting a compound represented by formula (b) into a compound represented by formula (c): The reaction is cooled to below 10° C. before combining with

[0066] D. Preparation of Compounds of Formula (a') In some embodiments, methods for preparing compounds having formula (a') are also provided herein. [ka] (In the formula, R 1b , H, C 1~8 Alkyl, C 1~8 alkoxy, and halogen; Selected; R 2b is independently selected from the group consisting of H, CN, and halo; R 3 , H, C 1~8 alkyl, and halogen).

[0067] Compounds of formula (a') may, in some embodiments, be of the formula: i) A compound of formula (a'y) [ka] with a cyanating reagent to obtain a compound of formula (a'x) [ka] (In the formula, R 1b , H, C 1~8 Alkyl, C 1~8 alkoxy, and halogen; independently selected; R 2b is independently selected from the group consisting of H, CN, and halo; R 3 , H, C 1~8 alkyl, and halogen) preparing a ii) contacting the compound of formula (a'y) with a Grignard reagent and CO2 to obtain a compound of formula (a'x): to obtain a compound of formula (I); It can be prepared by

[0068] Cyanation can be carried out using cyanating agents known in the art, including Copper-mediated cyanidation, including but not limited to CuCN and KFe(CN) In one embodiment, the cyanation is carried out by the addition of CuC in the presence of NaNO and HCl. This is done using N.

[0069] Regarding step ii), the Grignard reagent is typically of the general formula R-Mg-X where X is a halogen and R is an organic carbon group. Examples of Grignard reagents are Examples include, but are not limited to, methyl magnesium chloride, phenyl magnesium bromide, and isopropyl magnesium chloride. Step ii) was performed with iPrMgCl in the presence of LiCl, THF, and CO2. can be. EXAMPLES

[0070] Example 1: Trifluoropyrimidines to give hydroxypyrimidines (and chloropyrimidines) Ethanol-assisted condensation of β-ketoesters [ka]

[0071] Step 1: 12M HCl at room temperature (aq) (26 mL) and water (26 mL), 3-Bromo-2-methylaniline (18.6 g, 100 mmol) was added dropwise to form a fine white A colored suspension formed. The mixture was cooled to 0° C. and diluted with sodium nitrite in water (15.1 mL). A solution of 1,2-dichlorophenyl ether (7.31 g, 106 mmol) was added dropwise. The mixture was stirred at 0° C. for 30 min. To the resulting homogeneous mixture at 0° C., sodium bicarbonate was added at a rate that avoided excessive gas evolution. The aqueous phase of the resulting brown suspension was dissolved in about 7 ml of water. The pH of the suspension was found to be 0. The suspension was maintained at 0°C.

[0072] 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 obtain a homogeneous solution. The above suspension was added to this solution at 60° C. with stirring to avoid excessive gas evolution. After the addition, the mixture was stirred at 100° C. for 30 min. The mixture was cooled and MT BE (200 mL) was added, the mixture was stirred, filtered to remove solids, and washed with MTBE. The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by vacuum distillation. Purification afforded the desired product as a pale orange solid (13.6 g, 69%).

[0073] Step 2: In a 2-L two-neck flask, add aryl bromide (101.9 g, 520 mL). (mmol, 1.0 equiv.) was dissolved in THF (520 mL) under N2 atmosphere, and the mixture was added to ice water. The mixture was cooled in a bath. iPrMgCl LiCl (400 mL, 1.3 M in THF, 520 (mmol, 1.0 equiv) was added via cannula. After the addition was complete, the ice bath was removed. After 4 hours, cool the flask in an ice-water bath and place in a dry place to prevent overheating or boiling over. The mixture was cooled to room temperature and cooled to 37°C (approximately 230 g, 5.2 mol, 10 equiv.) was added in portions (Note: the solid dried Instead of using a chair, CO2 gas can be bubbled into the solution. After completion of the reaction, the mixture was diluted with MTBE (500 mL) and 2 M HCl (250 mL). The layers were separated and the aqueous layer was washed with additional MTBE (500 mL). The organic layer was washed with 10% Na Extract with OH (190 mL x 2), cool the combined aqueous layer in an ice-water bath, and a white precipitate forms. The precipitate was separated by filtration, washed with water, and then heated at 80°C. The benzoic acid was obtained as a white solid (64.1 g, yield 76%).

