Method for producing alkynyl ketone derivatives

Abstract

The present invention relates to a method for preparing an alkynyl ketone derivative. The present invention also relates to a compound containing N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide.

Description

[0001] The present invention is a divisional application of the invention application with the original application number 201580035589.1 (international application number PCT / JP2015 / 065336), the application date May 28, 2015, and the invention name “Method for producing alkynyl ketone derivatives” (application number: 201910474682.2). Technical Field

[0002] The present invention relates to a compound having dual inhibitory activity against both EGF receptor tyrosine kinase and HER2 tyrosine kinase, a method for producing a compound substituted with 1-oxo-2-butyn-1-yl useful as a production intermediate thereof, and a crystal of the intermediate compound. The present invention further relates to a novel compound and its crystal for controlling the generation of reaction heat when producing the intermediate compound. Background Art

[0003] It is known that tyrosine kinases are enzymes that phosphorylate tyrosine residues in proteins and play an important role in cell differentiation and proliferation and intracellular information transduction systems. In particular, it is also known that growth factor receptor tyrosine kinases (hereinafter, receptor tyrosine kinases) such as HER2 (also known as ErbB2 or Neu) and EGF receptors are deeply involved in the formation of cancer, and in human cancers, receptor tyrosine kinase activity is hyperactive (Non-Patent Documents 1, 2, and 3).

[0004] In addition, it is known that the carcinogenesis caused by the EGF receptor alone is further accelerated by the co-expression of the EGF receptor and HER2 (Non-Patent Document 4), and that dual inhibitors that inhibit the tyrosine kinases of both the EGF receptor and HER2 are superior to compounds that act only on a single kinase in that they are applicable to a wider range of diseases and have a strong therapeutic effect obtained through the synergistic effect of dual inhibition.

[0005] A quinazoline derivative (VI) having a substituent having an alkoxyimino structure at the 6-position is one of such dual inhibitors and is expected to be used as a new anticancer agent (Patent Document 1).

[0006] [Chemical formula 1]

[0007]

[0008] (Where R 2 is a hydrogen atom, a halogen, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted alkynyloxy group, or a group of the formula: -YR y The group shown (wherein Y is -O-, -S-, -SO2-, or may be intercalated with -O-, -S- or -N (R z )-alkylene; Ry is a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; R z is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted acyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted alkenyloxycarbonyl group, or a substituted or unsubstituted aralkyloxycarbonyl group); R 3 and R 4 R is independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted alkynyloxy group, a halogen, a hydroxyl group, a mercapto group, a cyano group, or a substituted or unsubstituted amino group; 5 is a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted amino group, R 6 is a substituted or unsubstituted C1-3 alkylene group. )

[0009] The quinazoline derivative (VI) is produced by reacting a compound (III) substituted with a 1-oxo-2-butyn-1-yl group at the 6-position with an alkoxyamine derivative. The compound (III) is an important production intermediate for producing the quinazoline derivative (VI).

[0010] [Chemical formula 2]

[0011]

[0012] (Where R 2 , R 3 and R 4 Same as above)

[0013] In addition, Patent Document 2 describes a method for producing a compound represented by formula (III), characterized in that reaction A and reaction B in which a product of reaction A is reacted with 1-propynyl metal acetylide are continuously carried out as essentially one step, wherein reaction A is to react a compound represented by formula (I) with a compound represented by formula: (R b O-)N(-R a )H(where R a and R b The method comprises reacting a compound represented by (each independently of the other) a substituted or unsubstituted C1-C3 alkyl group and at least one metal reagent selected from the group consisting of a Grignard reagent, sodium hydride, alkyl lithium, alkenyl lithium, alkynyl lithium, phenyl lithium and lithium amide.

[0014] [Chemical formula 3]

[0015]

[0016] [Where R 1For the formula -OR x or -SR x (Where R x is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, etc.); R 2 is a hydrogen atom, a halogen, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted alkynyloxy group, or a group of the formula: -YR y The group shown (wherein, -Y- is -O-, -S-, -SO2-, or may be intercalated with -O-, -S- or -N (R z )-alkylene; R y is a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; R z is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted acyl group, etc.); R 3 and R 4 each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, etc.].

[0017] [Chemical formula 4]

[0018]

[0019] (Where R 2 , R 3 and R 4 Same as above).

[0020] Non-Patent Documents 5 to 9 describe the Sonogashira carbonylation reaction, but all of them are reactions using liquid alkynes, and the Sonogashira carbonylation reaction using gaseous alkynes (e.g., acetylene and propyne) is still unknown.

[0021] Although N,N-dimethylglycine is recorded as an effective ligand for copper in Non-Patent Document 10, there is no report that the ligand is related to the precipitation of palladium metal. In addition, in various Sonogashira reactions recorded in Non-Patent Document 11, there is no example of adding a ligand (additive) effective for copper in order to suppress the precipitation of palladium metal.

[0022] Non-Patent Document 12 describes a Sonogashira carbonylation reaction using iodobenzene, carbon monoxide, phenylacetylene, triethylamine and a palladium catalyst. An example of the formation of triethylamine hydroiodide as a by-product is described, but no description is given about the novel compound of the present invention and its crystal.

[0023] Prior art literature

[0024] Patent Literature

[0025] Patent Document 1: International Publication No. 2006 / 090717

[0026] Patent Document 2: International Publication No. 2010 / 074150

[0027] Non-patent literature

[0028] Non-patent document 1: Cancer Res., 1991, Vol. 51, p. 4430-4435

[0029] Non-patent document 2: Cancer Res., 1992, Vol. 52, p. 3636-3641

[0030] Non-patent document 3: Cancer Chemother. Pharmacol., 1993, Vol. 32, p. 1-19

[0031] Non-patent document 4: Cell, 1989, Vol. 58, p. 287-292

[0032] Non-patent document 5: Synlett, 1995, p.823-824

[0033] Non-patent document 6: Journal of the Chemical Society, Chemical Communications (JCS Chem. Comm.), 1981, p. 333-334

[0034] Non-patent document 7: Synthesis, 1994, p.1149-1151

[0035] Non-patent document 8: ORGANIC LETTERS, 2003, Vol. 5, No. 17, p. 3057-3060

[0036] Non-patent document 9: The Journal of Organic Chemistry (J.Org.Chem.), 2005, Vol. 70, p.6097-6100

[0037] Non-patent document 10: ORGANIC LETTERS, 2004, Vol. 6, No. 11, p. 1809-1812

[0038] Non-patent document 11: Chemical Reviews (Chem. Rev.), 2007, Vol. 107, p. 874-922

[0039] Non-patent document 12: Journal of the Chemical Society of Japan (Journal of the Chemical Society of Japan), 1985, No. 3, p. 537-546

[0040] Summary of the Invention

[0041] Problems to be solved by the invention

[0042] Reference Example 1 of Patent Document 1 discloses a method for producing a compound represented by formula (VII-4) from a compound represented by formula (III-1) through three steps.

[0043] [Chemical formula 5]

[0044]

[0045] Patent Document 2 discloses a method for producing a compound represented by formula (IV) by a one-step reaction (reaction B) using a compound represented by formula (I-1) via methoxymethylamide (reaction A) without isolation.

[0046] Compared with Patent Document 1, it is known that the production method described in Patent Document 2 can produce the compound represented by formula (IV) [the compound represented by formula (VII-4) in Patent Document 1] by a production method with one less step.

[0047] [Chemical formula 6]

[0048]

[0049] However, the production methods described in Patent Documents 1 and 2 cannot be said to be sufficient, and there is room for improvement.

[0050] As shown below, the present invention relates to a method for producing a compound represented by formula (II) by Sonogashira carbonylation reaction of a compound represented by formula (I) and a compound represented by formula (III).

[0051] [Chemical formula 7]

[0052]

[0053] (wherein, ring A is a substituted or unsubstituted aromatic heterocycle, or a substituted or unsubstituted aromatic carbocycle; X is a leaving group; and R is hydrogen or methyl)

[0054] Solutions to Solve Problems

[0055] As described in detail in the examples of the present application, for example, as shown below, the compound represented by formula (II") can be produced by the Sonogashira carbonylation reaction of the compound represented by formula (I'') with propyne gas.

[0056] [Chemical formula 8]

[0057]

[0058] That is, in the production method described in Patent Document 1, the compound represented by formula (III-1) (iodine body) is used to produce the compound represented by formula (VII-4) (alkynyl ketone body) through three steps; in contrast, the present invention can use the compound represented by formula (I'') (iodine body) to produce the compound represented by formula (II") (alkynyl ketone body) through one step. Therefore, compared with the known production method, the alkynyl ketone body can be produced with fewer steps.

[0059] In addition, in the present invention, the reaction proceeds even when an aromatic carbon ring (e.g., a benzene ring) is used in addition to the aromatic heterocyclic ring (quinazoline ring) shown above for ring A of formula (I). The present invention can be applied to various substrates, and since an alkynyl ketone body can be obtained from an iodine body in one step, it can be said to be an industrially excellent production method.

[0060] The Sonogashira carbonylation reaction requires the treatment of two gases, carbon monoxide and propyne gas. However, since propyne gas has a higher solubility in a solvent than carbon monoxide, arylacetylene without carbon monoxide is produced as a byproduct, which greatly reduces the yield and quality of the target product. The present inventors have found a method for obtaining the target product with a high yield even in the Sonogashira carbonylation reaction using the two gases.

[0061] It is also known that in a reaction using a palladium catalyst, the palladium catalyst is deactivated during the reaction and palladium black is precipitated, which causes a decrease in the quality of the crystals of the product and a decrease in the reaction rate. The present inventors have found that the amount of palladium black precipitation can be significantly reduced by adding a ligand (additive) effective for copper.

[0062] Furthermore, the Sonogashira carbonylation reaction is highly exothermic and poses the risk of increased internal pressure and runaway reaction during large-scale synthesis. Therefore, it has been found that by pre-adding crystals of the novel compound of the present invention to the system before the start of the reaction, it is possible to easily control the exothermic reaction during large-scale synthesis.

[0063] The present invention relates to the following items 1) to 43).

[0064] 1) A method for producing a compound represented by formula (II), characterized in that a compound represented by formula (I) is reacted with carbon monoxide and a compound represented by formula (III) in the presence of a palladium catalyst, a phosphine ligand, a catalyst containing an element of Group 11 and a base.

[0065] [Chemical formula 9]

[0066]

[0067] (wherein, Ring A is a substituted or unsubstituted aromatic heterocycle, or a substituted or unsubstituted aromatic carbocycle, and X is a leaving group)

[0068] [Chemical formula 10]

[0069]

[0070] (where R is a hydrogen atom or a methyl group)

[0071] [Chemical formula 11]

[0072]

[0073] (wherein, ring A and R have the same meanings as above).

[0074] 2) The production method according to item 1) above, wherein R is a methyl group.

[0075] 3) The production method according to item 1) or item 2), wherein the palladium catalyst is Pd2(dba)3, PdCl2dppf, PdCl2(PPh3)2, Pd(OAc)2, Pd(PPh3)4, Pd / C, PdCl2, Pd-PEPPSI TM -IPr, biscinnamylpalladium chloride, PdCl2(Xantphos) or Pd(OH)2.

[0076] 4) A production method according to any one of items 1) to 3) above, wherein the phosphine ligand is Xantphos, P(2-furyl)3, PPh3, P(o-tol)3, P(OPh)3, P(OMe)3, dppp, dppb, dppf, BINAP, X-Phos, P(t-Bu)3, P(Oi-Pr)3, P(p-MeOPh)3 or DPEpHos.

[0077] 5) The production method according to any one of items 1) to 4) above, wherein the catalyst containing a Group 11 element is cuprous (I) iodide, copper (II) iodide, cuprous (I) chloride, cupric (II) chloride, cuprous (I) acetate, cupric (II) acetate, copper (II) oxide, cuprous (I) bromide, copper (II) bromide or silver acetate.

[0078] 6) The production method according to any one of items 1) to 5) above, wherein the base is N-methylmorpholine, triethylamine, diisopropylethylamine, pyridine, DABCO, N,N-dimethylbenzylamine, N,N-dimethylaniline, sodium acetate, potassium carbonate, sodium carbonate or potassium phosphate.

[0079] 7) The production method according to any one of the above items 2) to 6), wherein the compound represented by formula (II) is a compound represented by formula (II'),

[0080] [Chemical formula 12]

[0081]

[0082] (Where R 1 is a hydrogen atom, a halogen, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted alkynyloxy group, or a group of the formula: -YR y The group shown (wherein, -Y- is -O-, -S-, -SO2-, or may be intercalated with -O-, -S- or -N (R z )-alkylene; R y is a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group; R z is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted acyl group, a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted alkenyloxycarbonyl group, or a substituted or unsubstituted aromatic carbocyclic alkoxycarbonyl group);

[0083] R 2 and R 3 Each is independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted alkynyloxy group, a halogen, a hydroxyl group, a mercapto group, a cyano group, or a substituted or unsubstituted amino group).

[0084] 8) The manufacturing method according to item 7) above, wherein R 1 Formula: -YR y The group shown (wherein, -Y- is an alkylene group which may be inserted with -O-; R yphenyl or unsubstituted phenyl substituted with a substituent selected from Substituent Group P (Substituent Group P: halogen, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxycarbonyl and substituted or unsubstituted amino), pyridyl or unsubstituted pyridyl substituted with a substituent selected from Substituent Group P, furanyl or unsubstituted furanyl substituted with a substituent selected from Substituent Group P, thienyl or unsubstituted thienyl substituted with a substituent selected from Substituent Group P, thiazolyl or unsubstituted thiazolyl substituted with a substituent selected from Substituent Group P, or oxazolyl or unsubstituted oxazolyl substituted with a substituent selected from Substituent Group P);

[0085] R 2 is substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, or halogen; and

[0086] R 3 A hydrogen atom.

