HK1245268B - Production method for nitrogen-containing heterocyclic compound, and intermediate of said nitrogen-containing heterocyclic compound - Google Patents

Description

Method for producing nitrogen-containing heterocyclic compounds and intermediates thereof

Technical Field

The present invention relates to a method for producing a nitrogen-containing heterocyclic compound useful as an Fms-like tyrosine kinase 3 inhibitor and intermediates thereof.

Background Art

Fms-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase protein with five immunoglobulin-like motifs in its N-terminal extracellular domain and two kinase domains at its C-terminus. FLT3 is expressed on normal CD34-positive human bone marrow progenitor cells and dendritic progenitor cells, playing a crucial role in the proliferation and differentiation of these cells. Furthermore, FLT3's ligand (FL) is expressed in bone marrow stromal cells and T cells. It is a cytokine that influences the production of many hematopoietic cells and, through interaction with other growth factors, stimulates the proliferation of stem cells, progenitor cells, dendritic cells, and natural killer cells.

When FLT3 binds to FL, it dimerizes and becomes activated through autophosphorylation. This leads to the phosphorylation of AKT and ERK, which are involved in the PI3K and RAS signaling pathways. FLT3 plays a crucial role in the proliferation and differentiation of hematopoietic cells.

In normal bone marrow, FLT3 expression is limited to early precursor cells, but in blood cancers, FLT3 is expressed at high concentrations or mutated, thereby contributing to the proliferation and deterioration of cancer through the activation of the above-mentioned signaling pathway. Examples of blood cancers include acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell leukemia (ATL), myelodysplastic syndrome (MDS), and myeloproliferative disease (MPD).

For example, a nitrogen-containing heterocyclic compound having excellent FLT3 inhibitory activity and useful as a pharmaceutical raw material and a method for producing the same have been reported (Patent Documents 1 and 2).

Previous technical literature

Patent Literature

Patent Document 1: International Publication No. 2013/157540 Pamphlet

Patent Document 2: International Publication No. 2015/056683 Pamphlet

Summary of the Invention

Technical issues to be solved by the invention

There is a need for an industrial method for producing a nitrogen-containing heterocyclic compound that has excellent FLT3 inhibitory activity and is useful as a raw material for pharmaceuticals.

The problem to be solved by the present invention is to provide an industrial production method for a nitrogen-containing heterocyclic compound having excellent FLT3 inhibitory activity and useful as a raw material for pharmaceuticals, and an intermediate thereof.

Means for solving technical problems

Under such circumstances, the present inventors have conducted intensive research and have discovered that a nitrogen-containing heterocyclic compound having excellent FLT3 inhibitory activity and useful as a pharmaceutical raw material can be industrially produced by the production method shown below. Furthermore, the present inventors have discovered that the compound represented by the general formula [14] is a useful intermediate, thereby completing the present invention.

That is, the present invention provides the following.

＜1＞

A method for producing a compound represented by general formula [5] or a salt thereof,

[Chemical Formula 5]

In the formula, ^R1 represents a _C1-6 alkyl group which may be substituted, and the method comprises:

A step of reacting a compound represented by the general formula [1] or a salt thereof with a compound represented by the general formula [2] or a salt thereof or hexamethylenetetramine to produce a compound represented by the general formula [3] or a salt thereof, and then, if necessary, subjecting the obtained compound or salt thereof to a deprotection reaction or a hydrolysis reaction.

[Chemical Formula 1]

In the formula, ^R1 represents a _C1-6 alkyl group which may be substituted; ^X1 represents a leaving group,

[Chemical Formula 2]

In the formula, ^R2 represents a hydrogen atom or an amino-protecting group; ^R3 represents a hydrogen atom or an amino-protecting group, or ^R2 and ^R3 are combined to represent a phthaloyl group which may be substituted.

[Chemical Formula 3]

In the formula, ^R4 represents a group represented by the general formula [4] or a hexamethylenetetraminium group; ^R1 has the same meaning as above,

[Chemical Formula 4]

In the formula, * represents a bonding position; R ² and R ³ have the same meanings as above.

＜2＞

A method for producing a compound represented by general formula [5] or a salt thereof,

[Chemical Formula 12]

In the formula, R ¹ has the same meaning as above, and the method comprises:

(1) a step of reacting a compound represented by the general formula [6] or a salt thereof with 4-aminobenzonitrile or a salt thereof to produce a compound represented by the general formula [7] or a salt thereof;

[Chemical Formula 6]

In the formula, ^X2 represents a leaving group; ^X3 represents a leaving group; ^R1 has the same meaning as above,

[Chemical Formula 7]

In the formula, ^R1 and ^X2 have the same meanings as above,

(2) a step of reacting a compound represented by the general formula [7] or a salt thereof with a compound represented by the general formula [8] to produce a compound represented by the general formula [1] or a salt thereof; and

[Chemical Formula 8]

In the formula, ^X1 has the same meaning as above,

[Chemical Formula 9]

In the formula, ^R1 and ^X1 have the same meanings as above,

(3) a step of reacting the compound represented by the general formula [1] or a salt thereof with the compound represented by the general formula [2] or a salt thereof or hexamethylenetetramine to produce the compound represented by the general formula [3] or a salt thereof, and then, if necessary, subjecting the obtained compound or salt thereof to a deprotection reaction or a hydrolysis reaction,

[Chemical Formula 10]

In the formula, ^R2 and ^R3 have the same meanings as above,

[Chemical Formula 11]

In the formula, ^R1 and ^R4 have the same meanings as above.

＜3＞

The production method according to <1> or <2>, wherein R ¹ is a C _2-4 alkyl group.

＜4＞

The production method according to any one of <1> to <3>, wherein R ² is a C _1-6 alkoxycarbonyl group; and R ³ is a C _1-6 alkoxycarbonyl group.

＜5＞

The production method according to any one of <2> to <4>, wherein ^X2 is an iodine atom and ^X3 is a chlorine atom.

＜6＞

A method for producing a compound represented by general formula [13] or a salt thereof,

[Chemical Formula 21]

In the formula, R ¹ , R ⁶ and R ⁷ have the same meanings as above. The method comprises:

(1) a step of reacting a compound represented by the general formula [1] or a salt thereof with a compound represented by the general formula [2] or a salt thereof or hexamethylenetetramine to produce a compound represented by the general formula [3] or a salt thereof, and then, if necessary, subjecting the obtained compound or salt thereof to a deprotection reaction or a hydrolysis reaction to produce a compound represented by the general formula [5] or a salt thereof;

[Chemical Formula 13]

In the formula, ^R1 and ^X1 have the same meanings as above,

[Chemical Formula 14]

In the formula, ^R2 and ^R3 have the same meanings as above,

[Chemical Formula 15]

In the formula, ^R1 and ^R4 have the same meanings as above,

[Chemical Formula 16]

In the formula, ^R1 has the same meaning as above,

(2) a step of reacting the compound represented by the general formula [5] or a salt thereof with the compound represented by the general formula [9] or a salt thereof to produce the compound represented by the general formula [10] or a salt thereof;

[Chemical Formula 17]

In the formula, R ⁵ represents an amino protecting group, X ⁴ represents a hydroxyl group or a leaving group,

[Chemical Formula 18]

In the formula, ^R1 and ^R5 have the same meanings as above,

(3) a step of subjecting the compound represented by the general formula [10] or its salt to a deprotection reaction to produce the compound represented by the general formula [11] or its salt; and

[Chemical Formula 19]

In the formula, ^R1 has the same meaning as above,

(4) a step of reacting the compound represented by the general formula [11] or a salt thereof with the compound represented by the general formula [12] or a salt thereof,

[Chemical Formula 20]

In the formula, R ⁶ represents a hydrogen atom or a C _1-6 alkyl group which may be substituted; R ⁷ represents a C _1-6 alkyl group which may be substituted; and X ⁵ represents a hydroxyl group or a leaving group.

＜7＞

The production method according to <6>, wherein ^R1 is a _C2-4 alkyl group.

＜8＞

The production method according to <6> or <7>, wherein R ² is a C _1-6 alkoxycarbonyl group; and R ³ is a C _1-6 alkoxycarbonyl group.

＜9＞

The production method according to any one of <6> to <8>, wherein ^R6 is a _C1-4 alkyl group; and ^R7 is a _C1-4 alkyl group.

＜10＞

A compound represented by the general formula [14] or a salt thereof,

[Chemical Formula 22]

In the formula, R ⁸ represents a leaving group, a group represented by the general formula [4a] or a hexamethylenetetraminium group; R ¹ has the same meaning as above,

[Chemical Formula 23]

In the formula, R ^2a represents a C _1-6 alkoxycarbonyl group; R ^3a represents a C _1-6 alkoxycarbonyl group; and * has the same meaning as above.