[0074] Step 3: Benzoic acid (50 g, 311 mmol, 1.0 equiv) suspended in CH2Cl2 Then, oxalyl chloride (40 mL, 466 mmol, 1.5 equiv.) was added, followed by DMF (approximately 30 drops) was added. Immediate gas evolution was observed, and the reaction flask was heated under positive N2 pressure. The starting material was dissolved in 100 mL of 10 ... After complete consumption of the acid, the reaction mixture was concentrated. Excess salt was removed by azeotropic distillation with toluene. Removal of the oxalyl chloride gave the corresponding acid chloride as a brown solid.

[0075] In a separate two-neck flask equipped with an overhead stirrer, add potassium ethyl malonate. (66.1 g, 388 mmol, 1.25 equiv.), triethylamine (108 mL, 77 7 mmol, 2.5 equiv.), and MeCN (777 mL) were cooled in a salt / ice-salt bath. 100 mg of MgCl2 (74 g, 777 mmol, 2.5 equiv.) was added and the resulting suspension was stirred for approx. The mixture was stirred vigorously at -10°C. After 1 h, the solid acid chloride was dissolved in a thick suspension. The suspension quickly became homogenous and the stirring speed was reduced to avoid splashing. The ice bath was removed. After complete consumption of the starting material as determined by TLC analysis, the reaction mixture was The mixture was cooled in an ice-water bath and 2 M HCl (971 mL, 1.9 mol, 6.25 equiv.) was added. After 30 min, the layers were separated and the aqueous layer was extracted with MTBE. The layers are washed with saturated NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated. This afforded the ketoester as a brown solid (67 g, 93% yield).

[0076] Step 4: In a round-bottom flask, add 42.0 g (181.8 mmol) of β-ketoester , 32.7 g (181.8 mmol) of guanidine carbonate, and 227 mL of trifluoroacetate. Ethanol was charged, and the suspension was then heated to reflux under N2 for 16 h.

[0077] Workup: The reaction was cooled to room temperature and the solvent was evaporated under reduced pressure to give a viscous red oil. The oil was redissolved in 250 mL of H2O, and the aqueous solution was diluted with dichloromethane (2 × 2 The aqueous phase was then extracted with 1.0 M HCl (50 mL). (aq) Use a pH level of about 2 to 3. The precipitated product was collected by filtration, washed thoroughly with H2O, and then heated at 70 °C. Dried in an empty oven. Yield 30.81 g (75%), purity >99%.

[0078] Step 5: In a round-bottom flask, add 50.0 g (221.2 mmol) of Pyrimidone and 100.8 g (442.2 mmol) of benzyltriethylammonium chloride The mixture was suspended in 442.2 mL of dry acetonitrile and 31.0 mL of L (331.8 mmol) of POCl3 was added. The cloudy solution was heated to reflux under N2 for 4 h.

[0079] Workup: The reaction was cooled to room temperature and approximately 200 g of crushed ice was added. The mixture was then Stir for 30 min, then add ice-cold 15% NH4OH solution dropwise until pH reaches approximately 10-11. (Note: To avoid rapid heat generation due to quenching of excess POCI3, low-temperature NH4 (It is recommended to add OH slowly.) The suspension is then left at room temperature for another 1.5 h. The precipitated product was collected by filtration, washed thoroughly with H2O, and cooled to 70°C in a vacuum oven. Drying in oven. Yield 48.2g (89%), purity >99%.

[0080] HPLC conditions HPLC: Agilent 1100 Column: YMC-HPLC column; 250×4.6; S-5 μm, 20 nm; AQ20S 05-2546WT;No.0425058945 Solvent: H2O / MeCN containing 0.1% HCO2H Flow rate: 0.8mL / min Column temperature: 30℃ method: [ka]

[0081] Example 2: Comparative pyrimidine coupling Utilizing boronic ester benzonitriles to link phenyl and pyrimidine rings 3-[2-amino-6-(1-{[6-(2-hydroxypropan-2-yl)pyridinyl] Lysine-2-yl]methyl}-1H-1,2,3-triazol-4-yl)pyrimidine The synthetic route for preparing [-4-yl]-2-methylbenzonitrile is shown below. is also shown in WO2018 / 136700. [ka]

