Synthesis method and intermediates

Abstract

This provides a new synthetic route and a new synthetic intermediate for N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. [Solution] A synthesis method comprising converting compound X6b and compound F6 to compound F7, wherein: TIFF2026082843000085.tif54170 A synthesis method is provided in which X and Y are independently Cl, Br, or I, and P is an amine protecting group.

Description

[Technical Field]

[0001] This invention relates to N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy (C)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl New synthetic routes and chemical reactions useful in the preparation of 2-fluorobenzamide And provides new synthetic intermediates. [Background technology]

[0002] N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrim Zin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-f Luolobenzamide, also known as remibrutinib, is a highly potent and selective oral Bruton-type tyrofoaminamide. It is a syn kinase (BTK) inhibitor: [ka]

[0003] Remibrutinib was filed on November 28, 2014, under International Publication No. 2015 / 079. This was first disclosed in Brochure No. 417, Example 6. International Publication No. 2015 / 07 Pamphlet No. 9417 is incorporated in its entirety by reference. International Publication No. 2015 In Brochure No. 079417, Example 6(2), remibrutinib is described as "INT "INT9" is obtained by cross-coupling "INT8" with "5". : [ka]

[0004] INT9 is then deprotected with TFA (Example 6(3)) and reacts with acrylic acid. It is then purified to obtain remibrutinib (Example 6(4)). INT5 is used in this process. It is a key intermediate in Seth and constitutes half of the structure of the final product, remibrutinib. The preparation of INT5 is described in Example 1 of International Publication No. 2015 / 079417. 5) The INT5 described in INT3 and INT4 is formed by amide coupling. It is prepared as follows: [ka]

[0005] However, INT3(5-fluoro-2-methyl-3-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl (aniline) has the potential to be mutagenic. It is a compound that possesses this property, and therefore has been found to be a harmful intermediate in the synthesis of pharmaceuticals. The genotoxicity of INT3 is reported for the first time in this application.

[0006] Therefore, the objective of the present invention is to minimize contact with genotoxic reagents such as INT3. The objective is to provide a new synthetic route for brutinib. In addition, the present invention offers a higher yield. For the preparation of INT9 (referred to as F7 in this specification) and DCM ( (cancerous), DME (damages fertilization ability), DMF (damages fertilization ability), 1,2- An improved design that avoids the need to use harmful solvents such as dichloromethane (a carcinogen). Provides coupling conditions. [Overview of the project]

[0007] In the first embodiment, the present invention converts compound X6b and compound F6 to compound F7. A synthesis method that includes: [Chemical formula] X and Y are each independently F, Cl, Br or I and P is an amine protecting group, and provides a synthesis method. There is.

[0008] In a second embodiment, the present invention provides a synthesis method comprising the boronation of X6b to obtain X6a: That is: [Chemical formula] X is F, Cl, Br or I, n is 0 or 1 and R is F, Cl , Br or I, OH, OC1-C6 alkyl, N(C1-C6 alkyl)2, aryl Or two or three R groups other than F, Cl, Br, I or OH are together A cyclic boronic acid ester, such as pinacol boronic acid or N-methyliminodiacetic acid (M IDA) boronate can be formed, and provides a synthesis method.

[0009] In a third embodiment, the present invention provides a synthetic intermediate X6b: [Chemical formula] X is Cl, Br or I, preferably Br, and provides the synthetic intermediate X6b.

Brief Description of Drawings

[0010] [Figure 1] Figure 1 provides an overview of a convergent and atom-efficient synthetic route for preparing remibrutinib. X6b is a key intermediate in this synthetic route. [Figure 2] Figure 2 shows exemplary reaction conditions for the route from F1 to F6. [Figure 3]Figure 3 shows exemplary reaction conditions for the route from N6e to X6b. [Figure 4] Figure 4 shows exemplary reaction conditions for the route from X6i to X6b. [Figure 5] Figure 5 shows exemplary reaction conditions for the route from X6b to F11. [Modes for carrying out the invention]

[0011] The present invention is a highly potent and selective oral Bruton's tyrosine kinase (BTK) inhibitor. A certain N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyri Midine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2- It is useful in the preparation of fluorobenzamide, also known as remibrutinib: [ka]

[0012] In any embodiment described herein, the Remibrucini described herein B or any other compound may be provided as a salt. The term "salt" refers to the acid addition salt of the compound in this invention. This refers to a salt (n salt) or a base addition salt. This includes, in particular, "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salt" is defined in this invention. The biological effects and properties of the compound are preserved, and whether or not they are typically biological. Refers to a non-toxic salt. In many cases, the compounds of this invention have an amino group and / or a carboxyl group. The presence of a syl group or a similar group can form salts of acids and / or bases. Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids, for example. For example, acetate, aspartate, benzoate, besilate, bromide / hydrobromide, heavy Carbonates / carbonates, bisulfates / sulfates, camphor sulfonates, chlorides / hydrochlorides, chloro Luteophyllonate, citrate, ethane Disulfonate, fumarate, gluceptate, Gluconate, globuronate, hippurate, hydroiodide / iodide salt, isethionic acid Salt, lactate, lactobionate, lauryl sulfate, malate, maleate, malonic acid Salt, mandelate, mesylate, methyl sulfate, naphthoate, napsylate, nicotine Salts, nitrates, octadecanoate, oleates, oxalates, palmitates, pamo Salts, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturates, propionates , stearate, succinate, sulfosalicylate, tartrate, tosylate (tosy There are also late and trifluoroacetate salts. Inorganic acids that can derive salts include, for example, Includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and other similar substances. Derivation of salts. Organic acids that can produce this include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, Malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfate Fonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid and other similar substances This includes pharmaceutically acceptable base addition salts, which can be formed from inorganic and organic bases. Inorganic bases that can derive salts include, for example, ammonium salts and I-1 of the periodic table. It contains metals of the XII series. In certain embodiments, the salt is sodium, potassium, and Derived from monium, calcium, magnesium, iron, silver, zinc, and copper, and particularly suitable Salts include ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases that can induce this include, for example, primary, secondary, and tertiary amines, and naturally occurring ones. Substituted amines containing substituted amines, cyclic amines, basic ion exchange resins, and other similar materials. Includes certain types of organic amines, such as isopropylamine, benzathine, and corinthine. Diethanolamine, diethylamine, lysine, meglumine, piperazine and trim Contains trimethamine. The pharmaceutically acceptable salt of the present invention is conventional It can be synthesized from basic or acidic components by chemical methods. Generally speaking, These salts are formed by reacting the free acidic forms of these compounds with a theoretical amount of a suitable base. (Hydroxide, carbonic acid, sodium bicarbonate, Ca, Mg or K, or other similar substances) or These compounds are prepared by reacting the free base form with a theoretical amount of a suitable acid. Such reactions can occur. Typically, these reactions occur in water, in organic solvents, or in a mixture of these two. It is carried out in a mixture. Generally, ether, ethyl acetate, ethanol, isopropanol or The use of a non-aqueous medium such as acetonitrile is desirable if feasible. The list of salts is, for example, "Remington's Pharmaceutical" Sciences”, 20th ed., Mack Publishing Compa. ny, Easton, Pa., (1985); and “Handbook of Phar. Maceutical Salts:Properties,Selection,an d Use” by Stahl and Wermuth(Wiley-VCH,Wei This can be found in nheim, Germany, 2002.

[0013] Many organic solvents are suitable for the chemical reactions described herein. For example, The reactions described in the details may be carried out in aprotic organic solvents. Suitable examples include , including: acetonitrile; dimethyl sulfoxide (DMSO); dimethyl formaldehyde Mido (DMF); halogenated alkanes such as dichloromethane (DCM); benzene, tol Aromatic compounds such as ene, xylene, mesitylene and naphthalene; hexane, heptane and Alkanes such as octane; ketones such as acetone; diethyl ether, tetrahydrof Ether compounds such as THF (thoflavone), methyl THF, and other THF derivatives; ethyl acetate and ester compounds such as isopropyl acetate; amines such as pyridine; polyethylene glycerides Call (PEG); in particular, PEG200, PEG600, PEG1000 and PEG20 PEG, mono- or 00, having an average molecular weight of approximately 100 g / mol to approximately 2000 g / mol. This refers to dialkylPEG, particularly mono- or dimethyl PEG, mono- or diethyl PEG and mono- This includes dipropyl PEG and its derivatives; as well as polypropylene glycol (PPG). Rotonic solvents may also be used in the reactions described herein. The tonite solvent includes: water; C 1~10 Aliphatic branched or linear alcohols, especially C1~ Alcohols such as C6 alcohols; and carboxylic acids such as methaneic acid, acetic acid, and propanoic acid. Preferred solvents are toluene, ethanol, ethyl acetate, isopropyl acetate, and methyl ethyl acetate. It comprises HF, heptane, and isopropanol. Preferably, as described herein. The reaction involves DCM, DME, DMF, dioxane, and 1,2-dichloroethane or other carcinogenic substances. Alternatively, the process is carried out in a manner that avoids undesirable solvents such as teratogenic solvents. In a particular embodiment... In this case, the amount of solvent in the reaction mixture is 0.1% to 99% (v / v), 0.1% to 80% (v / v), 0.1%~75%(v / v), 0.1%~50%(v / v), 1%~40% (v / v), 2%~30%(v / v), 4%~25%(v / v) or 5%~20%(v / It is within the range of v).

[0014] Some of the chemical reactions described herein are performed under acidic conditions, for example, less than 7, 6 The following can be achieved at pH levels of 5 or less, 4 or less, 3 or less, 2 or less, or 1 or less. Acids suitable for a particular chemical reaction are known to those skilled in the art. Acids commonly used are inorganic acids, for example Sulfuric acid, phosphoric acid and nitric acid, boric acid; hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid. Any halo acid; organic acids, such as carboxylic acids and acetic acid, benzoic acid and its derivatives; and It contains halogenated acetic acids such as refluoroacetic acid and dichloroacetic acid. Preferably, the acid is , HF, HCl or H2SO4. Preferably, a fluorinated acid such as TFA is used. This is avoided to prevent the generation of fluorinated waste.

[0015] Some of the chemical reactions described herein are carried out under basic conditions, for example, with a pH greater than 7 and less than 7. At least 8, at least 9, at least 10, at least 11, at least 12, at least This can also be done at a pH of 13 or at least 14. Basic compounds suitable for the reaction are known to those skilled in the art. Commonly used bases are inorganic salts. Bases, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide and It contains hydroxides of alkali metals and alkaline earth metals such as calcium hydroxide. These bases can be produced by the addition of alkaline earth metals to hydrocarbons, amines, and dihydrogens. Examples include butyllithium, lithium diisopropylamide (LDA), and lithium diethyl Luamide (LDEA), sodium amide, sodium hydride (NaH), and lithium amide It contains (trimethylsilyl)amide. Weaker bases include ammonia and amines, for example. Trialkylamines such as triethylamine and diisopropylethylamine, and acetic acid Salts (e.g., sodium acetate), potassium acetate, and carbonates (e.g., sodium carbonate, potassium carbonate) It contains anions of weak acids such as lium.

[0016] The reactions described herein are those in which the reaction is completed or at least the product is acceptable. It can continue for as long as necessary to achieve the yield. For example, the reaction period is 1 Less than a minute, less than 5 minutes, less than 10 minutes, less than 30 minutes, less than 1 hour, less than 2 hours, less than 3 hours, 5 Less than 1 hour, less than 10 hours, less than 20 hours, less than 30 hours, less than 40 hours, less than 50 hours or The reaction time may be less than 60 hours. The reaction time may depend, in particular, on the scale of the reaction. Those skilled in the art can monitor physical changes such as color changes, or use NMR, FT, etc. -IR, XRPD, or chromatography, such as thin-layer chromatography (TLC) This uses analytical methods such as liquid chromatography (LC-MS) connected to mass spectrometry. The progress of a reaction can be monitored in many different ways, including by monitoring the reaction itself. It can be done.

[0017] Upon completion of the reactions described herein, the reaction mixture may be optionally purified. The purification techniques are known to those skilled in the art and include: chromatography (e.g., HPL C, which may be reversed phase or normal phase); for example, liquid-liquid fractions using multiple immiscible solvents Separation; and / or, for example, filtration, decantation, (re)crystallization, trituration, vaporization Liquid-solid separation using freezing and freeze-drying.

[0018] The reactions described herein may be carried out on any suitable scale. In this state, the reaction mixture is on an industrial scale. The reaction mixture is, for example, at least 1 liter. In particular, having a volume of at least 10 liters, at least 100 liters, or at least 1000 liters It may also be the case that the reaction mixture is on a microscopic scale. For example, a volume of 10 ml or less, especially 1 ml or less, 100 μl or less, 10 μl or less, or 1 μl or less of body It may have a product.

[0019] The reactions described herein may be part of a series of reactions including synthesis. If a number of reactions are described, these can be performed sequentially or in one pot. The reaction typically involves the completion of the first reaction, followed by the saturation of that reaction before the second reaction takes place. This includes cleaning and purification, and the reaction is continued until the desired product is produced. In particular, in a one-pot reaction, the first reaction may be completed, and then the second reaction may be isolated. The reaction may be carried out using one or more products of the first reaction without the involvement of one-pot. The reaction is advantageous because it avoids unnecessary purification steps and saves time and materials. In the synthesis of remibrutinib described herein, some or all The reaction may be carried out in one pot, or instead, some or all of the reactions may be carried out in one pot. It may be done sequentially.

[0020] As used herein, the expression "includes" has the literal meaning of "from" as well as the meaning of "from". The expressions "essentially become" and "consist of" are also included and refer specifically. Therefore, the expression "includes" "The subject "contains" the specifically listed elements may also contain further elements and / or The actual embodiments that include and the specifically enumerated elements of the subject matter further include This refers to embodiments that do not include this.

[0021] Numerical ranges described herein include the number defining the range. The headings provided are various aspects of the present invention, which can be read by referring to the entire specification. This does not limit the aspects or embodiments of the method. According to one embodiment, in this specification, the method Described as including a specific step in a combination or, in the case of a composition, including a specific component. The subject matter described herein refers to a subject consisting of each step or component. It is preferable to select and combine specific aspects and embodiments described, and specific implementations The specific subjects arising from each combination of states also exist as part of this disclosure.

[0022] This invention provides a novel synthetic route for remibrutinib that avoids the formation of the genotoxic intermediate INT3. This provides a solution. The key to avoiding INT3 is to prepare aryl halide X6b. Therefore, this does not contain boronic acid esters, and for that reason, as described below, INT3 Alternatively, it can be synthesized via N6a. Furthermore, the claimed process is precise Minimizing manufacturing steps, improving overall yield, and providing a more efficient process. It can also be done efficiently in green solvent.

[0023] Preparation of F7 The present invention relates to a synthesis method comprising converting compound X6b and compound F6 to compound F7. Yes: [ka] X and Y are independently Cl, Br, or I, and P is an amine protecting group. A synthesis method is provided.

[0024] In some embodiments, X is Cl or Br. And Y is Cl or Br. In some embodiments, X and Y are C It is l or Br. In some embodiments, X is Br. In this state, Y is Cl. In some embodiments, X is Br and Y is , Cl. These embodiments are X present in the synthetic precursors of X6b and F6, respectively. This applies to all examples of X and Y described herein, including the group and the Y group. ru.