[0087] 9) The production method according to item 7) or 8) above, wherein the compound represented by formula (II') is a compound represented by formula (II"),

[0088] [Chemical formula 13]

[0089]

[0090] 10) A methanesulfonate of a compound represented by formula (II"),

[0091] [Chemical formula 14]

[0092]

[0093] 11) A crystal of a methanesulfonate salt of a compound represented by formula (II"),

[0094] [Chemical formula 15]

[0095]

[0096] 12) The crystal according to item 11) above, which has peaks at diffraction angles (2θ) of 5.6°±0.2°, 9.8°±0.2°, 17.9°±0.2°, 24.4°±0.2°, and 26.4°±0.2° in its powder X-ray diffraction pattern.

[0097] 13) The crystal according to item 11) above, which has peaks at diffraction angles (2θ) of 5.6°±0.2°, 8.3°±0.2°, 9.8°±0.2°, 13.7°±0.2°, 17.0°±0.2°, 17.9°±0.2°, 21.3°±0.2°, 24.4°±0.2°, 26.0°±0.2°, and 26.4°±0.2° in its powder X-ray diffraction pattern.

[0098] 14) A complex comprising N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide.

[0099] 14') a compound of [chemical formula 16] The complex shown.

[0100] 15) The complex according to item 14) or 14') above, which is crystalline.

[0101] 16) The crystallization of the complex according to item 15) above, characterized by the following crystallographic data:

[0102] [Table 1]

[0103]

[0104] 17) A crystal of the complex according to item 15) above, wherein in a powder X-ray diffraction pattern, it has peaks at diffraction angles (2θ): 12.6°±0.2°, 16.9°±0.2°, 17.5°±0.2°, 26.3°±0.2°, and 28.9°±0.2°.

[0105] 18) The crystal of the complex according to item 15) above, wherein in the powder X-ray diffraction pattern, there are peaks at diffraction angles (2θ): 12.6°±0.2°, 16.9°±0.2°, 17.5°±0.2°, 19.5°±0.2°, 20.8°±0.2°, 25.8°±0.2°, 26.3°±0.2°, 27.0°±0.2°, 28.4°±0.2°, and 28.9°±0.2°.

[0106] 19) The method according to any one of items 1) to 5) above, characterized in that in the method for producing a compound represented by formula (II) wherein formula (I) is a compound represented by formula (I') and the base is N-methylmorpholine, the reaction is further carried out in the presence of a crystal of a complex containing N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide.

[0107] [Chemical formula 17]

[0108]

[0109] (wherein, ring A has the same meaning as in item 1) above)

[0110] 20) The method according to any one of items 2) to 5) above, characterized in that in the method for producing a compound represented by formula (I"), wherein formula (I) is a compound represented by formula (I"), the base is N-methylmorpholine, and formula (II) is a compound represented by formula (II'), the reaction is further carried out in the presence of a crystal of a complex containing N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide,

[0111] [Chemical formula 18]

[0112]

[0113] (Where R 1 , R 2 and R 3 Same meaning as in item 7) above)

[0114] [Chemical formula 19]

[0115]

[0116] (Where R 1 , R 2 and R 3 Same meaning as in item 7) above).

[0117] 21) The method according to any one of items 2) to 5) above, characterized in that in the method for producing a compound represented by formula (I''), wherein formula (I) is a compound represented by formula (I''), the base is N-methylmorpholine, and formula (II) is a compound represented by formula (II''), the reaction is further carried out in the presence of a crystal of a complex containing N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide.

[0118] [Chemical formula 20]

[0119]

[0120] [Chemical formula 21]

[0121]

[0122] 22) The method according to any one of items 1) to 6) and 19), characterized in that in the method for producing the compound represented by formula (II), the reaction is further carried out in the presence of the following compounds: N,N-dimethylglycine, picolinic acid, L-proline, N,N-diethyl-2-hydroxybenzamide, ethylene glycol, ethyl 2-cyclohexanonecarboxylate, 2-acetylcyclohexanone, 2-hydroxybenzoic acid, furan-2-carboxylic acid, diethyl malonate, N,N-dimethylethylenediamine, acetic acid, copper (I) 2-thiophenecarboxylate, glycine, N-methylglycine, D-proline, N-methylproline, imidazole-4-carboxylic acid, oxazole-4-carboxylic acid, thiazole -4-carboxylic acid, imidazole-2-carboxylic acid, oxazole-2-carboxylic acid, thiazole-2-carboxylic acid, pyrrole-2-carboxylic acid, isoxazole-5-carboxylic acid, isoxazole-3-carboxylic acid, alanine, valine, leucine, isoleucine, N,N-dimethyl-2-aminobenzoic acid, ethanolamide, formic acid, propionic acid, butyric acid, oxalic acid, maleic acid, trifluoroacetic acid, malonic acid ester, acetoacetic acid ester, ethylene glycol dimethyl ether, 2-methoxyethanol, glycolic acid, glycolic acid ester, 1,3-propylene glycol, 1,4-butylene glycol, 1,5-pentanediol, diethylene glycol, catechol, 2-hydroxymethyl-1,3-propanediol, N,N-dimethylurea, N,N-diphenylurea or N,N-dimethylglycinamide.

[0123] 23) The method according to item 7), 8) or 20) above, characterized in that in the method for producing the compound represented by formula (II'), the reaction is further carried out in the presence of the following compounds: N,N-dimethylglycine, picolinic acid, L-proline, N,N-diethyl-2-hydroxybenzamide, ethylene glycol, ethyl 2-cyclohexanonecarboxylate, 2-acetylcyclohexanone, 2-hydroxybenzoic acid, furan-2-carboxylic acid, diethyl malonate, N,N-dimethylethylenediamine, acetic acid, copper(I) 2-thiophenecarboxylate, glycine, N-methylglycine, D-proline, N-methylproline, imidazole-4-carboxylic acid, oxazole-4-carboxylic acid, thiazole- 4-carboxylic acid, imidazole-2-carboxylic acid, oxazole-2-carboxylic acid, thiazole-2-carboxylic acid, pyrrole-2-carboxylic acid, isoxazole-5-carboxylic acid, isoxazole-3-carboxylic acid, alanine, valine, leucine, isoleucine, N,N-dimethyl-2-aminobenzoic acid, ethanolamide, formic acid, propionic acid, butyric acid, oxalic acid, maleic acid, trifluoroacetic acid, malonic acid ester, acetoacetic acid ester, ethylene glycol dimethyl ether, 2-methoxyethanol, glycolic acid, glycolic acid ester, 1,3-propylene glycol, 1,4-butylene glycol, 1,5-pentanediol, diethylene glycol, catechol, 2-hydroxymethyl-1,3-propanediol, N,N-dimethylurea, N,N-diphenylurea or N,N-dimethylglycinamide.

[0124] 24) The method according to item 9) or 21) above, characterized in that in the method for producing the compound represented by formula (II"), the reaction is further carried out in the presence of the following compounds: N,N-dimethylglycine, picolinic acid, L-proline, N,N-diethyl-2-hydroxybenzamide, ethylene glycol, ethyl 2-cyclohexanonecarboxylate, 2-acetylcyclohexanone, 2-hydroxybenzoic acid, furan-2-carboxylic acid, diethyl malonate, N,N-dimethylethylenediamine, acetic acid, copper(I) 2-thiophenecarboxylate, glycine, N-methylglycine, D-proline, N-methylproline, imidazole-4-carboxylic acid, oxazole-4-carboxylic acid, thiazole-4- carboxylic acid, imidazole-2-carboxylic acid, oxazole-2-carboxylic acid, thiazole-2-carboxylic acid, pyrrole-2-carboxylic acid, isoxazole-5-carboxylic acid, isoxazole-3-carboxylic acid, alanine, valine, leucine, isoleucine, N,N-dimethyl-2-aminobenzoic acid, ethanolamide, formic acid, propionic acid, butyric acid, oxalic acid, maleic acid, trifluoroacetic acid, malonic acid ester, acetoacetic acid ester, ethylene glycol dimethyl ether, 2-methoxyethanol, glycolic acid, glycolic acid ester, 1,3-propylene glycol, 1,4-butylene glycol, 1,5-pentanediol, diethylene glycol, catechol, 2-hydroxymethyl-1,3-propanediol, N,N-dimethylurea, N,N-diphenylurea or N,N-dimethylglycinamide.

[0125] 25) A method for producing a compound represented by formula (V), characterized in that:

[0126] A compound represented by formula (II') is obtained by the method described in item 7), 8), 20) or 23), and the obtained compound represented by formula (II') is reacted with a compound represented by formula (IV),

[0127] Formula (IV): R 4 -R 5 -O-NH2,

[0128] (Where R 4 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted amino group, R 5 is a substituted or unsubstituted C1-3 alkylene group. )

[0129] [Chemical formula 22]

[0130]

[0131] (Where R 1 , R 2 and R 3 Same as in item 7) above, R 4 and R 5Same meaning as above).

[0132] 26) A method for producing a compound represented by formula (V'), characterized in that a compound represented by formula (II") is obtained by the method described in item 9), 21) or 24) above, and the obtained compound represented by formula (II") is reacted with a compound represented by formula (IV),

[0133] Formula (IV) R 4 -R 5 -O-NH2

[0134] (Where R 4 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted amino group, R 5 is a substituted or unsubstituted C1-3 alkylene group. ),

[0135] [Chemical formula 23]

[0136]

[0137] (Where R 4 and R 5 Same meaning as above).

[0138] 27) The production method according to any one of items 1) to 6) above, wherein ring A is a substituted or unsubstituted aromatic carbocyclic ring.

[0139] 28) The production method according to any one of items 1) to 6) and 27), wherein ring A is substituted or unsubstituted benzene.

[0140] 29) The production method according to any one of items 1) to 6) above, wherein ring A is a substituted or unsubstituted aromatic heterocycle.

[0141] 30) The method according to any one of items 1) to 6) and 29), wherein ring A is substituted or unsubstituted quinazoline, pyridine, thiazole, thiophene, imidazole, pyrazine, pyrimidine or furan.

[0142] 31) The production method according to item 19) above, wherein ring A is a substituted or unsubstituted aromatic carbocyclic ring.

[0143] 32) The production method according to item 31) above, wherein ring A is substituted or unsubstituted benzene.

[0144] 33) The production method according to item 19) above, wherein ring A is a substituted or unsubstituted aromatic heterocycle.

[0145] 34) The production method according to item 33) above, wherein ring A is substituted or unsubstituted quinazoline, pyridine, thiazole, thiophene, imidazole, pyrazine, pyrimidine or furan.

[0146] 35) The production method according to item 22) above, wherein ring A is a substituted or unsubstituted aromatic carbocyclic ring.

[0147] 36) The production method according to item 35) above, wherein ring A is substituted or unsubstituted benzene.

[0148] 37) The production method according to item 22) above, wherein ring A is a substituted or unsubstituted aromatic heterocycle.

[0149] 38) The production method according to item 37) above, wherein ring A is substituted or unsubstituted quinazoline, pyridine, thiazole, thiophene, imidazole, pyrazine, pyrimidine or furan.

[0150] 39) A palladium cross-coupling reaction, characterized in that the reaction is carried out in the presence of the following compounds: N,N-dimethylglycine, picolinic acid, L-proline, N,N-diethyl-2-hydroxybenzamide, ethylene glycol, ethyl 2-cyclohexanonecarboxylate, 2-acetylcyclohexanone, 2-hydroxybenzoic acid, furan-2-carboxylic acid, diethyl malonate, N,N-dimethylethylenediamine, acetic acid, copper (I) 2-thiophenecarboxylate, glycine, N-methylglycine, D-proline, N-methylproline, imidazole-4-carboxylic acid, oxazole-4-carboxylic acid, thiazole-4-carboxylic acid, imidazole-2-carboxylic acid, oxazole-2-carboxylic acid acid, thiazole-2-carboxylic acid, pyrrole-2-carboxylic acid, isoxazole-5-carboxylic acid, isoxazole-3-carboxylic acid, alanine, valine, leucine, isoleucine, N,N-dimethyl-2-aminobenzoic acid, ethanolamide, formic acid, propionic acid, butyric acid, oxalic acid, maleic acid, trifluoroacetic acid, malonic acid esters, acetoacetic acid esters, ethylene glycol dimethyl ether, 2-methoxyethanol, glycolic acid, glycolic acid esters, 1,3-propylene glycol, 1,4-butylene glycol, 1,5-pentanediol, diethylene glycol, catechol, 2-hydroxymethyl-1,3-propanediol, N,N-dimethylurea, N,N-diphenylurea or N,N-dimethylglycinamide.

[0151] 40) The reaction according to item 39) above, characterized in that the reaction is carried out in the presence of the following compounds: N,N-dimethylglycine, picolinic acid, L-proline, N,N-diethyl-2-hydroxybenzamide, ethylene glycol, ethyl 2-cyclohexanonecarboxylate, 2-acetylcyclohexanone, 2-hydroxybenzoic acid, furan-2-carboxylic acid, diethyl malonate, N,N-dimethylethylenediamine, acetic acid, and copper(I)-2-thiophenecarboxylate.

[0152] 41) The reaction according to item 39) or 40) above, characterized in that the reaction is carried out in the presence of the following compounds: N,N-dimethylglycine, picolinic acid, ethylene glycol.