＜11＞

The compound or salt thereof according to <10>, wherein R ¹ is C _2-4 alkyl; and R ⁸ is a leaving group.

＜12＞

The compound or salt thereof according to <10>, wherein R ¹ is a C _2-4 alkyl group; R ⁸ is a group represented by the general formula [4a],

[Chemical Formula 24]

In the formula, R ^2a , R ^3a and * have the same meanings as above.

＜13＞

N ² -(4-cyanophenyl)-5-iodo-N ⁴ -propylpyrimidine-2,4-diamine hydrochloride.

Effects of the Invention

The production method of the present invention is useful as an industrial production method for a nitrogen-containing heterocyclic compound that has excellent FLT3 inhibitory activity and is useful as a raw material for pharmaceuticals.

The compound of the present invention is useful as an intermediate in an industrial production process for a nitrogen-containing heterocyclic compound that has excellent FLT3 inhibitory activity and is useful as a raw material for pharmaceuticals.

DETAILED DESCRIPTION

The present invention will be described in detail below.

In the present invention, % means mass % unless otherwise specified.

In the present invention, unless otherwise specified, each term has the following meaning.

The halogen atom refers to a chlorine atom, a bromine atom or an iodine atom.

The C _1-6 alkyl group refers to a linear or branched C 1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 2-pentyl, 3 _- pentyl and hexyl.

C _1-4 alkyl refers to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl.

C _2-4 alkyl refers to ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl.

Aryl refers to phenyl or naphthyl.

Aryl C _1-6 alkyl groups include benzyl, diphenylmethyl, trityl, phenethyl, 2-phenylpropyl, 3-phenylpropyl and naphthylmethyl _groups .

The C _1-6 alkoxy group refers to a linear or branched C _1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

C _1-6 alkoxy C _1-6 alkyl refers to C _1-6 alkoxy C _1-6 alkyl such as methoxymethyl and 1-ethoxyethyl.

The C _2-6 alkanoyl group refers to a linear or branched C _2-6 alkanoyl group such as acetyl, propionyl, valeryl, isovaleryl and pivaloyl.

Aroyl refers to benzoyl or naphthoyl.

The heterocyclic carbonyl group refers to a furoyl group, a thenoyl group, a pyrrolidinylcarbonyl group, a piperidinylcarbonyl group, a piperazinylcarbonyl group, a morpholinylcarbonyl group or a pyridylcarbonyl group.

The acyl group is a formyl group, a C _2-6 alkanoyl group, an aroyl group or a heterocyclic carbonyl group.

The C _1-6 alkoxycarbonyl group refers to a linear or branched C _1-6 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, and 1,1-dimethylpropoxycarbonyl.

The C _3-6 alkoxycarbonyl group refers to a linear or branched C _3-6 alkoxycarbonyl group such as a propoxycarbonyl group, an isopropoxycarbonyl group, a tert-butoxycarbonyl group, and a 1,1-dimethylpropoxycarbonyl group.

The aryl C _1-6 alkoxycarbonyl group includes aryl C _1-6 alkoxycarbonyl groups such as benzyloxycarbonyl and phenethoxycarbonyl.

The aryloxycarbonyl group refers to a phenoxycarbonyl group or a naphthoxycarbonyl group.

The C _1-6 alkylamino group refers to a linear or branched C _1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino, and hexylamino.

The di(C _1-6 alkyl)amino group refers to a linear or branched di(C 1-6 alkyl)amino group such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, di(tert-butyl)amino, pentylamino, di-n-hexylamino, (ethyl)(methyl)amino, and (methyl)( _propyl )amino.

The C _1-6 alkylsulfonyl group refers to a C _1-6 alkylsulfonyl group such as a methylsulfonyl group, an ethylsulfonyl group, and a propylsulfonyl group.

The arylsulfonyl group refers to a benzenesulfonyl group, a p-toluenesulfonyl group or a naphthylsulfonyl group.

The C _1-6 alkylsulfonyloxy group refers to a C _1-6 alkylsulfonyloxy group such as a methylsulfonyloxy group and an ethylsulfonyloxy group.

The arylsulfonyloxy group refers to a benzenesulfonyloxy group or a p-toluenesulfonyloxy group.

The silyl group refers to a trimethylsilyl group, a triethylsilyl group or a tributylsilyl group.

The leaving group is a halogen atom, a C _1-6 alkylsulfonyloxy group or an arylsulfonyloxy group. The C _1-6 alkylsulfonyloxy group and the arylsulfonyloxy group may be substituted with one or more groups selected from the substituent group A.

Substituent Group A and Substituent Group B respectively refer to the following groups.

Substituent group A: fluorine atom, halogen atom, cyano group, optionally protected amino group, optionally protected hydroxyl group, C _1-6 alkyl group, aryl group, C _1-6 alkoxy group, C _1-6 alkylamino group, di(C _1-6 alkyl)amino group, and oxo group.

Substituent group B: fluorine atom, halogen atom, C _1-6 alkyl group, C _1-6 alkoxy group.

As amino-protecting groups, all groups that can be used as conventional amino-protecting groups are included, and examples thereof include those described in Greene's Protective Groups in Organic Synthesis, 5th edition, pages 895-1193, 2014, John Wiley & Sons, Inc. Specifically, examples include aryl C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, acyl, C _1-6 alkoxycarbonyl, aryl C _{1-6 alkoxycarbonyl, aryloxycarbonyl, C 1-6 alkylsulfonyl} , arylsulfonyl, and silyl. These groups may be substituted with one or more groups selected from Substituent Group A.

The hydroxyl protecting group includes all groups that can be used as a conventional hydroxyl protecting group, for example, the groups described in Greene's Protective Groups in Organic Synthesis, 5th edition, pages 17-471, 2014, John Wiley & Sons, Inc. Specific examples include C _1-6 alkyl, aryl C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, acyl, C _1-6 alkoxycarbonyl, aryl C _1-6 alkoxycarbonyl, C _1-6 alkylsulfonyl, arylsulfonyl, silyl, tetrahydrofuranyl, or tetrahydropyranyl. These groups may be substituted with one or more groups selected from substituent group A.

The aliphatic hydrocarbons include pentane, hexane, heptane, cyclohexane, methylcyclohexane or ethylcyclohexane.

Halogenated hydrocarbons refer to dichloromethane, chloroform or dichloroethane.

The ethers include diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether or diethylene glycol diethyl ether.

Alcohols include methanol, ethanol, propanol, 2-propanol, butanol, 2-methyl-2-propanol, ethylene glycol, propylene glycol, or diethylene glycol.

Ketones refer to acetone, 2-butanone or 4-methyl-2-pentanone.

Esters refer to methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate or butyl acetate.

Amides refer to N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone.

Nitriles refer to acetonitrile or propionitrile.

The sulfoxide is dimethyl sulfoxide or sulfolane.

Aromatic hydrocarbons refer to benzene, toluene or xylene.

The inorganic base refers to sodium hydroxide, potassium hydroxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium bicarbonate, sodium carbonate, potassium carbonate, tripotassium phosphate, potassium acetate, cesium fluoride or cesium carbonate.

The organic base refers to triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), pyridine, 4-naphthoylpyridine or N-methylmorpholine.

Examples of salts of the compounds of the general formulae [1], [2], [3], [5], [6], [7], [9], [10], [11], [12], [13] and [14] include salts of generally known basic groups such as amino groups and acidic groups such as hydroxyl groups and carboxyl groups.

Examples of the salt of the basic group include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid; salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid, and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid.

Examples of the base in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dicyclohexylamine, N-bromo-β-phenylethylamine, 1-diphenylhydroxymethylamine, and N,N'-dibenzylethylenediamine.

Among the above-mentioned salts, preferred salts include pharmacologically acceptable salts.

R ¹ is a C _1-6 alkyl group which may be substituted.

The C _1-6 alkyl group of R ¹ may be substituted by one or more groups selected from the substituent group A.

R ¹ is preferably a C _1-6 alkyl group, more preferably a C _2-4 alkyl group, and further preferably a propyl group.

^R2 is a hydrogen atom or an amino protecting group.

R ² is preferably an amino protecting group, more preferably a C _1-6 alkoxycarbonyl group, further preferably a C _3-6 alkoxycarbonyl group, and particularly preferably a tert-butoxycarbonyl group.

R ³ is a hydrogen atom or an amino protecting group.

R ³ is preferably an amino protecting group, more preferably a C _1-6 alkoxycarbonyl group, further preferably a C _3-6 alkoxycarbonyl group, and particularly preferably a tert-butoxycarbonyl group.