[0025] Protecting group P is stable during any of the chemical changes described herein. It can be a suitable amine protecting group (except for the deprotection step). The amine protecting group is particularly It may be removed by certain conditions, such as acid, base, hydrogenation, light, heat, etc. Suitable mesh Examples of protecting groups include 9-fluorenylmethyl carbamate (Fmoc) and t- carbamate. Carbamic acid protecting groups such as butyl (Boc) or benzyl carbamate (Cbz); acetate Acetamide protecting groups such as toamide, trifluoroacetamide, or benzylamide; and It contains a sulfonamide protecting group such as p-toluenesulfonamide.

[0026] X6b and F6, according to coupling conditions suitable for forming a carbon-carbon bond, It can be converted to F7. For example, the coupling of X6b and F6 is an organometallic chromatid. This can be achieved using a coupling reaction, thereby separating the two fragments into metals. They are coupled together with the help of a catalyst. Used in the coupling of X6b and F6. The cross-coupling conditions that may be possible include: Kumada coupling; Negishi coupling Plunging; Still coupling; Suzuki-Miyaura coupling and Hiyama coupling. In a type cross-coupling reaction, type RM (R = first organic fragment, M = metal) Compounds of type R'-X (or typical compounds) are of type R'-X (R' = second organic fragment, X = halogenation). It reacts with organic halides and forms a new carbon-carbon bond at product R-R'. do.

[0027] Therefore, in some embodiments, the preparation of F7 involves the "M" of Y, a metal-containing component or This includes the conversion of F6 to its precursor F6' by substitution with a main group element-containing component, for example, M is Zn (Negishi), B (Suzuki / Miyaura), Mg (Kumada), Sn (Still), or Si (Hiyama) Contains: [ka] P is an amine protecting group, such as Boc.

[0028] F6' reacts with X6b under cross-coupling conditions to obtain F7. In some embodiments, conversion of F6 to F6' and cross-coupling of F6' with X6b are performed. The ring is carried out in a one-pot reaction. In some embodiments, F6 of F6 The conversion to ' and the cross-coupling of F6' with X6b occur in a sequential reaction. .

[0029] Instead, the preparation of F7 involves replacing X's "M," a metal-containing component, or a main-group element-containing component. This includes the conversion of X6b to its precursor compound X6b', for example, M is Zn(Negishi), Contains B (Suzuki / Miyaura), Mg (Kumada), Sn (Still), or Si (Hiyama): [ka]

[0030] The precursor compound X6b' reacts with F6 under cross-coupling conditions to obtain F7. This is possible. In some embodiments, the conversion of X6b to X6b' and the F6 of X6b' are performed. Cross-coupling with is carried out in a one-pot reaction. In some embodiments The conversion of X6b to X6b' and the cross-coupling of X6b' with F6 are performed sequentially. It occurs in a reaction.

[0031] Preparation of X6a - Boration reaction The present invention provides a synthesis method comprising the borylation of X6b to obtain X6a: [ka] X is F, Cl, Br, or I, n is 0 or 1, and R is F, Cl , Br or I, OH, OC1-C6 alkyl, N(C1-C6 alkyl)2, Ally If two or three R groups other than F, Cl, Br, I, or OH are together Cyclic boronic acid esters, for example, pinacolboronic acid or N-methyliminodiacetic acid (M IDA) Boronate can be formed.

[0032] Boration of X6b involves one or more catalysts, one or more ligands, or one or more or multiple boronating agents, one or more bases and / or one or more additives This can be achieved using one or Multiple catalysts, one or more ligands, one or more boronating agents, and one or more salts It contains a group. In some embodiments, the boration includes one or more additional additives. nothing.

[0033] Boronating agents typically convert organic halogen compounds into boron under metal catalyst cross-coupling conditions. It is a boron-containing compound that can be converted into an acid or a boronic acid ester. In terms of application methods, the boronating agent is a diboron compound, boronic acid, borane, or boron trihalide. The boronating agent is selected from the group consisting of elements and borates. In some embodiments, the boronating agent is selected from the group consisting of elements and borates. , Bis(Pinacolato) Diboron, B2(NMe2)4, B2F4, B2Cl4, B2B r4, B2l4, bisboronic acid, pinacolborane, HB(NMe2)2, B(OH)3 , BF3, BCl3, BBr3, BI3, C1-C6 borate mono, di or trialkyl, mono, di or trimethyl borate, mono, di or triethyl borate and mono, di or Selected from the group consisting of tritripropyl, preferably bis(pinacolate)diborone or It is bisboronic acid. Bisboronic acid is pinacolborane or bis(pinacolate)di Compared to boron, it allows for the use of less catalyst and milder reaction conditions. The use of bisboronic acid is attractive because it avoids the formation of pinacol-related impurities. It may be. Bisboronic acid also allows the use of green solvents such as alcohol solvents. This also allows for milder reaction conditions (e.g., lower temperatures).

[0034] The metal catalyst used in the boronation reaction is palladium, nickel, or copper or so The combination may contain the following, preferably palladium.

[0035] In some embodiments, the metal catalyst is a complex of the catalyst precursor, for example, a phosphine compound Provided as a Buchwald G1, G2, G3, or G4 catalyst precursor that forms a complex with a ligand. The Buchwald catalyst precursor undergoes rapid deprotonation and reductive elimination to induce insights. It is used to generate activated Pd(0). The catalyst precursor allows for the use of less catalyst. Furthermore, it is stable against air, moisture, and heat, and has good solubility, making it useful. These catalyst precursors have been further improved in function and solubility from the 1st to 4th generations (G1 to G4). It has been optimized to achieve this. The catalyst precursor has a phenyl or 1,1-biphenyl skeleton. It consists of a paradacycle (shown below), where L is the bound phosphine coordination AmiAmi shows and combines child objects, such as XPhos, SPhos, etc. (see below). The substituents and leaving groups (Cl, OMs) vary depending on the generation.

[0036] Buchwald catalyst precursors that form complexes with palladium and exemplary XPhos ligands An example is shown below.

[0037] [Table 1]

[0038] Any other phosphine ligand described herein is XPh in the table above. It may be used as L instead of os.

[0039] Other catalyst precursors for borylation include Pd(TFA)2, PdBr2, or Pd(MeC It may contain N)2Cl2. This catalyst precursor is Ph2P(t-Bu);Cy3P -HBF4;RuPHOS;S-PHOS, Cy-BIPHEP;SPHOS-SO3N It can be used in the presence of ligands such as a.

[0040] In some embodiments, the boration of X6b forms part of the complex of the catalyst precursor. In addition to ligand L, it includes further ligands. In other embodiments, the further ligands are , not required. In some embodiments, the boration of X6b is performed without a catalyst precursor. A catalyst and ligand are used (Pd(0) catalyst; e.g., Pd(PPh3)4).

[0041] A wide range of ligands can be used in boration reactions, and the ligands react with the reagents. It can affect the properties. For example, ligands increase the electron density at the metal center of a metal complex. This can improve the oxidative addition step. In addition, bulky The position is useful in the reductive elimination step. In some embodiments, X6b Ligands used in boration include organophosphines, N-heterocyclic carbenes, and diazas. The selection is made from the group consisting of butadiene, dibenzylideneacetone, and combinations thereof.

[0042] In a preferred embodiment, the ligand is an organophosphine ligand, for example, XPhos. APhos, CPhos, RuPhos, SPhos, cataCXium, DaveP hos, JohnPhos, MePhos, XantPhos, Cy3P-HBF4, C y-BIPHEP, SPhos-SO3Na, PPh3, tBuPPh2 and combinations thereof An organophosphine selected from the group consisting of X, preferably XPhos, APhos, C Phos, RuPhos, SPhos, cataCXium, more preferably XPhos cataCXium and tBuPPh2, most preferably tBuPPh2. The Finn ligands are shown in the table below.

[0043] [Table 2]

[0044] [Table 3]

[0045] The borylation of X6b may include a base. In some embodiments, the base is , NaOH, Ca(OH)2, Na2CO3, K2CO3, K3PO4, Cs2CO3, KOAc, KOPh or NaOAc, diisopropylethylamine (DIPEA), These are organic or inorganic salts of tertiary amines such as triethylamine, or combinations thereof. Preferably, the base is DIPEA, KOAc, or KOH, most preferably KOAc. .

[0046] Boronation of X6b involves the addition of additives, such as alcohols like ethylene glycol. This is possible. In some embodiments, the boration of X6b is additive-free.

[0047] The borylation of X6b can be carried out in any suitable solvent. Examples include polar solvents, nonpolar solvents, protic solvents, aprotic solvents, and polar protic solvents. and a polar aprotic solvent. In one embodiment, boration is performed by t-amylalco ol, hexanol, pentanol, butanol (terto-butanol, isobutanol) (and n-butanol), propanol (isopropanol and n-propanol), ethanol This can be carried out in an alcohol solvent containing ol and / or methanol. Preferably Boration is most preferably carried out with methanol, toluene, and / or MeTHF. This is carried out in MeTHF. Other solvents, such as halides like dichloromethane, can also be used. Can solvents can also be used. These include dioxane, MeTHF, THF, and diethyl Ether-based solvents such as dialkyl ethers can also be used. Boronation can also be carried out in aqueous environments, including micelle environments. In the embodiment, a mixture of solvents is used.

[0048] Boration of X6b involves one or more catalysts, one or more ligands, or one or more Or multiple boronating agents, one or more bases and / or one or more of any choice This can be achieved using several additives. Those skilled in the art will be able to determine the appropriate amounts of these reagents. It is possible. Nevertheless, in some embodiments of the borylation reaction: i) The catalyst or catalyst precursor is present in an amount of 0.01 mol% to 3 mol% compared to the number of moles of X6b. , 0.05mol%~2mol%, 0.1mol%~2mol%, 0.1~1mol%, Preferably present in an amount of 0.25 mol%, more preferably 0.5 mol%; ii) The ligand is present in amounts of 0.02 mol% to 6 mol% and 0.1 mol compared to the number of moles of X6b. Amounts of %~2mol%, 0.2mol%~1mol%, 0.5mol%, or 1mol% is; iii) The number of moles of ligands shall be 2 or 3 times the number of moles of catalyst or catalyst precursor; preferably Or twice as much; iv) The amount of boronating agent is 1 to 3 molar equivalents compared to X6b, and is preferable compared to X6b. The amount is typically 1 to 2 molar equivalents, more preferably 1.05 or 1.5 molar equivalents; v) The amount of base is 2 to 5 molar equivalents, preferably 2 to 3 molar equivalents, compared to the number of moles of X6b. Preferably, the amount is 2.5 or 3 molar equivalents; and / or vi) Additives are optional and, if present, in an amount of 2 to 5 molar equivalents compared to X6b. It is; preferably, no additives are present.

[0049] A borylation reaction may be characterized by any one of the above i) to vi). The response may be characterized by any two of the above i) to vi). The boration reaction is as described above. Any three of the above i) to vi) may be characteristic. The boration reaction is characterized by i) to vi) Any four of the above may be used as characteristics. The boration reaction is characterized by any five of the above i) to vi). It may also be characterized by one of the above. The boration reaction may be characterized by all of the above i) to vi). stomach.

[0050] The boration reaction may be characterized by the above i) and ii). The boronation reaction may be characterized by i) and iii). The boration reaction may be characterized by the above i) and v). The boration reaction may be characterized by the above i) and vi). The boration reaction is characterized by the above ii) and iii The boration reaction may be characterized by the above ii) and iv). The boration reaction may be characterized by the above ii) and v). The boration reaction is characterized by the above i The boration reaction may be characterized by i) and vi). This may also be the case. The borylation reaction may be characterized by the above iii) and v). Boration The reaction may be characterized by iii) and vi) above. The borylation reaction is characterized by iv) above. The boration reaction may also be characterized by the above iv) and vi). Good. The boration reaction may be characterized by the above v) and vi).

[0051] In one example, a boration reaction with excellent yield and minimal byproducts is described below. You may get off: [ka]

[0052] In one embodiment, a boration reaction having excellent yield and minimal byproduct formation is described as follows: Characterized by at least one of the following: i) The catalyst is present in an amount of 0.1 mol% to 2 mol% compared to the number of moles of X6b, or the number of moles of X6b In comparison, 0.1 mol% to 1.5 mol%, preferably 0.25 mol%, or more preferably Alternatively, it is 0.5 mol% of Pd(MeCN)2Cl2; ii) The ligand is present in an amount of 0.2 mol% to 4% compared to the number of moles of X6b, compared to the number of moles of X6b The concentration is 0.2 mol% to 3 mol%, preferably 0.5 mol%, or more preferably 1 mol. % of tBuPPh2 is; iii) The catalyst is Pd(MeCN)2Cl2, and the ligand is tBuPPh2. The number of moles of tBuPPh2 is 2 or 3 times the number of moles of Pd(MeCN)2Cl2. Preferably, it is twice the number of moles of Pd(MeCN)2Cl2; iv) The boronating agent should be in an amount of 1 to 2 molar equivalents compared to X6b, preferably about 1 molar equivalent compared to X6b. It is 0.5 molar equivalents of bis(pinacolate)diborone; v) The amount of base should be 2 to 5 molar equivalents compared to X6b, preferably 2.5 equivalents compared to X6b. It is KOAc of; and vi) No additives are present; and / or vii) The reaction temperature is 30°C to 120°C, for example 40°C to 50°C, preferably 60°C or The temperature is 70°C.

[0053] A boration reaction may be characterized by any one of the above i) to vii). The reaction may be characterized by any two of the above i) to vi). The boration reaction is as described above. Any three of the above i) to vii) may be used as characteristics. The boration reaction is characterized by the above i) to v ii) may be characterized by any four of the above. The boration reaction is characterized by i) to vii) Any five of the above may be used as characteristics. The boration reaction is one of six of the above i) to vii) The boration reaction may be characterized by all of the above i) to vii). stomach.

[0054] The boration reaction may be characterized by the above i) and ii). The boronation reaction may be characterized by i) and iii). The boration reaction may be characterized by the above i) and v). The boration reaction may be characterized by the above i) and vi). The boration reaction may be characterized by the above ii) and iii). The boronation reaction may be characterized by the above ii) and iv). The boronation reaction may be characterized by the above ii) and vi). The borylation reaction may be characterized by the above ii) and vii). The reaction may be characterized by the above iii) and iv). The boration reaction is characterized by the above iii The boration reaction may be characterized by iii) and vi) above. The borylation reaction may be characterized by the above iii) and vii). The reaction may be characterized by the above iv) and v). The borylation reaction is characterized by the above iv) and vi) may also be a characteristic. The boration reaction may also be characterized by iv) and vii) above. Good. The boration reaction may be characterized by the above v) and vi). The boration reaction is The boration reaction may be characterized by the above v) and vii). It could also be considered a characteristic.

