Improved process for production of osimertinib

Abstract

The present specification relates to an improved process for the production of osimertinib. # imgabs0 #

Description

[0001] The present invention relates to an improved method for producing osimertinib.

[0002] introduction

[0003] Osimertinib (AZD9291) is a third-generation EGFR tyrosine kinase inhibitor (TKI). Osimertinib is disclosed in WO2013 / 014448, the contents of which are incorporated by reference. Osimertinib has the following chemical structure:

[0004]

[0005] Osimertinib mesylate is approved for the treatment of non-small cell lung cancer (NSCLC) and is also known as TAGRISSO TM .

[0006] WO 2013 / 014448 discloses the synthesis of osimertinib as follows.

[0007]

[0008] The synthesis method comprises preparing a compound having formula (I) (wherein R 1 =CH3) step (step A herein). WO 2013 / 014448 discloses the use of p-toluenesulfonic acid and 2-pentanol at 85°C for 3 hours in this step. CN 109134435 discloses acetonitrile (MeCN) as an alternative solvent in this step, wherein the reaction is heated to 85°C for 12 hours.

[0009]

[0010] After step A, WO 2013 / 014448 discloses that a compound having formula (I) (wherein R 1 =CH3) and dried under vacuum. WO2013 / 014448 discloses that the compound of formula (I) is then converted into the compound of formula (IV) by reaction 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 h (step B herein).

[0011]

[0012] While the synthetic route disclosed in WO 2013 / 014448 provides a reliable method for producing osimertinib, it is desirable to improve the economics of this method for large-scale production in order to minimize environmental impact and reduce the cost of goods.

[0013] To this end, a new telescoped method was developed to combine step A and step B.

[0014]

[0015] This new streamlined method avoids the need to separate compounds with formula (I), improving the overall economics of producing EGFR TKI (such as osimertinib). However, one disadvantage of this method is that a high relative volume of acetonitrile (MeCN) is required. As mentioned above, the first reaction to form a compound with formula (I) requires 25 relative volumes of acetonitrile, while another 10 relative volumes of acetonitrile are added in the second reaction to form a compound with formula (IV). After the second reaction is completed, the reaction mixture is diluted with another 15 relative volumes of acetonitrile and purified by hot filtration to remove inorganic matter, and washed with another 2 relative volumes of acetonitrile. Therefore, a total of 52 relative volumes of acetonitrile are required. If less acetonitrile is used, it is observed that the compound with formula (IV) crystallizes before hot filtration. This uncontrolled crystallization of the compound with formula (IV) is not conducive to the purity of the separated material. In addition, this uncontrolled crystallization makes it more difficult to separate the compound with formula (IV) from any inorganic solid present at the end of the reaction by filtration.

[0016] Therefore, there is a need for a further improved process for the synthesis of compounds of formula (IV) as part of the production of EGFR TKIs such as osimertinib.

[0017] General Description

[0018] According to one aspect of the present specification, a method for producing a compound having formula (I) is provided:

[0019]

[0020] or a salt thereof, the method comprising making a compound having formula (II):

[0021]

[0022] or a salt thereof and a compound having formula (III):

[0023]

[0024] or a salt thereof, wherein the reaction is carried out in the presence of an acid and benzonitrile,

[0025] Where R 1 It is C 1-3 Alkyl or cyclopropyl.

[0026] In another aspect of the present specification, a method for producing a compound having formula (IV) is provided.

[0027]

[0028] or a salt thereof, the method comprising the following steps:

[0029] (i) producing a compound having formula (I) or a salt thereof, comprising reacting a compound having formula (II) or a salt thereof with a compound having formula (III) or a salt thereof in the presence of an acid and benzonitrile; and

[0030] (ii) producing a compound having formula (IV) or a salt thereof, comprising reacting a compound having formula (I) or a salt thereof with a compound having formula (V) in the presence of benzonitrile

[0031]

[0032] or its salt reaction,

[0033] Where R 1 It is C 1-3 Alkyl or cyclopropyl.

