Method for producing 7H-pyrrolo[2,3-d]pyrimidine-4-amine derivative

Abstract

The present invention provides a method for producing a compound represented by formula (I) suitable for mass synthesis as API. Provided according to one aspect of the present invention is a method for producing a compound represented by formula (I) or a salt thereof, the method including deprotecting a protecting group represented by R1 in formula (II) under basic conditions to thereby form a compound represented by formula (I) or a salt thereof.

Description

Method for producing 7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives

[0001] The present invention relates to a method for producing 7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives, and to 7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives that can be mass-produced.

[0002] When active pharmaceutical ingredients (APIs) are industrially produced, the process of producing APIs from raw materials requires a small number of steps and a high yield. Furthermore, since APIs must be mass-produced, procedures that are not suitable for mass production are undesirable. The quality of APIs produced by such processes must meet standards set by the International Council on Harmonization (ICH), including impurities, residual solvents, and residual metals contained in the APIs.

[0003] Patent Document 1 discloses N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (hereinafter also referred to as compound (1)) as a compound having an EGFR inhibitory activity. As an example of a method for producing the compound, a compound represented by formula (XXII) and a compound represented by formula (XXIII) are reacted by Sonogashira coupling to obtain R １ -C≡C- group (R １ is a hydrogen atom or an optionally substituted C1-C3 alkyl) to obtain a compound represented by formula (XXIV), which is then converted to formula (XXV) by deprotection of the amine, and finally subjected to an acylation reaction to synthesize a compound of formula (XXVI).

[0004] International Publication No. WO2020 / 166680 Pamphlet

[0005] However, there is room for further investigation of a synthetic route for the compound that is more suitable for mass production. Under these circumstances, there is a need for a method for producing compound (1) or a compound represented by formula (I) described below that is suitable for mass synthesis as an API. In particular, there is a need for a method for producing compound (1) or a compound represented by formula (I) described below that is excellent in one or more of the properties suitable for mass synthesis as an API, namely, low impurity contamination and high yield.

[0006] As a result of intensive research, the present inventors have completed a method for producing a compound represented by formula (I) which has one or more properties suitable for large-scale synthesis by deprotecting the protecting group of the terminal acetylene under basic conditions.

[0007] That is, the present invention provides, for example, the following [1] to

[14] . [1] A compound represented by the formula (II) under basic conditions. R １ By deprotecting the protecting group represented by formula (I), (In the above formulas (I) and (II), R １ represents a protecting group, R ２ represents an amino (amine) which may have a protecting group, a halogen atom, or a leaving group; R ３ [2] A method for producing a compound represented by formula (I) or a salt thereof, comprising forming a compound represented by formula (I) or a salt thereof, wherein R １ represents a silicon-linked protecting group, R ２ represents amino (amine), and R ３represents pyrazinyl which may have methyl. [3] The production method according to [1] or [2], wherein the compound represented by formula (I) is N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof. [4] (1) Linking a compound represented by formula (III-1) with a compound represented by formula (VIII) to derive a compound represented by formula (III-2), or linking a compound represented by formula (III-1) with a compound represented by formula (IV) to produce a compound represented by formula (V-1), (2) By linking a compound represented by formula (III-2) with a compound represented by formula (IV), or by linking a compound represented by formula (V-1) with a compound represented by formula (VIII), a compound represented by formula (II) is derived; and (3) Under basic conditions, R １ and deprotecting the protecting group represented by: (In the above formulas (I), (II), (III-1), (III-2), (IV), (V-1) and (VIII), R １ represents a protecting group, R ２ represents an amino (amine) which may have a protecting group, a halogen atom, or a leaving group; R ３ represents an optionally substituted 5- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group, ５ and R ５ Each ' independently represents a hydrogen atom or an amino (amine) protecting group, or NR ５ R ５ [5] A method for producing a compound represented by formula (I) or a salt thereof, comprising the steps of: (I), (II), (III-1), (III-2), (IV) and (V-1), wherein R １represents a silicon-linked protecting group; R ２ represents amino (amine), R ３ represents pyrazinyl optionally having methyl; R ５ represents a hydrogen atom or Boc, R ５ [6] The production method according to [4], wherein the compound represented by formula (I) is N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof. [7] The production method according to [4] or [5], wherein the compound represented by formula (VI) and reacting a compound of formula (VII) (wherein L represents a halogen atom or a leaving group) to obtain a compound of formula (IX). (In formula (VI) and formula (IX), R ４ is NR ５ R ５ ', and R ５ and R ５ Each ' independently represents a hydrogen atom or an amino (amine) protecting group, or NR ５ R ５ [8] The method according to [4], further comprising obtaining a compound represented by formula (III-1) from a compound represented by formula (IX) and a compound represented by formula (VI), (VII) and (IX), wherein R ４ is NR ５ R ５ ', and R ５ represents Boc, R ５ [9] The method according to any one of [4] to [8], wherein the compound represented by formula (I) and a salt thereof produced by the method are represented by formula (I-1): (In the formula, R ３

[11] A composition obtained by the method of any one of [1] to

[10] , which contains a compound represented by formula (I) or a salt thereof.

[12] A composition obtained by the method of any one of [1] to

[10] , which contains a compound represented by formula (II): (In the formula, R １ represents a protecting group, R ２ represents an amino (amine) which may have a protecting group, a halogen atom, or a leaving group; R ３

[13] A compound represented by the formula (II) or a salt thereof, wherein R １ represents a silicon-linked protecting group, R ２ represents amino (amine), and R ３

[14] The compound or a salt thereof according to

[12] or

[13] , wherein the compound represented by formula (II) is N-(4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof.

[0008] The production method according to one aspect of the present invention can provide a production method for compound (1) or a compound represented by formula (I), which is excellent in one or more of the properties suitable for large-scale synthesis as an API, namely, low impurity contamination and high yield. The production method according to a preferred aspect of the present invention can provide a production method which further has one or more of the properties of not using a fluorine-containing reagent, not using an explosive reagent, and avoiding purification by column chromatography.

[0009] According to one aspect of the present invention, R of a compound represented by formula (II) is prepared under basic conditions. １By deprotecting the protecting group represented by:

[0023] , a method for producing the compound represented by formula (I) or a salt thereof without purification by column chromatography is provided. On the other hand, the method described in Patent Document 1 may require purification by silica gel column chromatography. (where R １ represents a protecting group, R ２ represents an amino group which may have a protecting group, a halogen atom, or a leaving group; R ３ represents an optionally substituted 5- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group. (where R ２ and R ３ is the same as above.)

[0010] The process for deriving formula (I) from formula (II) is described below.

[0011] In this specification, R １ represents a protecting group, which is a substituent for protecting the hydrogen atom of the terminal acetylene in formula (I). Terminal acetylene refers to an acetylene in which one of the two hydrogen atoms is substituted, and refers to -C≡CH (also called ethynyl) in formula (I). In one embodiment of the present invention, R １ Any protecting group can be used for R as long as it can be deprotected under basic conditions. １Examples of the protecting group in the formula (I) include a protecting group that substitutes a hydrogen atom of the terminal acetylene with a carbon atom (carbon-linked protecting group), a protecting group that substitutes with a silicon atom (silicon-linked protecting group), and a protecting group that substitutes with a phosphorus atom (phosphorus-linked protecting group). As used herein, examples of the carbon-linked protecting group include tert-butyl, cyclopropyl, 2-hydroxypropan-2-yl, and dimethylaminomethyl, with 2-hydroxypropan-2-yl being preferred. As used herein, examples of the silicon-linked protecting group include TMS (trimethylsilyl), TES (triethylsilyl), TBS (tert-butyldimethylsilyl), TIPS (triisopropylsilyl), and TBDPS (tert-butyldiphenylsilyl). Preferred is TES or TIPS, and more preferred is TES. As used herein, examples of the phosphorus-linked protecting group include -PPh ２ (diphenylphosphine) and -P(O)Ph ２ and the like, and preferably -P(O)Ph ２ (Ph represents phenyl).

[0012] R in one embodiment of the present invention １ is a protecting group that can be deprotected under basic conditions, and therefore, at the same time as the deprotection, analogs of the compound represented by formula (I-1) that may be generated as by-products during the reaction process can be converted into the target compound. This conversion can reduce the inclusion of impurities, and, due to the high yield, can achieve high purity as a pharmaceutical raw material. (where R ３ is the same as above.)

[0013] In one embodiment of the present invention, R １ is preferably a protecting group selected from the group consisting of carbon-linked protecting groups, silicon-linked protecting groups, and phosphorus-linked protecting groups, more preferably a silicon-linked protecting group, more preferably TMS (trimethylsilyl), TES (triethylsilyl), TBS (tert-butyldimethylsilyl), TIPS (triisopropylsilyl), and TBDPS (tert-butyldiphenylsilyl), and especially preferably TES (triethylsilyl).

[0014] R of the compound used in the production method according to one embodiment of the present invention ２ represents an amino group which may have a protecting group, a halogen atom, or a leaving group.