[0055] In one embodiment, a boration reaction having a good yield and minimal byproduct formation is described as follows: It is characterized by at least one of the following: i) The catalyst is in an amount of 0.05 mol% to 0.5 mol% compared to the number of moles of X6b, preferably X The catalyst precursor is Pd-XPhos-2G in an amount of 0.25 mol% compared to the mole amount of 6b. is; ii) The ligand is present in an amount of 0.1 mol% to 1 mol% compared to the number of moles of X6b; preferably X6 This is 0.5 mol% of XPhos compared to the number of moles of b; iii) The catalyst is Pd-XPhos-2G, the ligand is XPhos, and XPh The number of moles of os is twice the number of moles of Pd-XPhos-2G; iv) The boronating agent is 1 to 3 molar equivalents compared to X6b, preferably 1 molar equivalent compared to X6b. It is 0.5 molar equivalents of bisboronic acid; v) The base is potassium acetate in an amount of 2 to 5 molar equivalents, preferably 3 molar equivalents, compared to X6b. is; vi) Additives should be added in an amount of 2 to 5 molar equivalents compared to X6b, preferably 3 molar equivalents compared to X6b. The amount of ethylene glycol; and vii) The reaction temperature is 30°C to 70°C, preferably 40°C to 50°C, more preferably 5°C. It is 0℃.

[0056] A boration reaction may be characterized by any one of the above i) to vii). The reaction may be characterized by any two of the above i) to vi). The boration reaction is as described above. Any three of the above i) to vii) may be used as characteristics. The boration reaction is characterized by the above i) to v ii) may be characterized by any four of the above. The boration reaction is characterized by i) to vii) Any five of the above may be used as characteristics. The boration reaction is one of six of the above i) to vii) The boration reaction may be characterized by all of the above i) to vii). stomach.

[0057] The boration reaction may be characterized by the above i) and ii). The boronation reaction may be characterized by i) and iii). The boration reaction may be characterized by the above i) and v). The boration reaction may be characterized by the above i) and vi). The boration reaction may be characterized by the above ii) and iii). The boronation reaction may be characterized by the above ii) and iv). The boronation reaction may be characterized by the above ii) and vi). The borylation reaction may be characterized by the above ii) and vii). The reaction may be characterized by the above iii) and iv). The boration reaction is characterized by the above iii The boration reaction may be characterized by iii) and vi) above. The borylation reaction may be characterized by the above iii) and vii). The reaction may be characterized by the above iv) and v). The borylation reaction is characterized by the above iv) and vi) may also be a characteristic. The boration reaction may also be characterized by iv) and vii) above. Good. The boration reaction may be characterized by the above v) and vi). The boration reaction is The boronation reaction may be characterized by the features of v) and vii) described above. This may be considered a characteristic feature.

[0058] In another embodiment, the boration reaction may be as follows: [ka]

[0059] In one embodiment, a boration reaction having a good yield and minimal byproduct formation is described as follows: It is characterized by at least one of the following: i) The amount of catalyst is 0.001 mol% to 0.5 mol%, preferably, compared to the number of moles of X6b. This is 0.05 mol% of Pd-cataCXium-3G compared to the mole count of X6b. ; ii) The ligand is present in an amount of 0.02 mol% to 1% compared to the number of moles of X6b, preferably the amount of X6b. This is 0.1 mol% of cataCXium compared to the number of moles; iii) The catalyst is Pd-cataCXium-3G, and the ligand is cataCXiu m is the number of moles of cataCXium, and the number of moles of Pd-cataCXium-3-3G is the number of moles of Pd-cataCXium-3-3G. It is twice the number; iv) The boronating agent should be 1 to 3 molar equivalents compared to X6b, preferably 1.5 molar equivalents compared to X6b. It is bisboronic acid in molar equivalent amounts; v) The base is 2 to 5 molar equivalents compared to X6b, preferably an equivalent amount of N compared to X6b. It is N-diisopropylethylamine; and vi) No additives are present; and / or vii) The reaction temperature is 30°C to 70°C, preferably 40°C to 50°C, more preferably 5°C. It is 0℃.

[0060] A boration reaction may be characterized by any one of the above i) to vii). The reaction may be characterized by any two of the above i) to vi). The boration reaction is as described above. Any three of the above i) to vii) may be used as characteristics. The boration reaction is characterized by the above i) to v ii) may be characterized by any four of the above. The boration reaction is characterized by i) to vii) Any five of the above may be used as characteristics. The boration reaction is one of six of the above i) to vii) The boration reaction may be characterized by all of the above i) to vii). stomach.

[0061] The boration reaction may be characterized by the above i) and ii). The boronation reaction may be characterized by i) and iii). The boration reaction may be characterized by the above i) and v). The boration reaction may be characterized by the above i) and vi). The boration reaction may be characterized by the above ii) and iii). The boronation reaction may be characterized by the above ii) and iv). The boronation reaction may be characterized by the above ii) and vi). The borylation reaction may be characterized by the above ii) and vii). The reaction may be characterized by the above iii) and iv). The boration reaction is characterized by the above iii The boration reaction may be characterized by iii) and vi) above. The borylation reaction may be characterized by the above iii) and vii). The reaction may be characterized by the above iv) and v). The borylation reaction is characterized by the above iv) and vi) may also be a characteristic. The boration reaction may also be characterized by iv) and vii) above. Good. The boration reaction may be characterized by the above v) and vi). The boration reaction is The boronation reaction may be characterized by the features of v) and vii) described above. This may be considered a characteristic feature.

[0062] For example, the reaction may be as follows: [ka]

[0063] Coupling of X6a and F6 In some embodiments of the present invention, the boration of X6b to obtain X6a is performed by the compound It is used in a method for synthesizing substance F7. In such an embodiment, X6b This is converted to X6a, and then X6a is cross-coupling to generate F7. It is reacted with F6 under the following conditions. In a preferred embodiment, the conversion of X6b to X6a and X6 Cross-coupling of a with F6 is carried out in a one-pot reaction. Several implementations In terms of configuration, the conversion of X6b to X6a and the cross-coupling of X6a with F6 are performed sequentially. This will occur in the following reaction.

[0064] According to the present invention, borated compound X6a is used in cross-coupling reactions. It can react with aryl rogenides. In one embodiment, the coupling reaction is One or more catalysts, one or more ligands, one or more bases and / or This is carried out using one or more additives. In one embodiment, coupling reaction The response is carried out using one or more catalysts, one or more ligands, and one or more bases. In some embodiments, the coupling is performed by adding one or more additives. include.

[0065] The metal catalysts used in cross-coupling reactions include palladium, nickel, and It may contain copper or a combination thereof, and preferably palladium.

[0066] A wide range of ligands can be used in the cross-coupling of X6a and F6. Ligands can affect the reactivity of coupling reagents. For example, ligands can be metal complexes. This can increase the electron density at the metal center of the body, which improves the oxidative addition step. This is possible. In addition, bulky ligands are useful in the reductive elimination step. In some embodiments, the ligand used in the coupling of X6a and F6 is , organophosphine, N-heterocyclic carbene, diazabutadiene, dibenzylideneacetone Selected from the group consisting of and combinations thereof. In a preferred embodiment, the ligand is Organophosphine ligands, e.g., XPhos, APhos, CPhos, RuPhos, SPhos, cataCXium, DavePhos, JohnPhos, MePhos Select from the group consisting of XantPhos, PPh3, tBuPPh2, and combinations thereof. The organophosphine is preferably XPhos, APhos, CPhos, or RuPhos. SPhos, cataCXium, more preferably XPhos, cataCXium and Of the two, tBuPPh2 is most preferably tBuPPh2.

[0067] In the coupling of X6a and F6, the metal catalyst and ligand are a complex of the catalyst precursor. For example, phosphine ligands, such as XPhos, APhos, CPhos, RuPho s, SPhos, cataCXium, DavePhos, JohnPhos, MePh os, XantPhos, Cy3P-HBF4, Cy-BIPHEP, SPHOS-SO Organic hydroxypropyl alcohol selected from the group consisting of 3Na, PPh3, tBuPPh2, and combinations thereof. Sphinx, preferably XPhos, APhos, CPhos, RuPhos, SPhos cataCXium, more preferably XPhos, cataCXium and tBuPP Buchwald G1, G2, G3, or more preferably Buchwald G1, G2, G3, which form a complex with h2, most preferably with tBuPPh2. The catalyst precursor may be provided as G4, preferably as G2.

[0068] In some embodiments, a catalyst precursor containing a phosphine ligand is used, The phosphine ligand is not used. Instead, the precatalyst containing the phosphine ligand is used. A carrier is used, and additional phosphine ligands are also used. Examples of catalyst precursors for this purpose are Pd(TFA)2, PdBr2, or Pd(MeCN)2Cl2. These catalyst precursors may include Ph2P(t-Bu);Cy3P-HBF 4;RuPHOS;S-PHOS, Cy-BIPHEP;SPHOS-SO3Na, etc. It can be used in the presence of ligands.

[0069] The coupling of X6a and F6 may include a base. In some embodiments... The bases are KOH, NaOH, Ca(OH)2, Na2CO3, K2CO3, and K3P. O4, Cs2CO3, KOAc, KOPh or NaOAc, diisopropylethyl Tertiary amines such as mine (DIPEA), triethylamine, or combinations thereof It is an organic or inorganic salt. Preferably, the base is triethylamine or KOH, most preferably It is KOH.

[0070] The coupling of X6a and F6 can be optionally performed with an additive, such as PdXPho. When the s-2G / XPhos complex is used, it contains alcohols such as ethylene glycol. It is possible.

[0071] The coupling of X6a and F6 can be carried out in any suitable solvent. Examples of organic solvents include polar solvents, nonpolar solvents, protic solvents, aprotic solvents, and polar protic solvents. This includes rotonic solvents and polar aprotic solvents. In a preferred embodiment, crosscut The Pulling reaction involves t-amyl alcohol, hexanol, pentanol, and butanol (t). n-butanol, isobutanol and n-butanol), propanol (isopropano Alcohol solvents (including ethanol and n-propanol), ethanol, and / or methanol. This can be done in other solvents, such as halogenated alkanes like dichloromethane. Solvents can also be used. Dioxane, MeTHF, THF and diethyl A Ether-based solvents such as dialkyl ethers can also be used. Plapping can also be performed in aqueous environments, including micelle environments. In embodiments, a mixture of solvents, such as MeTHF and water, is used. If used, the reaction mixture may be precipitated to simplify purification.

[0072] The coupling of X6a and F6 involves one or more catalysts and one or more coordination groups. A child, one or more boronating agents, one or more bases and / or one or more This can be achieved using several additives. Those skilled in the art will be able to determine the appropriate amounts of these reagents. Common knowledge can be used to accomplish this.

[0073] In one embodiment, a coupling reaction having excellent yield and minimal byproduct formation is described as follows: , characterized by at least one of the following i) The amount of catalyst or catalyst precursor is 0.1 mol% compared to the number of moles of F6 or X6a. 5mol%, 0.25mol%~3mol%, 0.5mol%~1.5mol%, preferred It is present in an amount of 0.5 mol% or more preferably 1 mol%; ii) The number of moles of ligands, if present, is twice the number of moles of catalyst or catalyst precursor. It is 3 times, preferably 2 times; iii) The molar ratio of F6:X6a is 2:1 to 1:2, i.e., 1.5:1 to 1:1.5. 1.2:1 ~ 1:1.2 or 1:1; iv) Additives are optional and, if present, are 2-5 times more effective than F6 or X6a. It is the amount of the equivalent; and / or v) The amount of base is 2 to 5 molar equivalents compared to the number of moles of F6 or X6a, preferably 2 to The amount is 3 mole equivalents, most preferably 3 mole equivalents.

[0074] A coupling reaction may be characterized by any one of the above i) to v). The coupling reaction may be characterized by any two of the above i) to v). The coupling reaction may be characterized by any three of the above i) to v). The coupling reaction may be characterized by any four of the above i)~v). All of them could be considered characteristics.

[0075] The coupling reaction may be characterized by the above i) and ii). The coupling reaction may be characterized by the above i) and iii). The coupling reaction may be characterized by the above i) and v). The coupling reaction may be characterized by the above ii) and iii). The response may be characterized by the above ii) and iv). The coupling reaction is as described in ii) The coupling reaction may be characterized by the above iii) and iv). The coupling reaction may be characterized by the above iii) and v). The ring reaction may be characterized by the above iv) and v).

[0076] In one embodiment, a coupling reaction having good yield and minimal byproduct formation is , characterized by at least one of the following: i) The catalyst and ligand shall be present in an amount of 0.5 mol% to 2 mol% compared to the mole amount of F6 or X6a. It is provided as a catalyst precursor-ligand complex in quantities of Pd and X-Phos-2G; ii) The base is added in an amount of 2 to 5 molar equivalents, preferably 3 molar equivalents, compared to F6 or X6a. It is ethylamine; iii) The additive shall be added in an amount of 2 to 5 molar equivalents, preferably 3 molar equivalents, compared to F6 or X6a. It is ethylene glycol; iv) The reaction is carried out in an alcohol solvent, preferably methanol; and v) The reaction temperature is 30°C to 70°C, preferably 40°C to 50°C, more preferably 50°C. That is the case.

[0077] A coupling reaction may be characterized by any one of the above i) to v). The coupling reaction may be characterized by any two of the above i) to v). The coupling reaction may be characterized by any three of the above i) to v). The coupling reaction may be characterized by any four of the above i)~v). All of them could be considered characteristics.

[0078] The coupling reaction may be characterized by the above i) and ii). The coupling reaction may be characterized by the above i) and iii). The coupling reaction may be characterized by the above i) and v). The coupling reaction may be characterized by the above ii) and iii). The response may be characterized by the above ii) and iv). The coupling reaction is as described in ii) The coupling reaction may be characterized by the above iii) and iv). The coupling reaction may be characterized by the above iii) and v). The ring reaction may be characterized by the above iv) and v).

[0079] In a preferred embodiment, coupling has excellent yield and minimal byproduct formation. The reaction is characterized by at least one of the following: i) The catalyst is present in an amount of 0.25 mol% to 2 mol% compared to the number of moles of X6b, and the number of moles of X6b is Compared to 0.25 mol% to 1.5 mol%, preferably 0.5 mol%, or more preferably 0.5 mol%. This is 1 mol% of Pd(MeCN)2Cl2; (the conversion of X6b to X6a is approximately 9 (8%) ii) The ligand shall be present in an amount of 0.5 mol% to 4% compared to the number of moles of X6b, preferably the same amount as X6b. The amount of tBuPPh2 is 1 mol% or 2 mol% compared to the number of tBuPh2; in particular, the catalyst is Pd The compound is (MeCN)2Cl2, the ligand is tBuPPh2, and the number of moles of tBuPPh2 This is twice the number of moles of Pd(MeCN)2Cl2; iii) The base is added in an amount of KOH of 2 to 5 molar equivalents, preferably 3 molar equivalents, compared to X6b. be; iv) The reaction is carried out in a mixture of MeTHF and water; and v) The reaction temperature is 30°C to 70°C, preferably 60°C.

[0080] A coupling reaction may be characterized by any one of the above i) to v). The coupling reaction may be characterized by any two of the above i) to v). , It may be characterized by any three of the above i) to v). The coupling reaction may be characterized by any four of the above i ) to v). The coupling reaction may be characterized by all of the above i) to v).