[0082] The following scheme illustrates the above process and subsequent reactions to form compounds of formula (I). Used to prepare the boronic acid ester benzonitrile used in the reaction with imidine In particular, the desired bond between the pyrimidine and the phenyl is less than 50% gives a yield of [ka]

[0083] The following scheme converts β-diketoesters to pyrimidines using guanidine. The synthetic route used to prepare compounds of formula (I) is shown below. The process gives a yield of 75%. [ka]

[0084] This invention relates to a method and apparatus for carrying out the invention, including the best mode known to the inventors for carrying out the invention. Certain embodiments are described herein. Upon reading the above description, those skilled in the art will be Variations of the disclosed embodiments may be apparent to those working in the art, and those It is expected that vendors will be able to adopt such variations as necessary. The disclosure is not intended to be practiced otherwise than as specifically described herein. and the present invention is not limited to any of the claimed subject matter disclosed herein, and is hereby incorporated by reference in its entirety as permitted by applicable law. It is intended to include all modifications and equivalents of the subject matter recited in the claims. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated herein. Unless otherwise indicated or clearly contradicted by context, they are encompassed herein.

[0085] All publications, patent applications, accession numbers, and other references cited herein are incorporated by reference in their entirety. The references are provided unless specifically and individually indicated to be incorporated by reference. No. 6,399,413, which are incorporated herein by reference as if fully set forth herein. The present invention provides, for example, the following items. (Item 1) Compounds represented by formula (I): [ka] (In the formula, R 1a and R 1b , H, C 1~8 Alkyl, C 1~8 alkoxy, and halogen; independently selected; R 2a and R 2b is independently selected from the group consisting of H, CN, and halo; R 3 , H, C 1~8 selected from the group consisting of alkyl, and halogen; X is a leaving group selected from the group consisting of halogens and O-sulfonates. A method for preparing a) A compound of formula (A) [ka] (In the formula, R 4 is selected from the group consisting of C1-C8 alkyl and C3-C8 cycloalkyl. Each of these is optionally selected from 1 to 6 elements independently selected from the group consisting of F and Cl. (optionally substituted) is contacted with a guanidine reagent and a solvent system containing at least one halogenated alcohol. Contacting the compound of formula (B) [ka] to obtain; and b) substituting the hydroxyl group of formula (B) to form a compound of formula (I); The preparation method comprising: (Item 2) Step b) is the reaction of a compound of formula (I) in which X is a sulfonic acid ester of a hydroxyl group. The method according to item 1, which is a sulfonation process which provides (Item 3) The sulfonation process may include methanesulfonyl chloride, 4-toluenesulfonyl chloride, a sulfonating agent selected from the group consisting of fluorosulfonic acid anhydride, and trifluoromethanesulfonic anhydride; The method according to item 2, wherein (Item 4) Step b) is a halogenation process giving a compound of formula (I) in which X is a halogen The method according to item 1. (Item 5) The halogenation process is POCl3, PSCl3, SOCl2, (COCl)2, PC l5, PBr3, N-chlorosuccinimide (NCS), and N-bromosuccinimide ( The method according to item 4, wherein a halogenating agent selected from the group consisting of NBS) is used. (Item 6) The guanidine reagent may be guanidine, guanidine HCl, guanidine carbonate, guanidine Guanidine HBr, Guanidine Nitrate, Guanidine HI, Guanidine Acetate, Guanidine Sulfate, Guanidine hydrogen sulfate, guanidine thiocyanate, guanidine sulfamate, guanidine selected from the group consisting of guanidine phosphate and guanidine 4-benzenesulfonate; The method according to item 1. (Item 7) R 4 Methyl, ethyl, isopropyl, tert-butyl, and 2,2,2-triphenyl The method according to item 1, wherein the compound is selected from the group consisting of fluoroethyl. (Item 8) R 4 The method according to claim 1, wherein is ethyl. (Item 9) The guanidine reagent is selected from the group consisting of guanidine HCl and guanidine carbonate. The method according to item 1, (Item 10) The solvent system comprising at least one halogenated alcohol is 2,2,2-trifluoromethyl-2,4-dihydro-2,5-trifluoromethyl-2,5-dihydro-2,6-trifluoromethyl-2,6-dihydro-2,7-trifluoromethyl ... 