[0034] Surprisingly, the use of benzonitrile as a solvent to produce a compound of formula (I) produces a crude reaction mixture suitable for use in the production of a compound of formula (IV) without the need to isolate the compound of formula (I). The streamlined sequence of steps A and B reduces environmental impact and improves the overall cost of goods for the production of EGFR TKIs such as osimertinib.

[0035] Furthermore, by using benzonitrile as solvent, the sequence can be streamlined using a smaller relative volume of solvent than acetonitrile. This is because when benzonitrile is used, the compound of formula (IV) remains in solution at a significantly higher concentration than would be the case if acetonitrile was used.

[0036] In an embodiment, the reaction of a compound of formula (I) or its salt with a compound of formula (V) or its salt is carried out in the presence of DBU. This has the further advantage of avoiding the need for hot filtration to remove solid impurities at the end of the reaction to form a compound of formula (IV). Therefore, the need for special hot filtration equipment can be avoided and production time can be reduced.

[0037] As used herein, the term "molar equivalent" (or "equivalent") refers to the molar equivalent relative to the compound having formula (II) or a salt thereof.

[0038] As used herein, the term "relative volume" or "rel vol" means the volume of solvent (in liters) required relative to the feed of the compound of formula (II) or a salt thereof (in kilograms).

[0039] As used herein, the term "MsOH" is methanesulfonic acid and "MeCN" refers to acetonitrile.

[0040] As used herein, the term “C 1-3 "Alkyl" refers to straight-chain or branched saturated hydrocarbon groups having 1, 2 or 3 carbon atoms. 1-3 Examples of alkyl groups are methyl, ethyl, n-propyl and isopropyl.

[0041] As used herein, the term "streamlined" refers to a process in which two reactions are performed sequentially without isolating the product of the first reaction. Square brackets are used herein to indicate that no material is separated before performing the next reaction in the sequence.

[0042] Units, prefixes and symbols are expressed in their form accepted by the International System of Units (SI). Numerical ranges are inclusive of the numbers defining the range.

[0043] Detailed Description

[0044] As mentioned above, this specification provides a method for producing a compound having formula (I)

[0045]

[0046] or a salt thereof, the method comprising making a compound having formula (II):

[0047]

[0048] or a salt thereof and a compound having formula (III):

[0049]

[0050] or a salt thereof, wherein the reaction is carried out in the presence of an acid and benzonitrile,

[0051] Where R 1 It is C 1-3 Alkyl or cyclopropyl.

[0052] In R 1In the case of 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.

[0053] In R 1 In the case of 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 chloropyrimidinyl). In an embodiment, the compound of formula (II) is 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole. The compound of formula (II) may also be known by the name 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole.

[0054] 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.

[0055] Suitable acids are Bronsted acids, for example carboxylic acids, sulfonic acids and mineral acids.

[0056] In an embodiment, the acid is selected from sulfonic acid, carboxylic acid, and inorganic acid.

[0057] In embodiments, the acid is a sulfonic acid. In further embodiments, the sulfonic acid is selected from methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0058] In embodiments, the acid is methanesulfonic acid.

[0059] In an embodiment, the acid is a carboxylic acid. In another embodiment, the carboxylic acid is selected from (C 1-7 In another embodiment, the carboxylic acid is selected from acetic acid and trifluoroacetic acid.

[0060] In embodiments, the acid is an inorganic acid. In further embodiments, the inorganic acid is selected from hydrochloric acid, sulfuric acid and phosphoric acid.