[0081] The coupling reaction may be characterized by the above i) and ii). The coupling reaction , may be characterized by the above i) and iii). The coupling reaction may be characterized by the above i) and i v). The coupling reaction may be characterized by the above i) and v). . The coupling reaction may be characterized by the above ii) and iii). The coupling reaction may be characterized by the above ii) and iv). The coupling reaction may be characterized by the above ii) [[ID=!18]] and v). The coupling reaction may be characterized by the above iii) and iv). The coupling reaction may be characterized by the above iii) and v). The coupling reaction may be characterized by the above iv) and v).

[0082] In a preferred embodiment, the borylation of X6b to X6a and the cross-coupling of X6a and F6 are carried out in a one-pot reaction.

[0083] Preparation of X6b X6b is an intermediate key in the novel synthesis described herein. Accordingly, the present invention provides the synthetic intermediate, X6b: [Chemical formula] X is F, Cl, Br or I. Preferably, X is Br.

[0084] X6b can be synthesized by any suitable means per se. The present invention provides a synthetic intermediate This provides a method for preparing body X6b: [ka] X is F, Cl, Br, or I, preferably Br.

[0085] In some embodiments, the method involves reacting compound X6d with compound N6a. Includes, [ka] X is Cl, Br, or I, preferably Br.

[0086] Carboxylic acid coupling reactions, including amidation reactions, are well known to those skilled in the art, and are typical. Specifically, reacting an amine with a carboxylic acid under coupling conditions or more easily with an amine This involves converting a carboxylic acid group into an activated group that can react with a certain agent.

[0087] Therefore, in one embodiment, the synthesis of X6b is performed by activating the carboxylic acid group of X6d This includes using a method to convert to a carboxylic acid group. For example, the method involves the chemical reaction of compound X6d It can include conversion to X6c: [ka] R 10 This refers to an activated carboxylic acid group, such as an acyl anhydride, an acyl halogenate, or an acyl anhydride. The phosphoric acid is phosphate and X is Cl, Br, or I. For example, the corresponding phosphate of X6d is phosphate. The conversion to toluene can be achieved using thionyl chloride. The solvent is toluene, etc. It may be an aromatic solvent. The base may be pyridine. X6c is then compounded. It can react with N6a to form substance X6b. These reactions can be carried out as a one-pot synthesis or sequentially. The formation of N6a from N6b can also lead to this one-pot synthesis. X6c and N6a are prepared separately but then coupled.

[0088] Alternatively, X6b is directly prepared from X6d and N6a by using a carboxylic acid activation reagent. Carboxylic acid activation reagents are well-known and include HBT, HATU, HBTU, TBTU, HOBt, PyAOP, HCTU, PyClocK, TFFH, carbodiimide (e.g., DCC), carbonyl diimidazole (CDI), and phosphonium salts (e.g., BOP, PyBOP).

[0089] The coupling of X6d or X6c and N6a can be carried out in the presence of a base, preferably a tertiary alkylamine base such as triethylamine or DIPEA or an arylamine base such as pyridine. The coupling of X6d or X6c and N6a can be carried out in isopropyl acetate, toluene, or preferably a mixture thereof.

[0090] X6d can be prepared from X6e:

Chemical formula

[0091] In one embodiment, X6d is prepared by contacting X6e with a base that converts a cyano group to a carboxylic acid group, such as sodium hydroxide.

[0092] X6e can be prepared from X6f: ​​​​​ [ka] X is Cl, Br, or I.

[0093] X6e was prepared by contacting X6f with X6g under cross-coupling conditions. To be done: [ka] X is F, Cl, Br, or I, m is 2 or 3, and R is F, Cl , Br or I, OH, OC1-C6 alkyl, N(C1-C6 alkyl)2, Ally If two or three R groups other than F, Cl, Br, I, or OH are together Cyclic boronic acid esters, for example, pinacolboronic acid or N-methyliminodiacetic acid (M IDA) Boronate can be formed. The coupling of organoboron and aryl halide compounds is X6b and F7 coupling. The conditions described above in relation to the process, and similar conditions, can be used for the formation of X6e. It is possible.

[0094] X6f can be prepared from X6h: [ka] X is Cl, Br, or I.

[0095] X6f is converted by diazoting X6h with nitrite or sodium nitrite under acidic conditions, for example. Next, the cyanification of diazonium compounds using, for example, CuCN and / or NaCN. It can be prepared by [method].

[0096] The X6h can be prepared from the X6i: [ka]

[0097] X6h is X6i with a halogenating agent, for example, AlCl3 or N-chlorosuccinate. Chlorinating agents such as mid, N-bromosuccinate, 1,3-dibromo-5,5-dimethylhydroxypropyl alcohol Dantoin (DBDMH), N-bromosuccinimide, TBAB, phosphorus tribromide, chloride odor Aluminum tribromide, Br2 and FeBr3, HBr, tribromoisocyanuric acid, Selected from the group consisting of ozone, ammonium bromide, TBBDA, and combinations thereof. By contacting it with a brominating agent or an iodinating reagent such as N-iodosuccinimide, X6h can also be prepared via the Sandmaier reaction. .

[0098] Preparation of N6a N6a is used in the preparation of X6b. N6a can be prepared from N6b. Kill: [ka] Y is either Cl, Br, or I.

[0099] N6a is brought into contact with N6b using a reducing agent, for example, a reducing agent selected from the group consisting of the following. It can be prepared by: H2 and Pt(V) / C; Raney nickel catalyst and H2; Urushihara nickel catalyst and H2; Adams catalyst (PtO2) and H2; TiCl3 H2; HCl and iron; NH4Cl and iron; HCl and SnCl2; samarium and NH 4Cl;FeCl3, hydrazine hydrate; sodium hydrosulfite; hydrogen sulfide and Bi base; hydroiodic acid; 1,3-dimethyl-2-imidazolidinone and sodium triglyceride Chilsilantiolate; and combinations thereof. In some embodiments, this reaction This is carried out under micelle conditions.

[0100] N6b can be prepared from N6c: [ka]

[0101] N6b is X6h with a halogenating agent, for example, AlCl3 or N-chlorosuccinate. Chlorinating agents such as mid, N-bromosuccinate, N-bromosuccinimide, 1,3-di Bromo-5,5-dimethylhydantoin (DBDMH), TBAB, phosphorus tribromide, chloride odor Aluminum tribromide, Br2 and FeBr3, HBr, tribromoisocyanuric acid, Selected from the group consisting of ozone, ammonium bromide, TBBDA, and combinations thereof. By contacting it with a brominating agent or an iodinating reagent such as N-iodosuccinimide, X6h can also be prepared via the Sandmaier reaction. .

[0102] N6c can be prepared from N6d: [ka]

[0103] N6c is a nitrating agent, for example, a nitrating agent selected from the group consisting of the following, and N6d is It can be prepared by contact: nitric acid and sulfuric acid; nitric acid and acetic anhydride; tetranitrate Lachloromethane, nitric acid, and phosphorus pentoxide; isopentyl nitrate, trifluoromethanesulfone Acids and 1-ethyl-3-methylimidazolium triflate; H-beta zeolite catalysts and N2O5; acetyl nitrate; and combinations thereof.

[0104] N6d can be prepared from N6e: [ka]

[0105] N6d is nitrite or sodium nitrite, a diazotizing agent, under acidic conditions, followed by HF It can be prepared by contacting N6e with a fluorinating agent such as [mention specific fluorinating agent here].

[0106] Preparation of F6 F6 is used in the preparation of F7 and is prepared by any suitable method. This is possible. In one embodiment of the present invention, F6 is prepared from F2 and F3: [ka] Y is independently Cl, Br, or I.

[0107] In some embodiments, the preparation of F6 involves compound F2 to obtain compound F4. This includes reacting with compound F3: [ka]

[0108] The reactions of F2 and F3 involve a phosphine compound such as PPh3 (optionally, a resin support). (above) and azodicarbosilates such as DIAD or DEAD It can be carried out under Mitsunobu conditions in the presence of late. In one embodiment, The process is carried out in an aromatic solvent such as toluene. In one embodiment, the solvent is 0. Dry the product to a moisture content of less than 5 wt%, for example, 0.1 wt%.

[0109] The preparation of F6 may include the conversion of F4 to F6: [ka]

[0110] The conversion of F4 to F6 can be done with any suitable amination reagent, such as ammonium hydroxide or water. and ammonia may also be used. In one embodiment, the solvent is iPrOH Which alcoholic solvent is it?

[0111] The reaction of F2 with F3 to obtain F4, and the conversion of F4 to compound F6, are carried out in sequential reactions. This may be carried out in a one-pot reaction.

[0112] Alternatively, F2 can be converted to F2' via amination. The amination reagent is The reaction involves water and ammonia or ammonium hydroxide, and this reaction is carried out by an ammonia such as iPrOH. This may be carried out in a polar solvent such as Cohl's solvent. F2 is then used to obtain F6. Optionally, under Mitsunobu conditions, phosphine compounds such as PPh3 and DIAD or It can react with F3 in the presence of azodicarbosylates such as DEAD. : [ka]

[0113] These reactions can be carried out sequentially or in a single pot.

[0114] Preparation of F11 None of the reactions described herein can be used in the synthesis of compound F11. It is possible to: [ka]

[0115] In one embodiment of the method of the present invention, F7 is used in one or more synthesis steps. It is converted to 11. For example, in one embodiment, the method of the present invention obtains F8 It may further include the deprotection of F7: [ka]

[0116] In some embodiments, P is a Boc group, and deprotection is performed with an acid, such as HCl. It is achieved by using it.

[0117] The method of the present invention may further include the conversion of F8 to F11: [ka]

[0118] The conversion of F8 to F11 can be achieved by making F8 contact F9. : [ka]

[0119] The formation of F11 from F8 and F9 involves a base such as Na2CO3 and suitable materials such as ethyl acetate. This can be achieved in the presence of a suitable solvent. Alternatively, the reaction can be carried out in a suitable solvent. It can be run without a base. Instead of F9, use HBT, HATU, HBTU, T BTU, HOBt, PyAOP, HCTU, PyClocK, TFFH, Carbodiimide (e.g., DCC), carbonyldiimidazole (CDI), or phosphonium salt (e.g., T Along with carboxylic acid activating reagents such as 3P, SOCl2BOP, and PyBOP, chloride activators Liroyl or acrylic acid can be used. However, Unlike acrylic acid, acrylic anhydride avoids the need for chromatography. It is preferable.

[0120] Products prepared according to the process of the present invention and their use This invention provides a synthetic route for the compound remibrutinib. Therefore, the results arising from this application The protection granted by the patent is the direct process of remibrutinib as described herein. The process may be extended to include the products of the reaction.

[0121] The present invention is prepared or can be prepared by the processes described herein. This specification provides compound F11 (remibrutinib). The synthesis of the nib does not involve INT3 at any stage. Therefore, in one embodiment, Remibrutinib prepared or prepareable by the process described in the specification is INT3(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3 (2-dioxaborolan-2-yl)aniline is virtually absent. For example, the amount of INT3 This includes less than 100 ppm (parts per million), less than 10 ppm, less than 1 ppm, and 100 ppb (tenths per million). It may be less than (parts per billion), less than 10 ppb, or less than 1 ppb. In one embodiment, Remibrutinib prepared or prepareable by the processes described herein. , INT3(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1, It does not contain 3,2-dioxaborolan-2-yl(aniline). Instead or in addition, Remibrutinib prepared or prepareable by the processes described herein. (3-amino-5-fluoro-2-methylphenyl)boronic acid is virtually absent. The amount of (3-amino-5-fluoro-2-methylphenyl)boronic acid is 100 ppm. Less than (parts per million), less than 10 ppm, less than 1 ppm, less than 100 ppb (parts per billion), 1 It may be less than 0 ppb or less than 1 ppb. In one embodiment, as specified herein Remibrutinib prepared or prepareable by the process described is 3-amino- It does not contain 5-fluoro-2-methylphenyl)boronic acid.

[0122] The present invention is also prepared or can be prepared by the processes described herein. We also provide pharmaceutical compositions containing remibrutinib, and therefore INT3 may be substantially absent. In one embodiment, the composition also includes at least one pharmaceutically acceptable excipient. They contain, and often, at least two or more pharmaceutically acceptable excipients. Such suitable excipients are disclosed herein. Other known in the art The excipients may be used without departing from the intent and scope of this application.

[0123] As used herein, the term “pharmaceutically acceptable excipient” means “a pharmaceutically acceptable excipient” as used by those skilled in the art. All solvents, carriers, diluents, dispersions, coatings that may be known surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents, antioxidants), isotonic agents Absorption retarders, salts, drug stabilizers, binders, additives, bulking agents, disintegrants, lubricants, sweeteners This includes fragrances, colorants and other similar substances, as well as combinations thereof (e.g., Remingt) on's Pharmaceutical Sciences,18th Ed.Mac See k Printing Company, 1990, pp. 1289-1329. (I would like to use it.) Any therapeutic composition or pharmaceutical combination, unless the conventional excipients are incompatible with the active ingredient. It is understood that the use of any conventional excipients in the finished product is assumed by this application. It should.

[0124] Pharmaceutical compositions are administered via specific routes of administration, such as oral, parenteral, and rectal administration. It can be formulated for this purpose. In addition, the pharmaceutical composition of the present invention may be in solid form (with limitations). (including capsules, tablets, pills, granules, powders or suppositories) or liquid form (not limited to) Pharmaceutical compositions can be prepared as liquids, suspensions, or emulsions without the need for other substances. , which can be subjected to conventional pharmaceutical operations such as sterilization, and / or conventional inert diluents, Lubricants, carriers or buffers, as well as solvents, preservatives, stabilizers, wetting agents, emulsifiers, and bulking agents. It may contain auxiliary agents such as fertilizers.

[0125] Typically, a pharmaceutical composition contains an active ingredient together with at least one excipient, such as the following: It is a tablet or capsule: a) Diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol Cellulose, cellulose, and / or glycine; b) Lubricants, such as silica, talc, stearic acid, its magnesium salt or calcium Salt and / or polyethylene glycol; for tablets, further c) Binders, such as magnesium aluminum silicate, starch paste, gelatin, etc. Laganth, methylcellulose, sodium carboxymethylcellulose and / or polymethylcellulose Nilpyrrolidone; if desired; d) Captisol, PEG, glycerin, cyclodextrin, or other similar substances. Carriers such as aqueous vehicles containing cosolvating materials; e) Tablet decomposition substances, such as starch, agar, alginic acid or its sodium salt or Foaming mixtures; and / or f) Absorbents, colorants, flavorings, and sweeteners.

[0126] The tablets are film-coated or enteric-coated according to methods known in the art. They may be coated. Preferably, the compound or composition may be, for example, a tablet or capsule. Prepared for oral administration, and optionally, for storing unit doses of pharmaceutical products and / or It is packaged in a multi-dose form suitable for dispensing. An example of suitable packaging is a sealed foil container. This includes unit dose containers (e.g., vials), blister packaging and strip packaging, but It is not limited to them.