[0153] 42) The reaction according to any one of items 39) to 41) above, characterized in that the reaction is carried out in the presence of N,N-dimethylglycine.

[0154] 43) The reaction according to any one of items 39) to 42) above, wherein the palladium cross-coupling reaction is Negishi, Heck, Suzuki, Sonogashira, Stille or Buchwald-Hartwig.

[0155] The meaning of each term is explained below. Each term is used in this specification with a unified meaning, and is used with the same meaning when used alone or in combination with other terms.

[0156] In the present specification, the "leaving group" includes halogen, p-toluenesulfonyl, trifluoromethanesulfonyl, and methanesulfonyl. Examples thereof include halogen.

[0157] In the present specification, the term "halogen" includes fluorine, chlorine, bromine and iodine.

[0158] In this specification, "alkyl" used alone or in combination with other terms includes: a linear or branched monovalent hydrocarbon group having 1 to 10 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc. Examples include: C1 to C10 alkyl. Examples include: C1 to C6 alkyl. Examples include: C1 to C4 alkyl.

[0159] In the present specification, examples of the "alkoxy group" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy, n-nonyloxy, and n-decyloxy groups.

[0160] For example, C1 to C6 alkoxy groups can be mentioned. For example, C1 to C3 alkoxy groups can be mentioned.

[0161] In the present specification, examples of "alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, etc. Examples include C1-C6 alkoxycarbonyl. Examples include C1-C3 alkoxycarbonyl.

[0162] In this specification, the above-mentioned "alkyl" is included, which is substituted with the above-mentioned "halogen" at 1 to 8 positions, for example, 1 to 5 positions. Examples thereof include trifluoromethyl, trichloromethyl, difluoroethyl, trifluoroethyl, dichloroethyl, trichloroethyl, etc. For example, C1 to C6 alkyl is substituted with the above-mentioned "halogen" at 1 to 5 positions.

[0163] In this specification, "alkenyl" includes: a linear or branched monovalent hydrocarbon group having 2 to 8 carbon atoms and having 1 or more double bonds. It may also have a triple bond in the chain. Examples include: vinyl, allyl, 1-propenyl, 2-propenyl, various butenyl isomers, etc. Examples include: C2 to C6 alkenyl. Examples include: C2 to C4 alkenyl.

[0164] In the present specification, examples of "alkenyloxy" include vinyloxy, allyloxy, 1-propenyloxy, 2-propenyloxy, and various butenyloxy groups. Examples include C2 to C6 alkenyloxy groups. Examples include C2 to C4 alkenyloxy groups.

[0165] In the present specification, examples of "alkenyloxycarbonyl" include vinyloxycarbonyl, allyloxycarbonyl, 1-propyleneoxycarbonyl, 2-propyleneoxycarbonyl, and various butenyloxycarbonyl groups. Examples include C2 to C6 alkenyloxycarbonyl. Examples include C2 to C4 alkenyloxycarbonyl.

[0166] In this specification, "alkynyl" includes: a linear or branched monovalent hydrocarbon group having 2 to 8 carbon atoms and having one or more triple bonds. Examples include: ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, various pentynyl isomers, etc. Examples include: C2 to C6 alkynyl. Examples include: C2 to C4 alkynyl.

[0167] In the present specification, examples of the "alkynyloxy group" include ethynyloxy, propynyloxy, butynyloxy, pentynyloxy, etc. Examples include C2-C6 alkynyloxy groups. Examples include C2-C4 alkynyloxy groups.

[0168] In this specification, "alkylene" used alone or in combination with other terms includes: a linear or branched divalent hydrocarbon group having 1 to 4 carbon atoms. Examples include: methylene, ethylene, propylene, butylene, etc. Examples include: C1 to C3 alkylene. Examples include: C1 to C2 alkylene.

[0169] In this specification, "aromatic carbocyclic group" used alone or in combination with other terms includes monocyclic or condensed ring aromatic hydrocarbons. Examples include: phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, etc. Examples include: phenyl, 1-naphthyl, 2-naphthyl. Examples include: phenyl.

[0170] In the present specification, the term "aromatic carbocyclic ring" includes a ring derived from the above-mentioned "aromatic carbocyclic group" and having a bond at any substitutable position. Examples thereof include benzene, naphthalene, and anthracene. Examples thereof include benzene.

[0171] In this specification, "aralkyl" includes a group in which the above-mentioned "alkyl" is substituted with one or more of the above-mentioned "aromatic carbocyclic groups", and these can be substituted at all possible positions. For example, benzyl, phenethyl (such as 2-phenethyl, etc.), phenylpropyl (such as 3-phenylpropyl, etc.), naphthylmethyl (such as 1-naphthylmethyl, 2-naphthylmethyl, etc.), anthracenemethyl (such as 9-anthracenemethyl, etc.), etc. For example, benzyl and phenethyl can be mentioned.

[0172] In this specification, "aromatic heterocyclic group" used alone or in combination with other terms includes: a 5-6-membered aromatic ring group containing one or more arbitrarily selected oxygen atoms, sulfur atoms or nitrogen atoms in the ring. It can also be condensed with the above-mentioned "aromatic carbocyclic group" or other aromatic heterocyclic groups at all possible positions. In the case where the aromatic heterocycle is either a monocyclic ring or a condensed ring, it can be combined at all possible positions. For example, pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl), isothiazolyl (e.g., 3-isothiazolyl), isoxazolyl (e.g., 3-isoxazolyl), oxazolyl (e.g., 2-oxazolyl), thiazolyl (e.g., 2-thiazolyl, 5-thiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazinyl (e.g., 2-pyrazinyl), pyrimidine yl (e.g., 2-pyrimidinyl, 4-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), triazolyl, tetrazolyl (e.g., 1H-tetrazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), indolizinyl (e.g., 2-indolizinyl, 6-indolizinyl), isoindolyl (e.g., 2-isoindolyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl), indazolyl (e.g., 3-indazolyl), purinyl (e.g., 8-purinyl), quinolizinyl (e.g., 2-quinolizinyl), isoquinolyl (e.g., 3-isoquinolyl), quinolyl (e.g., 2-quinolyl), , 5-quinolyl), phthalazinyl (e.g., 1-phthalazinyl), naphthyridinyl (e.g., 2-naphthyridinyl), quinazolinyl (e.g., 2-quinazolinyl), cinnolinyl (e.g., 3-cinnolinyl), pteridinyl (e.g., 2-pteridinyl), carbazolyl (e.g., 2-carbazolyl, 4-carbazolyl), phenanthridinyl (e.g., 2-phenanthridinyl, 3-phenanthridinyl), acridinyl (e.g., 1-acridinyl, 2-acridinyl), dibenzofuranyl (e.g., 1-dibenzofuranyl, 2-dibenzofuranyl), benzimidazolyl (e.g., 2-benzimidazolyl), benzisoxazolyl (e.g., 3-benziisoxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl), yl), benzoxadiazolyl (e.g. 4-benzoxadiazolyl), benzisothiazolyl (e.g. 3-benzoisothiazolyl), benzothiazolyl (e.g. 2-benzothiazolyl), benzofuranyl (e.g. 3-benzofuranyl), benzothiophenyl (e.g. 2-benzothiophenyl), 4,5-dihydronaphtho[1,2-d]thiazolyl, 4H-chromeno[4,3-d]thiazolyl, 4H-thiochromeno[4,3-d]thiazolyl, 4,5-dihydrothiazolo[5,4-c]quinolyl, 8H-indeno[1,2-d]thiazolyl, 5,6-dihydro-4H-3-thio-1-aza-benzo[e]azulyl, and the like.

[0173] In this specification, "aromatic heterocyclic ring" includes: a ring derived from the above-mentioned "aromatic heterocyclic group" and having a bond at any substitutable position. For example, pyrrole, furan, thiophene, imidazole, pyrazole, isothiazole, isoxazole, oxazole, thiazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, tetrazole, oxadiazole, thiadiazole, indolizine, isoindolizine, indole, indazole, purine, quinolizine, phthalazine, naphthyridine, quinazoline, cinnoline, pteridine, carbazole, phenanthridine, acridine, dibenzofuran, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzisothiazole, benzothiazole, benzofuran, benzothiophene, etc. For example, quinazoline can be mentioned.

[0174] In the present specification, the term "non-aromatic heterocyclic group" used alone or in combination with other terms includes groups derived from the following rings: non-aromatic 5- to 7-membered rings containing one or more arbitrarily selected oxygen atoms, sulfur atoms or nitrogen atoms in the ring, or rings formed by condensation of the non-aromatic 5- to 7-membered rings with one or more other "non-aromatic heterocyclic rings" or "aromatic heterocyclic rings". Examples thereof include pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl), pyrrolinyl (e.g., 3-pyrrolinyl), imidazolidinyl (e.g., 2-imidazolidinyl), imidazolinyl (e.g., imidazolinyl), pyrazolidinyl (e.g., 1-pyrazolidinyl, 2-pyrazolidinyl), pyrazolinyl (e.g., pyrazolinyl), piperidinyl (e.g., piperidino, 2-piperidinyl), piperazinyl (e.g., 1-piperazinyl, 2-piperazinyl), indolyl (e.g., 1-indolyl), isoindolyl (e.g., isoindolyl), morpholinyl (e.g., morpholino , 2-morpholinyl, 3-morpholinyl), tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, dioxolanyl, tetrahydrothiophenyl, dihydrothiopyranyl, tetrahydrothiofuranyl, decahydroisoquinolinyl, oxepinyl, dihydrooxepinyl, tetrahydrooxepinyl, oxepinyl, 4,5,6,7-tetrahydrothieno[3,2]pyridinyl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, hexahydropyrazolyl[2.1-b][1,3]oxazin-8-yl, and the like.

[0175] In this specification, "non-aromatic carbocyclic group" used alone or in combination with other terms refers to a monocyclic or bicyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group. "Non-aromatic carbocyclic group" with more than two rings also includes a group in which a ring in the above "aromatic carbocyclic group" is condensed on a monocyclic or bicyclic non-aromatic carbocyclic group.

[0176] Furthermore, the "non-aromatic carbocyclic group" also includes a group that is cross-linked as described below, or a group that forms a spiro ring.

[0177] [Chemical formula 24]

[0178]

[0179] The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like.

[0180] Examples of the non-aromatic carbocyclic group having two or more rings include indanyl, indenyl, acenaphthenyl, tetrahydronaphthyl and fluorenyl.

[0181] In the present specification, the term "acyl" includes formyl, alkylcarbonyl whose alkyl part is the above-mentioned "alkyl", haloalkylcarbonyl whose haloalkyl part is the above-mentioned "haloalkyl", alkenylcarbonyl whose alkenyl part is the above-mentioned "alkenyl", aralkylcarbonyl whose aralkyl part is the above-mentioned "aralkyl", aromatic carbocyclic carbonyl whose aromatic carbocyclic part is the above-mentioned "aromatic carbocyclic group", aromatic heterocyclic carbonyl whose aromatic heterocyclic part is the above-mentioned "aromatic heterocyclic group", non-aromatic heterocyclic carbonyl whose non-aromatic heterocyclic part is the above-mentioned "non-aromatic heterocyclic group", or non-aromatic carbocyclic carbonyl whose non-aromatic carbocyclic part is the suffix "non-aromatic carbocyclic group". Examples thereof include acetyl, propionyl, butyryl, trifluoromethylcarbonyl, vinylcarbonyl, phenylacetyl, benzoyl, and the like. The "alkyl group", "alkenyl group", "aralkyl group", "aromatic carbocyclic group", "aromatic heterocyclic group", "non-aromatic heterocyclic group" and "non-aromatic carbocyclic group" may be substituted by the substituents described below.

[0182] In the present specification, the alkyl part of "hydroxyalkyl", "alkylcarbonyl", "alkylthio" and "alkylsulfonyl" means the above-mentioned "alkyl".

[0183] In the present specification, the alkoxycarbonyl part of the "aromatic carbocyclic alkoxycarbonyl group" means the above-mentioned "alkoxycarbonyl group".

[0184] In the present specification, the aromatic carbocyclic portion of “aromatic carbocyclic alkoxycarbonyl”, “aromatic carbocyclic oxycarbonyl”, “aromatic carbocyclic carbonyloxy”, “aromatic carbocyclic carbonyl”, “aromatic carbocyclic thio”, “aromatic carbocyclic sulfonyl”, and “aromatic carbocyclic oxy” refers to the above-mentioned “aromatic carbocyclic group”.

[0185] In the present specification, the non-aromatic carbocyclic portion of “non-aromatic carbocyclic oxycarbonyl”, “non-aromatic carbocyclic carbonyloxy”, “non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic thio”, “non-aromatic carbocyclic sulfonyl”, and “non-aromatic carbocyclic oxy” refers to the above-mentioned “non-aromatic carbocyclic group”.

[0186] In the present specification, the aromatic heterocyclic moiety of "aromatic heterocyclic oxycarbonyl", "aromatic heterocyclic carbonyloxy", "aromatic heterocyclic carbonyl", "aromatic heterocyclic thio", "aromatic heterocyclic sulfonyl" and "aromatic heterocyclic oxy" means the above-mentioned "aromatic heterocyclic group".

[0187] In the present specification, the non-aromatic heterocyclic moiety of “non-aromatic heterocyclic oxycarbonyl”, “non-aromatic heterocyclic carbonyloxy”, “non-aromatic heterocyclic carbonyl”, “non-aromatic heterocyclic thio”, “non-aromatic heterocyclic sulfonyl”, and “non-aromatic heterocyclic oxy” refers to the above-mentioned “non-aromatic heterocyclic group”.