2-Fluoroethanol, methanol, ethanol, propanol, 2-fluoroethanol, -Chloroethanol, 2-methoxyethanol, and 2-(methanesulfonyl)ethane- Item 1, in combination with an alcohol selected from the group consisting of 1-ols. How to. (Item 11) The solvent system comprising at least one halogenated alcohol is 2. The method according to claim 1, wherein the ethanol is used alone. (Item 12) 2. The method according to item 1, wherein step b) is carried out in a polar aprotic organic solvent. (Item 13) The polar aprotic organic solvent is acetonitrile, DMF, DMSO, NMP, and 13. The method according to item 12, selected from the group consisting of these combinations. (Item 14) Step b) uses POCl3 to give compounds of formula (I) where X is Cl. wherein the guanidine reagent is guanidine carbonate and the polar 13. The method according to item 12, wherein the aprotic organic solvent is acetonitrile. (Item 15) 15. The method according to any one of claims 1 to 14, wherein step b) is carried out at a temperature of about 67 to 83°C. Method of posting. (Item 16) The compound of formula (A), the guanidine reagent, and 2,2,2-trifluoroethanol 2. The method of claim 1, wherein the solvent system containing the ethanol is heated to reflux temperature. (Item 17) Prior to step b), a by-product of formula (i) [ka] wherein the compound of formula (B) is triturated with an organic solvent to remove 1. The method according to claim 1. (Item 18) The organic solvent is ethanol, methanol, acetonitrile, dichloromethane, ethyl acetate, 18. The compound according to claim 17, selected from the group consisting of methyl tert-butyl ether, ... and methyl tert-butyl ether. Method of posting. (Item 19) 13. The method according to item 12, wherein step b) is carried out using a base additive. (Item 20) The base additive is trimethylamine, diisopropylethylamine, dimethylaniline Benzyltrimethylammonium chloride, and benzyltriethylammonium chloride 20. The method of claim 19, wherein the compound is selected from the group consisting of aryl and aryl halide. (Item 21) Item 19. The base additive according to item 19, wherein the base additive is benzyltriethylammonium chloride. How to. (Item 22) The compound of formula (A) i) A compound of formula (a) [ka] with a halogenating agent to prepare a compound of formula (b). [ka] (In the formula, Y is a halogen; R la and R lb , H, C 1~8 Alkyl, C 1~8 alkoxy, and halogen; independently selected; R 2a and R 2b is independently selected from the group consisting of H, CN, and halo; R 3 , H, C 1~8 selected from the group consisting of alkyl, and halogen; ii) reacting the compound of formula (b) with a compound of formula (c) in the presence of a base [ka] to form a compound of formula (A) [ka] (In the formula, R 4 is C 1~8 Alkyl and C 3~8 cycloalkyl, Each of these is optionally selected from 1 to 6 elements independently selected from the group consisting of F and Cl. may be substituted); The method according to item 1, which is prepared by (Item 23) 23. The method according to item 22, wherein the compound of formula (a) is a compound of formula (a'): [ka] (In the formula, R 1b , H, C 1~8 Alkyl, C 1~8 alkoxy, and halogen; Selected; R 2b is independently selected from the group consisting of H, CN, and halo; R 3 , H, C 1~8 alkyl, and halogen). (Item 24) The compound of formula (a') i) A compound of formula (a'y) [ka] with a cyanating agent to obtain a compound of formula (a'x) [ka] (In the formula, R 1b , H, C 1~8 Alkyl, C 1~8 alkoxy, and halogen; independently selected; R 2b is independently selected from the group consisting of H, CN, and halo; R 3 , H, C 1~8 alkyl, and halogen) preparing a ii) contacting the compound of formula (a'y) with a Grignard reagent and CO2 to obtain a compound of formula ( Obtaining a compound of formula a'x); 24. The method according to claim 23, wherein the compound is prepared by (Item 25) Compounds of formula (II): [ka] (In the formula, R 1a and R 1b , H, C 1~8 Alkyl, C 1~8 alkoxy, and halogen; independently selected; R 2a and R 2b is independently selected from the group consisting of H, CN, and halo; R 3 , H, C 1~8 alkyl, and halogen) A method for preparing a') preparing a compound of formula (I) according to the method according to any one of items 1 to 24 thing; b') reacting the compound of formula (I) with a compound of formula (C) [ka] Converting into; and c') reacting the compound of formula (C) with an azide compound of formula (D) [ka] to form a compound of formula (II); The preparation method comprising: (Item 26) Step b') b'-l) reacting the compound of formula (I) with a silyl-protected compound of formula (I) in the presence of a palladium catalyst and a copper cocatalyst and contacting the reactant with acetylene to produce an intermediate of formula (C'): [ka] (In the formula, R 5 is a silyl protecting group); b'-2) contacting the compound of formula (C') with a desilylation reagent to obtain the compound of formula (C); To generate things; 26. The method according to item 25, comprising: (Item 27) The silyl protecting group is triisopropylsilyl, trimethylsilyl, thexyldimethylsilyl. Silyl, benzyldimethylsilyl, biphenyldiisopropylsilyl, and tris(biphenyl)silyl. 26. The method according to item 25, wherein the silyl group is selected from the group consisting of (phenyl-4-yl)silyl. (Item 28) the palladium catalyst is Pd(PPh3)2Cl2 and the copper co-catalyst is CuI; Item 26. The method according to item 25. (Item 29) Step b'-1) uses Sonogashira coupling conditions with an amine base, item 25- 28. The method according to any one of claims 27 to 29. (Item 30) The amine base is triethylamine or N,N-diisopropylethylamine 29. The method according to item 29. (Item 31) The desilylation reagent is tetrabutylammonium fluoride (TBAF), tetrabutylammonium fluoride (TBAF), ethylammonium hydroxide, sodium tetrachloroaurate(III), and acetone chloride. The method according to any one of items 25 to 30, wherein the compound is selected from the group consisting of chiral. (Item 32) 32. The method according to any one of items 25 to 31, wherein step c') further comprises a copper catalyst. (Item 33) The copper catalyst is selected from the group consisting of CuSO4, CuI, CuBr, copper(II) triflate, and copper acetate. 33. The method according to item 32, wherein the compound is selected from the group consisting of (II). (Item 34) Compound of formula (IIa) [ka] A method for preparing a') Producing a compound of formula (Ia) according to the method of any one of items 1 to 21 [ka] preparing a b') reacting the compound of formula (Ia) with a compound of formula (Ca) [ka] Converting into; and c') reacting the compound of formula (Ca) with an azide compound of formula (D) [ka] to form a compound of formula (IIa); The preparation method comprising: (Item 35) Step b') b'-l) The compound of formula (Ia) is reacted with triisopropylsilyl ether under Sonogashira coupling conditions. with acetylene to produce an intermediate of formula (Ca'): [ka] generating b'-2) contacting the compound of formula (Ca') with a desilylation reagent to obtain the compound of formula (Ca) To produce a compound; 35. The method according to item 34, comprising: (Item 36) Item 35. The Sonogashira coupling conditions include a palladium catalyst and a copper cocatalyst. How to. (Item 37) The palladium catalyst is Pd(PPh3)2Cl2 or Pd(OAc)2, and the copper promoter is 37. The method of claim 36, wherein the catalyst is CuI. (Item 38) 38. Any one of items 35 to 37, wherein the Sonogashira coupling conditions further include an amine base. The method according to (Item 39) The amine base is triethylamine or N,N-diisopropylethylamine 39. The method according to item 38. (Item 40) The desilylation reagent is tetrabutylammonium fluoride (TBAF), tetrabutylammonium fluoride (TBAF), Triethylammonium hydroxide (TBAH), sodium tetrachloroaurate (III), and acetyl chloride. method. (Item 41) 38. The method according to any one of items 31 to 37, wherein step c') further comprises a copper catalyst. (Item 42) The copper catalyst is CuSO4, CuI, CuBr, copper(II) triflate, and copper acetate ( The method according to item 38, wherein the compound is selected from the group consisting of: II).

Claims

[Claim 1] The invention described in the present specification.

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