R ² and R ³ may be combined to form a phthaloyl group which may be substituted.

The phthaloyl group formed by combining R ² and R ³ may be substituted with one or more groups selected from the substituent group A.

It is preferred that R ² and R ³ be combined to form a phthaloyl group.

R ^2a is a C _1-6 alkoxycarbonyl group.

R ^2a is preferably a C _3-6 alkoxycarbonyl group, more preferably a tert-butoxycarbonyl group.

R ^3a is a C _1-6 alkoxycarbonyl group.

R ^3a is preferably a C _3-6 alkoxycarbonyl group, more preferably a tert-butoxycarbonyl group.

R ⁴ is the general formula [4]

[Chemical Formula 25]

(wherein R ² , R ³ and * have the same meanings as above) or a hexamethylenetetraminium group.

R ⁴ is preferably a group represented by the general formula [4].

Preferred R ² is the same as described above.

Preferred R ³ is the same as described above.

^R5 is an amino protecting group.

R ⁵ is preferably a C _1-6 alkoxycarbonyl group, more preferably a tert-butoxycarbonyl group.

R ⁶ is a hydrogen atom or an optionally substituted C _1-6 alkyl group.

The C _1-6 alkyl group of R ⁶ may be substituted by one or more groups selected from the substituent group A.

R ⁶ is preferably a C _1-6 alkyl group, more preferably a C _1-4 alkyl group, and further preferably a methyl group.

R ⁷ is a C _1-6 alkyl group which may be substituted.

The C _1-6 alkyl group of R ⁷ may be substituted by one or more groups selected from the substituent group A.

R ⁷ is preferably a C _1-6 alkyl group, more preferably a C _1-4 alkyl group, and further preferably a methyl group.

R ⁸ is a leaving group, general formula [4a]

[Chemical Formula 26]

(wherein R ^2a , R ^3a and * have the same meanings as above) or a hexamethylenetetraminium group.

R ⁸ is preferably a leaving group or a group represented by the general formula [4a].

When R ⁸ is a leaving group, it is preferably a halogen atom, more preferably a chlorine atom.

When R ⁸ is a group represented by the general formula [4a], preferably, R ^2a is a C _3-6 alkoxycarbonyl group and R ^3a is a group represented by the general formula [4a] in which R 2a is a C 3-6 alkoxycarbonyl group and R 3a is a C _3-6 alkoxycarbonyl group, and more preferably, it is a di(tert-butoxycarbonyl)amino group.

Preferred R ^2a are the same as described above.

Preferred R ^3a are the same as described above.

^X1 is a leaving group.

^X1 is preferably a halogen atom, a _C1-6 alkylsulfonyloxy group which may be substituted with one or more groups selected from the substituent group B, or an arylsulfonyloxy group which may be substituted with one or more groups selected from the substituent group B, more preferably a halogen atom, and even more preferably a chlorine atom.

^X2 is a leaving group.

^X2 is preferably a halogen atom, more preferably an iodine atom.

X ³ is a leaving group.

X ³ is preferably a halogen atom, more preferably a chlorine atom.

^X4 is a hydroxyl group or a leaving group.

X ⁴ is preferably a hydroxyl group.

When ^X4 is a leaving group, ^X4 is preferably a halogen atom, more preferably a chlorine atom.

^X5 is a hydroxyl group or a leaving group.

X ⁵ is preferably a hydroxyl group.

When X ⁵ is a leaving group, X ⁵ is preferably a halogen atom, more preferably a chlorine atom.

When the compound of the general formula [14] or a salt thereof has isomers (eg, optical isomers, geometric isomers, and tautomers), the present invention encompasses these isomers, including anhydrides, solvates, hydrates, and crystals of various shapes.

Next, the compound of the present invention is described.

The compound of the present invention is of the general formula [14]

[Chemical Formula 27]

(wherein R ¹ and R ⁸ have the same meanings as above) or a salt thereof.

Preferred R ¹ is the same as described above.

Preferred R ⁸ is the same as described above.

Next, the production method of the present invention will be described.

[Manufacturing method A]

[Chemical Formula 28]

(wherein, R ¹ , X ¹ , X ² and X ³ have the same meanings as above)

＜Step 1＞

As the compound represented by the general formula [6], for example, 2-chloro-5-iodo-N-propylpyrimidin-4-amine is known.

The compound represented by the general formula [7] or a salt thereof can be produced by reacting the compound represented by the general formula [6] or a salt thereof with 4-aminobenzonitrile or a salt thereof in the presence of an acid.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may also be used as a mixture.

Preferred solvents include amides, more preferably N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, and further preferably N-methylpyrrolidone.

The amount of the solvent used is not particularly limited, but may be 1 to 500 times (v/w) the amount of the compound represented by the general formula [6] or a salt thereof.

Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and camphorsulfonic acid. Preferred are hydrochloric acid and camphorsulfonic acid, and more preferred is hydrochloric acid.

The amount of the acid used may be 0.5 to 5 times the molar amount of the compound represented by the general formula [6] or a salt thereof.

The amount of 4-aminobenzonitrile used is 1 to 50 times the mole, preferably 1 to 5 times the mole, of the compound represented by the general formula [6] or a salt thereof.

The reaction can be carried out at -30 to 150°C, preferably at 0 to 100°C, for 30 minutes to 48 hours.

The compound represented by the general formula [7] is preferably isolated as a salt. A preferred salt is a hydrochloride. By isolating it as a hydrochloride, the compound represented by the general formula [7] can be obtained with high yield, high purity, and simple operation.

＜Step 2＞

As the compound represented by the general formula [8], for example, 5-chloro-1-pentyne is known.

The compound represented by the general formula [1] or a salt thereof can be produced by reacting the compound represented by the general formula [8] with the compound represented by the general formula [7] or a salt thereof in the presence of a palladium catalyst, a copper salt and a base.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may also be used as a mixture.

Preferred solvents include ethers and amides, more preferred are tetrahydrofuran and N,N-dimethylformamide, and even more preferred is tetrahydrofuran.

The amount of the solvent used is not particularly limited, but may be 1 to 500 times (v/w) the amount of the compound represented by the general formula [7] or a salt thereof.

The amount of the compound represented by the general formula [8] used is 1 to 50 times the mole, preferably 1 to 5 times the mole, of the compound represented by the general formula [7] or a salt thereof.

The palladium catalyst used in the reaction includes metal palladium such as palladium-carbon and palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; (2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-diyl)(2-(2-aminoethyl)phenyl)palladium(II); tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)di Organic palladium complexes such as chloropalladium (II), 1,1'-bis(dimethylphosphino)ferrocene dichloropalladium (II), (E)-bis(μ-acetate)bis(o-(o-xylylphosphino)benzyl)dipalladium (II) and tris(dibenzylideneacetone)dipalladium (0), and polymer-supported organic palladium complexes such as bis(acetate)trimethylphosphine palladium (II) and polymer-supported bis(acetate)dicyclohexylphosphine palladium (II), etc., are preferred.

The amount of the palladium catalyst used is 0.0001 to 2 times the mole of the compound represented by the general formula [7] or a salt thereof, preferably 0.001 to 0.2 times the mole.

Examples of the copper salt used in the reaction include copper (I) chloride, copper (I) bromide, copper (I) iodide, and copper (II) acetate, with copper (I) iodide being preferred.

The amount of the copper salt used is 0.0001 to 2 times the mole of the compound represented by the general formula [7] or a salt thereof, preferably 0.001 to 0.5 times the mole.

Examples of the base used in this reaction include organic bases, preferably triethylamine and N,N-diisopropylethylamine, and more preferably triethylamine.

The amount of the base used is 0.1 to 50 times the mole, preferably 1 to 10 times the mole, of the compound represented by the general formula [7] or a salt thereof.

The reaction can be carried out at -30 to 150°C, preferably at 0 to 100°C, for 30 minutes to 48 hours.

As this step, a method for producing 5-chloro-1-pentyne is preferably used.

By using the production method of 5-chloro-1-pentyne, the compound represented by the general formula [1] or a salt thereof can be produced with high yield, high purity and simple operation.

Furthermore, the compound represented by the general formula [1] or a salt thereof is a stable compound and can be easily handled.

As a method for producing the compound represented by the general formula [1] or a salt thereof from the compound represented by the general formula [7] or a salt thereof, the following method can also be used.

[Chemical Formula 29]

(wherein, R ¹ , X ¹ and X ² have the same meanings as above)

The compound represented by the general formula [15] or a salt thereof can be produced by reacting the compound represented by the general formula [7] or a salt thereof with 4-pentyn-1-ol in the presence of a palladium catalyst, a copper salt and a base.