[0188] The substituents in the “substituted aromatic heterocycle”, “substituted aromatic carbocycle”, “substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted alkoxy”, “substituted alkoxycarbonyl”, “substituted alkenyloxy”, “substituted alkenyloxycarbonyl”, “substituted alkynyloxy”, “substituted aromatic carbocycle alkoxycarbonyl”, “substituted alkylene”, “substituted aromatic carbocyclic group”, “substituted non-aromatic carbocyclic group”, “substituted aromatic heterocyclic group”, “substituted non-aromatic heterocyclic group”, “substituted acyl group” and “substituted amino group” are, for example, selected from the group consisting of hydroxyl, carboxyl, halogen, halogenated alkyl (e.g., CF3, CH2CF3, CH2CCl3), alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl) ), alkenyl (e.g., vinyl), alkynyl (e.g., ethynyl), non-aromatic carbocyclic groups (e.g., cyclopropyl, cyclopropenyl), alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), halogenated alkoxy (e.g., OCF3), alkenyloxy (e.g., vinyloxy, allyloxy), aromatic carbocyclic oxy (e.g., phenoxy), alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl), nitro, nitroso, substituted amino (e.g., alkylamino (e.g., methylamino, ethylamino, dimethylamino), acylamino (e.g., acetylamino, benzoylamino), aralkylamino (e.g., benzylamino, triphenylmethylamino), hydroxyamino, alkoxycarbonylamino, alkylsulfonylamino, carbamoylamino, non-aromatic heterocyclic carbonylamino, aromatic carbocyclic sulfonylamino), azide, aromatic carbocyclic group (e.g., phenyl), aralkyl (e.g., benzyl), cyano, isocyano, isocyanate, thiocyanate, isothiocyanate, mercapto, alkylthio (e.g., methylthio), alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl), alkylsulfonyloxy (e.g., methylsulfonyloxy, ethylsulfonyloxy), substituted carbamoyl (e.g., alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl), alkylsulfonylcarbamoyl), sulfamoyl, acyl (e.g., formyl, acetyl), formyloxy , haloformyl, oxalyl (oxalo), thioformyl, thiocarboxyl, dithiocarboxyl, thiocarbamoyl, sulfino, sulfo, sulfonyl, sulfinyl, sulfoamino, hydrazine, azide, urea, amidino, guanidino, phthalimide, oxo, non-aromatic carbocyclic group, aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, alkylene, substituted alkylenedioxy (-O-CH2-O-, -O-CH2-CH2-O-, -O-CH2-CH2-CH2-O-, etc.), aromatic carbocyclic oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, alkoxycarbonyl, aromatic carbocyclic oxycarbonyl,Non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, alkylcarbonyloxy, aromatic carbocyclic carbonyloxy, non-aromatic carbocyclic carbonyloxy, aromatic heterocyclic carbonyloxy, non-aromatic heterocyclic carbonyloxy, alkylcarbonyl, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, alkylthio, aromatic carbocyclic thio, non-aromatic carbocyclic thio, aromatic heterocyclic thio, non-aromatic heterocyclic thio, alkylsulfonyl, aromatic carbocyclic sulfonyl, non-aromatic carbocyclic sulfonyl, aromatic heterocyclic sulfonyl, non-aromatic heterocyclic sulfonyl, thiocarbamoyl, sulfamoyl, etc. It may be substituted by 1 to 4 of these substituents.

[0189] In the present specification, examples of the "substituted or unsubstituted aromatic heterocyclic ring" in ring A include quinazoline, pyridine, thiazole, thiophene, imidazole, pyrazine, pyrimidine or furan. Examples of the "substituted or unsubstituted aromatic carbocyclic ring" in ring A include benzene.

[0190] In the present specification, examples of the leaving group for X include iodine.

[0191] In the present specification, examples of R include a methyl group.

[0192] In this specification, R 1 , can be listed as: Formula -YR y The group shown (wherein, -Y- is an alkylene group which may be inserted with -O-; R y phenyl or unsubstituted phenyl substituted with a substituent selected from Substituent Group P (Substituent Group P: halogen, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxycarbonyl and substituted or unsubstituted amino), pyridyl or unsubstituted pyridyl substituted with a substituent selected from Substituent Group P, furanyl or unsubstituted furanyl substituted with a substituent selected from Substituent Group P, thienyl or unsubstituted thienyl substituted with a substituent selected from Substituent Group P, thiazolyl or unsubstituted thiazolyl substituted with a substituent selected from Substituent Group P, or oxazolyl or unsubstituted oxazolyl substituted with a substituent selected from Substituent Group P).

[0193] In this specification, R 1 , can be listed as: Formula -YR y (wherein, -Y- is an alkylene group which may be inserted with -O-; R y It is a phenyl group substituted with a substituent selected from Substituent Group P or an unsubstituted phenyl group (Substituent Group P: halogen, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxycarbonyl and substituted or unsubstituted amino).

[0194] In this specification, R 1 , can be listed as: Formula -YR y(wherein, -Y- is a C1-C3 alkylene group which may be inserted with -O-; R y is phenyl substituted by halogen or unsubstituted phenyl).

[0195] In this specification, R 2 , examples include: a hydrogen atom or a halogen.

[0196] In this specification, R 3 , examples include: a hydrogen atom or a halogen.

[0197] In this specification, R 4 Examples thereof include a substituted or unsubstituted non-aromatic heterocyclic group, and a substituted or unsubstituted amino group.

[0198] In this specification, R 4 , examples include substituted or unsubstituted non-aromatic heterocyclic groups.

[0199] In this specification, R 4 The "non-aromatic heterocyclic group" in the formula (a) includes morpholinyl, pyrrolidinyl and piperazinyl.

[0200] In this specification, R 4 As for the substituent of the "substituted amino group", for example, an alkyl group (including a hydroxyalkyl group and an alkoxyalkyl group) and a non-aromatic carbocyclic group can be mentioned.

[0201] In this specification, R 4 The substituent of the "substituted non-aromatic heterocyclic group" in the above-mentioned may be, for example, a hydroxyl group.

[0202] In this specification, R 5 , examples include substituted or unsubstituted C1-C3 alkylene.

[0203] In this specification, R 5 , examples include unsubstituted C1-C3 alkylene.

[0204] In this specification, R 5 , examples include substituted or unsubstituted C1-C2 alkylene groups.

[0205] In this specification, R 5 , examples include unsubstituted C1-C2 alkylene.

[0206] In the present specification, "the compound represented by formula (I)", "the compound represented by formula (I')", "the compound represented by formula (I")", "the compound represented by formula (I'")", "the compound represented by formula (II)", "the compound represented by formula (II')", "the compound represented by formula (II")", "the compound represented by formula (III)", "the compound represented by formula (IV)", "the compound represented by formula (V)" and "the compound represented by formula (V')" can form salts. For example, the compound can form salts with alkali metals (such as lithium, sodium, potassium, etc.), alkaline earth metals (such as calcium, barium, etc.), magnesium, transition metals (such as zinc, iron, etc.), ammonia, organic Salts with bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline, etc.) and amino acids; or salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.). In particular, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid, etc. can be mentioned. These salts can be formed by commonly performed methods.

[0207] In addition, the above-mentioned compound can form a solvate. For example, sometimes a solvate (such as a hydrate, etc.) and / or a polymorph is formed, and the present invention also includes such various solvates and polymorphs. With respect to a "solvate", the compound can be coordinated with any number of solvent molecules (such as water molecules, etc.). This includes the case where moisture is absorbed by placing the compound or its salt in the atmosphere, adsorbed water is attached, and a hydrate is formed. In addition, sometimes these polymorphs are formed by recrystallizing the compound or its salt.

[0208] Effects of the Invention

[0209] The Sonogashira carbonylation reaction can produce compounds represented by formula (II), (II') and (II") which are useful as manufacturing intermediates in high yield. In addition, the compounds represented by formula (II), (II') and (II") can be produced with fewer steps than the existing methods (Patent Document 1 and Patent Document 2), which is an industrially excellent production method.

[0210] Furthermore, in large-scale synthesis, a rapid increase in heat generation is dangerous. However, if the Sonogashira carbonylation reaction is carried out in the presence of crystals of the novel compound of the present invention, the reaction heat can be controlled.

[0211] Furthermore, by adding an appropriate ligand (additive) to the Sonogashira carbonylation reaction, the precipitation of palladium black in the reaction vessel can be suppressed.

[0212] Furthermore, the novel crystal of the compound represented by formula (II") can be used as an intermediate of useful drugs.

[0213] A brief description of the diagram

[0214] Figure 1 The powder X-ray diffraction pattern of the crystals of Compound 3 [methanesulfonate of the compound represented by formula (II”)] is shown.

[0215] Figure 2 The structure of the asymmetric unit of the crystal of Compound 4 (a complex containing N-methylmorpholine, hydroiodic acid, and dimethyl sulfoxide) is shown.

[0216] Figure 3 The figure shows a powder X-ray diffraction pattern of crystals of Compound 4 (a complex containing N-methylmorpholine, hydroiodic acid, and dimethyl sulfoxide).

[0217] Figure 4 The DSC analysis results of the crystals of Compound 4 (a complex containing N-methylmorpholine, hydroiodic acid, and dimethyl sulfoxide) are shown.

[0218] Figure 5 The heat of reaction of the Sonogashira carbonylation reaction in the absence of a complex crystal containing N-methylmorpholine, hydroiodic acid, and dimethyl sulfoxide is shown.

[0219] Figure 6 The heat of reaction of the Sonogashira carbonylation reaction in the presence of a complex crystal containing N-methylmorpholine, hydroiodic acid, and dimethyl sulfoxide is shown.

[0220] Figure 7 The TG / DTA analysis results of the crystals of Compound 4 (a complex containing N-methylmorpholine, hydroiodic acid, and dimethyl sulfoxide) are shown. DETAILED DESCRIPTION

[0221] The present invention comprises a process for producing a compound represented by formula (II), characterized in that the compound represented by formula (I) is reacted with carbon monoxide and a compound represented by formula (III) in the presence of a palladium catalyst, a phosphine ligand, a catalyst containing an element of Group 11, and a base.

[0222] [Chemical formula 25]

[0223]

[0224] (wherein, Ring A is a substituted or unsubstituted aromatic heterocycle, or a substituted or unsubstituted aromatic carbocycle; X is a leaving group)

[0225] [Chemical formula 26]

[0226]

[0227] (where R is a hydrogen atom or a methyl group)

[0228] [Chemical formula 27]

[0229]

[0230] (wherein, ring A and R have the same meanings as above).

[0231] The compound represented by formula (I) among the starting materials can be produced according to the method described in Patent Document 1. Alternatively, it can be produced according to a known method using a commercially available reagent, or a commercially available product can be used.

[0232] The solvent is not particularly limited as long as it does not inhibit the reaction, and dimethylacetamide (DMA), tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) and mixed solvents thereof can be used. For example, a mixed solvent of tetrahydrofuran and dimethyl sulfoxide can be used.

[0233] The reaction temperature is usually carried out in the range of room temperature to solvent reflux temperature. For example, it can be carried out in the range of -10 to 60°C. For example, it can be carried out in the range of 20 to 30°C.

[0234] The compound represented by formula (III) can be used in an amount of usually 1.0 to 5.0 equivalents, for example 2.0 to 3.0 equivalents, for example 2.2 to 2.5 equivalents, relative to the compound represented by formula (I).

[0235] The compound represented by formula (III) may be introduced into the reaction vessel by bubbling. As another method, a solution in which the compound represented by formula (III) is dissolved in a solvent in advance may be prepared and the solution may be introduced into the reaction vessel.

[0236] In the case of large-scale synthesis, the compound represented by formula (III) can be introduced into the reaction vessel for a period of time generally from 0.2 to 10 hours, for example from 6 to 8 hours.

[0237] As a method for introducing carbon monoxide into the reaction container, the interior of the reaction container may be replaced with carbon monoxide before the start of the reaction. As another method, carbon monoxide may be introduced by bubbling.

[0238] The reaction can be carried out under atmospheric pressure or under increased pressure as for the pressure in the reaction container.

[0239] When the reaction is carried out under pressure, the pressure in the reaction container can be, for example, 0.01 to 0.5 MPa, for example, 0.1 to 0.3 MPa.

[0240] As palladium catalyst, Pd2(dba)3, PdCl2dppf, PdCl2(PPh3)2, Pd(OAc)2, Pd(PPh3)4, Pd / C, PdCl2, Pd-PEPPSI can be used. TM -IPr, bis-cinnamoyl palladium chloride, PdCl2 (Xantphos), Pd(OH)2, etc. Commercially available palladium catalysts used in various cross-coupling reactions (Negishi, Heck, Suzuki, Sonogashira, Stille, Buchwald-Hartwig, etc.) can be used. In addition, it can be synthesized by a known method from a commercially available palladium catalyst precursor. For example, the following palladium catalysts can be used.

[0241] Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0),

[0242] PdCl2dppf: [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct; [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct,

[0243] PdCl2(PPh3)2: Bis(triphenylphosphine)palladium(II)dichloride;

[0244] Pd(OAc)2: Palladium(II) acetate; Palladium(II)diacetate,

[0245] Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0),

[0246] Pd / C: Palladium on carbon;

[0247] PdCl2: Palladium(II) chloride;

[0248] Pd-PEPPSI TM -IPr: [1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)dichloride; [1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloro pyridyl)palladium(II)dichloride,

[0249] Bis[cinnamyl palladium(II)chloride]

[0250] PdCl2(Xantphos): Dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II);

[0251] Pd(OH)2: Palladium hydroxide.