[0015] R ２ The protecting group of the "amino which may have a protecting group" in the formula (I) is not particularly limited, and examples thereof include carbamate protecting groups such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz or Z), 9-fluorenylmethyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), and 2,2,2-triethoxycarbonyl (Troc); sulfonamide protecting groups such as o-nitrobenzenesulfonyl (o-Ns, Ns, nosyl, or o-nosyl), p-nitrobenzenesulfonyl (p-Ns or p-nosyl), 2,4-dinitrobenzenesulfonyl (DNs), and SES (2-trimethylsilylethanesulfonyl); ２ is phthaloyl (Phth), preferably amino, amino having a carbamate protecting group, and phthalimide, more preferably amino and amino having one or two protecting groups selected from the group consisting of Boc, Cbz, Fmoc, Alloc, and Troc, more preferably amino and amino having one or two protecting groups selected from the group consisting of Boc, Cbz, and Fmoc, and particularly preferably amino. ２ Examples of the halogen atom in R include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a chlorine atom is preferred. ２ The leaving group in ２ C ｎ F ｎ＋２ (n represents an integer of 1 to 4), -SO ２ C ｎ F ｎ＋２ , mesylate (-OMs; Ms represents mesyl), mesyl, tosylate (-OTs; Ts represents p-tosyl), p-tosyl, nosylate (-ONs or -Op-Ns), p-nosyl, -OSO ２ Ph (Ph represents phenyl), -SO ２Examples of the leaving group include -Ph, phenoxy (-OPh), and the like, and preferably mesyl. Alternatively, the leaving group is -OSO ２ C ｎ F ２ｎ＋１ (n represents an integer of 1 to 4), -SO ２ C ｎ F ２ｎ＋１ , mesylate (-OMs; Ms represents mesyl), mesyl, tosylate (-OTs; Ts represents p-tosyl), p-tosyl, nosylate (-ONs or -Op-Ns), p-nosyl, -OSO ２ Ph (Ph represents phenyl), -SO ２ It may be phenoxy (-Ph), phenoxy (-OPh), etc.

[0016] R of the compound used in the production method according to one embodiment of the present invention ２ is an amino group which may have a protecting group, a halogen atom, or a leaving group, or R ２ is phthalimide. Preferred are amino, amino having one or two protecting groups selected from the group consisting of Boc, Cbz, Fmoc, Alloc, Troc, and Ns, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, -OSO ２ C ｎ F ｎ＋２ (n represents an integer of 1 to 4), -SO ２ C ｎ F ｎ＋２ , mesylate, mesyl, tosylate, p-tosyl, nosylate, p-nosyl, -OSO ２ Ph, -SO ２ Ph, and phenoxy, or R ２ is phthalimido, more preferably amino, Boc, Cbz, Fmoc, a chlorine atom, and mesyl, more preferably amino, a chlorine atom, and mesyl, and particularly preferably amino. ２ represents an amino group having one or two protecting groups selected from the group consisting of amino, Boc, Cbz, Fmoc, Alloc, Troc, and Ns, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or —OSO ２ C ｎ F ２ｎ＋１ (n represents an integer of 1 to 4), -SO２ C ｎ F ２ｎ＋１ , mesylate, mesyl, tosylate, p-tosyl, nosylate, p-nosyl, -OSO ２ Ph, -SO ２ Ph, and phenoxy, or R ２ may be phthalimide.

[0017] In one embodiment of the present invention, R of the compound of formula (I) or formula (II) ３ is an optionally substituted 5- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group. The "optionally substituted 5- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group" is preferably a 5- to 10-membered monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, more preferably pyridazinyl, pyrimidinyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridinyl, imidazolyl, furanyl, isoxazolyl, triazolopyridinyl, triazolyl, triazinyl, thiazolyl, thiadiazolyl, imidazopyrazinyl, or pyrazolyl, even more preferably isoxazolyl, pyrazolyl, oxazolyl, oxadiazolyl, pyrazinyl, or pyridazinyl, even more preferably pyrazolyl, oxazolyl, oxadiazolyl, pyrazinyl, or pyridazinyl, and particularly preferably pyrazinyl.

[0018] In one embodiment of the present invention, R ３Examples of the "substituent" in the "optionally substituted 5- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group" represented by the formula (I) include a halogen atom, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 mono- or dialkylamino, C1-C6 alkylsulfonyl, C3-C7 cycloalkyl, or a C6-C10 aromatic hydrocarbon. Preferred are a fluorine atom, chlorine atom, cyano, oxo, C1-C6 alkyl, monofluoromethyl, methoxyethyl, methoxy, monofluoromethoxy, dimethylamino, methylsulfonyl, cyclopropyl, or phenyl, more preferably C1-C6 alkyl, and even more preferably methyl. In this specification, the number of substituents may be one or more.

[0019] In one embodiment of the present invention, R ３ is an optionally substituted 5- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group, preferably an optionally substituted 5- to 10-membered monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group having 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, more preferably pyridazinyl, pyrimidinyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridinyl, imidazolyl, furanyl, isoxazolyl, triazolopyridinyl, triazolyl, triazinyl, thiazolyl, thiadiazolyl, imidazopyrazinyl or pyrazolyl, each of which may have a substituent, more preferably pyrazinyl which may have a substituent, more preferably pyrazinyl which may have a C1-C6 alkyl, more preferably pyrazinyl which has a methyl group, and more preferably 5-methylpyrazin-2-yl.

[0020] In a preferred embodiment of the present invention, the compound represented by formula (I) is N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide. As shown in Patent Document 1, this compound is preferred because it has excellent inhibitory activity.

[0021] In one embodiment of the present invention, the by-product generated when the compound represented by formula (II) is derived to the compound represented by formula (I) is not particularly limited as long as it is a compound other than the compound represented by formula (I), but is preferably a by-product that is converted to the compound represented by formula (I) under basic conditions, and more preferably a compound represented by formula (I-1). (In the formula, R ３ The definitions and embodiments of are the same as above. For example, R ３ is 5-methylpyrazin-2-yl, the compound represented by formula (I-1) is N-(4-(6-ethynyl-4-(5-methylpyrazine-2-carboxamide)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (hereinafter referred to as compound (2)), and has the following structure:

[0022] In the present invention, "under basic conditions" refers to a state in which the reaction system is adjusted to basicity by a base. The base is not particularly limited as long as the reaction proceeds, and examples thereof include inorganic bases such as metal hydroxides (sodium hydroxide, calcium hydroxide, etc.), metal hydrides (lithium hydride, sodium hydride, etc.), and metal carbonates (sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, magnesium carbonate, and sodium bicarbonate), and organic bases such as metal alkoxides (sodium methoxide, potassium tert-butoxide, etc.), metal amides (sodium amide, lithium diisopropylamide, etc.), alkyl metal compounds (n-butyllithium, trimethylaluminum, etc.), alkylamines (triethylamine, tetramethylethylenediamine, piperidine, 1,4-diazabicyclo[2.2.2]octane, etc.), heterocyclic amines (diazabicycloundecene, pyridine, imidazole, etc.), and quaternary ammonium fluorides (tetra-n-butylammonium fluoride). Preferably, the base does not contain fluoride ions, more preferably, a metal carbonate or a salt containing potassium does not contain fluoride ions, and even more preferably, potassium carbonate. These can be used alone or in combination in the production method of the present invention. The amount of the reagent used is not particularly limited as long as the reaction proceeds, but for example, 0.1 to 50 moles can be used per mole of the compound represented by formula (II). The amount is preferably 0.1 to 10 moles, and more preferably 0.1 to 2 moles.

[0023] The solvent used in the deprotection step is not particularly limited as long as it can adjust the reaction system to a basic state with the aid of a base and can dissolve the compounds used in the reaction. Examples of the solvent include C5 to C10 hydrocarbons, C6 to C14 aromatic hydrocarbons, C1 to C6 alcohols, C3 to C10 aliphatic carboxylic acid esters, C3 to C10 ketones, C4 to C10 ethers, aprotic polar organic solvents, and mixed solvents thereof. In this specification, the term "C" refers to the number of carbon atoms, and refers to the total number of carbon atoms contained in the compound.

[0024] C5 to C10 hydrocarbons are hydrocarbons having 5 to 10 carbon atoms, and examples thereof include pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and cyclodecane.

[0025] The C6 to C14 aromatic hydrocarbons are aromatic hydrocarbons having 6 to 14 carbon atoms, and examples thereof include benzene, naphthalene, anthracene, toluene, xylene, cumene, styrene, and phenanthrene.

[0026] The C1 to C6 alcohol is an alcohol having 1 to 6 carbon atoms, and examples thereof include methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, n-pentanol, and n-hexanol.

[0027] The C3 to C10 aliphatic carboxylic acid ester is an aliphatic carboxylic acid ester having 3 to 10 carbon atoms, and examples thereof include propyl formate, methyl acetate, ethyl acetate, propyl acetate, methyl propionate, ethyl propionate, propyl propionate, methyl butanoate, and ethyl butanoate.

