Improved process for manufacturing osimertinib

Abstract

The present specification relates to an improved process for producing osimertinib. [Formula 1] TIFF2025511404000023.tif36160

Description

[Technical field]

[0001] The present specification relates to an improved process for producing osimertinib. [Background technology]

[0002] Introduction Osimertinib (AZD9291) is a third generation EGFR tyrosine kinase inhibitor (TKI). Osimertinib is disclosed in Patent Document 1, the contents of which are incorporated by reference. Osimertinib has the following chemical structure: [ka]

[0003] Osimertinib mesylate is an approved treatment for non-small cell lung cancer (NSCLC) and is also known as TAGRISSO™.

[0004] Patent Document 1 discloses the following synthesis of osimertinib. [ka]

[0005] The synthesis process comprises the steps of: preparing a compound of formula (I) (wherein R 1 =CH3) (herein referred to as Step A). ​​Patent Document 1 discloses the use of p-toluenesulfonic acid and 2-pentanol at 85°C for 3 hours in this step. Patent Document 2 discloses acetonitrile (MeCN) as an alternative solvent in this step, where the reaction is heated to 85°C for 12 hours. [ka]

[0006] After step A, Patent Document 1 describes a compound represented by formula (I) (wherein R 1=CH3) was isolated and dried under vacuum. Patent Document 1 discloses that the compound of formula (I) is then converted to a compound of formula (IV) (Step B in this specification) by reacting the compound of formula (I) with a compound of formula (V) (N,N',N'-trimethyl-ethane-1,2-diamine) in the presence of N,N-diisopropylethylamine (DIPEA) and 2,2,2-trifluoroethanol at 140°C for 1 hour. [ka]

[0007] Although the synthetic route disclosed in US Pat. No. 6,399,633 is a reliable method for producing osimertinib, it is desirable to improve the economics of the process for large-scale manufacturing, minimize the environmental impact, and reduce the cost of goods.

[0008] To this end, a novel shortened process for combining steps A and B was developed. [ka]

[0009] This novel shortened process avoids the need to isolate the compound of formula (I) and improves the overall economics of manufacturing EGFR TKIs such as osimertinib. However, one drawback of this process was the need for a high relative volume of acetonitrile (MeCN). As noted above, 25 relative volumes of acetonitrile were required for the first reaction to form the compound of formula (I), and an additional 10 relative volumes of acetonitrile were added for the second reaction to form the compound of formula (IV). Upon completion of the second reaction, the reaction mixture was diluted with an additional 15 relative volumes of acetonitrile, purified by hot filtration to remove inorganics, and washed with an additional 2 relative volumes of acetonitrile. Thus, a total of 52 relative volumes of acetonitrile were required. When less acetonitrile was used, it was observed that the compound of formula (IV) crystallized before hot filtration. This unregulated crystallization of the compound of formula (IV) was detrimental to the purity of the isolated material. Furthermore, this disordered crystallization made it more difficult to isolate the compound of formula (IV) by filtration from any inorganic solids present at the end of the reaction.

[0010] Therefore, there is a need for further and improved processes for the synthesis of the compound of formula (IV) as part of the manufacture of EGFR TKIs such as osimertinib. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] International Publication No. 2013 / 014448 Brochure [Patent Document 2] CN109134435 specification Summary of the Invention [Means for solving the problem]

[0012] According to one aspect of the present specification, a compound of formula (I): [ka] or a salt thereof, comprising the steps of: [ka] or a salt thereof, and a compound of formula (III): [ka] or a salt thereof, the reaction being carried out in the presence of an acid and benzonitrile; In the formula, R 1 is C 1~3 is alkyl or cyclopropyl.

[0013] In another aspect of the present specification, a compound of formula (IV) [ka] or a salt thereof, comprising the steps of: (i) producing a compound of formula (I), or a salt thereof, comprising reacting a compound of formula (II), or a salt thereof, with a compound of formula (III), or a salt thereof, in the presence of an acid and benzonitrile; and (ii) a compound of formula (I) or a salt thereof and a compound of formula (V) [ka] or a salt thereof in the presence of benzonitrile, In the formula, R 1 is C 1~3 is alkyl or cyclopropyl.