[0252] For example, PdCl2dppf, PdCl2(PPh3)2, Pd2(dba)3, and Pd(OAc)2 can be mentioned.

[0253] For example, Pd2(dba)3 can be cited.

[0254] The amount of the palladium catalyst used is usually a catalytic amount, for example, 0.001 to 0.1 equivalents, for example 0.001 to 0.01 equivalents, relative to the compound represented by formula (I).

[0255] As the phosphine ligand, Xantphos, P(2-furyl)3, PPh3, P(o-tol)3, P(OPh)3, P(OMe)3, dppp, dppb, dppf, BINAP, X-Phos, P(t-Bu)3, P(Oi-Pr)3, P(p-MeOPh)3 or DPEpHos etc. can be used. Commercially available phosphine ligands used in various cross-coupling reactions (Negishi, Heck, Suzuki, Sonogashira, Stille, Buchwald-Hartwig etc.) can be used. In addition, it is possible to synthesize by a known method from a commercially available phosphine ligand precursor. For example, the following phosphine ligands can be used.

[0256] Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene,

[0257] P(2-furyl)3: Tri(2-furyl)phosphine;

[0258] PPh3: Triphenylphosphine; Triphenylphosphine,

[0259] P(o-tol)3: Tri(o-tolyl)phosphine,

[0260] P(OPh)3: Triphenyl phosphite;

[0261] P(OMe)3: Trimethyl phosphite;

[0262] dppp: 1,3-Bis(diphenylphosphino)propane; 1,3-Bis(diphenylphosphino)propane,

[0263] dppb: 1,4-bis(diphenylphosphino)butane; 1,4-Bis(diphenylphosphino)butane,

[0264] dppf: 1,1'-Bis(diphenylphosphino)ferrocene; 1,1'-Bis(diphenylphosphino)ferrocene,

[0265] BINAP: 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl,

[0266] X-Phos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl,

[0267] P(t-Bu)3: Tri-tert-butylphosphine;

[0268] P(Oi-Pr)3: Triisopropyl phosphite,

[0269] P(p-MeOPh)3: Tris(4-methoxyphenyl)phosphine,

[0270] DPEPhos: Bis[2-(diphenylphosphino)phenyl]ether; Bis[2-(diphenylphosphino)phenyl]Ether.

[0271] For example, PPh3, P(o-tol)3, P(OPh)3, P(2-furyl)3, and Xantphos can be mentioned.

[0272] For example, Xantphos can be mentioned.

[0273] The phosphine ligand can be used in a catalytic amount, for example, 0.001 to 0.1 equivalents, for example 0.01 to 0.03 equivalents, relative to the compound represented by formula (I).

[0274] Group 11 elements include copper, silver and gold.

[0275] Examples of the catalyst containing an element of Group 11 include copper (I) iodide, copper (II) iodide, cuprous (I) chloride, copper (II) chloride, cuprous (I) acetate, copper (II) acetate, copper (II) oxide, cuprous (I) bromide, copper (II) bromide, or silver acetate.

[0276] For example, cuprous chloride (I), cuprous acetate (I), and cuprous bromide (I) can be mentioned.

[0277] For example, copper (I) chloride can be mentioned.

[0278] The amount of the catalyst containing an element of Group 11 to be used is usually a catalytic amount, for example, 0.001 to 0.5 equivalents, for example, 0.01 to 0.1 equivalents, relative to the compound represented by formula (I).

[0279] Examples of the base include N-methylmorpholine, triethylamine, diisopropylethylamine, pyridine, DABCO (1,4-diazabicyclo[2.2.2]octane), N,N-dimethylbenzylamine, N,N-dimethylaniline, sodium acetate, potassium carbonate, sodium carbonate or potassium phosphate, metal hydrides (e.g., sodium hydride), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), metallic sodium, and alkyl lithiums (n-BuLi, sec-BuLi, tert-BuLi).

[0280] Examples of the base include N-methylmorpholine, triethylamine, diisopropylethylamine, pyridine, DABCO (1,4-diazabicyclo[2.2.2]octane), N,N-dimethylbenzylamine, N,N-dimethylaniline, sodium acetate, potassium carbonate, sodium carbonate or potassium phosphate.

[0281] For example, N-methylmorpholine, triethylamine, diisopropylethylamine, and pyridine can be mentioned.

[0282] For example, N-methylmorpholine can be mentioned.

[0283] The base can be used in an amount of usually 2 to 10 equivalents, for example 2 to 8 equivalents, for example 3 to 5 equivalents, relative to the compound represented by formula (I).

[0284] The above step can be further reacted in the presence of the following compounds: N,N-dimethylglycine, picolinic acid, L-proline, N,N-diethyl-2-hydroxybenzamide, ethylene glycol, ethyl 2-cyclohexanonecarboxylate, 2-acetylcyclohexanone, 2-hydroxybenzoic acid, furan-2-carboxylic acid, diethyl malonate, N,N-dimethylethylenediamine, acetic acid, copper (I) 2-thiophenecarboxylate, glycine, N-methylglycine, D-proline, N-methylproline, imidazole-4-carboxylic acid, oxazole-4-carboxylic acid, thiazole-4-carboxylic acid, imidazole-2-carboxylic acid, oxazole-2-carboxylic acid, thiazole- 2-carboxylic acid, pyrrole-2-carboxylic acid, isoxazole-5-carboxylic acid, isoxazole-3-carboxylic acid, alanine, valine, leucine, isoleucine, N,N-dimethyl-2-aminobenzoic acid, ethanolamide, formic acid, propionic acid, butyric acid, oxalic acid, maleic acid, trifluoroacetic acid, malonic acid ester, acetoacetate, ethylene glycol dimethyl ether, 2-methoxyethanol, glycolic acid, glycolic acid ester, 1,3-propylene glycol, 1,4-butanediol, 1,5-pentanediol, diethylene glycol, catechol, 2-hydroxymethyl-1,3-propanediol, N,N-dimethylurea, N,N-diphenylurea or N,N-dimethylglycinamide, etc.

[0285] The reaction can be carried out in the presence of compounds such as N,N-dimethylglycine, picolinic acid, L-proline, N,N-diethyl-2-hydroxybenzamide, ethylene glycol, ethyl 2-cyclohexanonecarboxylate, 2-acetylcyclohexanone, 2-hydroxybenzoic acid, furan-2-carboxylic acid, diethyl malonate, N,N-dimethylethylenediamine, acetic acid, and copper(I)-2-thiophenecarboxylate.

[0286] The reaction can be carried out in the presence of compounds such as N,N-dimethylglycine, picolinic acid, and ethylene glycol.

[0287] The reaction can be carried out in the presence of, for example, N,N-dimethylglycine.

[0288] The above step can be carried out in the presence or absence of the above compound.

[0289] When the above step is carried out in the presence of the above compound, a catalytic amount may be used relative to the compound represented by formula (I). For example, 0.01 to 0.5 equivalents, or 0.02 to 0.1 equivalents may be used.

[0290] As described in Test Example 3 below, when the above step is carried out in the presence of the above compound, deactivation of the palladium catalyst can be suppressed.

[0291] It should be noted that the above compounds can be used in other reactions using a palladium catalyst (for example, Negishi, Heck, Suzuki, Sonogashira, Stille, Buchwald-Hartwig, etc.) in addition to the Sonogashira carbonylation reaction of the present invention.

[0292] In the above step, when the compound represented by formula (I) is a compound represented by formula (I'), formula (I"), or formula (I'") and the base is N-methylmorpholine, the reaction can be further carried out in the presence of a crystal of a complex containing N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide.

[0293] [Chemical formula 28]

[0294]

[0295] (wherein, ring A has the same meaning as above):

[0296] [Chemical formula 29]

[0297]

[0298] (Where R 1 , R 2 and R 3 Same meaning as above):

[0299] [Chemical formula 30]

[0300]

[0301] The above step can be carried out in the presence or absence of a crystal of a complex containing N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide.

[0302] When the above step is carried out in the presence of a crystal of a complex containing N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide, 0.1 to 61%, for example 1 to 10%, for example 2 to 4%, based on the compound represented by formula (I'), formula (I") or formula (I'") can be used.

[0303] As described in Experimental Example 1 below, when the above step is carried out in the presence of a crystal of a complex containing N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide, a rapid increase in reaction heat can be prevented.

[0304] In this specification, the complex includes crystalline and amorphous.

[0305] In the present specification, the term "crystals of a complex containing N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide" includes crystals of a complex containing hydroiodide of N-methylmorpholine and a dimethyl sulfoxide solvate.

[0306] In the present specification, the term “crystal of a complex containing N-methylmorpholine, hydroiodic acid, and dimethyl sulfoxide” includes a co-crystal containing hydroiodide of N-methylmorpholine and a dimethyl sulfoxide solvate.

[0307] When the compound represented by formula (II) is the following compound, the reaction can be carried out under the same reaction conditions as above.

[0308] [Chemical formula 31]

[0309]

[0310] In addition, in the compound represented by formula (II), when ring A is a substituted or unsubstituted aromatic heterocycle (e.g., benzene, etc.), or a substituted or unsubstituted aromatic carbocycle (e.g., quinazoline, pyridine, thiazole, thiophene, imidazole, pyrazine, pyrimidine or furan, etc.), the reaction can also be carried out under the same reaction conditions as above.

[0311] Furthermore, the present invention includes a step of obtaining a mesylate salt of the compound represented by formula (II") or a crystal thereof obtained by the above step.

[0312] After the reaction in the above step is completed, methanesulfonic acid is added to the reaction solution, thereby producing a methanesulfonate salt of the compound represented by formula (II") or a crystal thereof.

[0313] As the solvent, the solvent used in the above step can be used. In addition, after the reaction in the above step is completed, the solvent can be added again. For example, acetonitrile and tetrahydrofuran can be used. For example, acetonitrile can be used.

[0314] The reaction temperature can be in the range of -10°C to 40°C. For example, the reaction can be in the range of -5°C to 25°C.

[0315] The amount of methanesulfonic acid used can be generally 2 to 10 equivalents, for example 3 to 8 equivalents, for example 4.0 to 5.5 equivalents, relative to the compound represented by formula (I'').

[0316] The present invention includes a step of converting a methanesulfonate salt or crystals thereof of a compound represented by formula (II”) into a free form of the compound represented by formula (II”). The free form of the compound represented by formula (II”) can be produced by treating a methanesulfonate salt or crystals thereof of the compound represented by formula (II”) with a base.

[0317] The solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include methanol, ethanol, isopropanol, etc. For example, methanol can be used.

[0318] The reaction temperature can be in the range of -20°C to 40°C. For example, the reaction can be in the range of -5°C to 10°C.

[0319] As the base, the bases described in the above step can be used, and for example, N-methylmorpholine can be used.

[0320] The base can be used in an amount of usually 1 to 5 equivalents, for example, 1 to 3 equivalents, for example, 1 to 1.5 equivalents, relative to the methanesulfonate of the compound represented by formula (II") or its crystals.

[0321] Furthermore, the present invention includes a step of producing a crystal of a complex containing N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide.

[0322] Commercially available N-methylmorpholine, hydroiodic acid (preferably an aqueous solution), and dimethyl sulfoxide (DMSO) can be used as starting materials.

[0323] The solvent is not particularly limited as long as it does not inhibit the reaction, and tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) and a mixed solvent thereof can be used.

[0324] The reaction temperature can usually be in the range of -20°C to 70°C, for example, 0°C to 30°C, for example, 5°C to 25°C.

[0325] The amount of hydroiodic acid (aqueous solution) used can usually be 1.0 to 2 equivalents, for example 1.0 to 1.5 equivalents, for example 1.0 to 1.1 equivalents, relative to N-methylmorpholine.

[0326] The amount of dimethyl sulfoxide (DMSO) used relative to N-methylmorpholine may generally be the amount of the solvent used, and can be, for example, 80% to 3000%, for example 80% to 800%.

[0327] As another method, the Sonogashira carbonylation reaction described above can be carried out using a compound represented by formula (I'), formula (I") or formula (I'") as a starting material, using N-methylmorpholine as a base, and using dimethyl sulfoxide or a mixed solvent thereof (for example, a mixed solvent with tetrahydrofuran (THF)) as a solvent, and using crystals of a complex containing N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide obtained as a by-product.

[0328] The method for identifying the crystal of the present invention is described below.

[0329] Unless otherwise stated, the numerical values ​​described in this specification and claims are approximate values. The numerical values ​​may vary due to device calibration, device error, material purity, crystal size, sample size, and other factors.

[0330] As used in this specification, "crystal" refers to a structure in which atoms, ions, molecules, etc. constituting a solid have a regular and orderly arrangement and thus have a periodic and anisotropic structure. The crystallinity of a crystalline form can be measured by a variety of techniques including, for example, powder X-ray diffraction measurement, water adsorption and desorption measurement, differential scanning calorimetry, solution colorimetry, and solubility characteristics.

[0331] Typically, crystalline organic compounds are composed of atoms arranged periodically in three-dimensional space. The structural periodicity usually manifests itself in physical properties that can be clearly distinguished by most spectroscopic probes (e.g., X-ray diffraction, infrared spectroscopy, Raman spectroscopy, and solid-state NMR).

[0332] Among them, powder X-ray diffraction (XRPD) is one of the most sensitive and excellent analytical methods for measuring the crystallinity of solids. When X-rays are irradiated to crystals, reflections occur on the lattice planes and interfere with each other, and only the intensity of the diffraction lines in the direction that satisfies the conditions that can be predicted by the Bragg rule increases, showing ordered diffraction lines corresponding to the periodicity of the structure. On the other hand, for amorphous solids, no wide range of ordered diffraction lines is observed. Amorphous solids usually do not have an ordered repetition period in their structure, so no diffraction phenomenon occurs, showing a wide XRPD pattern called a halo pattern.

[0333] The crystals of the methanesulfonate salt of the compound represented by formula (II") and the crystals of the complex containing N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide disclosed in the present invention have a powder X-ray diffraction pattern.

[0334] For example, crystals can be identified by the presence of characteristic diffraction peaks. The characteristic diffraction peaks used in this specification are peaks selected from the observed diffraction patterns. Preferably, the characteristic peaks are selected from about 20, more preferably about 10, and most preferably about 5 in the diffraction pattern.

[0335] Generally, the diffraction angle (2θ) in powder X-ray diffraction can have an error within the range of ±0.2°, so the above-mentioned diffraction angle value needs to be understood as also including a numerical value within the range of about ±0.2°. Therefore, not only crystals with completely consistent diffraction angles of peaks in powder X-ray diffraction, but also crystals with consistent diffraction angles of peaks within an error of about ±0.2° are included in the present invention.

[0336] It is generally known that the intensity of the peaks shown in the tables and figures described below may vary due to a variety of factors: for example, the selective orientation effect of crystals on the X-ray beam, the influence of coarse particles, the purity of the analyzed substance, or the crystallinity of the sample. In addition, the peak position may also move based on changes in the sample height. Further, when different wavelengths are used for measurement, different displacements will be obtained according to the Bragg equation (nλ=2dsinθ), and such different XRPD patterns obtained by using different wavelengths are also included in the scope of the present invention.

[0337] Single crystal structure analysis (see "Handbook of X-ray Structure Analysis" by Toshio Sakurai, published by Sanghuafang (1983), X-Ray Structure Determination: A Practical Guide by Stout & Jensen, Macmillan Co., New York (1968), etc.) is one of the methods for identifying crystals, which can obtain the crystallographic parameters in the crystals, and further obtain the atomic coordinates (values ​​representing the spatial position relationship of each atom) and the three-dimensional structure model. Single crystal structure analysis is useful in identifying the structure of the crystals of the composite of the present invention.

[0338] The crystals of the methanesulfonate salt of the compound represented by formula (II") and the crystals of the complex containing N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide produced in the above step are stable and easy to handle for the above step, and therefore are useful crystals as intermediates for producing pharmaceutical compositions.

[0339] The crystals of the present invention can also be identified by thermal analysis.

[0340] Among them, DSC (differential scanning calorimetry) is one of the main measurement methods of thermal analysis, and is a method for measuring the thermal properties of a substance in the form of an aggregate of atoms and molecules.

[0341] The temperature or time-dependent heat changes of active pharmaceutical ingredients are measured by DSC, and the obtained data are plotted against temperature or time to obtain a differential scanning calorimetry curve. From the differential scanning calorimetry curve, the starting point temperature of the active pharmaceutical ingredient when it melts, the maximum value of the endothermic peak curve accompanying the melting, and enthalpy-related information can be obtained.

[0342] Regarding DSC, it is known that the observed temperature can depend on the temperature change rate and the sample preparation method and specific equipment used. Therefore, the "melting point" in DSC refers to the starting point temperature that is not easily affected by the sample preparation method. The error range of the starting point temperature obtained from the differential scanning calorimetry curve is about ±2°C. In determining the sameness of crystals, not only the melting point but also the overall pattern is important, which can vary slightly due to the measurement conditions and measurement equipment.

[0343] Among them, TG / DTA (differential thermal / thermogravimetric simultaneous measurement) is one of the main measurement methods of thermal analysis, and is a method for measuring the weight and thermal properties of a substance in the form of an aggregate of atoms and molecules.

[0344] TG / DTA is a method for measuring the weight and caloric changes of active pharmaceutical ingredients in relation to temperature or time. By plotting the obtained data against temperature or time, TG (thermogravimetric) and DTA (differential thermal) curves are obtained. From the TG / DTA curve, information on the weight and caloric changes associated with the decomposition, dehydration, oxidation, reduction, sublimation, and evaporation of active pharmaceutical ingredients can be obtained.

[0345] Regarding TG / DTA, it is known that the observed temperature and weight changes may depend on the temperature change rate and the sample preparation method and specific equipment used. Therefore, the "melting point" in TG / DTA refers to the starting point temperature that is not easily affected by the sample preparation method. In determining the crystal homogeneity, not only the melting point but also the overall pattern is important, which may vary slightly due to the measurement conditions and measurement equipment.

[0346] The present invention is further described in detail by the following examples. These do not limit the present invention. Although efforts are made to ensure the accuracy of numerical values ​​(such as amounts, temperatures, etc.), slight errors and deviations should also be taken into account. Unless otherwise specified, % represents the weight % of the component and the weight % of the total weight of the composition. Unless otherwise specified, the pressure is atmospheric pressure or a pressure close to atmospheric pressure.

[0347] Other abbreviations used in this manual are defined as follows:

[0348] g: grams

[0349] L: Lift

[0350] mg: milligram

[0351] mL: milliliters

[0352] MeCN: Acetonitrile

[0353] DMSO: dimethyl sulfoxide

[0354] THF: Tetrahydrofuran

[0355] DMA: dimethylacetamide

[0356] MsOH: Methanesulfonic acid

[0357] NMM: N-methylmorpholine

[0358] CO: Carbon monoxide

[0359] rt: room temperature

[0360] HPLC: High Performance Liquid Chromatography

[0361] (Determination of powder X-ray diffraction pattern)

[0362] The powder X-ray diffraction measurement of the crystals obtained in each example was performed in accordance with the powder X-ray diffraction measurement method described in the Common Test Methods of the Japanese Pharmacopoeia under the following measurement conditions.

[0363] (Method A)

[0364] (Device)

[0365] RINT-TTRIII manufactured by Rigaku

[0366] (Operation method)

[0367] The samples were measured under the following conditions.

[0368] Measurement method: Reflectometer

[0369] Type of light source: Cu tube ball

[0370] Use wavelength: CuKα ray

[0371] Tube current: 300mA

[0372] Tube voltage: 50kV

[0373] Sample plate: Aluminum

[0374] X-ray incident angle (θ): 2-40°

[0375] Sampling amplitude: 0.020°

[0376] (Method B)

[0377] (Device)

[0378] Buker D-8Discover

[0379] (Operation method)

[0380] The samples were measured under the following conditions.

[0381] Measurement method: Reflectometer

[0382] Type of light source: Cu tube ball

[0383] Use wavelength: CuKα ray

[0384] Tube current: 40mA

[0385] Tube voltage: 40kV

[0386] Sample plate: Glass

[0387] X-ray incident angle: 3-40°

[0388] (Single crystal structure analysis)

[0389] Single crystal diffraction data were collected using a single crystal automatic X-ray structure analysis device (R-AXIS RAPIDII-R) manufactured by Rigaku Corporation. CuKα monochromated by a graphite monochromator was irradiated at -173.0°C in a light-shielded environment using a sample blowing cryostat. Data were measured and processed using the program RAPID AUTO (Rigaku, 2006) manufactured by Rigaku Co., Ltd. The data were subjected to Lorentz and polarization corrections and absorption corrections.

[0390] The crystal structure was phase determined using the direct method program SHELXS97 (Sheldrick, 2008), and the full-matrix least squares method was used for refinement using SHELXL97 (Sheldrick, 2008). The temperature factors of non-hydrogen atoms were all refined by anisotropy. The hydrogen atoms on nitrogen (N1) were derived from the difference Fourier map, and the remaining hydrogen atoms were imported by calculation using the default parameters of SHELXL97 and all were treated as riding atoms. R1 (I>2.00s(I)) was 0.0532, and the final difference Fourier confirmed the absence of missing and misplaced electron density.

[0391] Figure 2 In the plotting of , PLUTON (Spek, 1991) / ORTEP (Johnson, 1976) (50% probability level) was used.

[0392] (DSC data measurement)

[0393] About 1 mg of each crystal obtained in each example was weighed, placed in a gold-plated stainless steel high pressure plate, and measured in a closed system. The measurement conditions are as follows.

[0394] (Measurement conditions)

[0395] Device: DSC822e manufactured by Mettler-Toledo International GmbH

[0396] Measuring temperature range: 25℃-300℃

[0397] Heating rate: 10℃ / min

[0398] (TG / DTA data measurement)

[0399] About 10 mg of each crystal obtained in each example was weighed and placed in an aluminum pan, and the measurement was performed in an open system. The measurement conditions are as follows.

[0400] (Measurement conditions)

[0401] Device: TG / DTA7200 made by Hitachi Hakusui Co., Ltd.

[0402] Measuring temperature range: 30℃-300℃

[0403] Heating rate: 10℃ / min

[0404] (NMR measurement)

[0405] When NMR data are shown, not all measured peaks may be shown.

[0406] (HPLC determination)

[0407] (Method A)

[0408] Column: Unison UK-C18, φ4.6×150mm, 3μm (Imtakt)

[0409] Flow rate: 1.0 mL per minute

[0410] UV detection wavelength: 246nm

[0411] Mobile phase A: 0.01 mol / L ammonium acetate aqueous solution (pH 5.0)

[0412] Mobile phase B: acetonitrile for liquid chromatography

[0413] The gradient program is shown in Table 2.

[0414] [Table 2]

[0415] Time after injection (minutes) Mobile phase A (vol%) Mobile phase B (vol%) 0～10 40 60 10～20 40→10 60→90 20～25 10 90 25～25.1 10→40 90→60 25.1～30 40 60

[0416] (Method B)

[0417] Column: Unison UK-C18, φ4.6×150mm, 3μm (Imtakt)

[0418] Flow rate: 1.0 mL per minute

[0419] UV detection wavelength: 246nm

[0420] Mobile phase A: 0.01 mol / L ammonium acetate aqueous solution (pH 5.0)

[0421] Mobile phase B: acetonitrile for liquid chromatography

[0422] Table 3 shows the gradient program used for the purity measurement.

[0423] [Table 3]

[0424] Time after injection (minutes) Mobile phase A (vol%) Mobile phase B (vol%) 0～10 40 60 10～20 40→10 60→90 20～25 10 90 25～25.1 10→5 90→95 25.1～35 5 95 35～35.1 5→40 95→60 35.1～45 40 60

[0425] It should be noted that the retention time of HPLC should be understood to include a slight error.

[0426] Example 1

[0427] Synthesis of compound 2:

[0428] [Chemical formula 32]

[0429]

[0430] To aryl iodide (1) (4.04 g), Pd2(dba)3 (36.6 mg, 0.005 equivalent), Xantphos (92.6 mg, 0.02 equivalent), CuCl (15.8 mg, 0.02 equivalent) were added tetrahydrofuran (6 mL), N-methylmorpholine (4.04 g, 5 equivalent), and dimethyl sulfoxide (2 mL) in sequence. Under a carbon monoxide atmosphere and stirring at 25°C, a solution (about 2 mol / L) in which propyne gas (2.2 equivalent) was dissolved in tetrahydrofuran in advance was introduced over about 0.5 hours, followed by stirring for about 19 hours. After completion of the reaction, the interior of the container was replaced with nitrogen, acetonitrile (40.4 mL) was added, and the mixture was stirred at 0°C for about 1 hour, filtered, and the crystals were washed with cooled acetonitrile (12.1 mL) to obtain compound (2) (3.38 g, yield 95%, purity 81% (HPLC method B)).

[0431] 1 H-NMR (300MHz, DMSO-D6) δ: 10.33 (1.0H, s), 9.22 (1.1H, d, J=1.7Hz), 8.65 (0.8H, s) ), 8.43 (1.1H, dd, J = 8.6, 1.7Hz), 7.98 (0.9H, d, J = 2.4Hz), 7.87 (0.9H, d, J = 8.6Hz) , 7.71 (1.0H, dd, J=9.0, 2.4Hz), 7.47 (1.0H, ddd, J=8.0, 8.0, 5.8Hz), 7.34-7.30 (2 .0H,m),7.28(1.0H,d,J=9.0),7.21-7.14(0.9H,m),5.27(2.0H,s),2.28(2.9H,s).

[0432] Elemental Analysis:

[0433] Calculated values: C, 67.34; H, 3.84; N, 9.42; Cl, ​​7.95; F, 4.26

[0434] Found: C, 67.24; H, 3.92; N, 9.39; Cl, ​​7.81; F, 4.26

[0435] Example 2

[0436] Synthesis of compound 2:

[0437] [Chemical formula 33]

[0438]

[0439] (Synthesis of Compound 3 in Step 1)

[0440] Under nitrogen atmosphere, tetrahydrofuran (110 L), N-methylmorpholine (40 kg, 4 equivalents), and dimethyl sulfoxide (25 L) were added to aryl iodide (1) (50.0 kg), Pd2(dba)3 (0.68 kg, 0.0075 equivalents), Xantphos (1.72 kg, 0.03 equivalents), CuCl (0.59 kg, 0.06 equivalents), compound (4) obtained in Example 4 described later (1.5 kg), and N,N-dimethylglycine (0.41 kg, 0.04 equivalents) in this order. The mixture was stirred at 25° C. under carbon monoxide atmosphere, and propyne gas (9.1 kg, 2.3 equivalents) was introduced into the container over about 7 hours, followed by further stirring for about 5 hours. After completion of the reaction, the interior of the container was replaced with nitrogen, acetonitrile (500 L) was added at 20° C., and then methanesulfonic acid (47.5 kg, 5 equivalents) was added at 5° C. After stirring for 1 hour, the mixture was filtered and the crystals were washed with cooled acetonitrile (250 L) to obtain compound (3).