[0061] In embodiments, at least 0.02 molar equivalents of acid are used. In further embodiments, 0.02-1 molar equivalents of acid are used. In further embodiments, 0.02-0.30 molar equivalents of acid are used. In further embodiments, 0.04 to 0.30 molar equivalents of acid are used. In further embodiments, 0.02 to 0.15 molar equivalents of acid are used. In further embodiments, 0.04 to 0.15 molar equivalents of acid are used. In further embodiments, 0.06 to 0.15 molar equivalents of acid are used. In further embodiments, 0.04 to 0.12 molar equivalents of acid are used. In further embodiments, 0.06 to 0.12 molar equivalents of acid are used. In further embodiments, about 0.1 molar equivalents of acid are used. In further embodiments, 0.1 molar equivalents of acid are used. In further embodiments, about 0.075 molar equivalents of acid are used. In further embodiments, 0.075 molar equivalents of acid are used. It should be understood that the amount of acid (molar equivalent) is relative to the amount of the compound having formula (II) or a salt thereof.

[0062] 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 of at least 60°C. In a further 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 in the range of 60°C to 130°C. In a further embodiment, the reaction is carried out at a temperature in the range of 80°C to 130°C. In a further embodiment, the reaction is carried out at a temperature in the range of 60°C to 120°C. In a further embodiment, the reaction is carried out at a temperature in the range of 80°C to 120°C. In a further embodiment, the reaction is carried out at a temperature in the range of 90°C to 110°C. In a further embodiment, the reaction is carried out at a temperature in the range of 100°C 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.

[0063] 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 in the range of 60° C. to 130° C. for up to 24 hours. In other embodiments, the reaction is carried out at a temperature in the range of 80° C. to 120° C. for 3 to 5 hours. In other embodiments, the reaction is carried out at a temperature in the range of 90° C. to 110° C. for 3 to 5 hours.

[0064] 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 in the presence of at least 4 relative volumes of benzonitrile. In another embodiment, the reaction is carried out in the presence of 4 to 10 relative volumes of benzonitrile. In another embodiment, the reaction is carried out in the presence of 4 to 6 relative volumes of benzonitrile. In another embodiment, the reaction is carried out in the presence of about 5 relative volumes of benzonitrile. In another embodiment, the reaction is carried out in the presence of 5 relative volumes of benzonitrile.

[0065] 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 in the presence of at least 1 L of benzonitrile / mole of the compound of formula (II) or a salt thereof. In another embodiment, the reaction is carried out in the presence of 1 to 2.5 L of benzonitrile / mole of the compound of formula (II) or a salt thereof. In another embodiment, the reaction is carried out in the presence of 1 to 1.5 L of benzonitrile / mole of the compound of formula (II) or a salt thereof. In another embodiment, the reaction is carried out in the presence of about 1.2 L of benzonitrile / mole of the compound of formula (II) or a salt thereof. In another embodiment, the reaction is carried out in the presence of 1.2 L of benzonitrile / mole of the compound of formula (II) or a salt thereof.

[0066] 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 mmoles of the compound of formula (II) or a salt thereof. In another embodiment, the reaction is carried out with at least 80 mmoles of the compound of formula (II) or a salt thereof.

[0067] 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 1.0 molar equivalents of the compound of formula (III) or a salt thereof. In another embodiment, the reaction is carried out with 1.0-1.5 molar equivalents of the compound of formula (III) or a salt thereof. In another embodiment, the reaction is carried out with 1.0-1.3 molar equivalents of the compound of formula (III) or a salt thereof. In another embodiment, the reaction is carried out with 1.0-1.2 molar equivalents of the compound of formula (III) or a salt thereof. In another embodiment, the reaction is carried out with 1.05-1.2 molar equivalents of the compound of formula (III) or a salt thereof. In another embodiment, the reaction is carried out with 1.05-1.15 molar equivalents of the compound of formula (III) or a salt thereof. In another embodiment, the reaction is carried out with about 1.1 molar equivalents of the compound of formula (III) or a salt thereof. In another embodiment, the reaction is carried out with 1.1 molar equivalents of the compound of formula (III) or a salt thereof. It should be understood that the amount (molar equivalent) of the compound having formula (III) or a salt thereof is relative to the amount of the compound having formula (II) or a salt thereof.