[0127] The tablets are formulated with an active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for tablet manufacturing. It may contain ingredients. These excipients include, for example, calcium carbonate, sodium carbonate, Inert diluents such as lactose, calcium phosphate, or sodium phosphate; granulators and disintegrants. Decomposing agent, e.g., corn starch or alginic acid; binding agent, e.g., starch, gelatin or alginic acid Labia gum; and lubricants, such as magnesium stearate, stearic acid, or talc. Yes. Tablets are either uncoated or have a coating that delays disintegration and absorption in the gastrointestinal tract. Therefore, it is coated with a well-known technology, which allows it to last for a longer period of time. This provides a sustained effect. For example, glyceryl monostearate or distearate Time-delaying agents such as glyceryl can be used. Formulations for oral use are: The active ingredient is an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin. As a hard gelatin capsule mixed with , or as an active ingredient in a water or oily medium, for example, Soft gelatin capsules mixed with cassia oil, liquid paraffin, or olive oil It can be used for serving.

[0128] Since water may promote the breakdown of certain compounds, the present invention uses the active ingredient as described above. Remibrutinib, which is prepared or can be prepared by the method described in the details, is included in the following: Further information is provided on water-based pharmaceutical compositions and dosage forms.

[0129] The anhydrous pharmaceutical composition and dosage form of the present invention are anhydrous components or low-moisture-containing components and low-moisture conditions. Alternatively, it can be prepared using low humidity conditions. Anhydrous pharmaceutical compositions have the properties of anhydrous properties. It may be prepared and stored in such a way that it is maintained. Therefore, anhydrous compositions may be prepared in a suitable manner. The anhydrous composition is preferably designed to prevent exposure to water, so that it can be included in the kit. It is packaged using materials known to be effective. Examples of suitable packaging include airtight foil and plastic. Includes sticks, unit dose containers (e.g., vials), blister packaging, and strip packaging. However, it is not limited to these.

[0130] The present invention provides one or more methods for reducing the rate at which the compound of the present invention, as an active ingredient, decomposes. Further, pharmaceutical compositions and dosage forms containing the agent are provided. In this specification, the term "stabilizer" refers to the agent. Such drugs include acids such as ascorbic acid, pH buffers, or salt buffers. This includes, but is not limited to, anti-corrosion agents.

[0131] The pharmaceutical composition or combination of the present invention provides approximately 1 to 100 units for approximately 50 to 70 kg of subject matter. 0 mg of active ingredient(s) or approximately 1-500 mg or approximately 1-250 mg or approximately A single dose of the active ingredient in the following amounts: 1-150 mg, approximately 0.5-100 mg, or approximately 10-50 mg. The dosage can be approximately 1. The unit dosage can be 0 mg, approximately 25 mg, or approximately 50 mg. Compound, pharmaceutical composition The effective therapeutic dose or amount of a substance or combination thereof depends on the species, weight, age, and individual condition of the subject. It depends on the disability or disease being treated or its severity. A physician of average skill, clinical A physician or veterinarian may use the necessary resources to prevent, treat, or inhibit the progression of a disorder or disease. The effective amount of each sexual component can be easily determined.

[0132] The efficacy of the above-mentioned dosages applies to mammals such as mice, rats, dogs, monkeys, or The extracted organs, tissues, and preparations are conveniently used in in vitro and in vivo trials. This can be proven in tests. The compounds of the present invention are in the form of a liquid, for example, preferably an aqueous solution. In vitro and, for example, as a suspension or in an aqueous solution, enterally, parenterally, It can be advantageously administered intravenously in vivo. The dosage in vitro is , about 10 -3 Molar concentration ~10 -9 It may also be within a range of molar concentrations. In vivo The effective therapeutic dose depends on the route of administration, ranging from approximately 0.1 to 500 mg / kg or approximately 1 The dosage may be in the range of 100 mg / kg. Preferably, the therapeutic effect in vivo. The dosage is between approximately 10mg and 200mg per day, for example, approximately 10mg, approximately 20mg, and approximately 200mg per day. The dosage ranges from 5 mg, approximately 35 mg, approximately 50 mg, approximately 100 mg, or approximately 200 mg. In vivo effective doses are approximately 10 mg, 35 mg, and 50 mg once daily. Selected from g or approximately 100 mg. Furthermore, preferably, the therapeutically effective dose in vivo. The dosage is selected from approximately 10 mg, 25 mg, 50 mg, or 100 mg twice daily.

[0133] In another embodiment, the present invention also relates to recovery by BTK intervention or inhibition of BTK. A method for treating a disorder, which is prepared by the method described herein. Administer a therapeutically effective dose of remibrutinib, or a prepared dose, to patients requiring such treatment. We also provide methods that include doing so.

[0134] In another embodiment, the present invention also relates to recovery by BTK intervention or inhibition of BTK. For the preparation of pharmaceuticals for the treatment of disorders, by the method described herein The use of remibrutinib that can be manufactured or prepared is also provided.

[0135] In another embodiment, the present invention also relates to recovery by BTK intervention or inhibition of BTK. Prepared by the method described herein for use in the treatment of the disorder Alternatively, we also offer a prepareable remibrutinib.

[0136] Remibrutinib prepared or prepareable by the methods described herein is In the treatment of the following diseases or disorders that are mediated by or restored by BTK inhibition Useful for: autoimmune disorders, inflammatory diseases, allergic diseases, asthma, and chronic obstructive pulmonary disease Airway diseases such as COPD, transplant rejection; antibody production, antigen presentation, cytokine production Or abnormal or harmful diseases of lymphoid organ formation; rheumatoid arthritis, systemic juvenile idiopathic Arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus Myasthenia gravis, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenia Minor purpura, chronic urticaria (chronic idiopathic urticaria, induced urticaria), chronic allergy (atopic dermatitis) (Contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes Type 2 diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, pancreatitis, glomerulonephritis, Good's disease Schur syndrome, Hashimoto's thyroiditis, Graves' disease, antibody-mediated transplant rejection (AMR), transplantation 1 / 2 host disease, including B cell-mediated hyperacute, acute, and chronic transplant rejection; thromboembolic disorders myocardial infarction, angina pectoris, stroke, ischemic injury, pulmonary embolism; including but not limited to multiple myeloma. Cancers of hematopoietic origin that cannot be treated; leukemia; acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; Myeloid leukemia; non-Hodgkin lymphoma; lymphoma; polycythemia vera; essential thrombocythemia; myeloid leukemia Myelofibrosis with metaplasia; and Waldenström disease.

[0137] Remibrutinib prepared or prepareable by the methods described herein is Rheumatoid arthritis; chronic urticaria, preferably chronic idiopathic urticaria; Sjögren's syndrome, multiple It is particularly useful in the treatment of serosclerosing, atopic dermatitis, or asthma. [Examples]

[0138] The following non-limiting embodiments illustrate the present disclosure.

[0139] An overview of the synthesis routes described herein and illustrated below is provided in the figure. The reaction is described in more detail below.

[0140] Preparation of Example 1-F2 [ka] To a suspension of AlCl3 in xylene at 5°C, add a xylene solution of F1 for more than 40 minutes. Heat the mixture to over 30°C for 60 minutes, then stir at this temperature overnight. Add ¼ and bind. Quench the resulting solution with a 0.5N aqueous solution of HCl at 0°C for 1 hour. Mixture 2 Heat to 5°C and separate the phases. Discard the aqueous layer and concentrate the organic layer. The resulting thin layer Cool the turbidity to 20°C at 0.3 K / min. Filter out the solid, and remove the filtration cake with xylene and Wash with a 1:1 heptane solution, dry, and obtain as a white solid with approximately 83% yield. Obtain F2.

[0141] Preparation of Example 2-F6 [ka] Preparation of F3 solution: 13.0 g water, 2.4 g 30% sodium hydroxide solution, 68.0 Fill the reaction flask with g of toluene and 13.0 g of 2-methylaminoethanol. Adjust the internal temperature to 10-30°C. Stir the reaction mixture for 25-35 minutes. (No Boc) Add the aqueous solution (37.8g, 1.00 equivalent) dropwise, and allow the reaction mixture to continue for another 6-12 hours. Stir at 0°C. Quench the reaction with water (13.0 g) to obtain the resulting two-phase mixture. Stir the mixture for 25-35 minutes. Remove the water layer at the bottom, and add another 13.0g of water to the organic layer. Wash with ). Use the organic layer directly in the next step.

[0142] Mitsunobu reaction to F4: A solution of F3 in toluene (1.4 eq) is mixed with 0.07 wt% NMT. Dry by the Dean-Stark distillation method until moisture content is reached. 20-30°C Add triphenylphosphine (42g, 1.32eq) to the dried solution of F3, and a clear solution is formed. Stir the reaction mixture at room temperature until a liquid is observed. Inertize the reactor. e) Cool to approximately -30°C. Then add F2 (20g, 1.0eq), and then Then, DIAD (31.8g, 1.30eq) was administered while maintaining the internal temperature at -25℃. Add 4-8 hours or more. Warm the slightly cloudy solution to 10°C within 4 hours, then 5-15°C. Stir for a further 15-20 hours. After the reaction is complete, distill the toluene at 55°C. It produces a viscous yellowish-brown suspension. Cool the mixture to 10°C and add n-heptane (14 Add 0g). Stir the mixture for 2 hours until it turns a light brown color and is thoroughly stirred (stirrab ) Obtain a suspension. Filter the suspension and wash the filter cake with cooled n-heptane. Discard the filtration cake containing triphenylphosphine oxide and H2-DIAD. The mother liquor and washing solution combination is heated to approximately 55°C and 150 millibars in its initial volume. Concentrate to 1 / 3 of its original volume to produce a clear yellow solution of F4.

[0143] Amination to F6: The solvent of the F4 solution is then removed by distillation and the addition of iPrOH. Switch to iPrOH. Add H2O (3.5 w / ww) to the yellow solution of F4 in iPrOH. Add rt F2) and 25 wt% NH3 solution (3.5 w / w F2). As a result... Stir the resulting yellow solution at 70°C for 16 hours. As soon as it reaches 70°C, a small amount of gas will appear. NH3 release is observed. After the reaction is complete, the resulting yellow solution is left for 40 minutes. Cool to approximately 45°C, and add the F6 seed crystal as a suspension in iPrOH. Aging for 20 minutes. A dilute suspension is then cooled to 10-20°C at a rate of 10°C / hour. Then, age for another 30 minutes. Filter the suspension and filter the cake with H2O and iPrOH. Wash with a (1:1) mixture (40g). Remove the wet product under complete vacuum (full vacuum). Dry under acuum at 50°C (for approximately 20 hours) until a white liquid is obtained with a yield of approximately 70%. F6 is obtained as a crystalline solid.

[0144] Preparation of Example 3-X6b [ka] The synthesis of X6b involves the preparation of an N6a solution, the preparation of an acyl chloride X6c solution, and the combination of the two solutions. It is a highly convergent process that starts with a combination and forms X6b.

[0145] Autoclave: Preparation of N6a solution: Autoclave N6b (20g, 1.0 equivalent) under N2 Fill a slab and dilute with isopropyl acetate (105g). Then, for approximately 1 week Add t% moist Pt(V) / C (0.126g dry weight) and change the atmosphere from N2 to H2 To change this, hydrogenation is carried out under 3 bar H2 for 12 hours at an internal temperature of less than 30°C. At the end of the reaction, filter the suspension to remove the catalyst. Clean the reactor and filter cake with isoacetic acid. Rinse with propyl. The N6a solution can be removed by azeotropic distillation, or as is. It can be used.

[0146] Reactor A: Preparation of X6c solution: Under an N2 atmosphere, add X6d (17g, 1.1 equivalents) Suspend in ene (56g). Add a catalytic amount of pyridine and heat the reaction mixture to 50°C. Then, add thionyl chloride dropwise for over 2 hours, and ferment the resulting mixture at 50°C for 1 hour. Stir. Distill the turbid solution to half its volume, and rinse the reactor with toluene. Replenish to the specified volume and repeat the process to remove excess thionyl chloride from the X6c mixture. Next, the RT (Reverse Torque) is cooled.

[0147] Reactor A: Formation of X6b: In a solution of X6c (1.1 equivalents) in toluene, iPrOAc Add the previously prepared solution of N6a (1.0 equivalent) for more than 1 hour. At the end of the addition, DIP Carefully add EA (13.4g, 1.2 equivalents) over more than 2 hours. Add DIPEA to the reaction mixture. After the addition is complete, stir for 3 hours and quench the reaction with iPrOH (26.4g). Stir overnight in RT and filter the suspension. Soak the moist cake in iPrOH and iPrOH / water. Rinse thoroughly. Discard the cake and dry under reduced pressure. X6b is typically 87-93% It is isolated in yield.

[0148] Example 4a: Optimization of Suzuki conditions for converting X6a to F7 Previously, the coupling reaction between F6 and X6a was 1 eq of F6 and 1.15 eq of X6a. 6a, 5mol% Pd(PPh3)2Cl2, 3eq Na2CO3, 12vol D ME was run at 75°C for 8 hours using 10 vol of water, and the isolation yield of the conversion was 74%. It was reported that this occurred (DOI:10.1021 / acs.jmedchem.9b019). 16).

[0149] Cross-coupling reactions also reduce Pd usage and production costs, while using DME solvent. It was optimized to replace it with a Class 3 solvent suitable for commercial processes. [ka]

[0150] Details of the design and experiment 1) Suzuki's 12 catalyst precursors and 6 solvent systems (80°C: terto-amyl alcohol) CPME and toluene; 60℃: THF, Me-THF and MeCN, each combined with water (Combine) 3.0e at a 2.0mol% Pd level using 1.15eq.X6a Screening was performed in the presence of q.K3PO4, and the reaction was promoted after 16 hours. A series of catalyst precursor / solvent combinations that can be completely converted, with devolonate being the main byproduct. A match was found; all of the results were found in both toluene (80°C) and Me-THF (60°C). We decided to perform a screening of ligands. 2) Dissolve 48 types of ligands in 10.0 vol. Me-THF / 3.0 vol. water at 60°C. In a solution of 10.0 vol. toluene / 3.0 vol. water at 80°C, add 2.0 mol Using %Pd(OAc)2, 1.1eq. Boronate and 3.0eq. K3PO4 After cleaning, 16 hours later, 5 types of ligands (RuPhos, dppf, S-Phos, Cy3P·HBF4 and Ph2P(t-Bu) can accelerate the reaction and completely transform The mixture is converted to Prod / IS in Me-THF / water at 60°C, and devolonate is produced. It was found that by-products could be controlled at a level of 3% to 8%.

[0151] [Table 4]

[0152] 3) Maintain a P:Pd ratio of 2:1 and use 6 types of Pd precursors (Pd(OAc)2, [Pd(C3 H5)Cl]2, Pd(TFA)2, Pd(MeCN)2Cl2, Pd2(dab)3 and (PdBr2) was converted to RuPhos, dppf, and S- at a 1.0 mol% Pd level, respectively. Phos, in combination with Cy3P·HBF4 and Ph2P(t-Bu), yielded 3.0 eq. In the presence of K3PO4 and 1.05 eq. X6a, 10.0 vol. Me at 60°C -Screening was performed in THF / 3.0 vol. water, and after 16 hours, Cy3P·HBF 4 and Ph2P(t-Bu) are optimal ligand candidates, while Pd(TFA)2 and Pd (MeCN)2Cl2 and PdBr2 continue to be excellent Pd precursors.