[0441] 1 H-NMR(DMSO-D6)δ:11.62(0.7H,brs),9.33(1.2H,s),8.94(1.1H,s),8.63(1.1H, d,J=8.6Hz),7.96(2.0H,d,J=8.6Hz),7.90(2.0H,d,J=2.3Hz),7.63(1.1H,dd,J= 8.9, 2.3Hz), 7.48 (0.9H, ddd, J = 7.8, 7.8, 6.3Hz), 7.36 (1.0H, d, J = 8.9Hz), 7.34- 7.30 (2.0H, m), 7.22-7.16 (0.8H, m), 5.31 (2.0H, s), 2.32 (2.4H, s), 2.29 (3.0H, s)

[0442] The results of powder X-ray diffraction (XRPD method A) are shown in Figure 1 And Table 4.

[0443] [Table 4]

[0444] 2θ 5.620 8.280 9.760 13.740 14.520 16.460 16.960 17.860 18.320 19.240 19.760 20.500 21.260 21.760 22.600 23.080 24.420 25.960 26.360 27.840 29.120 36.720

[0445] In the powder X-ray diffraction pattern, peaks were confirmed at diffraction angles (2θ): 5.6°±0.2°, 9.8°±0.2°, 17.9°±0.2°, 24.4°±0.2°, and 26.4°±0.2°.

[0446] (Synthesis of Compound 2 in Step 2)

[0447] Methanol (475 L) was added to the compound (3) obtained in step 1, and N-methylmorpholine (11.0 kg, 1.1 equivalent) was added dropwise at 0° C. After stirring for about 1 hour, the mixture was filtered and the crystals were washed with cooled methanol to obtain compound (2) (41.4 kg, yield 94%, purity 93% (HPLC method B)).

[0448] Example 3

[0449] Synthesis of compound 3:

[0450] [Chemical formula 34]

[0451]

[0452] To aryl iodide (1) (27.5 g), Pd2(dba)3 (374 mg, 0.0075 equivalent), Xantphos (943 mg, 0.03 equivalent), CuCl (323 mg, 0.06 equivalent), N,N-dimethylglycine (224 mg, 0.04 equivalent) were added tetrahydrofuran (60.5 mL), N-methylmorpholine (22.0 g, 4 equivalent), and dimethyl sulfoxide (13.8 mL) in sequence. The mixture was stirred at 25°C under a carbon monoxide atmosphere, and propyne gas (2.2 equivalent) was introduced into the container over a period of about 7 hours, followed by further stirring for about 1 hour. After completion of the reaction, the interior of the container was replaced with nitrogen, acetonitrile (303 mL) was added at 20°C, and methanesulfonic acid (26.1 g, 5 equivalent) was added at 5°C. After storing overnight, the mixture was stirred at -5°C for 1 hour and then filtered. The crystals were washed with cooled acetonitrile (138 mL) to obtain Compound (3) (26.65 g, yield 90%, purity 88% (HPLC method B)).

[0453] Example 4

[0454] Synthesis of compound 4:

[0455] [Chemical formula 35]

[0456]

[0457] Tetrahydrofuran (4.98 kg) and dimethyl sulfoxide (7.40 kg) were added to N-methylmorpholine (1.12 kg), and 57% hydroiodic acid (2.48 kg, 1.0 equivalent) was added dropwise at 10°C to 20°C. After stirring for about 15 minutes, tetrahydrofuran (9.96 kg) was added. After stirring for about 40 minutes, the mixture was filtered and washed with tetrahydrofuran (4.48 kg) to obtain compound 4 (3.00 kg, yield 88%).

[0458] 1 H-NMR(CD3OD)δ:3.92(4H,brs),3.48(4H,brs),2.94(3H,s),2.67(6H,s)

[0459] Elemental Analysis:

[0460] Calculated values: C, 27.37; H, 5.91; N, 4.56; S, 10.44; I, 41.31

[0461] Found: C, 26.83; H, 5.76; N, 4.76; S, 10.41; I, 40.76

[0462] Table 5 shows the crystallographic data of single crystal X-ray diffraction.

[0463] [Table 5]

[0464]

[0465] (Here, V refers to the unit lattice volume and Z refers to the number of chemical units in the unit cell.)

[0466] In addition, the atomic coordinates of non-hydrogen atoms are shown in Table 6, and the atomic coordinates of hydrogen atoms are shown in Table 7.

[0467] [Table 6]

[0468] atom x y z Beq I1 -0.11884(4) 0.73719(3) 1.08563(2) 1.54(2) S1 0.2359(2) 0.6634(1) 0.88739(9) 1.77(3) O1 0.6214(4) 0.4722(4) 0.6416(3) 2.06(7) O2 0.3496(5) 0.6078(4) 0.8276(3) 2.07(7) N1 0.2607(5) 0.4596(4) 0.6767(3) 1.14(7) C1 0.4030(6) 0.3653(5) 0.7046(4) 1.57(9) C2 0.6012(6) 0.4126(5) 0.7257(4) 1.91(9) C3 0.4925(7) 0.5653(5) 0.6172(4) 1.88(9) C4 0.2900(6) 0.5252(5) 0.5922(4) 1.52(9) C5 0.0614(6) 0.4174(5) 0.6537(4) 1.77(9) C6 0.3224(7) 0.6047(6) 1.0077(4) 2.6(1) C7 0.0065(7) 0.6004(5) 0.8514(4) 1.86(9)

[0469] (Here, Beq refers to the equivalent isotropic temperature factor Beq = 8 / 3π 2 (U 11 (aa*) 2 +U 22 (bb*) 2 +U 33 (cc*) 2 +2U 12 (aa*bb*)cosγ+2U 13 (aa*cc*)cosβ+2U 23 (bb*cc*)cosα). )

[0470] [Table 7]

[0471] atom x y z Biso H1 0.2029 0.5910 0.5775 1.82 H2 0.2596 0.4768 0.5327 1.82 H3 0.5106 0.6065 0.5602 2.26 H4 0.5200 0.6181 0.6738 2.26 H5 0.6280 0.4646 0.7828 2.29 H6 0.6949 0.3502 0.7431 2.29 H7 0.3782 0.3099 0.6501 1.89 H8 0.3909 0.3260 0.7638 1.89 H9 0.2834 0.5081 0.7304 1.37 H10 0.0496 0.3712 0.7087 2.12 H11 0.0297 0.3716 0.5935 2.12 H12 -0.0262 0.4817 0.6438 2.12 H13 -0.0613 0.6213 0.7831 2.23 H14 -0.0653 0.6271 0.8948 2.23 H15 0.0195 0.5181 0.8565 2.23 H16 0.3162 0.5221 1.0033 3.11 H17 0.2441 0.6313 1.0478 3.11 H18 0.4547 0.6282 1.0383 3.11

[0472] (Here, Biso refers to the isotropic temperature factor.)

[0473] The structure in the asymmetric unit is further shown in Figure 2 .

[0474] As from Figure 2 As is clear from the atomic coordinates in Tables 6 and 7, it can be seen that the unit cell is composed of N-methylmorpholine, hydroiodic acid, and dimethyl sulfoxide (DMSO) in a ratio of 1:1:1.

[0475] In addition, there was proton transfer between N-methylmorpholine and hydroiodic acid, and it was confirmed that N-methylmorpholine and hydroiodic acid formed a salt.

[0476] It should be noted that the numbers of non-hydrogen atoms and hydrogen atoms in Tables 6 and 7 are respectively Figure 2 The numbers recorded in correspondence.

[0477] The results of powder X-ray diffraction (XRPD method B) are shown in Figure 3 And Table 8.

[0478] [Table 8]

[0479] 2θ 12.613 16.929 17.506 19.539 20.780 25.814 26.335 26.970 28.393 28.905

[0480] In the powder X-ray diffraction pattern, peaks were confirmed at diffraction angles (2θ): 12.6°±0.2°, 16.9°±0.2°, 17.5°±0.2°, 26.3°±0.2°, and 28.9°±0.2°.

[0481] The DSC analysis results are shown in Figure 4 The onset temperature was observed to be 125°C.

[0482] The TG / DTA analysis results are shown in Figure 7 An onset temperature of 115° C. was observed. The weight loss at TG was about 27%.

[0483] Example 5

[0484] Synthesis of compound 6:

[0485] [Chemical formula 36]

[0486]

[0487] Under nitrogen atmosphere, tetrahydrofuran (2 mL), N-methylmorpholine (4.06 g, 4 equivalents), and dimethyl sulfoxide (1 mL) were added to iodobenzene (5) (2.04 g), Pd2(dba)3 (69.8 mg, 0.0075 equivalents), Xantphos (174.0 g, 0.03 equivalents), CuCl (60.5 mg, 0.06 equivalents), the compound (4) obtained in Example 4 (154.2 mg), and N,N-dimethylglycine (40.0 mg, 0.04 equivalents) in sequence. Under carbon monoxide atmosphere, the mixture was stirred at about 25° C., and a solution (about 0.64 mol / L) in which propyne gas (2.3 equivalents) was dissolved in tetrahydrofuran in advance was introduced over about 0.5 hours, followed by further stirring for 22 hours. After completion of the reaction, the interior of the container was replaced with nitrogen, the precipitated solid was filtered out, and the filtrate was concentrated. The residue was purified by silica gel chromatography (hexane:ethyl acetate=80:20 and 95:5) to obtain 6 as a yellow oil in an amount of 1.13 g in a yield of 78%.

[0488] 1 H-NMR(CDCl3)δ:8.14(2H,d,J=6Hz),7.60(1H,t,J=6Hz),7.48(2H,t,J=6Hz),2.16(3H,s)

[0489] 13 C-NMR(CDCl3)δ:178.22,136.85,133.91,129.58,128.48,92.46,4.32

[0490] Example 6

[0491] Synthesis of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-((S)-morpholin-2-ylmethoxyimino)-2-butyn-1-yl)quinazoline dihydrochloride (V'-1):

[0492] [Chemical formula 37]

[0493]

[0494] Compound (II") was prepared according to Example 2 above.

[0495] (2) Synthesis of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-((S)-morpholin-2-ylmethoxyimino)-2-butyn-1-yl)quinazoline dihydrochloride:

[0496] 2.21 ml of 2 mol / L methanesulfonic acid aqueous solution was added to a suspension of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-oxo-2-butyn-1-yl)quinazoline (II") (786 mg) and (S)-2-aminooxymethyl-morpholine-4-carboxylic acid tert-butyl ester (614 mg) in 31 ml of 1,4-dioxane, and the mixture was stirred at 80°C for 22 hours. 1.32 ml of 2 mol / L methanesulfonic acid aqueous solution was added, and the mixture was further stirred for 5.5 hours. After the reaction was completed, the reaction solution was poured into an ice-sodium bicarbonate aqueous solution and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and all the organic layers were combined and washed with water, and then dried over anhydrous magnesium sulfate. After the filtrate was concentrated, the residue was purified by silica gel column chromatography (eluted with chloroform: methanol = 9: 1) to obtain a yellow oil. The oil was dissolved in 50 ml of ethyl acetate, filtered, and 0.95 ml of 4 mol / L hydrochloric acid-ethyl acetate solution was added while stirring, and stirred at room temperature for 1 hour. After filtering the precipitate, it was washed with ethyl acetate and hexane in sequence. The filtrate was recrystallized from methanol-ethyl acetate to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-((S)-morpholin-2-ylmethoxyimino)-2-butyn-1-yl)quinazoline dihydrochloride (V'-1) (839 mg) as yellow crystals.

[0497] 1H-NMR(d6-DMSO,δ):11.69(1H,bs),9.49-9.37(2H,m),9.05(1H,s),8.88(1H,s),8.38(1H,d d,J=1.5Hz,J=8.7Hz),7.96(1H,d,J=8.7Hz),7.89(1H,d,J=2.7Hz),7.64(1H,dd,J=2.4Hz,J= 9.0Hz),7.52-7.45(1H,m),7.36-7.30(3H,m),7.23-7.16(1H,m),5.31(2H,s),4.36-4.34(1H ,m),4.25-4.22(1H,m),4.04-3.98(1H,m),3.84-3.77(1H,m),3.04-2.85(3H,m),2.28(3H,s).

[0498] Example 7

[0499] Synthesis of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-ethylaminoethoxyimino)-2-butyn-1-yl)quinazoline (V'-2):

[0500] [Chemical formula 38]

[0501]

[0502] The compound represented by formula (II") was prepared according to the above Example 2.

[0503] (2) Synthesis of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-hydroxyethoxyimino)-2-butyn-1-yl)quinazoline (VI-1):

[0504] 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-oxo-2-butyn-1-yl)quinazoline (II") (10 g) was dissolved in 300 ml of 1,4-dioxane, and 1.5 equivalents of 2-(acetoxy)ethoxyamine were added, followed by 28 ml of a 2 mol / L methanesulfonic acid aqueous solution, and the mixture was stirred at 60°C for 17 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution, and the mixed solution was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. The residue obtained by concentrating the filtrate was recrystallized with aqueous ethanol-water, filtered and dried to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-hydroxyethoxyimino)-2-butyn-1-yl)quinazoline (VI-1) (7.6 g) as a colorless solid.

[0505] 1H NMR(d6-DMSO,δ):10.07(1H,s),8.74(1H,s),8.58(1H,s),8.22(1H,d,J=8.8Hz) ,7.96(1H,d,J=2.4Hz),7.80(1H,d,J=8.8Hz),7.69(1H,dd,J=2.4Hz,J=8.8Hz), 7.50-7.45(1H,m),7.35-7.24(3H,m),7.20-7.16(1H,m),5.27(2H,s),4.79(1H, tJ=5.6Hz), 4.29(2H, tJ=5.6Hz), 3.75(2H,dd,J=5.2Hz, J=10.4Hz), 2.26(3H,s).