[0068] In an embodiment, there is provided a reaction of a compound having formula (II) or a salt thereof with a compound having formula (III) or a salt thereof, wherein R 1 It is C 1-3 Alkyl groups, such as methyl.

[0069] In another aspect of the present specification, a method for producing a compound having formula (IV) is provided.

[0070]

[0071] or a salt thereof, the method comprising the following steps:

[0072] (i) producing a compound having formula (I) or a salt thereof, comprising reacting a compound having formula (II) or a salt thereof with a compound having formula (III) or a salt thereof in the presence of an acid and benzonitrile; and

[0073] (ii) producing a compound having formula (IV) or a salt thereof, comprising reacting a compound having formula (I) or a salt thereof with a compound having formula (V) in the presence of benzonitrile

[0074]

[0075] or its salt reaction,

[0076] Where R 1 It is C 1-3 Alkyl or cyclopropyl.

[0077] In an embodiment, step (i) is as described in any one of the preceding embodiments.

[0078] In R 1 In the case where 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-phenylenediamine (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-phenylenediamine. In R 1 In the case of methyl, the compound of formula (IV) may also be referred to as N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-N 4 -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine is known.

[0079] 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) may also be known by the name N 1 ,N 1 ,N 2 -Trimethylethane-1,2-diamine is known.

[0080] 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 base. A suitable base is a Bronsted base, such as an organic base or an inorganic base.

[0081] In embodiments, the base is an amidine base or a guanidine base.

[0082] In embodiments, 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 further embodiments, the base is DBU.

[0083] In an embodiment, 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).

[0084] 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 at least 2 molar equivalents of a base. In another embodiment, the reaction is carried out in the presence of at least 2.2 molar equivalents of a base. In another embodiment, the reaction is carried out in the presence of 2.0 to 2.5 molar equivalents of a base. In another embodiment, the reaction is carried out in the presence of 2.0 to 2.4 molar equivalents of a base. In another embodiment, the reaction is carried out in the presence of 2.2 to 2.5 molar equivalents of a base. In another embodiment, the reaction is carried out in the presence of 2.2 to 2.4 molar equivalents of a base. In another embodiment, the reaction is carried out in the presence of about 2.3 molar equivalents of a base. In another embodiment, the reaction is carried out in the presence of 2.3 molar equivalents of a base. It should be understood that the amount of base (molar equivalent) is relative to the amount of the compound of formula (II) or a salt thereof.

[0085] 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 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).

[0086] 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 at least 2 molar equivalents of a fluoride scavenger. In another embodiment, the reaction is carried out in the presence of at least 2.2 molar equivalents of a fluoride scavenger. In another embodiment, the reaction is carried out in the presence of 2.0 to 2.5 molar equivalents of a fluoride scavenger. In another embodiment, the reaction is carried out in the presence of 2.0 to 2.4 molar equivalents of a fluoride scavenger. In another embodiment, the reaction is carried out in the presence of 2.2 to 2.5 molar equivalents of a fluoride scavenger. In another embodiment, the reaction is carried out in the presence of 2.2 to 2.4 molar equivalents of a fluoride scavenger. In another embodiment, the reaction is carried out in the presence of about 2.3 molar equivalents of a fluoride scavenger. In another embodiment, the reaction is carried out in the presence of 2.3 molar equivalents of a fluoride scavenger. It should be understood that the amount of fluoride scavenger (molar equivalent) is relative to the amount of the compound having formula (II) or a salt thereof.

[0087] 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 with at least 1 molar equivalent of the compound of formula (V) or a salt thereof. In an embodiment, the reaction is carried out with at least 1.3 molar equivalents of the compound of formula (V) or a salt thereof. In an embodiment, the reaction is carried out with 1.3 to 3 molar equivalents of the compound of formula (V) or a salt thereof. In an embodiment, the reaction is carried out with 1.5 to 2.5 molar equivalents of the compound of formula (V) or a salt thereof. In an embodiment, the reaction is carried out with 1.5 to 2.2 molar equivalents of the compound of formula (V) or a salt thereof. In an embodiment, the reaction is carried out with 1.8 to 2.5 molar equivalents of the compound of formula (V) or a salt thereof. In an embodiment, the reaction is carried out with 1.8 to 2.2 molar equivalents of the compound of formula (V) or a salt thereof. In an embodiment, the reaction is carried out with about 2 molar equivalents of the 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 should be understood that the amount (molar equivalent) of the compound having formula (V) or a salt thereof is relative to the amount of the compound having formula (II) or a salt thereof.

[0088] In embodiments, 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 at a temperature of at least 40°C, such as at least 60°C. In further embodiments, the reaction is carried out at a temperature in the range of 40°C to 100°C. In further embodiments, the reaction is carried out at a temperature in the range of 60°C to 100°C. In further embodiments, the reaction is carried out at a temperature in the range of 60°C to 90°C. In further embodiments, the reaction is carried out at a temperature in the range of 70°C to 100°C. In further embodiments, the reaction is carried out at a temperature in the range of 70°C to 90°C. In further embodiments, the reaction is carried out at a temperature in the range of 70°C to 85°C. In further embodiments, the reaction is carried out at a temperature of about 70°C. In further embodiments, the reaction is carried out at a temperature of about 70°C. In further embodiments, the reaction is carried out at a temperature of about 80°C. In further embodiments, the reaction is carried out at a temperature of about 80°C.

[0089] In an embodiment, there is provided a reaction of a compound having formula (I) or a salt thereof with a compound having formula (V) or a salt thereof, wherein R 1 It is C 1-3 Alkyl groups, such as methyl.

[0090] In an embodiment, step (i) and step (ii) are performed sequentially without isolating the compound having formula (I) or a salt thereof from the benzonitrile of step (i). In another embodiment, step (ii) is performed without adding additional benzonitrile.

[0091] In an embodiment, step (i) and step (ii) are simplified.

[0092] Examples

[0093] Example 1: Simplified Synthesis of N-[2-(dimethylamino)ethyl]-5-methoxy-N-methyl-N'-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-2-nitro-1,4-phenylenediamine (AZD9291 nitrodiamine)

[0094]

[0095] Step A

[0096] To a stirred mixture of 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole (AZD9291 chloropyrimidine, 25.00 g, 1.00 molar equivalent) and 4-fluoro-2-methoxy-5-nitroaniline (AZD9291 nitroaniline, 21.00 g, 1.10 molar equivalent) in benzonitrile (125 mL, 5.0 rel vol) at 60°C was added methanesulfonic acid (0.99 g, 0.1 molar equivalent). The resulting mixture was heated to 100°C for 3.5-4 hours. The reaction mixture was then cooled to 40°C.

[0097] Step B

[0098] Then, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 37.8 g, 37.1 ml, 2.30 molar equivalents) was added to the reaction mixture, keeping the temperature below 45°C. Then, N,N,N'-trimethylethylenediamine (TriMEDA, 21.0 g, 26.3 mL, 2.0 molar equivalents) was added to the reaction mixture, keeping the temperature below 45°C. The reaction mixture was then heated to 80°C for 1 hour, and then cooled to 70°C and AZD9291 nitrodiamine seeds were added. The mixture was then maintained at 70°C for 1 hour and 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. 13 C NMR (126MHz, CDCl3, 27℃): 161.50,158.97,157.61,151.98,142.66,137.79,133.66,132.76,125.48,122.93, 122.06,121.03,120.41,116.02,113.40,109.85,107.90,101.38,56.78,55.76,53.90,45.61,40.93,33.16. [M+H] + :476.32.

[0099] AZD9291 nitrodiamine seeds may be prepared by recrystallising AZD9291 nitrodiamine (available according to WO 2013 / 014448) in benzonitrile.For example, AZD9291 nitrodiamine may be dissolved in a minimum amount of benzonitrile at 70°C and then cooled to 5°C at a rate of 0.1°C / min over 11 hours.