[0153] [Table 5]

[0154] 4) Maintain a P:Pd ratio of 2:1, and use Cy3P·HBF4 and / or Ph2P as ligands. (t-Bu) is used, and Pd(TFA)2, Pd(MeCN)2Cl2 and Pd Combined with Br2, use 0.1-2.0 mol% of Pd in ​​3.0 eq.K3PO4 And in the presence of 1.05 eq. X6a, 10.0 vol. Me-THF / at 60°C Screening was performed in 3.0 vol. water, and after 16 hours, Pd(MeCN)2Cl2 / Ph2P(t-Bu) is an excellent and optimal catalyst precursor combination, with a Pd usage of 0. It can be reduced to 3-0.5 mol%, and the devoronate / Prod can be controlled to about 1%. It was found that it is possible to do so.

[0155] [Table 6]

[0156] 5) The optimal catalyst precursor combination is Pd(MeCN)2Cl2 / Ph2P(tB Using u) and 1.05eq.X6a, the amount of Pd used is 0.1 to 0.5 mol% each The screening was performed in the presence of K2CO3, Cs2CO3, K3PO4, and KF. K3PO4 is the optimal base, and 0.3~0.5 mol% Pd(MeCN)2Cl2 / P It was found that the h2P(t-Bu) catalyst precursor is recommended for scale-up reactions.

[0157] Best conditions 1) 1. In 10.0 vol. Me-THF / 3.0 vol. water at 60°C for 16 hours. 0eq.F6 1.05eq.X6a, 0.5mol%Pd(MeCN)2Cl2, 1. The reaction of 0 mol% Ph2P(t-Bu) and 3.0 eq. K3PO4 achieves a complete conversion. The IPC purity measured by HPLC was 90.6%, and the devoronate / Prod content was 1%. there were. 2) 1. 0eq.F6, 1.05eq.X6a, 0.3mol%Pd(MeCN)2Cl2, 0. The reaction of 6 mol% Ph2P(t-Bu) and 3.0 eq. K3PO4 achieved a 99% conversion. The IPC purity measured by HPLC was 88.5%, and the devoronate / Prod ratio was 1%. there were. [ka]

[0158] Next, the optimal conditions 1) 1. In 10.0 vol. Me-THF / 3.0 vol. water at 60°C for 16 hours. 0eq.F6, 1.05eq.X6a, 0.8mol%Pd(TFA)2, 1.6mol The reaction of %Ph2P(t-Bu), 3.0eq.K3PO4 achieved a complete conversion, HP The IPC purity measured by LC was 90.9%, and the devoronate / prod content was 2%. 2) 1. 0eq.F6, 1.05eq.X6a, 0.8mol%Pd(MeCN)2Cl2, 1. The reaction of 6 mol% Ph2P(t-Bu) with 3.0 eq. K3PO4 achieved complete conversion. Furthermore, the IPC purity measured by HPLC was 91.2%, and the devoronate / Prod content was 2%. .

[0159] Example 4b - One-pot boron from X6b using the optimized conditions of Example 4a Preparation of F7 by chemical-Suzuki cross-coupling [ka] Miyaura Boration: X6b (1.0 equivalent), B2pin2 (1.06 equivalents) and KOAc( (2.5 equivalents) in an N2 atmosphere containing degassed Me-THF Fill the reactor. Measure the water content of the reaction mixture and adjust it to between 1000 and 2500 ppm. After inertization of the container, Pd in ​​the degassed MeTHF (MeCN)2Cl2 (0.5 mol%) solution and PPh2 in degassed MeTHF Continue adding the tBu (1.0 mol%) solution. The reaction mixture is then left to stand for 16 hours. Heat to 0°C.

[0160] Suzuki coupling: Once a complete conversion of X6b is achieved (X6b < 0.25%, change The reaction mixture is cooled to RT (approximately 98%), and the reaction mixture is dissolved in an aqueous solution of KOH (2 Quench with 1% wt / wt. Separate and discard the aqueous layer, and prepare a fresh aqueous solution of KOH (2 Add 1% wt / wt. Add F6 (0.96 equivalents compared to X6b) as a solid. Next, after proper degassing, another PPh2tBu(2mol) in the degassed MeTHF is used. %) and another Pd(MeCN)2Cl2 (1 mol%) in the degassed MeTHF are added. The reaction mixture is then heated to 60°C for approximately 24 hours. After the reaction is complete, N- An aqueous solution of acetylcysteine ​​is added to the reaction mixture at 60°C. After stirring for 2 hours, the aqueous layer... Discard it. Add another N-acetylcysteine ​​aqueous solution, and add the KOH aqueous solution. Therefore, adjust the pH to ≥9.5. After stirring for 2 hours, discard the aqueous layer. Next, the organic layer is 3 Wash with water for 0 minutes and discard the aqueous layer. Filter the solution through activated carbon at 60°C and distill the solution under reduced pressure. It is concentrated to half its volume by this method. n-heptane is gradually added, and the resulting Cool the suspension to 20°C, stir for 2 hours, and filter. Dilute the filtered cake with 1:5 Me-T Wash with a mixture of HF and n-heptane. If the purity is not satisfactory... Then, the moist cake is turned into a slurry again with Me-THF and n-heptane (1:5). It is possible to remove the cake and dry it under reduced pressure. F7 typically yields 92%. It is isolated.

[0161] Tetrahydroxydiborone is used in the preparation of Example 4c-F7. Development of Pot-Boronation / Suzuki Cross-Coupling One-pot boration / Suzuki cross-coupling using tetrahydroxydiborone is This was developed for the synthesis of F7 from X6b using BBA as the boration reagent. The process utilizes a significantly reduced amount of Pd catalyst and the final product contains pinacol water. To avoid precipitation and to use methanol as a green alcohol solvent throughout both steps This process is characterized by the use of bis(pinacola) as a borating agent. (To address some of the previous problems associated with the use of diboron, thus achieving greater atomic efficiency) This will be an efficient and cost-effective approach. Preliminary results will be obtained using a FlexyALR reactor. We demonstrated the feasibility of this one-pot process at a scale of 2.2g. [ka]

[0162] Results and Discussion Miyaura Boration: In order to develop the optimal reaction conditions for Miyaura boration using BBA, The researchers screened the extremely important reaction parameters such as the catalyst system, base, solvent, and temperature. This boration process promotes the rapid formation of Pd(0) by the Pd(II)-catalyst precursor. Limited to use. In fact, the second generation Buchwald catalyst combined with two equivalents of additional ligands. The inventors proved that using the precursor resulted in the best catalytic system for their reaction (Table 1). Entries 1-6). Of all the catalyst precursors screened, Pd-XPhos -2G alone provides the highest yield and selectivity for the formation of X6a, while the starting material A complete conversion was obtained (entry 2). Similarly, a complete conversion was obtained without ethylene glycol. Since this could not be achieved, the use of ethylene glycol as an additive was also not It has always proven to be beneficial (Entry 1 vs 2). BBA corresponds to boronic acid aesthetic treatment. It can be stabilized in insights through the formation of derivatives, and the rate of borylation can be increased. While doing so, the amounts of boronation reagent and Pd were reduced. Further attempts were made to reduce the amount of catalyst used. Entries 8-10). Surprisingly, by reducing the amount of catalyst used, X6b is still available. While obtaining a nearly complete conversion, a smaller amount of reduction and dimerization products IMP1 and IMP 2 was obtained (entry 8). Furthermore, higher conversions are achieved by increasing the reaction time. This was observed, and therefore suggested that BBA was still present in the reaction mixture (entry 9). These results indicate a degradation pathway in which the formed boronic acid is catalyzed by Pd(II). This may be due to the possibility of receiving a larger supply of Pd in ​​the presence of trace amounts of oxygen. We were able to show that this might facilitate the pathway. Finally, simply changing the reaction temperature by 5 By increasing the temperature to 0°C, complete conversion to the final product is achieved with high selectivity and yield. It was observed (Entry 10).

[0163] [Table 7]

[0164] The inventors also believe that they can further improve the results of the Miyaura boration and that the working contact To see if the amount of the medium can be increased, ethylene glycol is used as an amine salt. Evaluate the reactions that replace the base, DIPEA, and other Buchwald catalyst precursors. We decided to do so (Table 2, entries 1-5). Most catalysts work well under these conditions. It didn't work, but it succeeded by using Pd-cataCXium 3G. It was found that (Entry 5). A slightly larger amount of IMP1 and IMP2 had already been optimized. Formed under conditions compared to those specified, but when used in combination with DIPEA, cata Considering that CXium is superior to XPhos, these results were promising. (5 entries to 1). While considering these results, the inventors further refined them. To see if it can be improved, we will write down some critical response parameters. The process was refined (entries 6-9). Considering the inventors' previous results, the amount of catalyst used was reduced. They first investigated this (Entry 6). Importantly, the inventors found that 0.05 mol% Pd is reactive We found that it was sufficient to proceed to completion of the application, and under these conditions, Pd-cataC This suggests that the catalytic activity of xium-3G was much higher than that of Pd-XPhos-2G. Importantly, reducing the temperature resulted in an incomplete reaction, so up to 50°C. It was found that heating was optimal (Entry 7). Surprisingly, the inventors They discovered that the addition of ethylene glycol was detrimental to the transformation of the reaction, and therefore, cyclic This suggested that diborone species may not be very reactive under these conditions (E (8) Significantly high catalytic activity was observed under these newly optimized conditions, but the side The relative amounts of products IMP1 and IMP2 could not be further reduced, and Pd-Xphos The conditions based on the use of -2G, KOAc, and ethylene glycol remained advantageous.

[0165] [Table 8]

[0166] Suzuki cross-coupling: Boronic acid X by using BBA as the boronation reagent. While considering two sets of optimization conditions for the synthesis of 6a, the inventors considered the synthesis of F7. The ultimate goal is to develop a one-pot process for the subsequent Suzuki coupling The feasibility of the method was investigated. For this purpose, the inventors first used a 60°C motor. Lander previously developed (Gurung, SR, et al., Org. Proc (ess Res.Dev.2017,21,65-74) Under reaction conditions, X6a and F6 We attempted the Suzuki coupling (Table 3, Entry 1). However, contrary to expectations, X6a Furthermore, a non-uniform and incomplete conversion of F6 was observed after heating to 60°C for 17 hours. The inventors found that F6 is EtOH and S N Partially reacts through the Ar pathway, and the corresponding ether They discovered that it forms a rut. At this point, the inventors found that milder organic compounds such as amines could be used. I wondered if using a base could help reduce this side reaction. In fact, Et The use of 3N results in minimal formation of CO coupling products, and X6a and F6 This led to a uniform and nearly perfect conversion (Entry 2). Finally, the inventors demonstrated that MeOH is EtO Superior to H, resulting in complete conversion of X6a and F6 and higher yield coupling generation. I was surprised to learn that they would provide the material (Entry 3). Moreover, F7 is directly from the reaction mixture Precipitation occurred, thus considerably simplifying the final work-up purification. Reduction and dimerization products. The formation of IMP1 and IMP2 demonstrated the presence of trace amounts of oxygen in the reaction solvent, but the inventor They expected that scaling up the process would effectively eliminate this problem. Entries 1-3).

[0167] [Table 9]

[0168] One-pot boration and coupling: Pd-XPhos 2G and Pd-cataC Xium 3G proved to be an excellent catalyst precursor in the Miyaura borylation using BBA. The inventors used their optimization conditions in a one-pot process to achieve these two results. We decided to compare the efficiencies of the two catalysts (Table 4). As shown in Entry 1, Pd-XPhos 2G is superior to Pd-cataCXium 3G in one-pot procedures. It is superior, and starting from X6b, we obtained a purity of 78% and an isolation yield of 79% for F7. This was demonstrated. As expected, the workup and purification of F7 was performed by direct filtration and MeO This could be done by washing the precipitate formed with an H / H2O mixture.

[0169] [Table 10]

[0170] Scale-up: Using the same catalyst precursor under mild conditions in MeOH, both Having developed the step conditions, we can perform a one-pot reaction using Flexy ALR-1 300m We attempted this on a larger scale (2.2g of X6b) using a reactor of size 1 (Table 5).

[0171] X6b (2.20g, 1.0 equivalent), potassium acetate (1.76g, 3.0 equivalents), eth Mix 1.0 ml of lenglycol (3.0 equivalents) and 100 ml of MeOH into 300 ml of liquid. The FlexyALR reactor was filled. The reaction mixture was degassed through a continuous vacuum / N2 cycle. BBA (807mg, 1.5 equivalents), Pd XPhos 2G (12mg, 0.25 A solid mixture of mol%) and XPhos (14 mg, 0.50 mol%) was added under N2 conditions. After the second degassing, the reaction was heated to 50°C and stirred overnight. The mixture containing boronic acid The mixture was then cooled to 20°C, and F6 (1.73g, 0.95 equivalents), Pd XPhos 2g (24mg, 0.5mol%), Et3N (2.5ml), and deaerated water (30ml) The reaction was carried out under N2 conditions. The reaction was degassed for the third time and stirred overnight at 60°C. After that, the reaction was carried out The mixture was cooled to 40°C and concentrated under reduced pressure (approximately 40 ml of MeOH was removed). The mixture was then cooled to 20°C and stirred for 3 hours. The pale brown suspension was filtered and MeOH / Wash with a cold solution of H2O 4 / 1 (40 ml), dry, and obtain F as a brown solid. 7 (1.87g, 56%) was obtained.

[0172] [Table 11]

[0173] The inventors successfully performed the Miyaura boration of X6b, and thankfully obtained excellent yields and selections. In terms of selectivity, we found that we obtained the desired intermediate X6a. Interestingly, Pd-XPh As described by Morander regarding the use of OS 2G, the end of boration is white The reaction was demonstrated through the sudden color change of the mixture from a light orange-yellow to pale orange-yellow. Subsequently, Suzuki Cut Pulling is carried out by adding F6, another dose of catalyst, Et3N, and H2O to the reaction mixture. The final product was filtered and washed, yielding an isolation yield of 56% over both steps, and was processed using F7. The result was an IPC purity of 87%. Importantly, as the inventors predicted, the reactor By performing both steps in this process, all trace amounts of oxygen are removed. This minimized the formation of by-products IMP1 and IMP2.

[0174] Preparation of Example 5-F8: [ka] F7 is suspended in isopropyl acetate at 25°C, concentrated, and then hydrochloric acid (approximately 37% w / w). Add 4.1 equivalents) for over 2 hours to remove the Boc protecting group. As soon as the addition is complete... Next, stir the suspension for approximately 5 hours to ensure a complete conversion to F8. Add the water, Then, add the bis-hydrochloride of F8 at 25°C to dissolve it. The resulting biphasic Stir the mixture at 35°C for about 2 hours to ensure the dissolution of the desired product. Separation at 30°C: Transfer the lower aqueous phase (containing the product) to a tank, and the upper organic phase (F7 Discard the (original impurities) phase. Transfer the aqueous phase to a new reactor through a series filter. The IPC of the aqueous layer is then taken to ensure the absence of F7. F7 is perfectly converted. If not, raise the temperature to 40°C for 1 hour before cooling the solution to RT. The resulting aqueous solution containing the product is then subjected to hydroxyl acid until it reaches a pH value of 5.0 to 5.5. Neutralize with sodium hydroxide (approximately 30% w / w) at 25°C. Add ethanol, then... Add to the resulting suspension and increase the temperature to 60°C. Then add 1M sodium hydroxide Add thorium aqueous solution until the pH reaches 7.5-8.5. The suspension of the product is then prepared. Cool to 25°C for over 2 hours, then stir for approximately 1 hour. Isolate the F8 crystals by filtration. Wash the filtered cake with ethanol. Dry the wet product of F8 under reduced pressure at JT50°C. To dry.