[0028] The C3 to C10 ketones are ketones having 3 to 10 carbon atoms, and examples thereof include acetone, ethyl methyl ketone, diethyl ketone, isopropyl methyl ketone, and cyclohexanone.

[0029] The C4 to C10 ether is an ether having 4 to 10 carbon atoms, and examples thereof include diethyl ether, tert-butyl methyl ether, tetrahydrofuran, and 1,4-dioxane.

[0030] The aprotic polar organic solvent is a solvent that does not contain ionizable protons, and examples thereof include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, chloroform, and dichloromethane.

[0031] Among the above solvents, dichloromethane, methanol, ethanol, and N-methylpyrrolidone are preferred, and dichloromethane and methanol are more preferred. The amount of solvent is not particularly limited as long as the reaction proceeds, but is preferably 10 to 100 L, more preferably 15 to 50 L, and even more preferably 20 to 30 L per kg of the compound of formula (II).

[0032] The reaction time for the deprotection step is not particularly limited as long as it is a time that allows deprotection to be achieved, and can be set appropriately, for example, for 1 to 120 hours, preferably 6 to 48 hours, and more preferably 12 to 24 hours.

[0033] The reaction temperature for the deprotection step is not particularly limited as long as it is a temperature at which deprotection can be achieved, and can be set appropriately. For example, it is 0 to 60°C, preferably 10 to 50°C, and more preferably 20 to 40°C. (In the present invention, room temperature refers to 18 to 25°C.)

[0034] According to another aspect of the present invention, there is provided a compound represented by formula (II). The compound represented by formula (II) is a useful intermediate for producing the compound represented by formula (I). In one embodiment of the present invention, R １ , R ２ and R ３ Any of the above options can be combined as appropriate.

[0035] <Reaction Pathway> A production method according to one embodiment of the present invention includes the steps of: (1) reacting a compound represented by formula (III) with a compound represented by formula (IV) to produce a compound represented by formula (V); (In the above formulas (III) to (V), R １ represents a protecting group, R ２ represents an amino group which may have a protecting group, a halogen atom, or a leaving group; R ３ represents an optionally substituted 5- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group, ４ is NR ５ R ５ ', or NHCOR３ represents R ５ and R ５ Each ' independently represents a hydrogen atom or an amino protecting group, or NR ５ R ５ (2) R of formula (V) is reacted under basic conditions with １ and (3) optionally, removing the protecting group represented by R of the compound represented by formula (III) before the above (1). ４ NHCOR ３ or after the above (1) and before the above (2), R of the compound represented by formula (V) ４ NHCOR ３ The reaction (1) above includes a coupling reaction, and the reaction (3) above includes a condensation reaction. According to a preferred embodiment of the present invention, after the reaction (1) above and before the reaction (2) above, R of the compound represented by formula (V) is ４ NHCOR ３ To do so.

[0036] In one embodiment of the present invention, R of the compound represented by formula (III) ４ and / or R of the compound represented by formula (V) ４ NR ５ R ５ ' and R ５ and R ５ and wherein at least one of (1) and (2) is an amino-protecting group, and the method further comprises deprotecting the amino-protecting group. In a preferred embodiment of the present invention, the amino-protecting group is deprotected before (1) above, or after (1) above and before (2) above, and preferably after (1) above and before (2) above.

[0037] Next, the condensation reaction and Sonogashira coupling performed before deprotection in one embodiment of the present invention will be described. Here, "before deprotection in one embodiment of the present invention" can refer to either immediately before or before the above-mentioned "deprotection of the terminal acetylene protecting group." The order of the "condensation reaction" and "Sonogashira coupling" described here does not matter, and another reaction step may be performed between the "condensation reaction" and "Sonogashira coupling."

[0038] (R ４ NHCOR ３ In the compound of formula (III), R ４ NHCOR ３ In this case, the compound represented by formula (III-2) below is used as a starting material, and steps (1) and (2) are carried out to obtain a compound represented by formula (I). In this case, the compound represented by formula (I) can be obtained without carrying out step (3). In the following reaction scheme, "Deprotection" means "deprotection."

[0039] (R ４ NR ５ R ５ In one embodiment of the present invention, R ４ NR ５ R ５ ', the compound represented by formula (III-1) below is used as a starting material, and R ４ NHCOR ３ or after the above (1) and before the above (2), R of the compound represented by formula (V) ４ NHCOR ３ By finally carrying out deprotection under basic conditions, the compound of formula (I) can be produced.

[0040] The procedure for producing such a compound of formula (I) (Synthesis Route 1) is shown below: In Synthesis Route 1, "Condense" means "condensation reaction" and "Deprotection" means "deprotection".

[0041] In one embodiment of the present invention, R ５ and R ５ Each of the symbols ' independently represents a hydrogen atom or an amino-protecting group, or NR ５ R ５ ' represents phthalimido or nitro. ５ and / or R ５ ' is an amino protecting group, or NR ５ R ５ When R ′ is phthalimide, in the synthesis route 1, the compound represented by formula (III-1) is converted into the compound represented by formula (III-2), and the compound represented by formula (V-1) is converted into the compound represented by formula (II), ５ and / or R ５ The process includes a step of deprotecting R ５ and R ５ The "protecting group" in ' is R ２ The protecting groups are preferably the same as those listed in the above, and more preferably a carbamate protecting group, and more preferably Boc. ５ and R ５ Each ' independently represents a hydrogen atom or a protecting group, or NR ５ R ５ ' represents phthalimido or nitro, but preferably R ５ and R ５ Each of R ′ independently represents a hydrogen atom or a protecting group, and more preferably, R ５ and R ５ At least one of R ′ represents a protecting group, and more preferably R ５ and R ５ At least one of R ′ represents Boc, and particularly preferably R ５ is a hydrogen atom or Boc, and R ５ ' is a hydrogen atom. NR ５ R ５When " is nitro," in Synthetic Route 1, the derivation of a compound represented by Formula (III-1) into a compound represented by Formula (III-2), and the derivation of a compound represented by Formula (V-1) into a compound represented by Formula (II) include a step of reducing nitro to amino. Such reduction can be achieved by a commonly known method, specifically the method described in the "Condensation Reaction" section below. This synthetic route avoids the use of the Ohira-Bestmann method, and therefore the Sonogashira coupling, condensation reaction, and derivation of Formula (II) into Formula (I) can be performed in any order. However, it is preferable to produce the compound represented by Formula (I) in the following order (A) to (C) because it avoids the use of column chromatography, provides a high yield, and reduces the impurity content compared to the production method described in Patent Document 1. (A) Derivation of a compound represented by formula (III-2) by linking a compound represented by formula (III-1) with a compound represented by formula (VIII), or derivation of a compound represented by formula (V-1) by linking a compound represented by formula (III-1) with a compound represented by formula (IV). (B) Derivation of a compound represented by formula (II) by linking a compound represented by formula (III-2) with a compound represented by formula (IV), or linking a compound represented by formula (V-1) with a compound represented by formula (VIII). (C) Derivation of a compound represented by formula (II) from a compound represented by formula (I) under basic conditions.

[0042] For example, X is a bromine atom, R １ TES, R ２ Amino, R ３ is 5-methylpyrazin-2-yl, NR ５ R ５ ' is a Boc-protected amino (e.g., NHBoc, i.e., R ５ and R ５In the case where one of the groups 1 and 2′ is a hydrogen atom and the other is an amino-protecting group), compound (1) can be produced from tert-butyl (4-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2,2,1]heptan-1-yl)carbamate by Sonogashira coupling, deprotection of Boc (de Boc), and condensation reaction (Condense) in any order, followed by deprotection of TES (de TES).

[0043] Such a synthesis procedure (Synthetic Route 2) is shown below.

[0044] This synthetic route avoids the use of the Ohira-Bestmann method, and therefore Sonogashira coupling, deprotection of Boc (de Boc), condensation reaction (Condense), and deprotection of TES (de TES) can be carried out in any order. However, it is preferable to produce compound (1) in the following order (A) to (D) because it avoids the use of column chromatography, provides a high yield, and reduces the content of impurities compared to the production method described in Patent Document 1. (A) Coupling of tert-butyl (4-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2,2,1]heptan-1-yl)carbamate with triethylsilylacetylene (B) Deprotection of Boc of the compound obtained in (A) (C) Condensation of the compound obtained in (B) with 5-methylpyrazine-2-carboxylic acid (D) Deprotection of TES of the compound obtained in (C) under basic conditions It is more preferable to produce compound (1) in the following order of (A) to (D). (A) Palladium-catalyzed and copper-catalyzed coupling of tert-butyl (4-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2,2,1]heptan-1-yl)carbamate with triethylsilylacetylene; (B) Deprotection of Boc of the compound obtained in (A); (C) Condensation of the compound obtained in (B) with 5-methylpyrazine-2-carboxylic acid using a combination of EDC and HOBt; (D) Deprotection of TES of the compound obtained in (C) under basic conditions adjusted with a fluoride ion-free reagent.