This reaction may be carried out according to Production Method A <Step 2>.

The compound represented by the general formula [1] or a salt thereof can be produced by reacting a compound represented by the general formula [15] or a salt thereof with a sulfonyl halide in the presence of a base.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may also be used as a mixture.

Preferred solvents include halogenated hydrocarbons, ethers, and amides, with halogenated hydrocarbons being more preferred.

The amount of the solvent used is not particularly limited, but may be 1 to 500 times (v/w) the amount of the compound represented by the general formula [15] or a salt thereof.

Examples of the sulfonyl halide used in the reaction include methanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride.

Preferred examples of the sulfonyl halide include methanesulfonyl chloride and p-toluenesulfonyl chloride.

The amount of the sulfonyl halide used is 1 to 10 times the mole, preferably 1 to 5 times the mole, of the compound represented by the general formula [15] or a salt thereof.

Examples of the base used in this reaction include organic bases, with triethylamine and N,N-diisopropylethylamine being preferred.

The amount of the base used is 1 to 10 times the mole, preferably 1 to 5 times the mole, of the compound represented by the general formula [15] or a salt thereof.

The reaction can be carried out at -30 to 150°C, preferably at 0 to 100°C, for 30 minutes to 48 hours.

[Manufacturing method B]

[Chemical formula 30]

(wherein, R ¹ , R ² , R ³ , R ⁴ and X ¹ have the same meanings as above)

The compound represented by the general formula [5] or a salt thereof can be produced by reacting the compound represented by the general formula [1] or a salt thereof with the compound represented by the general formula [2] or a salt thereof or hexamethylenetetramine, and then, if necessary, subjecting the obtained compound or salt thereof to a deprotection reaction or a hydrolysis reaction.

(1a) Production method using ammonia [2a]

[Chemical Formula 31]

(wherein, ^R1 and ^X1 have the same meanings as above)

The compound represented by the general formula [5] or a salt thereof can be produced by reacting a compound represented by the general formula [1] or a salt thereof with ammonia [2a] or a salt thereof in the presence or absence of a base.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may also be used as a mixture.

Preferred solvents include amides, with N,N-dimethylacetamide being more preferred.

The amount of the solvent used is not particularly limited, but may be 1 to 50 times (v/w) the amount of the compound represented by the general formula [1] or a salt thereof.

Examples of ammonia salts include ammonium chloride, ammonium bromide, ammonium iodide, and ammonium carbonate, with ammonium iodide being preferred.

The amount of ammonia or a salt thereof used is 1 to 50 times the mole, preferably 1 to 10 times the mole, of the compound represented by the general formula [1].

Examples of the base used in this reaction as desired include organic bases, with triethylamine and N,N-diisopropylethylamine being preferred.

The amount of the base used is 1 to 50 times the mole, preferably 1 to 10 times the mole, of the compound represented by the general formula [1].

A salt may be added during this reaction, and examples of the salt include potassium iodide.

The amount of the salt used is 0.1 to 50 times the mole, preferably 0.1 to 10 times the mole, of the compound represented by the general formula [1].

The reaction can be carried out at -30 to 150°C, preferably at 0 to 100°C, for 30 minutes to 48 hours.

(1b) Method for producing a compound represented by general formula [2b] or a base thereof

[Chemical Formula 32]

(wherein, R ¹ , R ^2a , R ^3a and X ¹ have the same meanings as above)

As the compound represented by the general formula [2b], for example, di(tert-butoxycarbonyl)amine is known.

The compound represented by the general formula [3b] or a salt thereof can be produced by reacting the compound represented by the general formula [2b] or a salt thereof with the compound represented by the general formula [1] or a salt thereof in the presence of a base.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may also be used as a mixture.

Preferred solvents include amides, and N-methylpyrrolidone is more preferred.

The amount of the solvent used is not particularly limited, but may be 1 to 50 times (v/w) the amount of the compound represented by the general formula [1] or a salt thereof.

The amount of the compound represented by the general formula [2b] or a salt thereof used is 1 to 10 times the mole, preferably 1 to 5 times the mole, of the compound represented by the general formula [1] or a salt thereof.

Examples of the base used in the reaction include organic bases and inorganic bases, among which inorganic bases are preferred, and potassium carbonate is more preferred.

The amount of the base used is 1 to 50 times the mole, preferably 1 to 10 times the mole, of the compound represented by the general formula [1].

A salt may be added during this reaction, and examples of the salt include potassium iodide.

The amount of the salt used is 0.1 to 50 times the mole, preferably 0.1 to 10 times the mole, of the compound represented by the general formula [1].

The reaction can be carried out at -30 to 150°C, preferably at 0 to 100°C, for 30 minutes to 48 hours.

The compound represented by the general formula [5] or a salt thereof can be produced by subjecting the compound represented by the general formula [3b] or a salt thereof to a deprotection reaction.

This reaction can be carried out, for example, by the method described in Greene's Protective Groups in Organic Synthesis, 5th edition, pp. 895-1193, 2014, John Wiley & Sons, INC.

(1c) Production method using potassium phthalimide [2c]

[Chemical Formula 33]

(wherein, ^R1 and ^X1 have the same meanings as above)

The compound represented by the general formula [3c] or a salt thereof can be produced by reacting the compound represented by the general formula [1] or a salt thereof with potassium phthalimide [2c].

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may also be used as a mixture.

Preferred solvents include sulfoxides, with dimethyl sulfoxide being more preferred.

The amount of the solvent used is not particularly limited, but may be 1 to 50 times (v/w) the amount of the compound represented by the general formula [1] or a salt thereof.

The amount of potassium phthalimide used is 1 to 10 times the mole, preferably 1 to 5 times the mole, of the compound represented by the general formula [1] or a salt thereof.

Potassium phthalimide can be prepared in a system using, for example, phthalimide and potassium carbonate.

Preferably, a salt is added to the reaction.

Examples of the salt include sodium iodide, potassium iodide, and lithium iodide, with lithium iodide being preferred.

The amount of the salt used is 0.1 to 50 times the mole, preferably 0.1 to 10 times the mole, of the compound represented by the general formula [1].

The reaction can be carried out at -30 to 150°C, preferably at 0 to 100°C, for 30 minutes to 48 hours.

The compound represented by the general formula [5] or a salt thereof can be produced by subjecting the compound represented by the general formula [3c] or a salt thereof to a deprotection reaction.

This reaction can be carried out, for example, by the method described in Greene's Protective Groups in Organic Synthesis, 5th edition, pp. 895-1193, 2014, John Wiley & Sons, INC.

Specifically, there can be mentioned a method using hydrazine or ethylenediamine, and a method using ethylenediamine is preferred.

(1d) Production method using hexamethylenetetramine

[Chemical Formula 34]

(wherein, R ^4a represents a hexamethylenetetraminium group; R ¹ and X ¹ have the same meanings as above)

The compound represented by the general formula [3d] or a salt thereof can be produced by reacting the compound represented by the general formula [1] or a salt thereof with hexamethylenetetramine.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may also be used as a mixture.

Preferred solvents include amides.

The amount of the solvent used is not particularly limited, but may be 1 to 50 times (v/w) the amount of the compound represented by the general formula [1].

The amount of hexamethylenetetramine used is 1 to 10 times the mole, preferably 1 to 5 times the mole, of the compound represented by the general formula [1].

The reaction can be carried out at -30 to 150°C, preferably at 0 to 100°C, for 30 minutes to 48 hours.

The compound represented by the general formula [5] or a salt thereof can be produced by subjecting the compound represented by the general formula [3d] or a salt thereof to a hydrolysis reaction with hydrazine and/or an acid.

This reaction can be carried out, for example, by the method described in Experimental Chemistry Kozakō, 4th edition, Vol. 20, pp. 284-292, 1992, Maruzen.

In the production method B, when the compound represented by the general formula [1] or its salt is reacted with the compound represented by the general formula [2] wherein at least one of ^R2 and ^R3 is an amino-protecting group or its salt, or hexamethylenetetramine, the obtained compound or its salt can be subjected to a deprotection reaction or a hydrolysis reaction.

As the production method B, the production method (1a), the production method (1b) and the production method (1c) are preferred, the production method (1b) is more preferred, and the compound represented by the general formula [2b] wherein R ^2a is a C _3-6 alkoxycarbonyl group and R ^3a is a C _3-6 alkoxycarbonyl group, or the production method (1b) using a base thereof is further preferred, and the production method (1b) using di(tert-butoxycarbonyl)amine is particularly preferred.