[0014] Surprisingly, the use of benzonitrile as a solvent to produce the compound of formula (I) provides a crude reaction mixture suitable for producing the compound of formula (IV) without the need to isolate the compound of formula (I). This shortened sequence of steps A and B reduces the environmental impact and improves the overall cost of producing EGFR TKIs such as osimertinib.

[0015] Furthermore, the use of benzonitrile as a solvent allows the sequence to be shortened using a smaller relative volume of solvent compared to acetonitrile, since with benzonitrile the compound of formula (IV) remains in solution at a much higher concentration than is achievable using acetonitrile.

[0016] In an embodiment, the reaction of the compound of formula (I) or its salt with the compound of formula (V) or its salt is carried out in the presence of DBU.This has the further advantage that it avoids the need for hot filtration to remove solid impurities at the end of the reaction to form the compound of formula (IV).Therefore, it avoids the need for special hot filtration equipment, and can reduce production time.

[0017] As used herein, the term "molar equivalent" (or "eq.") refers to the molar equivalent amount with respect to a compound of formula (II), or a salt thereof.

[0018] As used herein, the term "relative volume" (or "rel vol") means the volume of solvent in liters required for a change in kilograms of a compound of formula (II), or a salt thereof.

[0019] As used herein, the term "MsOH" refers to methanesulfonic acid and the term "MeCN" refers to acetonitrile.

[0020] As used herein, "C 1~3The term "alkyl" refers to both straight- and branched-chain saturated hydrocarbon groups having 1, 2 or 3 carbon atoms. 1~3 Examples of alkyl are methyl, ethyl, n-propyl and i-propyl.

[0021] As used herein, the term "truncating" refers to the process of carrying out two reactions in succession without isolating the product of the first reaction. Square brackets are used herein to indicate that material is not isolated before being subjected to the next reaction in the sequence.

[0022] Units, prefixes and symbols are expressed in their International System of Units (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] As mentioned above, the present specification provides a compound of formula (I): [ka] or a salt thereof, comprising the steps of: [ka] or a salt thereof, and a compound of formula (III): [ka] or a salt thereof, the reaction being carried out in the presence of an acid and benzonitrile; In the formula, R 1 is C 1~3 alkyl or cyclopropyl.

[0024] R 1When is methyl, the free base of the compound of formula (I) is known by the chemical name N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)-2-pyrimidinamine. In an embodiment, the compound of formula (I) is N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)-2-pyrimidinamine.

[0025] R 1 When is methyl, the free base of the compound of formula (II) is known by the chemical name 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole (AZD9291 chloropyrimidine). In an embodiment, the compound of formula (II) is 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole. The compound of formula (II) is also known by the name 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole.

[0026] The free base of the compound of formula (III) is known by the chemical name 4-fluoro-2-methoxy-5-nitroaniline (AZD9291 nitroaniline). In an embodiment, the compound of formula (III) is 4-fluoro-2-methoxy-5-nitroaniline.

[0027] Suitable acids are Bronsted acids, such as carboxylic acids, sulfonic acids and mineral acids.

[0028] In embodiments, the acid is selected from sulfonic acids, carboxylic acids, and mineral acids.

[0029] In an embodiment, the acid is a sulfonic acid. In a further embodiment, the sulfonic acid is selected from methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0030] In an embodiment, the acid is methanesulfonic acid.

[0031] In an embodiment, the acid is a carboxylic acid. In a further embodiment, the carboxylic acid is (C 1~7 An example of a (C3 hydrocarbyl)-COOH is n-butanoic acid. An example of a (C6 hydrocarbyl)-COOH is benzoic acid. In a further embodiment, the carboxylic acid is selected from acetic acid and trifluoroacetic acid.

[0032] In an embodiment, the acid is a mineral acid. In a further embodiment, the mineral acid is selected from hydrochloric acid, sulfuric acid, and phosphoric acid.

[0033] In an embodiment, at least 0.02 molar equivalents of acid are used. In a further embodiment, 0.02 to 1 molar equivalents of acid are used. In a further embodiment, 0.02 to 0.30 molar equivalents of acid are used. In a further embodiment, 0.04 to 0.30 molar equivalents of acid are used. In a further embodiment, 0.02 to 0.15 molar equivalents of acid are used. In a further embodiment, 0.04 to 0.15 molar equivalents of acid are used. In a further embodiment, 0.06 to 0.15 molar equivalents of acid are used. In a further embodiment, 0.04 to 0.12 molar equivalents of acid are used. In a further embodiment, 0.06 to 0.12 molar equivalents of acid are used. In a further embodiment, about 0.1 molar equivalents of acid are used. In a further embodiment, 0.1 molar equivalents of acid are used. In a further embodiment, about 0.075 molar equivalents of acid are used. In a further embodiment, 0.075 molar equivalents of acid are used. It is to be understood that the amount of acid (molar equivalent) is relative to the amount of compound of formula (II), or a salt thereof.

[0034] In an embodiment, the reaction of the compound of formula (II), or a salt thereof, with the compound of formula (III), or a salt thereof, is carried out at a temperature of at least 60° C. In a further embodiment, the reaction of the compound of formula (II), or a salt thereof, with the compound of formula (III), or a salt thereof, is carried out at a temperature in the range of 60 to 130° C. In a further embodiment, the reaction is carried out at a temperature in the range of 80 to 130° C. In a further embodiment, the reaction is carried out at a temperature in the range of 60 to 120° C. In a further embodiment, the reaction is carried out at a temperature in the range of 80 to 120° C. In a further embodiment, the reaction is carried out at a temperature in the range of 90 to 110° C. In a further embodiment, the reaction is carried out at a temperature in the range of 100 to 110° C. In a further embodiment, the reaction is carried out at a temperature of about 100° C. In a further embodiment, the reaction is carried out at a temperature of 100° C. In a further embodiment, the reaction is carried out at a temperature of about 105° C. In a further embodiment, the reaction is carried out at a temperature of 105° C.

[0035] In an embodiment, the reaction of a compound of formula (II), or a salt thereof, with a compound of formula (III), or a salt thereof, is carried out at a temperature ranging from 60 to 130° C. for up to 24 hours. In a further embodiment, the reaction is carried out at a temperature ranging from 80 to 120° C. for 3 to 5 hours. In a further embodiment, the reaction is carried out at a temperature ranging from 90 to 110° C. for 3 to 5 hours.

[0036] In an embodiment, the reaction of a compound of formula (II), or a salt thereof, with a compound of formula (III), or a salt thereof, is carried out with at least 4 relative volumes of benzonitrile. In a further embodiment, the reaction is carried out with 4 to 10 relative volumes of benzonitrile. In a further embodiment, the reaction is carried out with 4 to 6 relative volumes of benzonitrile. In a further embodiment, the reaction is carried out with about 5 relative volumes of benzonitrile. In a further embodiment, the reaction is carried out with 5 relative volumes of benzonitrile.

[0037] In an embodiment, the reaction of the compound of formula (II), or a salt thereof, with the compound of formula (III), or a salt thereof, is carried out with at least 1 L of benzonitrile per mole of the compound of formula (II), or a salt thereof. In a further embodiment, the reaction is carried out with 1 to 2.5 L of benzonitrile per mole of the compound of formula (II), or a salt thereof. In a further embodiment, the reaction is carried out with 1 to 1.5 L of benzonitrile per mole of the compound of formula (II), or a salt thereof. In a further embodiment, the reaction is carried out with about 1.2 L of benzonitrile per mole of the compound of formula (II), or a salt thereof. In a further embodiment, the reaction is carried out with 1.2 L of benzonitrile per mole of the compound of formula (II), or a salt thereof.

[0038] In an embodiment, the reaction of a compound of formula (II), or a salt thereof, with a compound of formula (III), or a salt thereof, is carried out with at least 50 mmol of a compound of formula (II), or a salt thereof. In a further embodiment, the reaction is carried out with at least 80 mmol of a compound of formula (II), or a salt thereof.

[0039] In an embodiment, the reaction of the compound of formula (II), or a salt thereof, with the compound of formula (III), or a salt thereof, is carried out using at least 1.0 molar equivalent of the compound of formula (III), or a salt thereof. In a further embodiment, the reaction is carried out using 1.0 to 1.5 molar equivalents of the compound of formula (III), or a salt thereof. In a further embodiment, the reaction is carried out using 1.0 to 1.3 molar equivalents of the compound of formula (III), or a salt thereof. In a further embodiment, the reaction is carried out using 1.0 to 1.2 molar equivalents of the compound of formula (III), or a salt thereof. In a further embodiment, the reaction is carried out using 1.05 to 1.2 molar equivalents of the compound of formula (III), or a salt thereof. In a further embodiment, the reaction is carried out using 1.05 to 1.15 molar equivalents of the compound of formula (III), or a salt thereof. In a further embodiment, the reaction is carried out using about 1.1 molar equivalents of the compound of formula (III), or a salt thereof. In a further embodiment, the reaction is carried out with 1.1 molar equivalents of the compound of formula (III), or a salt thereof, it being understood that the amount (molar equivalent) of the compound of formula (III), or a salt thereof, is relative to the amount of the compound of formula (II), or a salt thereof.

[0040] In an embodiment, there is provided a reaction of a compound of formula (II), or a salt thereof, with a compound of formula (III), or a salt thereof, wherein R 1 C 1~3 Alkyl, for example methyl.

[0041] In another aspect of the present specification, a compound of formula (IV) [ka] or a salt thereof, comprising the steps of: (i) producing a compound of formula (I), or a salt thereof, comprising reacting a compound of formula (II), or a salt thereof, with a compound of formula (III), or a salt thereof, in the presence of an acid and benzonitrile; and (ii) a compound of formula (I) or a salt thereof and a compound of formula (V) [ka] or a salt thereof in the presence of benzonitrile, In the formula, R 1 is C 1~3 is alkyl or cyclopropyl.

[0042] In an embodiment, step (i) is as described in any of the preceding embodiments.

[0043] R 1 When R is methyl, the free base of the compound of formula (IV) is known by the chemical name N-[2-(dimethylamino)ethyl]-5-methoxy-N-methyl-N'-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-2-nitro-1,4-benzenediamine (AZD9291 nitrodiamine). In an embodiment, the compound of formula (IV) is N-[2-(dimethylamino)ethyl]-5-methoxy-N-methyl-N'-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-2-nitro-1,4-benzenediamine. 1 is methyl, the compound of formula (IV) is 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-N 4 It may also be known as -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine.

[0044] The free base of the compound of formula (V) is known by the chemical name N,N,N'-trimethylethylenediamine (TriMEDA). In an embodiment, the compound of formula (V) is N,N,N'-trimethylethylenediamine. The compound of formula (V) is N 1 ,N 1 ,N 2 It may also be known as -trimethylethane-1,2-diamine.

[0045] In an embodiment, the reaction of a compound of formula (I), or a salt thereof, with a compound of formula (V), or a salt thereof, is carried out in the presence of a base. Suitable bases are Bronsted bases, for example organic or inorganic bases.

[0046] In embodiments, the base is an amidine base or a guanidine base.

[0047] In an embodiment, the base is 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 7-methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD) or triazabicyclodecene (TBD). In a further embodiment, the base is DBU.

[0048] In embodiments, the base is selected from potassium carbonate (K2CO3), potassium bicarbonate (KHCO3), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), cesium hydroxide (CsOH), calcium hydroxide (Ca(OH)2), calcium carbonate (CaCO3), barium hydroxide (Ba(OH)2), and cesium carbonate (Cs2CO3).

[0049] In an embodiment, the reaction of the compound of formula (I), or a salt thereof, with the compound of formula (V), or a salt thereof, is carried out with at least 2 molar equivalents of base. In a further embodiment, the reaction is carried out with at least 2.2 molar equivalents of base. In a further embodiment, the reaction is carried out with 2.0 to 2.5 molar equivalents of base. In a further embodiment, the reaction is carried out with 2.0 to 2.4 molar equivalents of base. In a further embodiment, the reaction is carried out with 2.2 to 2.5 molar equivalents of base. In a further embodiment, the reaction is carried out with 2.2 to 2.4 molar equivalents of base. In a further embodiment, the reaction is carried out with about 2.3 molar equivalents of base. In a further embodiment, the reaction is carried out with 2.3 molar equivalents of base. It is to be understood that the amount of base (molar equivalents) is relative to the amount of the compound of formula (II), or a salt thereof.

[0050] In an embodiment, the reaction of the compound of formula (I), or a salt thereof, with the compound of formula (V), or a salt thereof, is carried out in the presence of a fluoride scavenger. In a further embodiment, the fluoride scavenger is a calcium salt. In a further embodiment, the fluoride scavenger is selected from calcium hydroxide (Ca(OH)2), calcium carbonate (CaCO3), calcium propionate (Ca(C2H5COO)2), calcium acetate ((Ca(OAc)2), calcium citrate, calcium gluconate, and calcium chloride (CaCl2).

[0051] In an embodiment, the reaction of a compound of formula (I), or a salt thereof, with a compound of formula (V), or a salt thereof, is carried out using at least 2 molar equivalents of a fluoride scavenger. In a further embodiment, the reaction is carried out using at least 2.2 molar equivalents of a fluoride scavenger. In a further embodiment, the reaction is carried out using 2.0 to 2.5 molar equivalents of a fluoride scavenger. In a further embodiment, the reaction is carried out using 2.0 to 2.4 molar equivalents of a fluoride scavenger. In a further embodiment, the reaction is carried out using 2.2 to 2.5 molar equivalents of a fluoride scavenger. In a further embodiment, the reaction is carried out using 2.2 to 2.4 molar equivalents of a fluoride scavenger. In a further embodiment, the reaction is carried out using about 2.3 molar equivalents of a fluoride scavenger. In a further embodiment, the reaction is carried out using 2.3 molar equivalents of a fluoride scavenger. It is to be understood that the amount (molar equivalent) of fluoride scavenger is relative to the amount of the compound of formula (II), or a salt thereof.

[0052] In an embodiment, the reaction of a compound of formula (I), or a salt thereof, with a compound of formula (V), or a salt thereof, is carried out using at least 1 molar equivalent of a compound of formula (V), or a salt thereof. In an embodiment, the reaction is carried out using at least 1.3 molar equivalents of a compound of formula (V), or a salt thereof. In an embodiment, the reaction is carried out using 1.3 to 3 molar equivalents of a compound of formula (V), or a salt thereof. In an embodiment, the reaction is carried out using 1.5 to 2.5 molar equivalents of a compound of formula (V), or a salt thereof. In an embodiment, the reaction is carried out using 1.5 to 2.2 molar equivalents of a compound of formula (V), or a salt thereof. In an embodiment, the reaction is carried out using 1.8 to 2.5 molar equivalents of a compound of formula (V), or a salt thereof. In an embodiment, the reaction is carried out using 1.8 to 2.2 molar equivalents of a compound of formula (V), or a salt thereof. In an embodiment, the reaction is carried out using about 2 molar equivalents of a compound of formula (V), or a salt thereof. In an embodiment, the reaction is carried out with 2 molar equivalents of the compound of formula (V), or a salt thereof, it being understood that the amount (molar equivalent) of the compound of formula (V), or a salt thereof, is relative to the amount of the compound of formula (II), or a salt thereof.