[0045] When the compound of formula (I) or a salt thereof is obtained in this manner, the content of the impurity represented by formula (I-1) is low. The content of the impurity can be determined by the percentage (%) of the peak area obtained at a specific wavelength in measurement by HPLC (high performance liquid chromatography) or UPLC (ultra performance high resolution liquid chromatography). The wavelength can be appropriately set depending on the properties of the compound. This is important for maintaining the quality of pharmaceuticals, and in consideration of the standards set by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), the content of the impurity represented by formula (I-1) is, for example, 0.2% or less. Preferably, it is 0.15% or less, more preferably 0.1% or less, and even more preferably 0.05% or less.

[0046] In the compound represented by formula (I) and a salt thereof produced by the production method according to one embodiment of the present invention, (In the formula, R ３ represents a 5- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group which may have a substituent) is 0.2% or less, preferably 0.15% or less, more preferably 0.1% or less, and even more preferably 0.05% or less. The compound represented by formula (I-1) does not have to be produced by the production method in one embodiment of the present invention, that is, the above ratio may be below the detection limit.

[0047] According to one aspect of the present invention, there is provided a composition obtained by the above method, which comprises a compound represented by formula (I) or a salt thereof. In one embodiment of the present invention, the composition comprises a compound represented by formula (I) or a salt thereof and a compound represented by formula (I-1). In a preferred embodiment, the proportion of the compound represented by formula (I-1) in the composition is 0.2% or less, preferably 0.15% or less, more preferably 0.1% or less, and even more preferably 0.05% or less.

[0048] Impurities generated in the production method can be detected by known methods using known devices, for example, by HPLC. A commercially available HPLC can be used.

[0049] In the present invention, the compound represented by formula (I-1) or a salt thereof can be used as a standard for quality control by confirming the stability of formulations or APIs containing compound (1) or a salt thereof, and the presence or absence of related substances in the production process thereof, by measuring infrared absorption (IR) spectrum, nuclear magnetic resonance (NMR) spectrum, and chromatography such as HPLC and thin layer chromatography (TLC). A preferred compound represented by formula (I-1) is N-(4-(6-ethynyl-4-(5-methylpyrazine-2-carboxamide)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide.

[0050] (Condensation Reaction) The condensation reaction carried out in the present invention is a step for condensing an amine of a compound represented by the following formula (III-1) or formula (V-1) with a carboxylic acid represented by the following formula (VIII) to derive an amide-containing compound represented by formula (III-2) or a compound represented by formula (II). That is, the condensation reaction is carried out by condensing an amine of a compound represented by formula (III-2) or a compound represented by formula (II) with an amide-containing compound represented by formula (III-2) or a compound represented by formula (II). ３ The purpose is to construct an amide bond represented by the formula:

[0051] (X represents a halogen atom or a leaving group, R ２ , R ５ and R ５ The definition and embodiments of "" are the same as above.)

[0052] (In each of the above formulas, X represents a halogen atom or a leaving group, and R １ , R ２ , R ３ , R ５ and R ５ The definition and embodiments of "" are the same as above.)

[0053] In the specification, X in the compound represented by formula (III-1) or formula (III-2) is a halogen atom or a leaving group. Examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and are preferably a chlorine atom, a bromine atom, and an iodine atom, more preferably a bromine atom and an iodine atom, and particularly preferably a bromine atom. Examples of the "leaving group" include the above-mentioned leaving groups, and are preferably -OSO ２ C ｎ F ｎ＋２ (n is an integer of 1 to 4), mesylate, tosylate, nosylate, and —OSO ２ Alternatively, the leaving group is preferably —OSO ２ C ｎ F ２ｎ＋１ (n is an integer of 1 to 4), mesylate, tosylate, nosylate, and —OSO ２ In the compound represented by formula (III-1) or formula (V-1) used in this condensation reaction, R ５ and R ５ When R is a hydrogen atom, an amide can be constructed by condensation with formula (VIII) by the method shown below. In this condensation reaction, the amount of the compound represented by formula (VIII) is, for example, 0.5 to 5.0 moles, preferably 0.7 to 2.5 moles, more preferably 0.8 to 1.5 moles, even more preferably 0.9 to 1.3 moles, and particularly preferably 0.9 to 1.1 moles, relative to 1 mole of the compound represented by formula (III-1) or formula (V-1). In the compound represented by formula (III-1) or formula (V-1) used in this condensation reaction, ５ and R ５ At least one of NR' represents an amino protecting group, ５ R ５ When R ′ represents phthalimide, the amino protecting group is deprotected by an appropriate method, and R ５ and R ５ ' must be introduced to a hydrogen atom. ５As a method for deprotecting the protecting group or for converting phthalimide to amino, a commonly known method can be adopted depending on the respective protecting group. Specifically, methods such as acidic conditions, basic conditions, reduction, and nucleophilic reaction can be adopted. Boc, Alloc, phthalimide, and Cbz can be deprotected under acidic conditions, Fmoc can be deprotected under basic conditions, and Cbz and Alloc can be deprotected under reducing conditions. In a nucleophilic reaction, phthalimide and Ns can be deprotected. In a fluoride ion reaction, SES can be deprotected. In the R of the present invention, ５ In the deprotection of NR, deprotection under acidic conditions is preferred, and deprotection of Boc under acidic conditions is more preferred. ５ R ５ When ' represents nitro, R ５ and R ５ It is necessary to derive the ' to a hydrogen atom. For this derivation, a commonly known method can be used, for example, reduction by catalytic hydrogenation using a metal such as Pd, Pt, or Ni and a hydrogen source, reduction using a metal such as Fe, Sn, or Zn and an acid such as ammonium chloride, hydrochloric acid, or acetic acid, or reduction using a hydride such as sodium borohydride or lithium aluminum hydride.

[0054] In the present invention, the above condensation reaction can be carried out either before or after the construction of the acetylene described below. That is, formula (III-1) and formula (V-1) can be converted into formula (III-2) and formula (II), respectively. It is preferable to carry out the condensation reaction after the construction of the terminal acetylene.

[0055] The condensing agent used in the condensation reaction is not particularly limited as long as it allows the reaction to proceed. For example, a carbodiimide condensing agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride (WSC or EDC), dicyclohexylcarbodiimide (DCC), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (CMC), diisopropylcarbodiimide (DIC), or 1,3-bis(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)carbodiimide (BDDC) may be used in combination with 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), ethyl (hydroxyimino)cyanoacetate (Oxyma), N-hydroxysuccinimide (HOSu), or phenoxyethanol. combinations of activated ester-forming alcohols such as tetrafluorophenol, uronium condensing agents such as O-(7-azabenzotriazo-1-yl)-N,N,N',N'-tetramethylhexauronium hexafluorophosphate (HATU), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU), 2-chloro-6-methyl-1,3-diphenylpyridinium tetrafluoroborate, 1-methyl-2-chloropyridinium 2-halo-N-alkylpyridinium salts (Mukaiyama condensation reagents) such as iodides, imidazole condensation agents such as N,N'-carbonyldiimidazole (CDI) and 1,1'-carbonyldi(1,2,4-triazole) (CDT), bromotripyrrolidinophosphonium hexafluorophosphate, chlorotripyrrolidinophosphonium hexafluorophosphate, 1H-benzotriazol-1-yloxytris(dimethylamino)hexafluorophosphate, ) phosphonium condensing agents such as (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP); 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM), 4,6-dimethoxy-1,3,Examples of suitable condensing agents include triazine condensing agents such as (5-triazin-2-yl)-(octoxy-2-oxoethyl)dimethylammonium trifluoromethanesulfonate, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P), and diphenylphosphoryl azide (DPPA). A combination of a carbodiimide condensing agent and an alcohol for constructing an activated ester is preferred, and a combination of EDC and HOBt is more preferred. These condensing agents include polymer-supported reagents.

[0056] The solvent used in the condensation reaction is not particularly limited as long as it allows the reaction to proceed. It can be selected from the same solvents as those used in the deprotection step of the silicon-linked protecting group. Dichloromethane, chloroform, ethyl acetate, dimethyl sulfoxide, diethyl ether, tetrahydrofuran, 1,4-dioxane, acetone, N,N-dimethylformamide, N-methylpyrrolidone, toluene, acetonitrile, and tetrahydrofuran are preferred, with dichloromethane, chloroform, ethyl acetate, dimethyl sulfoxide, and N,N-dimethylformamide being even more preferred. The amount of solvent used is not particularly limited as long as the reaction proceeds, but is preferably 5 to 100 L, more preferably 15 to 50 L, and even more preferably 25 to 35 L per 1 kg of reactant.

[0057] When this condensation reaction is carried out after the construction of a terminal acetylene, it is preferable to protect the terminal acetylene with a silicon-linked protecting group.