[0100] The above description of the illustrative embodiments is intended only to make other persons skilled in the art aware of the applicant's specification, its principles and its practical application, so that other persons skilled in the art can easily adapt and apply this specification in its many forms, as they may best suit the requirements of a particular purpose. This specification and its specific examples, although indicating embodiments of this specification, are intended only for illustrative purposes. Therefore, this specification is not limited to the illustrative embodiments described in this specification and can be modified differently. In addition, it should be understood that, for the sake of clarity, the different features of this specification described in the context of the separate embodiments can also be combined to form a single embodiment. On the contrary, for the sake of brevity, the different features of this specification described in the context of a single embodiment can also be combined to form their sub-combinations.

Claims

1. A method for producing a compound of formula (I): or a salt thereof, the method comprising making a compound having formula (II): or a salt thereof and a compound having formula (III): or a salt thereof, wherein the reaction is carried out in the presence of an acid and benzonitrile, Where R 1 It is C 1-3 Alkyl or cyclopropyl.

2. The method of claim 1, wherein: The reaction is carried out in the presence of 0.02 to 0.3 molar equivalents of the acid, such as 0.05 to 0.15 molar equivalents of the acid.

3. The method according to claim 1 or claim 2, wherein: The acid is a sulfonic acid.

4. The method according to claim 1 or claim 2, wherein: The acid is methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid.

5. The method of claim 1 or claim 2, wherein: The acid is methanesulfonic acid.

6. The method according to any one of claims 1 to 5, wherein: The reaction is carried out at a temperature in the range of 60°C to 130°C, such as 90°C to 110°C.

7. The method according to any one of claims 1 to 6, wherein: The reaction is carried out in the presence of 3 to 10 relative volumes of benzonitrile, such as 4 to 6 relative volumes of benzonitrile.

8. The method according to any one of claims 1 to 7, wherein: The reaction is carried out with 1.0 to 1.5 molar equivalents of the compound having the formula (III) or a salt thereof.

9. A method for producing a compound having formula (IV) or a salt thereof, the method comprising the following steps: (i) producing a compound of formula (I) or a salt thereof as claimed in any one of claims 1 to 8; as well as (ii) producing a compound having formula (IV) or a salt thereof, comprising reacting a compound having formula (I) or a salt thereof with a compound having formula (V) in the presence of benzonitrile or its salt reaction, Where R 1 It is C 1-3 Alkyl or cyclopropyl.

10. The method of claim 9, wherein: The reaction of the compound having the formula (I) or a salt thereof with the compound having the formula (V) or a salt thereof is carried out in the presence of a base.

11. The method of claim 10, wherein: The reaction of the compound having formula (I) or a salt thereof with the compound having formula (V) or a salt thereof is carried out in the presence of 2.0 to 2.5 molar equivalents of the base.

12. The method of claim 10 or claim 11, wherein: 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).

13. The method of claim 10 or claim 11, wherein: The base is DBU.

14. The method according to any one of claims 9 to 13, wherein: The reaction of the compound having the formula (I) or a salt thereof with the compound having the formula (V) or a salt thereof is carried out in the presence of a fluoride scavenger.

15. The method according to any one of claims 9 to 14, wherein: The reaction of the compound having formula (I) or a salt thereof with the compound having formula (V) or a salt thereof is carried out with 1.8 to 2.2 molar equivalents of the compound having formula (V) or a salt thereof.

16. The method according to any one of claims 9 to 15, wherein: 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 in the range of 40°C to 100°C, such as 70°C to 90°C.

17. The method according to any one of claims 9 to 16, wherein: Step (i) and step (ii) are performed sequentially without isolating the compound having the formula (I) or a salt thereof from the benzonitrile of step (i).

18. The method according to any one of claims 1 to 17, wherein: R 1 It's methyl.

Images