[0506] (3) Synthesis of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-sulfonyloxyethoxyimino)-2-butyn-1-yl)quinazoline (VI-2):

[0507] 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-hydroxyethoxyimino)-2-butyn-1-yl)quinazoline (VI-1) (7.6 g) was dissolved in 150 ml of tetrahydrofuran, 4.19 ml of triethylamine and 2.33 ml of methanesulfonyl chloride were added and stirred for 3.5 hours. After the reaction was completed, the reaction solution was poured into water, a saturated sodium bicarbonate aqueous solution was added, and extraction was performed with ethyl acetate. The organic layer was dried over sodium sulfate, and the filtrate was concentrated. Ethyl acetate was added to the concentrated residue and the mixture was allowed to stand at room temperature, resulting in the precipitation of crystals. Therefore, the crystals were filtered out after dilution with hexane to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-sulfonyloxyethoxyimino)-2-butyn-1-yl)quinazoline (VI-2) (7.66 g) as pale yellow crystals.

[0508] 1H NMR(d6-DMSO,δ):10.07(1H,s),8.77(1H,s),8.60(1H,s),8.24(1H,d,J=8 .8Hz),7.97(1H,d,J=2.4Hz),7.81(1H,d,J=8.8Hz),7.69(1H,dd,J=2.4Hz, J=8.8Hz),7.51-7.45(1H,m),7.35-7.27(3H,m),7.21-7.17(1H,m),5.27(2 H,s),4.58(2H,tJ=4.8Hz),4.54(2H,tJ=4.8Hz),3.24(3H,s),2.27(3H,s).

[0509] (4) Synthesis of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-ethylaminoethoxyimino)-2-butyn-1-yl)quinazoline (V'-1):

[0510] 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-sulfonyloxyethoxyimino)-2-butyn-1-yl)quinazoline (VI-2) (100 mg) was dissolved in 3 ml of N,N-dimethylformamide, 160 μl of a 70% aqueous solution of ethylamine was added, and the mixture was stirred at 60° C. for 14 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the concentrated residue of the filtrate was purified by chromatography using an amino column (eluted with ethyl acetate) to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-ethylaminoethoxyimino)-2-butyn-1-yl)quinazoline (V'-2) (53 mg) as a colorless solid.

[0511] 1H NMR(d6-DMSO,δ):10.08(1H,s),8.74(1H,s),8.59(1H,s),8.21(1H,d,J=8.4H z),7.96(1H,s),7.80(1H,d,J=8.8Hz),7.69(1H,d,J=8.0Hz),7.51-7.45(1H,m ),7.35-7.27(3H,m),7.21-7.16(1H,m),5.27(2H,s),4.31(2H,tJ=5.6Hz),2. 89(2H,t,J=6.0Hz), 2.61(2H,q,J=7.2Hz), 2.26(3H,s), 1.02(3H,t,J=7.6Hz).

[0512] In the amination, commercially available amines or amines synthesized according to the method described in J. Syn. Org. Chem., Jpn., 2001, 59: 779-789, Tetrahedron Lett., 1995, 36: 6373-6374, Synlett, 1999: 1301-1303, Tetrahedron, 2002, 58: 6267-6276 or salts thereof can be used.

[0513] Example 8

[0514] [Chemical formula 39]

[0515]

[0516] The same operation as in Example 6 or 7 was carried out to synthesize the compound represented by the formula (V'-3) to the compound represented by the formula (V'-17).

[0517] [Chemical formula 40]

[0518]

[0519] [Table 9]

[0520]

[0521] [Table 10]

[0522]

[0523] [Table 11]

[0524]

[0525] Example 9

[0526] Synthesis of compound 8

[0527] [Chemical formula 41]

[0528]

[0529] Under nitrogen atmosphere, tetrahydrofuran (2.3 mL), N-methylmorpholine (4.05 g, 4 equivalents), and dimethyl sulfoxide (1.2 mL) were added to 4-iodoanisole (7) (2.36 g), Pd2(dba)3 (69.9 mg, 0.0075 equivalents), Xantphos (173.0 mg, 0.03 equivalents), CuCl (61.2 mg, 0.06 equivalents), the compound (4) obtained in Example 4 (152.0 mg), and N,N-dimethylglycine (42.3 mg, 0.04 equivalents) in sequence. Under carbon monoxide atmosphere, the mixture was stirred at about 25°C, and a solution (about 0.50 mol / L) in which propyne gas (2.3 equivalents) was dissolved in tetrahydrofuran was introduced over 2 hours, followed by stirring at the same temperature for 2 hours. The mixture was then heated to about 40°C and stirred for 5 hours. After the reaction, the container was replaced with nitrogen, the precipitated solid was filtered out, and the filtrate was concentrated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=80:20 and 90:10) to obtain 8 as a white solid in the amount of 1.22 g with an isolated yield of 70%.

[0530] 1 H-NMR(CDCl3)δ:8.11(2H,d,J=8.9Hz), 6.94(2H,d,J=8.9Hz), 3.88(3H,s), 2.14(3H,s)

[0531] 13 C-NMR(CDCl3)δ:176.91,164.33,131.94,130.28,113.73,91.49,79.00,55.55,4.27

[0532] Example 10

[0533] Synthesis of compound 10

[0534] [Chemical formula 42]

[0535]

[0536] Under nitrogen atmosphere, tetrahydrofuran (2.7 mL), N-methylmorpholine (4.05 g, 4 equivalents), and dimethyl sulfoxide (1.4 mL) were added to 4-iodotrifluoromethylbenzene (9) (2.73 g), Pd2(dba)3 (71.7 mg, 0.0075 equivalents), Xantphos (175.0 mg, 0.03 equivalents), CuCl (59.5 mg, 0.06 equivalents), the compound (4) obtained in Example 4 (152.0 mg), and N,N-dimethylglycine (43.1 mg, 0.04 equivalents) in sequence. Under carbon monoxide atmosphere, the mixture was stirred at about 25°C, and a solution (about 0.50 mol / L) in which propyne gas (2.3 equivalents) was dissolved in tetrahydrofuran in advance was introduced over 2 hours, followed by stirring at the same temperature for 2 hours. The mixture was then heated to about 40°C and stirred for further 5 hours. After the reaction, the container was replaced with nitrogen, the precipitated solid was filtered out, and the filtrate was concentrated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=80:20 and 90:10) to obtain 10 as a brown solid in the amount of 1.30 g with an isolated yield of 61%.

[0537] 1 H-NMR(CDCl3)δ:8.25(2H,d,J=8.1Hz),7.75(2H,d,J=8.1Hz),2.20(3H,s)

[0538] 13 C-NMR(CDCl3)δ:176.85,139.32,135.54,135.22,134.89,134.57,129.80,127. 62,125.62,125.58,125.54,125.51,124.91,122.20,119.48,93.95,78.76,4.35

[0539] Embodiment 11

[0540] Synthesis of compound 12

[0541] [Chemical formula 43]

[0542]

[0543] Under nitrogen atmosphere, tetrahydrofuran (2.1 mL), N-methylmorpholine (4.05 g, 4 equivalents), and dimethyl sulfoxide (1.1 mL) were added to 2-iodothiophene (11) (2.10 g), Pd2(dba)3 (138.0 mg, 0.015 equivalents), Xantphos (347.0 mg, 0.06 equivalents), CuCl (120.0 mg, 0.12 equivalents), the compound (4) obtained in Example 4 (155.0 mg), and N,N-dimethylglycine (83.5 mg, 0.08 equivalents) in sequence. Under carbon monoxide atmosphere, the mixture was stirred at about 25°C, and a solution (about 0.98 mol / L) in which propyne gas (2.3 equivalents) was dissolved in tetrahydrofuran in advance was introduced over 1 hour, followed by stirring at the same temperature for about 3 hours. The mixture was then heated to about 40°C and stirred for about 3.5 hours. After the reaction, the container was replaced with nitrogen, the precipitated solid was filtered out, and the filtrate was concentrated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=90:10) to obtain 12 as a yellow oil in an isolated yield of 87% (1.31 g).

[0544] 1 H-NMR(CDCl3)δ:7.90(1H,dd,J=3.8,1.2Hz),7.68(1H,dd,J=4.9,1.2Hz),7.14(1H,dd,4.9,1.2Hz).2.13(3H,s)

[0545] 13 C-NMR(CDCl3)δ:170.02,144.93,135.01,134.88,128.18,90.98,78.60,4.22

[0546] Test Example 1 Exothermicity in Sonogashira Carbonylation Reaction

[0547] [Chemical formula 44]

[0548]

[0549] The reaction heat of the Sonogashira carbonylation reaction in the absence of a crystal of a complex containing N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide in the production method described in the above scheme is shown in Figure 5 .

[0550] The heat of reaction of the Sonogashira carbonylation reaction in the presence of a crystal of a complex containing N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide in the production method described in the above scheme is shown in Figure 6 .

[0551] Depend on Figure 5It is known that when the crystal does not exist, a complex containing N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide is precipitated as a by-product in the reaction system, and the reaction heat increases sharply. In addition, it is known that the ratio (%) to the total heat release does not follow the addition of propyne. Therefore, heat release cannot be controlled in large-scale production, which is very dangerous.

[0552] In contrast, in a reaction system in which a small amount of the crystal is added before the reaction starts (in the presence of the crystal), Figure 6 As is clear from the results, no drastic increase in reaction heat was observed. Furthermore, the ratio (%) to the total heat release substantially follows the addition of propyne, and heat release can be controlled even in large-scale production, thus enabling industrial-scale production.

[0553] Therefore, the Sonogashira carbonylation reaction of the present invention can obtain the target product more safely in the presence of the crystal, and can be said to be an industrially very excellent production method.

[0554] Test Example 2 Solubility test of the methanesulfonate of the compound represented by formula (II")

[0555] Crystals of the methanesulfonate salt of the compound represented by formula (II") and crystals of the free form of the compound represented by formula (II") were suspended in tetrahydrofuran and acetonitrile, stirred at 20°C to 25°C for more than 2 hours, and then the supernatant concentration was measured (HPLC method A). The results of HPLC of the supernatant are shown in Table 12.

[0556] [Table 12]

[0557]

[0558] As shown in Table 12, it can be seen that the solubility of the crystals of the methanesulfonate salt of the compound represented by formula (II") in each solvent is lower than the solubility of the crystals of the free form of the compound. Here, the crystals with low solubility mean that the amount eluted into the solution is small during the crystal washing using a solvent.

[0559] Furthermore, the concentrations of the crystals eluted into the solution at 0°C in step 1 (step of obtaining crystals of the mesylate salt) and step 2 (step of obtaining crystals of the free form) in Example 2 were measured using HPLC method A and compared (Table 12). It was found that 15.7% of the crystals of the free form of the compound represented by formula (II") were eluted into the solution, but only 3.1% of the crystals of the mesylate salt of the compound were eluted.

[0560] Therefore, the crystals of the methanesulfonate salt of the compound represented by formula (II") have low solubility in the solvent, so the amount eluted into the solution is small, and the loss during production is small, so it can be said that they are industrially excellent crystals.

[0561] Test Example 3 Palladium black precipitation inhibition test

[0562] Table 13 shows the production rate of the target product in the Sonogashira carbonylation reaction shown in the following scheme and the results of the precipitation of palladium black.

[0563] [Chemical formula 45]

[0564]

[0565] [Table 13]

[0566]

[0567] (*Area percentage of HPLC;

[0568] **Evaluation by visual confirmation: "-" means no precipitation, "+" means the degree of precipitation can be confirmed, "++" means thin precipitation on the entire flask wall, and "+++" means thick precipitation on the entire flask wall;

[0569] It is believed that the additives that are "++" after 22 hours of reaction are within the practical range.)

[0570] As is clear from Table 13 above, N,N-dimethylglycine, picolinic acid, L-proline, N,N-diethyl-2-hydroxybenzamide, ethylene glycol, ethyl 2-cyclohexanonecarboxylate, 2-acetylcyclohexanone, 2-hydroxybenzoic acid, furan-2-carboxylic acid, diethyl malonate, N,N-dimethylethylenediamine, acetic acid, and copper (I) 2-thiophenecarboxylate have the effect of inhibiting the precipitation of palladium black.

[0571] Possibility of Industrial Application

[0572] The present invention is useful as a method for producing a compound having dual inhibitory activity against both EGF receptor tyrosine kinase and HER2 tyrosine kinase, and an intermediate thereof.

Claims

1. A crystal of a complex comprising N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide, characterized in that: The crystallization of the complex was characterized by the following crystallographic data, [Table 1] 2. A crystal of a complex comprising N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide, characterized in that: The powder X-ray diffraction pattern has peaks at diffraction angles (2θ): 12.6°±0.2°, 16.9°±0.2°, 17.5°±0.2°, 26.3°±0.2°, and 28.9°±0.2°.

3. A crystal of a complex comprising N-methylmorpholine, hydroiodic acid and dimethyl sulfoxide, characterized in that: In the powder X-ray diffraction pattern, there are peaks at diffraction angles (2θ): 12.6°±0.2°, 16.9°±0.2°, 17.5°±0.2°, 19.5°±0.2°, 20.8°±0.2°, 25.8°±0.2°, 26.3°±0.2°, 27.0°±0.2°, 28.4°±0.2°, and 28.9°±0.2°.

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