[0058] The reaction time for the condensation step is not particularly limited as long as the condensation can be achieved within a certain time, and can be appropriately set, for example, from 1 to 120 hours, preferably from 2 to 48 hours, more preferably from 5 to 48 hours, preferably from 8 to 36 hours, and more preferably from 14 to 24 hours.

[0059] The reaction temperature in the condensation step is not particularly limited as long as it is a temperature at which condensation can be achieved, and can be appropriately set, for example, from 0 to 60°C, preferably from 10 to 50°C, and more preferably from 20 to 40°C.

[0060] In addition to the combination of the condensing agent represented by formula (VIII) used in the condensation reaction, a combination of the compound represented by formula (VIII-1) or the compound represented by formula (VIII-2) with a base can also be mentioned. In the formula, L represents a halogen atom or a leaving group, and (VIII-1) also includes mixed acid anhydrides, and the definitions and embodiments are the same as those described above. L is preferably a halogen atom, and more preferably a chlorine atom. Examples of the base to be combined with the compound represented by formula (VIII-1) or the compound represented by formula (VIII-2) include organic amines such as trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, diazabicycloundecene (DBU), diazabicyclononene (DBN), pyridine, and 4-dimethylaminopyridine (DMAP); and inorganic bases such as alkali metal hydroxides (lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like), alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, calcium acetate, and the like), alkali metal carbonates (sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, and the like), alkaline earth metal carbonates (barium carbonate, calcium carbonate), alkali metal phosphates (sodium phosphate, potassium phosphate, and the like), and acetates (magnesium acetate, potassium acetate, calcium acetate, cesium acetate, and the like).

[0061] Next, the construction of terminal acetylenes will be described. Methods for constructing terminal acetylenes generally include the Corey-Fuchs method, the Seyferth-Gilbert method, the Ohira-Bestmann method, and Sonogashira coupling. Because the Corey-Fuchs method requires an aldehyde as a precursor to the dihaloalkene, it is less versatile than Sonogashira coupling, which requires an aryl halide or the like. Furthermore, the Corey-Fuchs method requires the use of a strong base, so the substrate must be able to withstand strong basic conditions. Furthermore, the Seyferth-Gilbert method and the Ohira-Bestmann method require the use of explosive 1-diazo-2-oxypropylphosphonate, which raises concerns about the mass synthesis of pharmaceutical raw materials. On the other hand, Sonogashira coupling is a cross-coupling reaction between an acetylene derivative and an aryl halide or an alkyne halide, and has the advantage that it can be carried out without using a strong base or an explosive diazo compound. Furthermore, if the acetylene derivative is a compound represented by formula (IV) in which one of the two hydrogen atoms of the acetylene is substituted with a protecting group, it is possible to construct a terminal acetylene represented by general formula (I) or the like by deprotection. Specific examples of protecting groups include R １ As described above.

[0062] In the present invention, Sonogashira coupling can synthesize a compound of formula (V) by reacting a compound of formula (III) with a compound of formula (IV) below. (In each of the above formulas, X, R １ , R ２ is the same as defined above. ４ is NHCOR ３ or NR ５ R ５ ', and R ５ and R ５Each ' independently represents hydrogen or an amino protecting group, or NR ５ R ５ ' indicates phthalimido or nitro)

[0063] When introducing a compound represented by formula (IV) into a compound represented by formula (III) by Sonogashira coupling, the ratio of the amount of the compound represented by formula (III) to the amount of the compound represented by formula (IV), the ligand of the catalyst for the reaction, the type and amount of the solvent, and the order of addition are also important factors for achieving high purity. In Sonogashira coupling, the amount of the compound represented by formula (IV) is, for example, 1.0 to 5.0 moles, preferably 1.25 to 3.75 moles, and more preferably 1.5 to 2.5 moles per mole of the compound represented by formula (III).

[0064] The catalyst for Sonogashira coupling is not particularly limited as long as it can promote the reaction, but for example, a palladium catalyst can be used alone or, if necessary, in combination with an activator. Examples of palladium catalysts include, but are not limited to, palladium on carbon (Pd—C), palladium on alumina, palladium immobilized on silica gel, palladium acetate, dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II), tetrakis(triphenylphosphine)palladium(0), dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II), and dichlorobis(triphenylphosphine)palladium(II). The catalyst ligand is not particularly limited, but examples thereof include tri(o-tolyl)phosphine, tri(tert-butyl)phosphine, triphenylphosphine, dichlorobis(triphenylphosphine), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, [4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine, di-tert-butyl(4-dimethylaminophenyl)phosphine, tricyclohexylphosphine, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (Xantphos), bis(2-(diphenylphosphino)phenyl)ether, etc. The catalyst ligand may be coordinated to the palladium catalyst in advance, or the palladium catalyst and the catalyst ligand may be separately introduced into a solvent and coordinated in the reaction solvent. Examples of the palladium catalyst include those mentioned above, but dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II) is preferred. Its ligand is preferably di-tert-butyl(4-dimethylaminophenyl)phosphine or tricyclohexylphosphine. Examples of the activator that can be used include copper catalysts, silver catalysts, quaternary ammonium salts, and aqueous amine solutions.Examples of copper catalysts include salts containing monovalent copper ions, specifically copper(I) halides (copper(I) fluoride, copper(I) chloride, copper(I) bromide, copper(I) iodide, copper(I) trifluoromethanesulfonate, etc.). Examples of silver catalysts include salts containing monovalent silver ions, specifically silver(I) oxide. Examples of quaternary ammonium include quaternary ammonium hydroxides (tetra-n-butylammonium hydroxide: TBAOH, tetraethylammonium hydroxide: TEAOH, n-hexadecyltrimethylammonium hydroxide, choline hydroxide, etc.). Examples of aqueous amine solutions include aqueous solutions of ammonia, primary amines, secondary amines, tertiary amines, etc. The activator is preferably a copper catalyst, more preferably a salt containing monovalent copper ions, even more preferably copper(I) bromide, copper(I) iodide, or copper(I) trifluoromethanesulfonate, and particularly preferably copper(I) iodide. The base used in Sonogashira coupling is not particularly limited as long as it can achieve the introduction of an alkyne. Examples of the base include organic bases such as trimethylamine, diethylamine, diisopropylamine (DIPEA), triethylamine (TEA), N-methylmorpholine, diazabicyclononene (DBN), pyridine, 4-dimethylaminopyridine (DMAP), pyridine, morpholine, quinoline, piperidine, and diazabicycloundecene (DBU), and inorganic bases such as alkali metal hydroxides (lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, calcium acetate, etc.), alkali metal carbonates (sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkaline earth metal carbonates (barium carbonate, calcium carbonate), alkali metal phosphates (sodium phosphate, potassium phosphate, etc.), and acetates (magnesium acetate, potassium acetate, calcium acetate, cesium acetate, etc.). Preferably it is an organic base, more preferably diisopropylethylamine.

[0065] The solvent for Sonogashira coupling is not particularly limited as long as it is a solvent in which the reaction can be carried out, and examples thereof include N,N-diisopropylethylamine, N-methyl-2-pyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, 1,4-dioxane, and toluene. N-methyl-2-pyrrolidone, N,N-dimethylformamide, and N,N-dimethylacetamide are preferred.

[0066] The reaction time for Sonogashira coupling is not particularly limited as long as it is a time that allows introduction of the alkyne, and can be set appropriately, for example, 0.5 to 8 hours, preferably 0.5 to 5 hours, and more preferably 1 to 3 hours.

[0067] The reaction temperature for Sonogashira coupling is not particularly limited as long as it is a temperature at which the introduction of the alkyne can be achieved, and can be appropriately set, for example, 25 to 120°C, preferably 50 to 110°C, and more preferably 80 to 100°C.

[0068] The amino protecting group can be deprotected by a known method appropriate for the protecting group. Examples include deprotection under acidic conditions, deprotection under reducing conditions, deprotection under basic conditions, and deprotection using a palladium catalyst. For example, in the case of Boc, deprotection is generally performed under acidic conditions, and any acid may be used to set the acidic conditions as long as the deprotection proceeds. Preferred are trifluoroacetic acid, hydrochloric acid, and sulfuric acid. The amount of acid used to set the acidic conditions is not particularly limited as long as the reaction proceeds, but is preferably 1 to 100 moles, more preferably 2 to 50 moles, and even more preferably 3 to 10 moles, per mole of the compound represented by Formula (I), Formula (III), Formula (V), or Formula (VI).

[0069] The solvent used in the deprotection reaction of the amino protecting group is not particularly limited as long as the reaction proceeds. It can be selected from the same solvents as those used in the deprotection step of the silicon-linked protecting group. Preferred are methanol, ethanol, 2-propanol, acetonitrile, and tetrahydrofuran, more preferably methanol, ethanol, and 2-propanol, and even more preferably methanol. The amount of solvent used is not particularly limited as long as the reaction proceeds, but is preferably 1 to 100 L, more preferably 5 to 50 L, and even more preferably 10 to 30 L per kg of reactant.