By using di(tert-butoxycarbonyl)amine, the compound represented by the general formula [3b] or a salt thereof can be produced with high yield, high purity, and simple operation. Furthermore, the reaction time is shortened, and the reaction can be carried out at a lower temperature.

Furthermore, the compound represented by the general formula [3b] or a salt thereof has a high bulk density and is easy to handle.

Furthermore, by utilizing the compound represented by the general formula [3b] or a salt thereof, the compound represented by the general formula [5] or a salt thereof can be produced in high yield, high purity, and with a simple operation.

An example of the production method of the present invention is shown below.

[Chemical Formula 35]

On the other hand, the following production method is described in Patent Document 2.

[Chemical Formula 36]

The hydrochloride of the compound represented by formula [C] of the present invention is a novel compound.

The hydrochloride of the compound represented by formula [C] was obtained with a yield of 75% and a purity of 99% without requiring recrystallization. On the other hand, the production method described in Patent Document 2 required recrystallization and had a yield of 40%.

The production method of the present invention is more excellent than the production method described in Patent Document 2.

The hydrochloride of the compound represented by formula [C] is a useful compound.

The compound represented by formula [E] of the present invention is a novel compound.

By using the compound represented by formula [D] instead of the compound represented by formula [J], the amount of palladium catalyst and copper (I) iodide used can be significantly reduced. As a result, the residual metal content of the compound represented by formula [E] can be significantly reduced.

Furthermore, the compound represented by formula [D] is cheaper and more readily available than the compound represented by formula [J].

The production method of the present invention is more excellent than the production method described in Patent Document 2.

A production method using a compound represented by formula [D] is useful.

The compound represented by formula [E] and the compound represented by formula [G] are useful compounds.

[Manufacturing method C]

[Chemical Formula 37]

(wherein, R ¹ , R ⁵ , R ⁶ , R ⁷ , X ⁴ and X ⁵ have the same meanings as above)

＜Step 1＞

(1a) When X ⁴ is a hydroxyl group

As a compound represented by the general formula [9], for example, N-(tert-butoxycarbonyl)-N-methyl-L-alanine is known.

The compound represented by the general formula [10] or a salt thereof can be produced by reacting the compound represented by the general formula [9] or a salt thereof with the compound represented by the general formula [5] or a salt thereof in the presence of a condensing agent or an acid halide and in the presence of a base.

This reaction can be carried out by, for example, the method described in Chemical Reviews, Vol. 97, p. 2243, 1997, Chemical Synthesis of Natural Product Peptides: Coupling Methods for the Incorporation of Noncoded Amino Acids into Peptides, or Tetrahedron, Vol. 60, p. 2447, 2004, (Recent development of peptide coupling reagents in organic synthesis).

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may also be used as a mixture.

Preferred solvents include amides, with N,N-dimethylformamide or N-methylpyrrolidone being more preferred.

The amount of the solvent used is not particularly limited, but may be 1 to 500 times (v/w) the amount of the compound represented by the general formula [5] or a salt thereof.

Examples of the base used in this reaction include inorganic bases and organic bases.

Preferred bases include organic bases, more preferably triethylamine, N,N-diisopropylethylamine, and 4-methylmorpholine, and even more preferably N,N-diisopropylethylamine and 4-methylmorpholine.

The amount of the base used is 1 to 50 times the mole, preferably 1 to 10 times the mole, of the compound represented by the general formula [5] or a salt thereof.

Examples of the condensing agent used in the reaction include carbodiimides such as N,N'-diisopropylcarbodiimide (DIC), N,N'-di(tinyl)carbodiimide, N,N'-dicyclohexylcarbodiimide (DCC), N-(tert-butyl)-N'-ethylcarbodiimide (BEC), N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide (CMC), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC); imidazoliums such as 1,1'-carbonyldiimidazole (CDI) and 1,1'-carbonylbis(1,2,4-triazole) (CDT); and diphenylmethane. Acid azides such as 1,2-diethylphosphoryl azide; acid cyanides such as diethylphosphoryl cyanide; 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline; O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N’,N’-bis(tetramethylene)uridine hexafluorophosphate (HBPyU), O-(benzotriazol-1-yl)-N,N,N’,N’-bis(pentamethylene)uridine hexafluorophosphate hexafluorophosphate (HBPipU), O-(6-chlorobenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HCTU), O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HDBTU), O-(2-oxo-1(2H)pyridinyl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (TPTU), O-((ethoxycarbonyl)cyanomethyleneamino)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HOTU ), O-((ethoxycarbonyl)cyanomethyleneamino)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TOTU), N,N,N’,N’-tetramethyl-O-(N-succinimidyl)uridine hexafluorophosphate (HSTU), N,N,N’,N’-tetramethyl-O-(N-succinimidyl)uric acid tetrafluoroborate (TSTU), dipyrrolidine (N-succinimidyloxy)carbonium hexafluorophosphate (HSPyU) and S-(1-oxide-2-pyridyl)-N,N,N’,N’-tetramethylthiourea tetrafluoroborate (TOTT) and other urea compounds.

Preferred condensing agents include carbodiimides, and EDC is more preferred.

The amount of the condensing agent used is 1 to 50 times the mole of the compound represented by the general formula [5] or its salt, and preferably 1 to 5 times the mole.

When carbodiimides are used as the condensing agent, it is preferable to add an additive.

Examples of the additive include 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzotriazole (HOAT), and ethyl (hydroxyimino)cyanoacetate, with HOBT and ethyl (hydroxyimino)cyanoacetate being preferred.

The amount of the additive used is 0.01 to 10 times the mole, preferably 0.1 to 1 times the mole, of the compound represented by the general formula [5] or a salt thereof.

Examples of the acid halide used in the reaction include carboxylic acid halides such as acetyl chloride and trifluoroacetyl; sulfonic acid halides such as methanesulfonyl chloride and toluenesulfonyl chloride; and chloroformic acid esters such as ethyl chloroformate and isobutyl chloroformate.

The amount of the compound represented by the general formula [9] or its salt used is not particularly limited, but may be 1 to 10 times the molar amount of the compound represented by the general formula [5] or its salt.

The reaction can be carried out at -30 to 150°C, preferably at 0 to 100°C, for 30 minutes to 48 hours.

(1b) When X ⁴ is a leaving group,

The compound represented by the general formula [10] or a salt thereof can be produced by reacting the compound represented by the general formula [9] with the compound represented by the general formula [5] or a salt thereof in the presence of a base.

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include halogenated hydrocarbons, ethers, esters, amides, nitriles, and aromatic hydrocarbons. These solvents may also be used as a mixture.

The amount of the solvent used is not particularly limited, but may be 1 to 500 times (v/w) the amount of the compound represented by the general formula [5] or a salt thereof.

Examples of the base used in this reaction include inorganic bases and organic bases.

The amount of the base used is 1 to 50 times the mole, preferably 1 to 5 times the mole, of the compound represented by the general formula [5] or a salt thereof.

The amount of the compound represented by the general formula [9] or its salt used is not particularly limited, but may be 1 to 10 times the molar amount of the compound represented by the general formula [5] or its salt.

The reaction can be carried out at -30 to 150°C, preferably at 0 to 100°C, for 30 minutes to 48 hours.

As the first step, the production method (1a) is preferred, and a production method using N-(tert-butoxycarbonyl)-N-methyl-L-alanine is more preferred.

＜Step 2＞

The compound represented by the general formula [11] or a salt thereof can be produced by deprotecting the compound represented by the general formula [10] or a salt thereof.

This reaction can be carried out, for example, by the method described in Greene's Protective Groups in Organic Synthesis, 5th edition, pp. 895-1193, 2014, John Wiley & Sons, INC.

＜Step 3＞

The compound represented by the general formula [13] or a salt thereof can be produced by reacting the compound represented by the general formula [11] or a salt thereof with the compound represented by the general formula [12] or a salt thereof in the presence of a base, a condensing agent or an acid halide.

This reaction may be carried out according to Production Method C <Step 1>.

When the compound used in the above-mentioned production method exists in the form of a solvate, a hydrate, or various forms of crystals, these solvates, hydrates, or various forms of crystals can also be used.

Among the compounds used in the above-mentioned production methods, compounds having amino, hydroxyl or carboxyl groups, for example, are protected in advance with common protecting groups, and these protecting groups can be removed by known methods after the reaction.

The compound obtained by the above-mentioned production method can be derived into other compounds by subjecting the compound to known reactions such as condensation, polyaddition, oxidation, reduction, dislocation, substitution, halogenation, dehydration or hydrolysis, or by appropriately combining these reactions.

[Example]

Hereinafter, the present invention will be described with reference to reference examples and examples, but the present invention is not limited thereto.

Silica gel 60 (spherical) (KANTO CHEMICAL CO., INC.) was used as a support in silica gel column chromatography.

The mixing ratio in the eluent is the volume ratio.

¹ H-NMR spectra were measured using JNM-AL400 (JEOL Ltd.) using tetramethylsilane as an internal standard.

Mass spectrometry was measured using LCMS-2020 (SHIMADZU CORPORATION).

The following abbreviations have the following meanings.

Boc: tert-butyloxycarbonyl

Ms：Methylsulfonyl

Pr: Propyl

Reference Example 1

[Chemical Formula 38]

Under ice-cooling, 3.55 mL of propylamine was added to a solution of 5.77 g of 2,4-dichloro-5-iodopyrimidine (synthesized according to the method described in WO2008/155140A1) and 7.86 mL of N,N-diisopropylethylamine in 83 mL of tetrahydrofuran. The mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and washed sequentially with 1.0 mol/L aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The mixture was then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 6.44 g of 2-chloro-5-iodo-N-propylpyrimidin-4-amine as an oil.

MS m/z(M+H):298.3

Reference Example 2

[Chemical Formula 39]

Under a nitrogen atmosphere, 11.0 g of triethylamine, 0.17 g of bis(triphenylphosphine)palladium(II) dichloride, and 0.23 g of copper(I) iodide were added to a suspension of 5.00 g of N ² -(4-cyanophenyl)-5-iodo- ^{N 4} -propylpyrimidine-2,4-diamine hydrochloride in 35 mL of tetrahydrofuran. 1.32 g of 4-pentyn-1-ol was added at 40-45°C, and the mixture was stirred at the same temperature for 4 hours and 30 minutes. The reaction mixture was cooled to 30°C, and 25 mL of a 15% aqueous ammonium chloride solution was added. The organic layer was separated and washed with a 15% aqueous ammonium chloride solution. 0.25 g of N-acetyl-L-cysteine was added, and the mixture was stirred at 20-30°C for 30 minutes. 7.5 mL of tetrahydrofuran and 50 mL of methanol were added to the reaction mixture, and the mixture was stirred at 20-30°C for 30 minutes. 50 mL of water was added to the reaction mixture, and the mixture was stirred at 20-30°C for 30 minutes, and then at 0-10°C for 1 hour. The solid substance was filtered to obtain 3.06 g of 4-((5-(5-hydroxy-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile as a pale yellow solid.

¹ H-NMR (CDCl ₃ )δ: 8.00 (1H, s), 7.75 (2H, d, J = 8.8Hz), 7.57 (2H, d, J = 8.8Hz), 7.17 (1H, brs), 5.69 (2H, t, J = 5.2Hz), 3.84 (2H, t, J＝5.8Hz),3.50-3.42(2H,m),2.62(2H,t,J＝7.0Hz),1.93-1.84(2H,m),1.75-1.64(2H,m),1.02(3H,t,J＝7.6Hz).

Example 1

[Chemical Formula 40]

49.6 g of 4-aminobenzonitrile and 36 mL of hydrochloric acid were added to a solution of 31.3 g of 2-chloro-5-iodo-N-propylpyrimidin-4-amine in 125 mL of N-methylpyrrolidone at room temperature and stirred at 50-60°C for 5 hours. After cooling the reaction mixture to 30°C, 250 mL of methanol was added and the mixture was stirred at 30°C for 30 minutes. 250 mL of water was added to the reaction mixture and stirred at 28°C for 1 hour. The solid was filtered to obtain 32.9 g of N ² -(4-cyanophenyl)-5-iodo-N ⁴ -propylpyrimidine-2,4-diamine hydrochloride as a light yellow solid.

¹ H-NMR (DMSO-d ₆ )δ: 10.28(1H,brs),8.25(1H,s),7.87(2H,d,J＝8.8Hz),7.76(2H,d,J＝8.8Hz),7.5 6(1H,brs),3.38(2H,dd,J＝6.0,14.3Hz),1.65-1.53(2H,m),0.90(3H,t,J＝7.4Hz).

Example 2

[Chemical Formula 41]

0.23 g of triethylamine and 0.20 g of methanesulfonyl chloride were added to a suspension of 0.50 g of 4-((5-(5-hydroxy-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile in 5.0 mL of chloroform at 10°C, and the mixture was stirred at 0-10°C for 3 hours. 0.06 g of triethylamine and 0.05 g of methanesulfonyl chloride were added to the reaction mixture, and the mixture was stirred at 0-10°C for 3 hours. 0.06 g of triethylamine and 0.05 g of methanesulfonyl chloride were added to the reaction mixture, and the mixture was stirred at 0-10°C for 1 hour. Water and chloroform were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.62 g of (5-(2-(4-cyanoanilino)-4-(propylamino)pyrimidin-5-yl)-4-penten-1-yl)methanesulfonate as a pale yellow solid.

¹ H-NMR (CDCl ₃ )δ: 7.98 (1H, s), 7.76 (2H, d, J = 9.2Hz), 7.57 (2H, d, J = 9.2Hz), 7.54 (1H, brs), 5.86 (2H, t, J = 5.2Hz), 4.44 (2H, t, J = 5.6H z),3.51-3.42(2H,m),3.06(3H,s),2.68(2H,t,J＝6.6Hz),2.08-2.00(2H,m),1.74-1.65(2H,m),1.01(3H,t,J＝7.4Hz).

Example 3

[Chemical Formula 42]

0.53 g of thionyl chloride was added to a 5.0 mL suspension of 0.50 g of 4-((5-(5-hydroxy-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile in toluene, and the mixture was stirred at 80°C for 3 hours. After the reaction mixture was cooled to 20°C, tetrahydrofuran and a 5% aqueous sodium bicarbonate solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 0.47 g of 4-((5-(5-chloro-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile as a yellowish-brown solid.

¹ H-NMR (CDCl ₃ )δ: 8.01 (1H, s), 7.75 (2H, d, J = 9.0Hz), 7.57 (2H, d, J = 9.0Hz), 7.25 (1H, brs), 5.58 (2H, t, J = 5.4Hz), 3.72 (2H, t, J＝6.2Hz),3.52-3.42(2H,m),2.70(2H,t,J＝6.8Hz),2.12-2.03(2H,m),1.76-1.65(2H,m),1.02(3H,t,J＝7.4Hz).

Example 4

[Chemical Formula 43]

Under a nitrogen atmosphere, 132 g of triethylamine, 2.0 g of bis(triphenylphosphine)palladium(II) dichloride, and 2.8 g of copper(I) iodide were added to a suspension of 60.0 g of N ² -(4-cyanophenyl)-5-iodo- ^{N 4} -propylpyrimidine-2,4-diamine hydrochloride in 480 mL of tetrahydrofuran. 19.3 g of 5-chloro-1-pentyne was added at 30°C, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was cooled to 25°C, 30 mL of tributylphosphine was added, and the mixture was stirred at 20-30°C for 2 hours. 300 mL of 15% aqueous ammonium chloride solution was added to the reaction mixture. The organic layer was separated, washed twice with 300 mL of 15% aqueous ammonium chloride solution, and then 600 mL of methanol was added, followed by stirring at 20-30°C for 1 hour. 300 mL of water was added to the reaction mixture, and the mixture was stirred at 20-30°C for 30 minutes and then at 0-10°C for 1 hour. The solid substance was filtered off to obtain 45.8 g of 4-((5-(5-chloro-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile as a light yellow solid.

The amount of residual metals was measured and found to be 50 ppm or less of palladium and 50 ppm or less of copper.

¹ H-NMR (DMSO-d ₆ )δ: 9.80(1H,s),8.01(1H,s),7.96(2H,d,J＝8.8Hz),7.68(2H,d,J＝8.8Hz),6.94(1H,t,J＝6.5Hz),3.77(2H,t,J =6.5Hz),3.43-3.35(2H,m),2.62(2H,t,J＝7.1Hz),2.07-1.98(2H,m),1.67-1.54(2H,m),0.92(3H,t,J＝7.5Hz).

Example 5

[Chemical Formula 44]

2.5 mL of N,N-diisopropylethylamine and 2.05 g of ammonium iodide were added to a suspension of 0.50 g of 4-((5-(5-chloro-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile in 5.0 mL of N,N-dimethylacetamide and stirred at 50°C for 27 hours. After the reaction mixture was cooled to room temperature, 20 mL of ethyl acetate and 40 mL of water were added. The solids were filtered, 20 mL of 2-butanone and 20 mL of water were added, and the pH was adjusted to 13.5 with 25% aqueous sodium hydroxide solution. The organic layer was separated, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol = 5/1→3/1→2/1) to obtain 0.11 g of 4-((5-(5-amino-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile as a pale yellow solid.

¹ H-NMR (DMSO-d ₆ )δ: 9.78(1H,s),7.97(1H,s),7.96(2H,d,J＝8.6Hz),7.68(2H,d,J＝8.6Hz),7.09-6.99(1H,m),3.4 2-3.27(2H,m),2.67(2H,d,J＝6.6Hz),2.54-2.47(2H,m),1.72-1.54(4H,m),0.92(3H,t,J＝7.4Hz).

Example 6

[Chemical Formula 45]

A suspension of 45.0 g of 4-((5-(5-chloro-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile, 41.4 g of di(tert-butoxycarbonyl)amine, and 70.3 g of potassium carbonate in 135 mL of N-methyl-2-pyrrolidone was stirred at 70°C for 6 hours and 15 minutes. The reaction mixture was cooled to room temperature and allowed to stand overnight. The reaction mixture was heated to 55°C, and 315 mL of 2-butanone and 180 mL of water were added. The organic layer was separated, washed with a 10% aqueous sodium chloride solution, cooled to 40°C, and stirred at 35-40°C for 2 hours. After the reaction mixture was cooled to 25°C, 315 mL of a 50% aqueous methanol solution was added, and the mixture was stirred at 15-25°C for 3 hours and 30 minutes. The solid substance was filtered to obtain 63.5 g of tert-butyl-N-(tert-butoxycarbonyl)-N-(5-(2-(4-cyanoanilino)-4-(propylamino)pyrimidin-5-yl)-4-penten-1-yl)carbamate.

¹ H-NMR (DMSO-d ₆ )δ: 9.80(1H,s),8.00(1H,s),7.96(2H,d,J＝8.6Hz),7.68(2H,d,J＝8.6Hz),6.94(1H,t,J＝6.0Hz),3.65(2H,t,J＝7.1H z),3.45-3.36(2H,m),2.49-2.44(2H,m),1.83-1.73(2H,m),1.67-1.56(2H,m),1.45(18H,s),0.92(3H,t,J＝7.3Hz).

Example 7

[Chemical Formula 46]

A solution of 60.0 g of tert-butyl-N-(tert-butoxycarbonyl)-N-(5-(2-(4-cyanoanilino)-4-(propylamino)pyrimidin-5-yl)-4-penten-1-yl)carbamate in 540 mL of 2-butanone was added to a mixture of 111 g of 37% hydrochloric acid, 240 mL of acetonitrile, and 300 mL of water at 40-45°C. 60 mL of 2-butanone was added to the resulting mixture, which was then stirred at the same temperature for 6 hours and allowed to stand at room temperature overnight. The reaction mixture was heated to 45°C, and 180 mL of 25% aqueous sodium hydroxide solution was added. The organic layer was separated, and 30 mL of water and 60 mL of acetonitrile were added sequentially at 60°C. After adding 33.2 g of 37% hydrochloric acid, the mixture was stirred at 55-65°C for 1 hour. 300 mL of 2-butanone was added to the reaction mixture, and the mixture was stirred at 0-10°C for 2 hours. The solid substance was filtered out to obtain 43.9 g of 4-((5-(5-amino-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile dihydrochloride monohydrate as a white solid.

¹ H-NMR (DMSO-d ₆ )δ: 10.64(1H,brs),8.10(1H,s),8.03(3H,brs),7.89(2H,d,J＝8.8Hz),7.79(2H,d,J＝8.8Hz),3.42(2H,dd,J＝6.6 ,14.4Hz),2.97-2.85(2H,m),2.62(2H,d,J＝7.0Hz),1.92-1.77(2H,m),1.67-1.54(2H,m),0.92(3H,t,J＝7.5Hz).

Example 8

[Chemical Formula 47]

A suspension of 1.00 g of 4-((5-(5-chloro-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile, 6 mL of dimethyl sulfoxide, 0.68 g of potassium phthalimide, and 0.38 g of lithium iodide was stirred at 40°C for 19 hours. 10 mL of 50% aqueous 2-propanol was added at the same temperature, and the mixture was cooled to room temperature. The solid was filtered to obtain 1.12 g of 4-((5-(5-(1,3-dioxoisoindolin-2-yl)-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile as a pale yellow solid.

¹ H-NMR (DMSO-d ₆ )δ: 9.79(1H,s),7.96(2H,d,J＝8.8Hz),7.89-7.84(2H,m),7.84-7.79(2H,m),7.77(1H,s),7.68(2H,d,J＝8.8Hz),6.95(3H,t,J＝6 .0Hz),3.75(3H,t,J＝6.6Hz),3.45-3.25(2H,m),2.55-2.46(2H,m),1.96-1.85(2H,m),1.68-1.56(2H,m),0.93(3H,t,J＝7.4Hz).

Example 9

[Chemical Formula 48]

A solution of 0.50 g of 4-((5-(5-(1,3-dioxoisoindolin-2-yl)-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile in 2.5 mL of ethylenediamine was stirred at 80-90°C for 3 hours. The reaction mixture was cooled to room temperature, 0.2 mL of water was added, and the mixture was stirred at the same temperature for 4 hours. 10 mL of water was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The solid material was filtered to obtain 0.31 g of 4-((5-(5-amino-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile as a light yellow solid.

MS m/z(M-H): 333

¹ H-NMR (DMSO-d ₆ )δ: 9.78(1H,s),8.00-7.93(3H,m),7.71-7.65(2H,m),7.11-6.99(1H,m),3.55-3.15(2H,m),3.09(1H, dd,J＝6.6,12.2Hz),2.66(2H,t,J＝6.6Hz),2.53-2.43(2H,m),1.70-1.54(4H,m),0.92(3H,t,J＝7.4Hz).

Example 10

[Chemical Formula 49]

40.0 g of 4-((5-(5-amino-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile dihydrochloride monohydrate, 22.9 g of N-(tert-butoxycarbonyl)-N-methyl-L-alanine, 2.88 g of 1-hydroxybenzotriazole monohydrate, and 21.6 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially to a solution of 43.8 g of N,N-diisopropylethylamine in 160 mL of N-methyl-2-pyrrolidone, and the mixture was stirred at 20-30°C for 7 hours and 30 minutes. After 200 mL of 2-methyltetrahydrofuran was added to the reaction mixture, 200 mL of a 10% aqueous sodium chloride solution and 43.4 mL of a 25% aqueous sodium hydroxide solution were added sequentially. The organic layer was separated, and 200 mL of a 10% aqueous citric acid solution was added, followed by 28.0 mL of acetic acid. The organic layer was separated and washed with 10% aqueous sodium chloride solution.

After adding 80 mL of water to the resulting organic layer, 74.1 g of 37% hydrochloric acid was added at 40°C, and the mixture was stirred at the same temperature for 4 hours and 30 minutes. 280 mL of water was added to the reaction mixture, and after cooling to 30°C, 116 mL of 25% aqueous sodium hydroxide solution was added. After stirring at 20-30°C for 1 hour, the mixture was cooled to 10°C and stirred at the same temperature for 5 hours. The solid material was filtered to obtain 41.1 g of (S)-N-(5-(2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-4-penten-1-yl)-2-propionamide/dihydrate as a pale yellow solid.

¹ H-NMR (DMSO-d ₆ )δ: 9.78(1H,s),8.00-7.94(3H,m),7.92(1H,t,J＝6.0Hz),7.68(2H,d,J＝8.8Hz),7.20(1H,t,J＝5.6Hz),3.45-3.37(2H,m),3.29-3.23(2H, m),2.98-2.88(1H,m),2.45(2H,t,J＝7.0Hz),2.20(3H,s),1.89(1H,brs),1.74-1.55(4H,m),1.11(3H,d,J＝6.8Hz),0.92(3H,t,J＝7.5Hz).

Example 11

[Chemical Formula 50]

25.3 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 18.7 g of ethyl (hydroxyimino)cyanoacetate, and 40.0 g of 4-methylmorpholine were added sequentially to 200 mL of N,N-dimethylacetamide, then cooled to 10°C. 40.0 g of (S)-N-(5-(2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-4-penten-1-yl)-2-propionamide/dihydrate and 21.8 g of 4-dimethylaminocroton hydrochloride were added, and the mixture was stirred at 10-15°C for 5 hours and 45 minutes. 400 mL of 4-methyl-2-pentanone salt was added to the reaction mixture, followed by 400 mL of 15% aqueous sodium chloride solution. After standing at room temperature overnight, 48 mL of 25% aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was stirred at 30-40°C for 20 minutes. The organic layer was separated and washed with a 10% aqueous sodium chloride solution. 400 mL of water and 17.2 mL of acetic acid were added sequentially to the resulting organic layer. The aqueous layer was separated, 400 mL of methanol was added, and after cooling to 30°C, 35.1 mL of a 25% aqueous sodium hydroxide solution was added, and the mixture was stirred at 20-30°C for 2 hours. The reaction mixture was cooled to 10°C and stirred at 0-10°C for 2 hours. The solid material was filtered to obtain 43.1 g of (S,E)-N-(1-((5-(2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)-4-(dimethylamino)-N-methyl-2-butenamide as a pale yellow solid.

Industrial applicability

The production method of the present invention is useful as an industrial production method for nitrogen-containing heterocyclic compounds that have excellent FLT3 inhibitory activity and are useful as raw materials for pharmaceuticals. The compound of the present invention is useful as an intermediate for the industrial production method of nitrogen-containing heterocyclic compounds that have excellent FLT3 inhibitory activity and are useful as raw materials for pharmaceuticals.

Claims (13)

1. A method for manufacturing a compound or its salt represented by general formula [5], In the formula, ^R1 represents an optionally substituted _C1-6 alkyl group, and the method includes: The process involves reacting a compound or its salt represented by general formula [1] with a compound or its salt represented by general formula [2] or hexamethylenetetramine to produce a compound or its salt represented by general formula [3], and then, as needed, performing a deprotection reaction or a hydrolysis reaction on the resulting compound or its salt. In the formula, ^R1 represents an optional substituted _C1-6 alkyl group; ^X1 represents a chlorine atom. In the formula, ^R2 represents a hydrogen atom or an amino protecting group; ^R3 represents a hydrogen atom or an amino protecting group, or ^R2 and ^R3 can be combined to represent an optional substituted phthaloyl group. In the formula, ^R4 represents the group shown in general formula [4] or hexamethylenetetramineonium group; ^R1 has the same meaning as above. In the formula, * indicates the bonding position; ^R2 and ^R3 have the same meaning as above. 2. A method for manufacturing a compound or its salt represented by general formula [5], In the formula, ^R1 represents an optionally substituted _C1-6 alkyl group, and the method includes: (1) The process of producing the hydrochloride salt of the compound of general formula [7] by reacting the compound of general formula [6] or its salt with 4-aminobenzyl nitrile or its salt in the presence of hydrochloric acid; In the formula, ^R1 represents an optional substituted _C1-6 alkyl group; ^X2 represents a leaving group; ^X3 represents a leaving group. In the formula, ^R1 and ^X2 have the same meaning as described above. (2) The process of reacting the hydrochloride salt of the compound shown in general formula [7] with the compound shown in general formula [8] to produce the compound shown in general formula [1] or its salt; In the formula, ^X1 represents a chlorine atom. In the formula, ^R1 and ^X1 have the same meaning as described above. as well as (3) The process involves reacting a compound or its salt represented by general formula [1] with a compound or its salt represented by general formula [2] or hexamethylenetetramine to produce a compound or its salt represented by general formula [3], and then, as needed, performing a deprotection reaction or a hydrolysis reaction on the resulting compound or its salt. In the formula, ^R2 represents a hydrogen atom or an amino protecting group; ^R3 represents a hydrogen atom or an amino protecting group, or ^R2 and ^R3 can be combined to represent an optional substituted phthaloyl group. In the formula, ^R4 represents the group shown in general formula [4] or hexamethylenetetramineonium group; ^R1 has the same meaning as above. In the formula, * indicates the bonding position; ^R2 and ^R3 have the same meaning as above. 3. The manufacturing method according to claim 1 or 2, wherein, ^R1 is a _C2-4 alkyl group. 4. The manufacturing method according to claim 1 or 2, wherein, ^R2 is a _C1-6 alkoxycarbonyl group; ^R3 is a _C1-6 alkoxycarbonyl group. 5. The manufacturing method according to claim 2, wherein, ^X2 is an iodine atom; ^X3 is a chlorine atom. 6. A method for producing a compound or a salt thereof represented by general formula [13], In the formula, ^R1 represents an optionally substituted _C1-6 alkyl group; ^R6 represents a hydrogen atom or an optionally substituted _C1-6 alkyl group; ^R7 represents an optionally substituted _C1-6 alkyl group, and the method includes: (1) The process of reacting the compound or its salt shown in general formula [1] with the compound or its salt shown in general formula [2] or hexamethylenetetramine to produce the compound or its salt shown in general formula [3], and then, as needed, performing a deprotection reaction or hydrolysis reaction on the obtained compound or its salt to produce the compound or its salt shown in general formula [5]. In the formula, ^R1 represents an optional substituted _C1-6 alkyl group; ^X1 represents a chlorine atom. In the formula, ^R2 represents a hydrogen atom or an amino protecting group; ^R3 represents a hydrogen atom or an amino protecting group, or ^R2 and ^R3 can be combined to represent an optional substituted phthaloyl group. In the formula, ^R4 represents the group shown in general formula [4] or hexamethylenetetramineonium group; ^R1 has the same meaning as above. In the formula, * indicates the bonding position; ^R2 and ^R3 have the same meaning as above. In the formula, ^R1 has the same meaning as above. (2) The process of reacting a compound or salt of general formula [5] with a compound or salt of general formula [9] to produce a compound or salt of general formula [10]; In the formula, ^R5 represents an amino protecting group, and ^X4 represents a hydroxyl group or a leaving group, wherein the leaving group is a halogen atom, a _C1-6 alkylsulfonyloxy group, or an arylsulfonyloxy group, and the _C1-6 alkylsulfonyloxy group or arylsulfonyloxy group is optionally substituted by one or more groups selected from substituent group A. Substituent group A: halogen atom, cyano group, optionally protected amino group, optionally protected hydroxyl group, _C1-6 alkyl group, aryl group, _C1-6 alkoxy group, _C1-6 alkylamino group, di( _C1-6 alkyl)amino group, bridging group. In the formula, ^R1 and ^R5 have the same meaning as described above. (3) The process of producing a compound or salt of general formula [11] by performing a deprotection reaction on the compound or salt thereof. In the formula, ^R1 has the same meaning as above. as well as (4) The process of reacting a compound or salt of general formula [11] with a compound or salt of general formula [12] In the formula, ^R6 represents a hydrogen atom or an optionally substituted _C1-6 alkyl group; ^R7 represents an optionally substituted _C1-6 alkyl group; ^X5 represents a hydroxyl group or a leaving group, wherein the leaving group is a halogen atom, a _C1-6 alkylsulfonyloxy group, or an arylsulfonyloxy group, wherein the _C1-6 alkylsulfonyloxy group or the arylsulfonyloxy group is optionally substituted by one or more groups selected from substituent group A. Substituent group A: halogen atom, cyano, optionally protected amino, optionally protected hydroxyl, _C1-6 alkyl, aryl, _C1-6 alkoxy, _C1-6 alkylamino, di( _C1-6 alkyl)amino, bridging oxygen. 7. The manufacturing method according to claim 6, wherein, ^R1 is a _C2-4 alkyl group. 8. The manufacturing method according to claim 6 or 7, wherein, ^R2 is a _C1-6 alkoxycarbonyl group; ^R3 is a _C1-6 alkoxycarbonyl group. 9. The manufacturing method according to claim 6 or 7, wherein, ^R6 is a _C1-4 alkyl group; ^R7 is a _C1-4 alkyl group. 10. A compound of general formula [14] or a salt thereof, In the formula, ^R1 represents an optional substituted _C1-6 alkyl group; ^R8 represents a chlorine atom, a group represented by general formula [4a], or a hexamethylenetetramineonium group. In the formula, ^R2a represents a _C1-6 alkoxycarbonyl group; ^R3a represents a _C1-6 alkoxycarbonyl group; * indicates the bonding position. 11. The compound or salt thereof according to claim 10, wherein, ^R1 is a _C2-4 alkyl group; ^R8 is a chlorine atom. 12. The compound or salt thereof according to claim 10, wherein, ^R1 is a _C2-4 alkyl group; ^R8 is a group represented by general formula [4a]. In the formula, ^R2a represents a _C1-6 alkoxycarbonyl group; ^R3a represents a _C1-6 alkoxycarbonyl group; * indicates the bonding position. 13. The manufacturing method according to claim 6 or 7, wherein, The process further includes reacting the hydrochloride salt of the compound represented by general formula [7] with the compound represented by general formula [8] to produce the compound represented by general formula [1] or its salt. In the formula, ^R1 and ^X2 have the same meaning as described above. In the formula, ^X1 represents a chlorine atom.