[0175] Example 6: Preparation of F11 Suspend the starting material F8 in ethyl acetate. Add sodium carbonate (1.2 equivalents) to the suspension. Add. Heat the suspension to 50°C. Acrylic anhydride (F9, 1.05) in ethyl acetate. Add an equivalent volume of the solution to the suspension for at least 1 hour. Allow the reaction mixture to rise at 50°C for approximately 30 minutes. Stir intermittently. After adding water, stir the reaction mixture at 65°C for approximately 30 minutes. Separate the phases at 60°C. Then, remove the aqueous phase. Add 0.05 M sulfuric acid to the organic phase and stir at 60°C for approximately 15 minutes. Remove the aqueous phase at 60°C. Then, wash the organic phase with water and remove the aqueous phase at 60°C. The final organic phase is then subjected to low-in-particle filtration at 65°C. The process is carried out by distillation at an internal temperature of 60°C, using approximately 25% solvent. The mixture is removed under reduced pressure, and acetic acid is used to keep the solvent level roughly constant. Add ethyl acetate. This will reduce the water content. In the solution, the crystalline form of ethyl acetate State (anhydrous variety A disclosed in International Publication No. 2020 / 234779) Add the seed suspension. Stir the suspension for at least 15 minutes. Allow the internal temperature to reach 60°C. The second distillation is carried out under reduced pressure to remove approximately 12% of the solvent mixture, and the solvent level Add ethyl acetate at the same time to keep the temperature roughly constant. Leave the suspension at 30°C for 200 minutes. Cool to 30°C. Perform a third distillation under reduced pressure at an internal temperature of 30°C to bring the solvent level to approximately 1. Add ethyl acetate at the same time to maintain the temperature. Cool the suspension to 0°C within 200 minutes. Stir at 0°C for at least 240 minutes. Isolate the product by centrifugation and filter. Wash the peroxide twice with ethyl acetate. Dry the isolated wet product under vacuum at 40°C. The product is dried on a tray in a dryer. F11 is obtained as the product.

[0176] Example 7-5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)aniline (International Publication No. 2015 / 079417 Pan) Genotoxicity of Fret's "INT3" Compound INT3 is described in Example 6 of International Publication No. 2015 / 079417. INT3 is a key intermediate in the synthesis of remibrutinib, as described below. Therefore, in order to determine if there are any genotoxicity-related safety issues, AMES test The samples were subjected to a bacterial reverse mutation test (ST). The test conditions used were those specified, and the mutagenicity was standard. Applying the criteria, INT3 was found to be altered in the test strain TA97a in the presence of metabolic activation. It was found to have the potential to be heterogenic.

[0177] The purpose of the Salmonella / microsome assay is to determine the presence and absence of hepatic metabolic pathways. Therefore, the possibility of the test substance's mutagenicity was investigated by Salmonella typhimurice. It is evaluated by its effect on one or more histidine-requiring strains of imurium. The Ames assay analyzes potential gene activity at the nucleotide level. It is a rapid, reliable, and economical method for screening composites. A database has been accumulated through this assay, with a sensitivity and specificity of approximately 80-90%. This confirms its ability to detect genetically active compounds in most classes of chemicals. It has become such.

[0178] With the exception of strain TA102, these strains require biotin and histidine for growth. In strain TA102, a critical mutation in the histidine gene is located on the multicopy plasmid pAQ1. This strain is particularly sensitive to the activities of oxidative and crosslinking mutagens. Plasmid derivatives (TA98, TA100, TA97a, and TA102) have increased sensitivity to specific mutagens, and the pKM101 plasmid encodes an error-prone DNA repair system (). When exposed to mutagens, some bacteria in the treated population undergo genetic changes through chemical interactions with the compound, thereby reverting to a non-histidine-requiring state and becoming able to grow in the absence of exogenous histidine. Since each is mutated by a specific class of compounds, various test strains are used. A compound that is mutagenic in one strain need not be mutagenic in another strain. 1,3

[0179] (1,3)

[0180] Method Test substance: INT3, also known as 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Vehicle: Dimethyl sulfoxide (DMSO) Purity / content of the drug: 97.95%. Molecular structure:

Chemical formula

[0181] Strains of Salmonella typhimurium used (4 ,5,6) : TA98, TA100, TA1535, TA97a, and TA102. Metabolic activation system (2) ​​​​​​​​​​​​​: Liver S-9 mix derived from male rats, pre-processed with allocrol 1254 Pre-treatment. 0.5 mL of 5% S-9 mix was added per plate. Control R: The control treatment involves adding the same volume (0.1 mL) of the test substance solution to each plate. The positive control included additives. The negative control included treatment with the selected vehicle. The chemicals used for the IV control were procured and used as shown in the table below:

[0182] [Table 12]

[0183] result Concentrations to be tested (for mutagenicity investigation): 50, 158, 501, 1582, and 5000 μg / plate (use all strains + / - S-9). Precipitation and toxicity: Preliminary cytotoxicity and In mutagenicity tests, the test substance performed both in the presence and absence of metabolic activation. No cytotoxicity was observed in any of the strains. Furthermore, the test substance was metabolically activated. It did not precipitate to the highest concentration in both the presence and absence of [the substance]. Mutagenicity: Cont The data from the roll processing accurately confirms that the strain and assay are functioning correctly. It was deemed effective.

[0184] After treatment with INT3 in Experiment 1, recovery was more than twice that of the parallel vehicle control. An increase in the number of cells (2.3 times) was observed in the presence of metabolic activation at 5000 μg / plate. This was observed in TA97a. Further investigation is needed regarding these increases in the number of reverting mutants. To that end, further experiments will be conducted on strain TA97a in the presence and absence of metabolic activation. I left it behind.

[0185] After treatment with INT3 in Experiment 2, the reverting mutant surpassed the parallel vehicle control. Doubling of the number (officially the criterion for a positive response) is 5 in the presence of metabolic activation. It was not observed in strain TA97a at 000 μg / plate. However, the highest level of testing... A 1.8-fold increase was obtained at the test concentration. A 2.3-fold increase was observed in two independent experiments (test substance). An increase of 1.8 times (exceeding the threshold of 2x, which indicates the potential for mutagenicity) and the test substance, IN T3 may exhibit weak mutagenicity in strain TA97a in the presence of metabolic activation. This indicated that it would be considered to be.

[0186] At least twice as high as the parallel vehicle control (1 for strain TA102). No other increase in the number of revertant mutants (5 times) was observed after any other strain treatment. .

[0187] Acceptance Criteria: The assay was considered valid when all of the following criteria were met: 1. Vehicle control counts fell within the normal range; 2. When the positive control chemical was compared to a parallel vehicle control. This induces a 5- to 30-fold increase in the number of revertant mutants for various strains, and the phase between various strains Different and active S-9 preparations were identified.

[0188] Evaluation criteria: For valid data, the parallel vehicle control value must be ≥2 times (TA Co., Ltd.) (In 98, TA100, TA1535 or TA97a) or ≥ 1.5 times (TA Co., Ltd.) If an increase in the concentration correlation in the number of revertant mutants (in 102) is observed, the test substance It was considered mutagenic in this assay. If the above criteria are met, The test substance was considered positive in this assay. The above criteria were met. If the substance was not present, it was considered negative in this assay.

[0189] References (regarding Example 7) 1) Bruce N. Ames, Joyce Mccann and Edith Yamasaki, 1975. Methods for detecting c. arcinogens and mutagens with Salmonella / Mammalian-Microsome mutagenicity test. ut. Res.,31:347-364. 2) Bruce N. Ames, William E. Durston, Ed. ith Yamasaki and Frank D. Lee, 1973, Car cinogens are mutagens: A simple test sys tem combining liver homogenates for acti vation and bacteria for detection. Proc. Nat. Acad. Sci. USA., 70 No. 8: 2281-22 85. 3) Dorothy M. Maron and Bruce N. Ames, 19 83, Revised methods for the Salmonella m utagenicity test. Mut. Res., 113:173-215 . 4) ICH Harmonized Tripartite Guideline G uidance; S2 (R1), “On Genotoxicity Testi ng and Data Interpretation for Pharmaceu ticals Intended for Human Use”; At Step 4 of the Process the final draft is reco mmended for adoption to the regulatory b odies Current Step 4 version, dated 9 No vember 2011. 5) Lutz Mueller et. al., 1999, ICH-Harmo nised guidances on genotoxicity testing of pharmaceuticals: evolution, reasoning and impact. Mut. Res., 436:195-225. 6) OECD Guidelines for the Testing of Ch emicals; No.471; “Bacterial Reverse Muta tion Test”; Adopted 21st July 1997.

Claims

1. A synthesis method comprising converting compound X6b and compound F6 to compound F7: 【Chemistry 1】 X and Y are independently Cl, Br, or I, and P is an amine protecting group. , synthesis method.

2. P is 9-fluorenylmethyl carbamate (Fmoc), t-butyl carbamate ( Carbamic acid protecting groups such as Boc or benzyl carbamate (Cbz) or acetone Acetamide protecting groups such as amides, trifluoroacetamide or benzylamide The method according to claim 1, wherein the protecting group is a sulfonamide protecting group such as p-toluenesulfonamide. Law.

3. A synthesis method comprising the boration of X6b to obtain X6a, wherein: 【Chemistry 2】 X is F, Cl, Br, or I, n is 0 or 1, and R is F, C l, Br or I, OH, OC １ ~C ６ Alkyl, N(C) １ ~C ６ Alkyl) ２ , ant It is a group, or two or three R groups other than F, Cl, Br, I, or OH, together to cyclic boronic acid esters, for example, pinacolboronic acid or N-methyliminodiacetic acid ( A synthesis method that can form MIDA boronate.

4. The method according to claim 3, used in the method according to claim 1 or 2.

5. The boration described above involves one or more catalysts, one or more ligands, or Multiple boronating agents and / or one or more bases and one or more of an optional The method according to claim 3 or 4, wherein an additive is used.

6. The boronating agent is a diboron compound, a boronic acid, and an organic borate. The method according to claim 5, selected from the group consisting of ate).

7. The boronating agents mentioned above are bis(pinacolate)diborone, bis(catecolate)diborane, B ２ (NMe ２ ) ４ , bisboronic acid, C １ ~C ６ boric acid mono, di- or trialkyl, ho mono, di, or trimethyl borate, mono, di, or triethyl borate, mono, di, or tri Tripropyl, mono, di, or tripopenylate acid Selected from the group consisting of ), preferably bis(pinacolate)diborone or bisboronic acid The method according to claim 6, most preferably a bisboronic acid.

8. The metal catalyst contains palladium, nickel, or copper or a combination thereof, preferably The method according to any one of claims 5 to 7, wherein is palladium.

9. The aforementioned metal catalyst is a complex of a catalyst precursor, for example, PdCl ２ (PtBuPh ２ ) ２ or hos Buchwald G1, G2, G3, or G4 catalyst precursors that have formed complexes with fin ligands The method according to claim 8, provided as follows.

10. The aforementioned metal catalyst is a catalyst precursor, for example, Pd(MeCN) ２ Cl ２ , Pd(TFA) ２ , PdBr ２ as, t-BuPPh ２ The ligands provided together with the ligands described in claim 8. method.

11. The ligands mentioned above are organophosphines, N-heterocyclic carbenes, diazabutadienes, dibendienes. Any one of claims 5 to 10, selected from the group consisting of redenacetone and combinations thereof. The method described in item 1.

12. The ligand is an organophosphine ligand, for example, XPhos, APhos, CPhos, RuPhos, SPhos, cataCXium, DavePhos, JohnPhos 、MePhos、XantPhos、Cy ３ P-HBF ４ 、SPhos-SO ３ Na、C y-BIPHEP, t-BuPPh ２ and PPh ３ Select from the group consisting of the combination thereof. Selected organophosphines, preferably XPhos, APhos, CPhos, RuPho s, SPhos, cataCXium, more preferably XPhos, cataCXium and t-BuPPh ２ , most preferably t-BuPPh ２ The method described in claim 11. Law.

13. The ligand:catalyst molar ratio is 1:1 to 3:1, preferably 2:1, claim 11. Or 12 methods.

14. The aforementioned bases are KOH, NaOH, and Ca(OH) ２ Na ２ CO ３ _K ２ CO ３ , Cs ２ CO ３ , inorganic salts such as KOAc or NaOAc, diisopropylethylamine (DI PEA or a tertiary amine such as triethylamine or a combination thereof, preferably Alternatively, the base is KOAc or KOH, as described in any one of claims 5 to 13. method.

15. Claims 5-14, the additive is present and is an alcohol such as ethylene glycol. The method described in any one of the items.

16. The boration step is characterized by at least one of the following, according to claims 5 to 15. The method described in either item: i) The catalyst is preferably present in an amount of 0.05 mol% to 0.5 mol% compared to the number of moles of X6b. This is a pre-catalyst containing 0.25 mol% of Pd-XPhos-2G compared to the number of moles of X6b. It is the main body; ii) The ligand is present in an amount of 0.1 mol% to 1 mol% relative to the number of moles of X6b; preferably This is 0.5 mol% of XPhos compared to the number of moles of X6b; iii) The catalyst is Pd-XPhos-2G, and the ligand is XPhos. The number of moles of XPhos is twice the number of moles of Pd-XPhos-2G; iv) The boronating agent is 1 to 3 molar equivalents compared to X6b, preferably compared to X6b. This is 1.5 molar equivalents of bisboronic acid; v) The base is potassium acetate in an amount of 2 to 5 molar equivalents, preferably 3 molar equivalents, compared to X6b. Yes, that's right; vi) The additive is 2 to 5 molar equivalents compared to X6b, preferably 3 molar equivalents compared to X6b. It is ethylene glycol in an equivalent amount; and vii) The reaction temperature is 30°C to 70°C, preferably 40°C to 50°C, more preferably 5°C. It is 0°C.

17. The reaction is as follows, according to the method of claim 16: 【Transformation 3】

18. The boration step is as follows: i) The catalyst is preferably present in an amount of 0.001 mol% to 0.5 mol% compared to the number of moles of X6b. Compared to the number of moles of X6b, Pd-cataCXium-3G is used in an amount of 0.05 mol%. be; ii) The ligand is present in an amount of 0.02 mol% to 1% compared to the number of moles of X6b, preferably X6 This is 0.1 mol% of cataCXium compared to the number of moles of b; iii) The catalyst is Pd-cataCXium-3G, and the ligand is cata It is CXium, and the number of moles of cataCXium is Pd-cataCXium-3-3 It is twice the number of moles of G; iv) The boronating agent is 1 to 3 molar equivalents compared to X6b, preferably 1 molar equivalent compared to X6b. It is 5 molar equivalents of bisboronic acid; v) The base shall be in an amount of 2 to 5 molar equivalents compared to X6b, preferably an equivalent amount compared to X6b. It is N,N-diisopropylethylamine; vi) The amount of the additive is 2 to 5 molar equivalents compared to X6b; and / or vii) The reaction temperature is 30°C to 70°C, preferably 40°C to 50°C, more preferably 5°C. It is 0°C The method according to any one of claims 5 to 15, characterized by at least one of the above.