[0070] Deprotection of silicon-linked protecting groups under basic conditions as described above, Sonogashira coupling, R ３ By appropriately adjusting the order of conversion to and deprotection of the amino protecting group, the amounts of reagents, and solvents, it is possible to produce the target compound with high purity without purification by column chromatography.

[0071] Compound (1) produced via the above synthesis route may be amorphous or crystalline, and if crystalline, it may be a single crystal or a mixed crystal of multiple crystals. For crystallization, compound (1) may be used either directly after synthesis without being extracted as a crystal, or after being extracted as a crystal (crude crystal). It is also possible to obtain the desired single crystal by a known purification method. In this specification, the crystal may be either a hydrate or an anhydrous form.

[0072] A labeled form of compound (1) or a salt thereof, i.e., compound (1) or a salt of compound (1), or a compound in which one or more atoms are substituted with a radioactive isotope or a non-radioactive isotope, is also encompassed in one embodiment of the present invention.

[0073] In this specification, chemical purity refers to the purity measured by HPLC, and when referring to the chemical purity of compound (1), it refers to the purity of compound (1) measured by HPLC. In this case, the wavelength of the detector used for purity measurement can be appropriately set. Specifically, the chemical purity of the crystals of compound (1) is preferably 95% or more, more preferably 98% or more, and particularly preferably 99% or more.

[0074] (Avoidance of Use of Explosive Reagents) In Patent Document 1, acetylene is constructed by the Ohira-Bestmann method to produce compound (1), but the Ohira-Bestmann method is not used in the production method of the present invention. As a method for constructing a terminal acetylene without using the Ohira-Bestmann method, a commonly known method can be used. In one embodiment, a compound represented by formula (VI) and reacting a compound of formula (VII) (wherein L represents a halogen atom or a leaving group) to obtain a compound of formula (IX). (In formula (VI) and formula (IX), R ４ is NR ５ R ５ ', and R ５ and R ５ Each ' independently represents a hydrogen atom or an amino protecting group, or NR ５ R ５ and L represents a halogen atom or a leaving group) and a compound of formula (IX). The compound of formula (III-1) can be obtained from a compound of formula (IX) by, for example, the method described in Patent Document 1.

[0075] (Purification of Crystals and Other Procedures) The precipitated crystals can be isolated and purified from the solution in which the crystals are dissolved or the mixed solution by known separation and purification means such as filtration, washing with water or an organic solvent, and drying under reduced pressure.

[0076] (Activity and Use) The compound, or a salt or crystal thereof, obtained by the production method according to one embodiment of the present invention has excellent EGFR inhibitory activity. In particular, it has excellent inhibitory activity against EGFR (Del19 / C797S), EGFR (L858R / C797S), EGFR (Del19 / T790M / C797S), and EGFR (L858R / T790M / C797S), and is useful as an antitumor agent. Furthermore, the compound, or a salt or crystal thereof, obtained by the production method according to one embodiment of the present invention has the advantage of having excellent selectivity against mutant EGFR and having fewer side effects caused by wild-type EGFR and other kinases.

[0077] As used herein, "wild-type EGFR" refers to, for example, the amino acid sequence of GenBank Accession No. NP_005219.2. As used herein, "exon 19" refers to the region from 729 to 823 in the amino acid sequence of wild-type EGFR (for example, GenBank Accession No. NP_005219.2).

[0078] As used herein, "Del19" refers to a mutation in which one or more amino acids are deleted in the exon 19 region of wild-type EGFR. It also encompasses mutations in which one or more arbitrary amino acids are inserted in addition to the deletion of the region. Examples of exon 19 deletion mutations include a mutation in which five amino acids from glutamic acid at position 746 to alanine at position 750 in the exon 19 region are deleted (Del E746-A750 (also referred to as d746-750)), a mutation in which seven amino acids from leucine at position 747 to proline at position 753 in the exon 19 region are deleted followed by an insertion of serine (Del L747-P753insS), a mutation in which five amino acids from leucine at position 747 to threonine at position 751 in the exon 19 region are deleted (Del L747-T751), and a mutation in which four amino acids from leucine at position 747 to alanine at position 750 in the exon 19 region are deleted followed by an insertion of proline (Del L747-A750insP). A preferred mutation is a deletion of five amino acids from glutamic acid at position 746 to alanine at position 750 in the exon 19 region (Del E746-A750).

[0079] The compound or salt thereof obtained by the production method according to one embodiment of the present invention may be used in postoperative adjuvant chemotherapy carried out to prevent recurrence after surgical removal of a tumor, or in preoperative adjuvant chemotherapy carried out before surgical removal of a tumor.

[0080] The tumors that are the subject of the present invention are not particularly limited, and examples thereof include head and neck cancer, digestive cancers (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder / bile duct cancer, etc.), pancreatic cancer, colon cancer (colorectal cancer, colon cancer, rectal cancer, anal cancer, etc.)), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma (pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, testicular mesothelioma, etc.)), breast cancer, reproductive cancers (ovarian cancer, vulvar cancer, uterine cancer (cervical cancer, uterine cancer, endometrial cancer, etc.)), urinary cancers (kidney cancer, bladder cancer, prostate cancer, testicular tumor, urothelial carcinoma, renal pelvis cancer, urethral cancer, etc.), hematopoietic tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors, rhabdomyosarcoma, skin cancer, brain tumors, malignant neurinoma, neuroendocrine tumors, thyroid cancer, etc. Preferably, the cancer is head and neck cancer, breast cancer, colon cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, renal cancer, bladder cancer, skin cancer, or brain cancer, with lung cancer being particularly preferred. Here, cancer includes not only primary tumors but also cancers that have metastasized to other organs (such as the liver). Furthermore, the compound or a salt thereof, or a crystal thereof obtained by the production method according to one embodiment of the present invention has excellent inhibitory activity against mutant EGFR. Examples of such mutant EGFR include drug-resistant mutant EGFR and highly sensitive mutant EGFR. Therefore, the compound or a salt thereof of the present invention is useful as an antitumor agent against the aforementioned malignant tumors having mutant EGFR.

[0081] As used herein, the term "effective amount" of a compound refers to an amount of a compound of the present invention that elicits a biological or medical response in a subject, such as a reduction or inhibition of enzyme or protein activity, or that improves symptoms, alleviates a condition, or slows or delays the progression of a disease (a therapeutically effective amount). As used herein, the term "subject" includes mammals and non-mammals. In one embodiment, the subject is a human, and may be a human diagnosed with a need for treatment for a symptom, condition, or disease disclosed herein.

[0082] When using the compound (1) or its salt crystals or cocrystals produced by the above-mentioned production method as a pharmaceutical, various administration forms can be adopted depending on the therapeutic purpose, with or without pulverization of the crystals, and they can be used in dosage forms generally used for pharmaceuticals. Such forms may include, for example, oral preparations such as tablets, capsules, granules, fine granules, powders, and dry syrup; and parenteral preparations such as suppositories, inhalants, nasal drops, ointments, patches, and injections. Pharmaceutical compositions suitable for these administration forms can be produced using pharmaceutically acceptable carriers by formulation methods known and commonly used by those skilled in the art.

[0083] Pharmaceutically acceptable carriers include various organic or inorganic carrier substances commonly used as formulation materials, and include excipients, binders, disintegrants, lubricants, coating agents, etc. in solid formulations, and are incorporated as solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid formulations. Furthermore, formulation additives such as preservatives, antioxidants, colorants, sweeteners, stabilizers, etc. can also be used as needed.

[0084] When preparing oral solid preparations, excipients, and if necessary binders, disintegrants, lubricants, colorants, flavorings, and odorants, etc., are added to compound (1) and its crystals (i.e., crystals of the free form of compound (1) or crystals of compound (1) with an acid (crystals of a salt or co-crystals)) produced by the above-mentioned production method, and tablets, coated tablets, granules, powders, capsules, etc. can be produced by conventional methods. When preparing injections, pH adjusters / buffers, stabilizers, isotonicity agents, local anesthetics, etc. are added to compound (1) and its crystals (i.e., crystals of the free form of compound (1) or crystals of compound (1) with an acid (crystals of a salt or co-crystals)) produced by the above-mentioned production method, and subcutaneous, intramuscular, and intravenous injections can be produced by conventional methods.

[0085] The amount of compound (1) and its crystals (i.e., crystals of the free form of compound (1) or crystals of compound (1) with an acid (salt crystals or co-crystals)) produced by the above-mentioned production method to be incorporated into each dosage unit form varies depending on the symptoms of the patient to which it is to be administered or on the dosage form, etc., but generally, it is desirable that the amount per dosage unit form be about 0.05 to 1000 mg, about 0.1 to 500 mg, and about 1 to 1000 mg, calculated as the free form of compound (1), of oral agents, injections, and suppositories or external preparations, respectively.