[0053] In an embodiment, the reaction of the compound of formula (I), or a salt thereof, with the compound of formula (V), or a salt thereof, is carried out at a temperature of at least 40°C, such as at least 60°C. In a further embodiment, the reaction is carried out at a temperature in the range of 40 to 100°C. In a further embodiment, the reaction is carried out at a temperature in the range of 60 to 100°C. In a further embodiment, the reaction is carried out at a temperature in the range of 60 to 90°C. In a further embodiment, the reaction is carried out at a temperature in the range of 70 to 100°C. In a further embodiment, the reaction is carried out at a temperature in the range of 70 to 90°C. In a further embodiment, the reaction is carried out at a temperature in the range of 70 to 85°C. In a further embodiment, the reaction is carried out at a temperature of about 70°C. In a further embodiment, the reaction is carried out at a temperature of about 70°C. In a further embodiment, the reaction is carried out at a temperature of about 80°C. In a further embodiment, the reaction is carried out at a temperature of about 80°C.

[0054] In an embodiment, there is provided a reaction of a compound of formula (I), or a salt thereof, with a compound of formula (V), or a salt thereof, wherein R 1 C 1~3 Alkyl, for example methyl.

[0055] In an embodiment, steps (i) and (ii) are carried out sequentially without isolating the compound of formula (I), or a salt thereof, from the benzonitrile of step (i). In a further embodiment, step (ii) is carried out without adding additional benzonitrile.

[0056] In an embodiment, steps (i) and (ii) are shortened. EXAMPLES

[0057] Example 1: Short synthesis of N-[2-(dimethylamino)ethyl]-5-methoxy-N-methyl-N'-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-2-nitro-1,4-benzenediamine (AZD9291 nitrodiamine) [ka]

[0058] Process A To a stirred mixture of 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole (AZD9291 chloropyrimidine, 25.00 g, 1.00 mol eq.) and 4-fluoro-2-methoxy-5-nitroaniline (AZD9291 nitroaniline, 21.00 g, 1.10 mol eq.) in benzonitrile (125 mL, 5.0 rel vol) at 60° C. was charged methanesulfonic acid (0.99 g, 0.1 mol eq.). The resulting mixture was heated to 100° C. for 3.5-4 h. The reaction mixture was then cooled to 40° C.

[0059] Process B The reaction mixture was then charged with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 37.8 g, 37.1 ml, 2.30 mol eq.) while maintaining the temperature below 45° C. The reaction mixture was then charged with N,N,N′-trimethylethylenediamine (TriMEDA, 21.0 g, 26.3 mL, 2.0 mol eq.) while maintaining the temperature below 45° C. The reaction mixture was then heated to 80° C. for 1 hour, then cooled to 70° C., and AZD9291 nitrodiamine seeds were charged. The mixture was then held at 70° C. for 1 hour, then cooled to 5° C. at a rate of 0.1° C. / min over 11 hours. The solid material was isolated by vacuum filtration and washed twice with isopropanol (125 mL, then 75 mL). The solid material was dried under vacuum at 50° C. to give the title compound (42.1 g, 86.3%); 1 H NMR(500MHz, CDCl3, 27℃):9.55,8.38,8.37,8.26,8.16,8.15,7.52,7.40,7.38,7.32,7.31,7.30,7.30,7 .29,7.27,7.26,7.26,7.18,7.17,6.66,3.97,3.93,3.29,3.28,3.26,2.90,2.58,2.57,2.55,2.26,1.80. 13C NMR(126MHz, CDCl3, 27℃):161.50,158.97,157.61,151.98,142.66,137.79,133.66,132.76,125.48,122.93,12 2.06,121.03,120.41,116.02,113.40,109.85,107.90,101.38,56.78,55.76,53.90,45.61,40.93,33.16.[M+H] + :476.32.

[0060] AZD9291 nitrodiamine crystal seeds can be prepared by recrystallizing AZD9291 nitrodiamine in benzonitrile (available according to WO 2013 / 014448). For example, AZD9291 nitrodiamine may be dissolved in a minimum of benzonitrile at 70° C., then cooled to 5° C. at a rate of 0.1° C. / min over 11 hours.

[0061] The above description of the exemplary embodiments is intended only to familiarize others skilled in the art with the applicant's specification, its principles, and its practical application, so that they may readily adapt and apply the specification in its many forms as may be best suited to the requirements of a particular application. This description and its specific examples, while showing embodiments of the specification, are intended for illustrative purposes only. Thus, the specification is not limited to the exemplary embodiments described herein, but may be varied in various ways. Furthermore, it will be understood that various features of the specification described in the context of separate embodiments for reasons of clarity may be combined to form a single embodiment. Conversely, various features of the specification described in the context of a single embodiment for reasons of brevity may be combined to form subcombinations thereof.

Claims

1. Equation (I): 【Chemistry 1】 A process for producing a compound or salt thereof of formula (II): 【Chemistry 2】 A compound or salt thereof, and formula (III): 【Transformation 3】 The reaction comprises a reaction with a compound or salt thereof, and the reaction is carried out in the presence of an acid and benzonitrile. In the formula, R １ is C １～３ A process involving alkyl or cyclopropyl compounds.

2. The process according to claim 1, wherein the reaction is carried out using 0.02 to 0.3 molar equivalents of the acid, for example, 0.05 to 0.15 molar equivalents of the acid.

3. The process according to claim 1, wherein the acid is a sulfonic acid.

4. The process according to claim 1, wherein the acid is methanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid.

5. The process according to claim 1, wherein the acid is methanesulfonic acid.

6. The process according to claim 1, wherein the reaction is carried out at a temperature in the range of 60 to 130°C, for example, 90 to 110°C.

7. The process according to claim 1, wherein the reaction is carried out using 3 to 10 relative volumes of benzonitrile, for example, 4 to 6 relative volumes of benzonitrile.

8. The process according to claim 1, wherein the reaction is carried out using 1.0 to 1.5 molar equivalents of the compound of formula (III) or a salt thereof.

9. Formula (IV) 【Chemistry 4】 A process for producing a compound or salt thereof, comprising the following steps (i) Formation of the compound of formula (I) described in claim 1, or a salt thereof: and (ii) A compound of formula (I) or a salt thereof, and formula (V) 【Transformation 5】 The reaction of a compound of formula (IV) or a salt thereof with a compound of the same in the presence of benzonitrile includes the formation of a compound of formula (IV) or a salt thereof, In the formula, R １ is C １～３ A process involving alkyl or cyclopropyl compounds.

10. The process according to claim 9, wherein the reaction between the compound of formula (I) or a salt thereof and the compound of formula (V) or a salt thereof is carried out in the presence of a base.

11. The process according to claim 10, wherein the reaction between the compound of formula (I) or a salt thereof and the compound of formula (V) or a salt thereof is carried out using 2.0 to 2.5 molar equivalents of the base.

12. The process according to claim 10, wherein the base is 1,8-diazabicyclo(5.4.0)undeca-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 7-methyl-1,5,7-triazabicyclo(4.4.0)deca-5-ene (MTBD), or triazabicyclodecene (TBD).

13. The process according to claim 10, wherein the base is DBU.

14. The process according to claim 9, wherein the reaction between the compound of formula (I) or a salt thereof and the compound of formula (V) or a salt thereof is carried out in the presence of a fluoride scavenger.

15. The process according to claim 9, wherein the reaction between the compound of formula (I) or a salt thereof and the compound of formula (V) or a salt thereof is carried out using 1.8 to 2.2 molar equivalents of the compound of formula (V) or a salt thereof.

16. The process according to claim 9, wherein the reaction between the compound of formula (I) or a salt thereof and the compound of formula (V) or a salt thereof is carried out at a temperature in the range of 40 to 100°C, for example, 70 to 90°C.

17. The process according to claim 9, wherein steps (i) and (ii) are carried out sequentially without isolating the compound of formula (I) or a salt thereof from the benzonitrile of step (i).

18. R １ The process according to any one of claims 1 to 17, wherein is methyl.

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