19. The reaction is as follows, according to the method of claim 18: 【Chemistry 4】

20. The boration step is as follows: i. The catalyst is present in an amount of 0.1 mol% to 2 mol% compared to the number of moles of X6b. Compared to that, 0.1 mol% to 1.5 mol%, preferably 0.25 mol%, or more preferably More specifically, 0.5 mol% of Pd(MeCN) ２ Cl ２ It is; ii. The ligand is present in an amount of 0.2 mol% to 4% compared to the number of moles of X6b, and the amount of ligand is equal to the number of moles of X6b. In comparison, 0.2 mol% to 3 mol%, preferably 0.5 mol%, or more preferably 1 m 1% of tBuPPh ２ It is; iii. The catalyst is Pd(MeCN) ２ Cl ２ The ligand is tBuPPh ２ And tBuPPh ２ The number of moles is Pd(MeCN) ２ Cl ２ 2 or 3 times the number of moles Preferably Pd(MeCN) ２ Cl ２ It is twice the number of moles; iv. The boronating agent is in an amount of 1 to 2 molar equivalents compared to X6b, preferably about It is 1.05 molar equivalents of bis(pinacolate)diboron; v. The amount of the base is 2 to 5 molar equivalents compared to X6b, preferably 2.5 equivalents compared to X6b. The amount of KOAc; vi. The reaction temperature is 30°C to 120°C, for example 40°C to 50°C, preferably 60°C or It is 70℃ A method according to any one of claims 5 to 14, characterized by at least one of the above. 。

21. The method according to claim 20, wherein the reaction is as follows. 【Transformation 5】

22. X6a and F6 are converted to F7 via the Suzuki coupling, the Suzuki coupling The component consists of one or more catalysts, one or more ligands, and / or one or more The following is carried out using a base and optionally one or more additives, according to claims 3 to 21. The method described in any one of the items.

23. The aforementioned metal catalyst contains palladium, nickel, or copper, or a combination thereof, preferably The method according to claim 22, wherein the material is palladium.

24. The ligands mentioned above are organophosphines, N-heterocyclic carbenes, diazabutadienes, dibendienes. A selection from the group consisting of redenacetone and combinations thereof, according to claim 22 or 23. The method described in either of the above terms.

25. The ligand is an organophosphine ligand, for example, XPhos, APhos, CPhos, RuPhos, SPhos, Sphos-SO3Na, cataCXium, DaveP hos, ohn~hos, ellos, bellos, tomerin ２ ,PP h ３ An organophosphine selected from the group consisting of the and combination thereof, preferably XPho s, APhos, CPhos, RuPhos, SPhos, cataCXium, better Mashikuha XPhos, cataCXium, t-BuPPh ２ , most preferably t-Bu PPh ２ The method according to claim 24.

26. The aforementioned metal catalyst and ligand are complexes of catalyst precursors, such as XPhos, APhos, C Phos, RuPhos, SPhos, cataCXium, or combinations thereof, etc. The sphingine ligand and the Buchwald G1, G2, G3, or G4 catalyst precursor are used together as a complex. The method according to any one of claims 22 to 25, provided to [the present invention].

27. The aforementioned metal catalyst is a catalyst precursor (for example, Pd(MeCN) ２ Ph ２ ) as ligand (for example bat-BuPPh ２ The person described in any one of claims 22 to 25, provided together with ) Law.

28. The coupling is performed using an alcohol solvent, an ether-based solvent (e.g., THF, Me-THF) ), carried out in an aqueous solvent or a mixture thereof, as described in any one of claims 22 to 27. The method.

29. The aforementioned coupling is as follows: i. The amount of the catalyst or catalyst precursor is 0.1 mol compared to the number of moles of F6 or X6a. % ~ 5 mol%, 0.25 mol% ~ 3 mol%, 0.5 mol% ~ 1.5 mol%, 0 It is present in an amount of 5 mol%, or preferably 1 mol%; ii. The number of moles of ligands, if present, is twice the number of moles of catalyst or catalyst precursor. It is three times, preferably two times; iii. The molar ratio of F6:X6a is 2:1 to 1:2, i.e., 1.5:1 to 1:1.

5. 1.2:1 to 1:1.2 or 1:1; iv. The aforementioned additive is optional, and if present, it is 2- The amount is 5 mole equivalents; and / or v. The amount of the base is 2 to 5 molar equivalents compared to the number of moles of F6 or X6a, preferably. The amount is 2 to 3 molar equivalents, most preferably 3 molar equivalents. The method according to any one of claims 22 to 28, characterized by at least one of the above. Law.

30. The aforementioned coupling is as follows: i. The catalyst and ligand are present in a concentration of 0.5 mol% to 2 m³ compared to the number of moles of F6 or X6a. A catalyst precursor-ligand consisting of Pd and X-Phos-2G in an amount of ol%, preferably 1% It is provided as a complex; ii. The base is in an amount of 2 to 5 molar equivalents, preferably 3 molar equivalents, compared to F6 or X6a. The amount of triethylamine; iii. The additive is 2 to 5 molar equivalents, preferably 3 moles, compared to F6 or X6a. It is an equivalent amount of ethylene glycol; iv. The reaction is carried out in an alcohol solvent, preferably methanol; and / or v. The temperature of the above reaction is 30°C to 70°C, preferably 40°C to 50°C, more preferably 5°C. It is 0°C A method according to any one of claims 22 to 29, characterized by one or more of the above. 。

31. The reaction is as follows, according to the method of claim 30: 【Transformation 6】

32. The aforementioned coupling is as follows: i) The catalyst is present in an amount of 0.25 mol% to 2 mol% compared to the number of moles of X6b. Compared to the number, 0.25 mol% to 1.5 mol%, preferably 0.5 mol%, or more preferably Alternatively, 1 mol% of Pd(MeCN) ２ Cl ２ (The conversion of X6b to X6a is (Approximately 98%) ii) The ligand is present in an amount of 0.5 mol% to 4% compared to the number of moles of X6b, preferably X6b Compared to the number of moles, tBuPPh is 1 mol% or 2 mol% in quantity. ２ It is; in particular, the aforementioned contact The medium is Pd(MeCN) ２ Cl ２ The ligand is tBuPPh ２ and tBuPP h ２ The number of moles is Pd(MeCN) ２ Cl ２ It is twice the number of moles; iii) The base is KO in an amount of 2 to 5 molar equivalents, preferably 3 molar equivalents, compared to X6b. It is H; iv) The reaction is carried out in a mixture of MeTHF and water; and vi) The temperature of the reaction is 30°C to 70°C, preferably 60°C. The method according to any one of claims 22 to 29, characterized by at least one of the above. Law.

33. The method according to claim 32, wherein the reaction is as follows: 【Transformation 7】

34. The boration and coupling described above are carried out in a one-pot synthesis, claims 22-3 The method according to any one of claims 3 to 21, combined with the method according to any one of claims 3. Law.

35. The boration and coupling described above are carried out in a one-pot synthesis, as per claim 20 and Method 32.

36. The reaction is as follows, according to the method of claim 35: 【Transformation 8】

37. The above reaction is carried out using a polar organic solvent, such as an ether solvent like methyl THF or propanol. , carried out in an alcohol solvent such as ethanol or methanol, claims 1 to 3 The method described in any one of item 6.

38. Synthetic intermediate X6b: 【Chemistry 9】 A method for producing (where X is F, Cl, Br, or I); compound X6d Reacting with compound N6a: 【Chemistry 10】 A method comprising (where X is Cl, Br, or I, preferably Br).

39. Conversion of compound X6d to compound X6c: 【Chemistry 11】 R １０ This refers to an activated carboxylic acid group, such as an acyl anhydride, an acyl halogenate, or an acyl anhydride. The phosphoric acid and X are Cl, Br or I; and This involves reacting compound X6c with compound N6a to form compound X6b. The method described in item 38.

40. The conversion of X6d to X6c is carried out in an aromatic solvent such as toluene, claim. Method 39.

41. The coupling of X6d and N6a is performed using an activating reagent, such as HBT, HATU, or HBTU. 、TBTU、HOBt、PyAOP、SOCl ２ 、HCTU、PyClocK、TFFH , carbodiimide (e.g., DCC), carbonyldiimidazole (CDI), or phosphodiimide The present invention relates to any one of claims 38 to 40, comprising a um salt (e.g., BOP, PyBOP) method.

42. The coupling of X6d and N6a is carried out by a base, preferably triethylamine or This involves tertiary alkylamine bases such as DIPEA or arylamine bases such as pyridine. The method according to any one of claims 38 to 41, including the method according to any one of claims 38 to 41.

43. The formation of X6b is carried out in a mixture of solvents such as toluene and isopropyl acetate. or the method according to any one of claims 38 to 42.

44. The method according to any one of claims 38 to 43, which includes preparing X6d from X6e. Law. 【Chemistry 12】

45. X6d is prepared by contacting X6e with a base, such as sodium hydroxide. The method according to claim 44.

46. This includes preparing X6e from X6f: 【Chemistry 13】 The method according to claim 44 or 45, wherein X is Cl, Br, or I.

47. X6e under coupling conditions: 【Chemistry 14】 (X is F, Cl, Br or I, m is 2 or 3, and R is F, C l, Br or I, OH, OC １ ~C ６ Alkyl, N(C) １ ~C ６ Alkyl) ２ , ant If it is a single group, or if two or three R groups other than F, Cl, Br, I, or OH are together to cyclic boronic acid esters, for example, pinacolboronic acid or N-methyliminodiacetic acid ( By bringing X6f into contact with X6g using MIDA (which can form boronate), The method according to claim 46, which is prepared as follows.

48. This includes preparing X6f from X6h: 【Chemistry 15】 The method according to claim 46 or 47, wherein X is Cl, Br, or I.

49. X6f is converted by diazoting X6h with nitrite or sodium nitrite under acidic conditions, for example. Next, the cyanification of diazonium compounds using, for example, CuCN and / or NaCN. The method according to claim 48, which is prepared by...

50. The method according to claim 48 or 49, comprising preparing X6h from X6i. 【Chemistry 16】

51. X6h is X6i with a halogenating agent, for example, AlCl ３ or N-chlorosuccinate Chlorinating agents such as mid, N-bromosuccinate, N-bromosuccinimide, DBDMH TBAB, phosphorus tribromide, bromine chloride, aluminum tribromide, Br ２ and FeBr ３ HB r, tribromoisocyanuric acid, ozone and ammonium bromide, N,N,N',N'-teto From labromobenzene-1,3-disulfonamide (TBBDA) and its combinations Contact with a brominating agent selected from the group or an iodinating reagent such as N-iodosuccinimide. The method according to claim 50, which is prepared by causing [the process].

52. This includes preparing N6a from N6b: 【Chemistry 17】 The method according to any one of claims 1 to 51, wherein Y is Cl, Br, or I.

53. N6a is a reducing agent, for example: H ２ and Pt(V) / C; Raney nickel catalyst and H ２ ; Urushihara nickel catalyst and H ２ Adams catalyst (PtO ２ ) and H ２ ;TiCl ３ and H ２ HCl and iron; HCl and SnCl ２ ; Samarium and NH ４ Cl;NH ４ Cl and Iron; FeCl ３ , hydrazine hydrate; sodium hydrosulfite; hydrogen sulfide and Bases; hydroiodic acid; 1,3-dimethyl-2-imidazolidinone and sodium triethyl Lucilanthiolate; and a reducing agent selected from the group consisting of combinations thereof, and N6b The method according to claim 52, which is prepared by contact.

54. The method according to claim 52 or 53, comprising preparing N6b from N6c. 。 [Chemistry 18]

55. N6b is X6h as a halogenating agent, for example, AlCl ３ or N-chlorosuccinate Chlorinating agents such as mid, N-bromosuccinate, 1,3-dibromo-5,5-dimethylhydroxypropyl alcohol Dantoin (DBDMH), N-bromosuccinimide, TBAB, phosphorus tribromide, chloride odor Aluminum tribromide, Br ２ and FeBr ３ HBr, tribromoisocyanuric acid, Selected from the group consisting of ozone, ammonium bromide, TBBDA, and combinations thereof. By contacting it with a brominating agent or an iodinating reagent such as N-iodosuccinimide, The method according to claim 54, which is manufactured.

56. The method according to claim 54 or 55, comprising preparing N6c from N6d. 【Chemistry 19】

57. N6c is a nitrating agent, for example: nitric acid and sulfuric acid; nitric acid and acetic anhydride; tetrachloronitrate. Lomethan, nitric acid and phosphorus pentoxide; isopentyl nitrate, trifluoromethanesulfonic acid and 1-Ethyl-3-methylimidazolium triflate; H-beta zeolite catalyst and N ２ O ５ ;Acetyl nitrate; and a nitrating agent selected from the group consisting of combinations thereof and N The method according to claim 56, which is prepared by bringing 6d into contact.

58. The method according to claim 56 or 57, comprising preparing N6d from N6e. 【Chemistry 20】

59. N6d is a diazotizing agent such as nitrite or sodium nitrite under acidic conditions, followed by HF The method according to claim 58, which is prepared by contacting N6h with a fluorinating agent such as the above. Law.

60. Claims 1 to 1, comprising reacting compound F2 with compound F3 to obtain compound F6. The method described in any one of item 59. 【Chemistry 21】

61. The method described above includes reacting compound F2 with compound F3 to obtain compound F4. The method according to claim 60. 【Chemistry 22】

62. The reactions of F2 and F3 occur under Mitsunobu reaction conditions, for example, PPh ３ Phosphine compounds such as and in the presence of an azodicarbosylate such as DIAD or DEAD, preferably DIAD The method according to claim 61, performed in [location].

63. The method according to claim 62, wherein the reaction is carried out in an aromatic solvent such as toluene.

64. The method described in any one of claims 60 to 62, which includes converting compound F4 to compound F6. Method of loading. 【Chemistry 23】

65. The method according to claim 64, wherein the reaction is carried out using water and ammonia.

66. The reaction is carried out in an alcohol solvent such as iProOH, as in claim 64 or 65. Methods used.

67. The above method involves a one-pot reaction in which compound F2 is converted to compound F4. Claims 60 to 6 include reacting with 3 and converting compound F4 to compound F6. The method described in any one of item 5.

68. The method according to any one of claims 60 to 66, comprising preparing F1 to F2. 【Chemistry 24】

69. F2 is AlCl ３ Prepared from F1 using, and optionally the solvent is xylene. The method according to claim 68.

70. The above method is used in the synthesis of compound F11, any one of claims 1 to 69. Methods used. 【Chemistry 25】

71. The method according to any one of claims 1 to 70, comprising deprotecting F7 in order to obtain F8. 【Chemistry 26】

72. P is a Boc group, and the deprotection is achieved using an acid, such as HCl, claim The method described in item 71.

73. The method according to any one of claim 71 or 72, comprising the conversion of F8 to F11. 【Chemistry 27】

74. F11 is prepared by reacting F8 with acrylic anhydride (F9). The method described in item 73.

75. Synthetic intermediate X6b: 【Chemistry 28】 X is Cl, Br, or I, preferably Br.

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