[0086] Furthermore, the daily dose of compound (1) and its crystals produced by the above-described production method for pharmaceuticals having each dosage form (i.e., compound (1) and its crystals in free form or crystals of compound (1) with an acid (salt crystals or co-crystals) produced by the above-described production method) varies depending on the symptoms, body weight, age, sex, etc. of the patient and cannot be determined in general, but is usually about 0.05 to 5000 mg, preferably 0.1 to 1000 mg, of compound (1) in free form per day for an adult (body weight 50 kg).

[0087] (Exemplary Embodiments) Exemplary embodiments of the present invention will be described below, but the present invention is not limited to the following embodiments.

[0088] The method of the present invention for preparing a compound of formula (II) is １ The present invention relates to a method for producing a compound represented by formula (I) or a salt thereof by deprotecting a protecting group represented by formula (II) under basic conditions. １ and more preferably, the method is carried out under basic conditions adjusted using a reagent not containing fluoride ions, and more preferably, the method is carried out under basic conditions adjusted using a reagent not containing fluoride ions, and more preferably, １ is triethylsilyl.

[0089] In another embodiment, the production method of the present invention is a method for producing a compound represented by formula (I), which comprises the steps of (A) to (B) below in this order: (A) a step of reacting a compound represented by formula (III-2) with a compound represented by formula (IV) to produce a compound represented by formula (II); and (B) a step of deriving a compound represented by formula (II) into a compound represented by formula (I).

[0090] In another embodiment, the production method of the present invention is a production method of a compound represented by formula (I) or a salt thereof, comprising the following steps (A) to (C): (A) linking a compound represented by formula (III-1) with a compound represented by formula (VIII) to derive a compound represented by formula (III-2), or linking a compound represented by formula (III-1) with a compound represented by formula (IV) to produce a compound represented by formula (V-1), (B) linking a compound represented by formula (III-2) with a compound represented by formula (IV), or linking a compound represented by formula (V-1) with a compound represented by formula (VIII) to derive a compound represented by formula (II), and (C) reacting R of formula (II) under basic conditions. １ and deprotecting the protecting group represented by:

[0091] Preferably, the method for producing a compound represented by formula (I) or a salt thereof includes the following steps (A) to (C): (A) reacting a compound represented by formula (III-1) with a compound represented by formula (IV) to produce a compound represented by formula (V-1), (B) deriving the compound represented by formula (V-1) into a compound represented by formula (II), and (C) deriving the compound represented by formula (II) into a compound represented by formula (I) under basic conditions.

[0092] More preferably, R １ is a silicon-linked protecting group, and R ２ is amino, and R ３ is pyrazinyl optionally having methyl, and R ４ NR ５ R ５ ' and R ５ is a protecting group that can be deprotected under acidic conditions, and R５ a method for producing a compound represented by formula (I) or a salt thereof, wherein X' is a hydrogen atom, X is a halogen atom, and L is a halogen atom, and the method includes the following steps (A) to (C), and does not include a purification step by column chromatography: (A) reacting a compound represented by formula (III-1) with a compound represented by formula (IV) to produce a compound represented by formula (V-1), (B) deprotecting a protecting group that can be removed under acidic conditions in the compound represented by formula (V-1), and condensing the compound with a compound represented by formula (VIII) to derive a compound represented by formula (II), and (C) deriving a compound represented by formula (II) from the compound represented by formula (I) under basic conditions, wherein the compound represented by formula (III-1) is derived from a compound of formula (IX) obtained by reacting a compound represented by formula (VI) with a compound represented by formula (VII).

[0093] More preferably, R １ is a silicon-linked protecting group, and R ２ is amino, and R ３ is 5-methylpyrazin-2-yl, and R ４ NR ５ R ５ ' and R ５ is a protecting group that can be deprotected under acidic conditions, and R ５A method for producing compound (1) or a salt thereof, wherein X' is a hydrogen atom, X is a halogen atom, and L is a halogen atom, and the method includes the following steps (A) to (C), and does not include a purification step by column chromatography, and the content of compound (2) is 0.2% or less: (A) reacting a compound represented by formula (III-1) with a compound represented by formula (IV) to produce a compound represented by formula (V-1), (B) deprotecting a protecting group that can be deprotected under acidic conditions in the compound represented by formula (V-1), and deriving the compound represented by formula (II) by condensation with 5-methylpyrazine-2-carboxylic acid, and (C) deriving the compound represented by formula (II) from the compound represented by formula (II) under basic conditions, wherein the compound represented by formula (III-1) is derived from a compound of formula (IX) obtained by reacting a compound represented by formula (VI) with a compound represented by formula (VII).

[0094] Even more preferably, R １ is TES, and R ２ is amino, and R ３ is 5-methylpyrazin-2-yl, and R ４ NR ５ R ５ ' and R ５ is Boc, and R ５ A method for producing compound (1) or a salt thereof, wherein X' is a hydrogen atom, X is a bromine atom, and L is a chlorine atom, and the method includes the following steps (A) to (C), and does not include a purification step by column chromatography, and the content of compound (2) is 0.2% or less: (A) reacting a compound represented by formula (III-1) with a compound represented by formula (IV) using a palladium catalyst and a copper catalyst to produce a compound represented by formula (V-1), (B) deprotecting Boc of the compound represented by formula (V-1) and condensing it with 5-methylpyrazine-2-carboxylic acid to obtain a compound represented by formula (II), and (C) deriving the compound represented by formula (II) to compound (1) under basic conditions adjusted with a reagent not containing fluoride ions, wherein the compound represented by formula (III-1) is derived from a compound of formula (IX) obtained by reacting a compound represented by formula (VI) with a compound represented by formula (VII).

[0095] Particularly preferably, R １ is TES, and R ２ is amino, and R ３ is 5-methylpyrazin-2-yl, and R ４ NR ５ R ５ ' and R ５ is Boc, and R ５ a method for producing compound (1) or a salt thereof, wherein X′ represents a hydrogen atom, X represents a bromine atom, and L represents a chlorine atom, the method comprising the steps of (A) to (C) below, and the method does not include a purification step by column chromatography, and the content of compound (2) is 0.2% or less: (A) a step of reacting a compound represented by formula (III-1) with a compound represented by formula (IV) using dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II) and copper iodide(I) to produce a compound represented by formula (V-1); (B) a step of deprotecting Boc of a compound represented by formula (V-1) under acidic conditions, and condensing the compound with 5-methylpyrazine-2-carboxylic acid using a combination of EDC and HOBt to derive a compound represented by formula (II); and (C) a step of deriving a compound represented by formula (II) under basic conditions adjusted with potassium carbonate to give a compound represented by formula (I). Note that the compound represented by formula (III-1) is derived from a compound of formula (IX) obtained by reacting a compound represented by formula (VI) with a compound represented by formula (VII).

[0096] In another embodiment, the production method of the present invention is a method for producing a composition containing a compound represented by formula (I) or a salt thereof and a compound represented by formula (I-1). The method comprises the following steps (A) to (C) in this order, in which the ratio of the compound represented by formula (I-1) is 0.2% or less and does not include a purification step by column chromatography: (A) a step of reacting a compound represented by formula (III-1) with a compound represented by formula (IV) to produce a compound represented by formula (V-1); (B) a step of deriving the compound represented by formula (V-1) into a compound represented by formula (II); and (C) a step of deriving the compound represented by formula (II) into a compound represented by formula (I) under basic conditions.

[0097] In another embodiment, the production method of the present invention is a method for producing a composition containing a compound represented by formula (I) or a salt thereof and a compound represented by formula (I-1). The method comprises the following steps (A) to (C) in this order, in which the ratio of the compound represented by formula (I-1) is 0.2% or less and no purification step by column chromatography is included: (A) a step of deriving a compound represented by formula (III-1) into a compound represented by formula (III-2); (B) a step of deriving a compound represented by formula (III-2) into a compound represented by formula (II); and (C) a step of deriving a compound represented by formula (II) into a compound represented by formula (I) under basic conditions.

[0098] The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. Although the present invention has been fully explained with reference to examples, it is understood that various changes and / or modifications may be made by those skilled in the art. Therefore, as long as such changes and / or modifications do not deviate from the scope of the present invention, they are included in the present invention.

[0099] In the following compound examples, % means weight percent unless otherwise specified.

[0100] The operation of the equipment, including data processing, was carried out in accordance with the methods and procedures instructed by the equipment. Note that the values ​​obtained from various spectra may vary slightly depending on the measurement conditions, etc. Therefore, these values ​​should not be interpreted strictly. Apparatus: Waters UPLC (% indicates volume percent) Column: ACQUITY UPLC BEH C18 Column, 130 Å, 1.7 μm, 2.1 mm × 50 mm (Waters) Column temperature: 40°C Measurement wavelength: 254 nm Flow rate: 0.5 mL / min Mobile phase A: 0.1% formic acid aqueous solution Mobile phase B: 0.1% formic acid - acetonitrile Injection volume: 1 μL Gradient: 0 → 0.1 min: mobile phase B 5%, 0.1 → 2.1 min: mobile phase B 5 → 95%, 2.1 → 3.5 min: mobile phase B 95 → 98%, 3.5 → 5 min: mobile phase B 98 → 95%. The operation of the apparatus, including data processing, followed the methods and procedures specified for each apparatus.

[0101] Example 1: Production of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (compound (1))) (Step 1) Synthesis of tert-butyl (4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate. tert-Butyl (4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate was synthesized by the method described in Patent Document 1. N-methylpyrrolidone (1500 mL) was added to (4-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (65.9 g) and the mixture was stirred at 90°C under a nitrogen atmosphere for 30 minutes to dissolve. After cooling to 35°C, diisopropylethylamine (46.5 g), triethylsilylacetylene (33.7 g), copper(I) iodide (4.57 g), dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II) (8.50 g), and N-methylpyrrolidone (80 mL) were added and the mixture was stirred at 90°C under a nitrogen atmosphere for 2 hours. After cooling to 40°C, a 10% aqueous solution of sodium dihydrogen phosphate and ethyl acetate were added. The organic layer was washed with dilute aqueous ammonia and water, and activated carbon (33.0 g) and SH silica gel (65.9 g) were added, followed by stirring at 40°C for 1 hour and at room temperature for 2 hours. After filtering off insoluble matter through Celite, the solvent was evaporated under reduced pressure, and acetonitrile was added to the resulting residue, followed by stirring at room temperature for 15 hours. The precipitated solid was collected by filtration, washed with acetonitrile, and dried under reduced pressure to obtain the title compound (37.4 g, yield 51%).

[0102] (Step 2) Synthesis of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To the tert-butyl (4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (65.0 g) synthesized as described above, a 5-10% solution of hydrochloric acid in methanol (520 mL) was added and the mixture was stirred at 50°C for 3 hours under a nitrogen atmosphere. Under ice cooling, a 2 mol / L aqueous sodium hydroxide solution was added dropwise to adjust the pH to around 12. The precipitated solid was collected by filtration, washed with 50% methanol, and dried under reduced pressure to obtain the title compound (50.3 g, yield 93%).

[0103] (Step 3) Synthesis of N-(4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide To a mixture of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (48.3 g) obtained in Step 2, 5-methylpyrazine-2-carboxylic acid (13.4 g), 1-hydroxybenzotriazole monohydrate (16.0 g), diisopropylethylamine (24.6 g), and dichloromethane (1450 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.9 g) was added under a nitrogen atmosphere and stirred for 17 hours. The reaction solution was washed with 10% aqueous sodium dihydrogen phosphate, saturated aqueous sodium carbonate, and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the solvent was evaporated under reduced pressure. To the resulting residue, methanol was added and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with methanol, and dried under reduced pressure to obtain the title compound (54.8 g, yield 92%).

[0104] (Step 4) Synthesis of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound 1) To a mixture of N-(4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (80.0 g) obtained in Step 3, dichloromethane (1,000 mL), and methanol (1,000 mL) was added potassium carbonate (7.03 g) under a nitrogen atmosphere and stirred for 18 hours. The insoluble matter was filtered off using Celite, the solvent was evaporated under reduced pressure, and methanol and water were added to the resulting residue, which was then stirred for 1 hour. The precipitated solid was collected by filtration, washed with 50% methanol, and dried under reduced pressure to obtain the title compound (64.5 g, yield 99%) as a pale yellow solid. １ When analyzed by H-NMR, the same results as in Example 37 of Patent Document 1 were obtained.

[0105] Furthermore, analysis by UPLC revealed that the purity was 99.73%, and the content of N-(4-(6-ethynyl-4-(5-methylpyrazine-2-carboxamido)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide was below the detection limit (less than 0.05%).

[0106] Comparative Example 1 Synthesis of Compound (1) by a Method Having Condensation as the Final Step In accordance with the description of Example 37 of Patent Document 1, 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1 equivalent) obtained in Preparation Example 1 of Patent Document 1, 5-methylpyrazine-2-carboxylic acid (1 equivalent), and diisopropylethylamine (1.5 equivalents) were added to dimethyl sulfoxide in an amount of 20 mL per 1 g of the compound obtained in Preparation Example 1 of Patent Document 1, and HATU (1.2 equivalents) was added thereto and stirred at room temperature for 1.5 hours. After confirming the completion of the reaction, water in an amount approximately ⅓ the amount of the dimethyl sulfoxide was added, and the resulting precipitate was collected by filtration and dried to obtain compound (1) in a 93% yield. The obtained compound (1) was analyzed by UPLC and found to have a purity of 97.3% but to contain 1.42% of N-(4-(6-ethynyl-4-(5-methylpyrazine-2-carboxamide)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide.

[0107] All documents and publications mentioned herein are incorporated by reference in their entirety, regardless of their purpose. This specification also encompasses the disclosures of the claims, specification, and drawings of Japanese Patent Application No. 2022-071155 (filed April 22, 2022), the priority application of which this application claims priority. While several embodiments of the present invention have been described, these embodiments are presented as examples and are not intended to limit the scope of the invention. These novel embodiments may be embodied in various other forms, and various omissions, substitutions, and modifications may be made without departing from the spirit of the invention. These embodiments and their variations are within the scope and spirit of the invention, as well as within the scope of the inventions and their equivalents.

Claims

1. Under basic conditions, a compound of formula (II) R １ By deprotecting the protecting group represented by formula (I), (In the above formulas (I) and (II), R １ represents a protecting group, R ２ represents an amino group which may have a protecting group, a halogen atom, or a leaving group; R ３ represents an optionally substituted 5- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group), or a salt thereof.

2. In the formulas (I) and (II), R １ represents a silicon-linked protecting group, R ２ represents amino, R ３ The method according to claim 1 , wherein represents pyrazinyl which may have methyl.

3. The method according to claim 1 or 2, wherein the compound represented by formula (I) is N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof.

4. (1) Linking a compound represented by formula (III-1) with a compound represented by formula (VIII) to derive a compound represented by formula (III-2), or linking a compound represented by formula (III-1) with a compound represented by formula (IV) to produce a compound represented by formula (V-1); (2) By linking a compound represented by formula (III-2) with a compound represented by formula (IV), or by linking a compound represented by formula (V-1) with a compound represented by formula (VIII), a compound represented by formula (II) is derived; and (3) Under basic conditions, R １ and deprotecting the protecting group represented by: (In the above formulas (I), (II), (III-1), (III-2), (IV), (V-1) and (VIII), R １ represents a protecting group, R ２ represents an amino group which may have a protecting group, a halogen atom, or a leaving group; R ３ represents an optionally substituted 5- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group, ５ and R ５ Each ' independently represents a hydrogen atom or an amino protecting group, or NR ５ R ５ ' represents phthalimido or nitro, and X represents a halogen atom or a leaving group.

5. In the formulas (I), (II), (III-1), (III-2), (IV) and (V-1), R １ represents a silicon-linked protecting group; R ２ represents amino, R ３ represents pyrazinyl optionally having methyl; R ４ is NR ５ R ５ ', and R ５ represents a hydrogen atom or Boc, R ５ The method according to claim 4, wherein ' represents a hydrogen atom.

6. The method according to claim 4 or 5, wherein the compound represented by formula (I) is N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof.

7. A compound represented by formula (VI) reacting a compound of formula (VII) (wherein L represents a halogen atom or a leaving group) to obtain a compound of formula (IX). (In formula (VI) and formula (IX), R ４ is NR ５ R ５ ', and R ５ and R ５ Each ' independently represents a hydrogen atom or an amino protecting group, or NR ５ R ５ ' represents phthalimide or nitro, and L represents a halogen atom or a leaving group) and obtaining a compound represented by formula (III-1) from a compound of formula (IX).

8. In the formulas (VI), (VII) and (IX), R ４ is NR ５ R ５ ', and R ５ represents Boc, R ５ 8. The method according to claim 7, wherein ' represents a hydrogen atom, and L represents a chlorine atom.

9. The method of claim 4, which does not include purification by column chromatography.

10. In the compound represented by formula (I) and its salt produced by the method, the compound represented by formula (I-1) (In the formula, R ３ and represents an optionally substituted 5- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group), is 0.2% or less.

11. A composition obtained by the method according to claim 10, comprising a compound of formula (I) or a salt thereof.

12. Formula (II) (In the formula, R １ represents a protecting group, R ２ represents an amino group which may have a protecting group, a halogen atom, or a leaving group; R ３ represents an optionally substituted 5- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group), or a salt thereof.

13. In the formula (II), R １ represents a silicon-linked protecting group, R ２ represents amino, R ３ The compound according to claim 12 or a salt thereof, wherein represents pyrazinyl optionally having methyl.

14. The compound or salt thereof according to claim 12 or 13, wherein the compound represented by formula (II) is N-(4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof.