JP2009007259A - Method for producing 6-fluoro-3-(4-fluorobenzyl)-1,2,3,4-tetrahydroisoquinoline derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an intermediate for producing a tetrahydroisoquinoline compound useful as a medicine for preventing or treating diseases in which chemokine receptor 3 (CCR3) particitates, and to provide a method for producing the intermediate for the production. <P>SOLUTION: This method for producing the 6-fluoro-3-(4-fluorobenzyl)-1,2,3,4-tetrahydroisoquinoline represented by formula (3) or its salt is characterized by reacting 1-(3-fluorophenyl)-3-(4-fluorophenyl)-propane-2-amine represented by formula (4) or its salt with formaldehyde or a formaldehyde equivalent in the presence or absence of an acid. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an intermediate for producing a tetrahydroisoquinoline compound useful for the treatment or prevention of diseases involving chemokine receptor type 3 (CCR3) and a method for producing the intermediate.

Chemokine receptor type 3 (hereinafter referred to as CCR3), a member of the chemokine receptor family, is a seven-transmembrane G protein-coupled receptor expressed on a part of eosinophils, basophils, and helper T cells. Body (Non-Patent Document 1).
Eotaxin, which is a ligand of CCR3, is a chemokine named in the sense of a cytokine having cell chemotaxis, specifically binding to CCR3, resulting in an increase in intracellular calcium concentration and a change in cytoskeleton. It is known to cause enhancement of cell motility function (Non-patent Document 2). It has also been suggested that activation of CCR3 in eosinophils promotes infiltration of eosinophils into tissues by causing increased expression of adhesion molecules on the surface of eosinophils (non-patented). 3) Furthermore, it causes the secretion of basic proteins having cytotoxicity such as MBP (Major Basci Protein) and ECP (Eosinophil Cation Protein) present in intracellular granules, resulting in tissue damage. This is known (Non-Patent Document 4).

  In studies comparing the expression level of CCR3 with that of healthy subjects, the expression of both mRNA and protein levels was significantly increased in airway biopsy of asthmatic patients, and knockout in which CCR3 was deleted by genetic engineering. Reduces the number of eosinophils in bronchoalveolar lavage fluid and improves airway hypersensitivity in studies using mice, administration of neutralizing antibodies to CCR3 protein, antigen sensitization, induction-induced disease state model, etc. This has been reported (Non-Patent Documents 5 to 7).

  Based on the above findings, CCR3 is deeply involved in the development and progression of diseases such as asthma, allergic rhinitis, allergic conjunctivitis, and atopic dermatitis characterized by eosinophil infiltration at the lesion site. CCR3 antagonists are expected to be effective for the prevention or treatment of these diseases (Non-Patent Documents 8 to 14).

  So far, as CCR3 antagonists, linear alkylamine derivatives (Patent Document 1), piperidine derivatives (Patent Documents 2 to 4, Non-Patent Documents 11, 15 to 21), morpholine derivatives (Patent Documents 5 to 7), pyrrolidine Derivatives (Patent Documents 8 and 9), piperazine derivatives (Patent Documents 10 and 11), bicyclopiperidine derivatives (Non-Patent Document 22), azetidine derivatives (Patent Document 12), and the like have been reported. Further, as CCR3 antagonists having a tetrahydroisoquinoline skeleton, compounds described in Patent Documents 13 and 14 are known.

International Publication No. 02/59081 Pamphlet International Publication No. 00/53600 Pamphlet International Publication No. 05/09775 Pamphlet International Publication No. 06/13073 Pamphlet International Publication No. 02/26723 Pamphlet International Publication No. 03/99287 Pamphlet International Publication No. 06/28284 Pamphlet International Publication No. 00/51607 Pamphlet International Publication No. 04/58762 Pamphlet International Publication No. 03/68759 Pamphlet International Publication No. 06/015851 Pamphlet International Publication No. 05/26113 Pamphlet International Publication No. 02/26708 Pamphlet International Publication No. 03/41641 Pamphlet J. Biol Chem 270 (1995) 16491-16494 J.Clin.Invest. 99 (1997) 178-187 J.Clin.Invest. 101 (1998) 2017-2024 Blood. 95 (2000) 1911-1917 J Immunol 163 (1999) 6321-6329 Proc Natl Acad Sci USA. 99 (2002) 1479-1484 Am J Physiol Lung Cell Mol Physiol. 284 (2003) L169-L178 Expert Opin Investig Drugs. 9 (2000) 43-52 Allergy 59 (2004) 1243-1258 Curr Drug Targets Inflamm Allergy 2 (2003) 81-94 Bioorganic & Medicinal Chemistry Letters 11 (2001) 1219-1223 Biochem Biophys Res Commun. 339 (2006) 1217-1223 J. Org. Chem. 71 (2006) 8975-8977 Bioorganic & Medicinal Chemistry Letters 11 (2001) 1445-1450

  In addition to the CCR3 antagonists described in the above-mentioned patent documents and the like, the present inventors have used the following formula (1) or formula (2):

It has been found that a novel tetrahydroisoquinoline compound represented by the formula (1) or a salt thereof has a CCR3 antagonistic action and exhibits an action of suppressing eosinophil infiltration into the lung in a guinea pig eosinophil infiltration model.

  In the synthesis of the 1,2,3,4-tetrahydroisoquinoline skeleton, the Pictet-Spengler reaction is generally used. The Pictet-Spengler reaction is a reaction in which an imine formed from 2-phenethylamine and an aldehyde is closed with an acid to lead to tetrahydroisoquinoline, but a hydroxy group or a methoxy group is located at the 6-position corresponding to 1,2,3,4-tetrahydroisoquinoline. In the case of such an electron donating substituent, the cyclization reaction is a high yield, but in the absence of these groups, the cyclization reaction is a low yield. Further, when a benzyl group is present at the position corresponding to the 3-position of 1,2,3,4-tetrahydroisoquinoline, selectivity of the ring-closing position occurs as shown in the following figure.

（Ｒａ及びＲｂは置換基を示す。）

(Ra and Rb represent substituents.)

  It is an object of the present invention to have a CCR3 antagonistic activity and a disease involving CCR3 (in particular, asthma, allergic rhinitis, sinusitis, allergic conjunctivitis, atopic dermatitis, ulcerative colitis, Crohn's disease, rheumatoid arthritis Novel production intermediates that can be advantageously produced industrially for tetrahydroisoquinoline compounds useful as preventive or therapeutic agents for allergy or autoimmune diseases such as HIV infection and associated encephalitis and dementia) It is to provide a method for producing an intermediate.

で示される１−（３−フルオロフェニル）−３−（４−フルオロフェニル）−プロパン−２−アミン又はその塩と、酸の存在下又は非存在下、ホルムアルデヒド又はホルムアルデヒド等価体を反応させることを特徴とする、次の式（３）：

で示される６−フルオロ−３−（４−フルオロベンジル）−１,２,３,４−テトラヒドロイソキノリン又はその塩の製造方法。 Under such circumstances, as a result of intensive studies, the present inventors have determined that 2-amino-1- (3-fluorophenyl) -3- (4-fluorophenyl) propane is Pictet- with the amino group remaining unprotected. It has been found that ring closure reaction proceeds with high regioselectivity by carrying out Spengler reaction, and 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline is selectively obtained. The present invention has been completed.
That is, the present invention
1. The following formula (4):

Reacting 1- (3-fluorophenyl) -3- (4-fluorophenyl) -propan-2-amine or a salt thereof represented by the above with formaldehyde or formaldehyde equivalent in the presence or absence of an acid. Characteristic, the following formula (3):

A method for producing 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline or a salt thereof represented by the formula:

2. 2. The production method according to 1 above, wherein the acid is trifluoroacetic acid (TFA).
3. 3. The production method according to 1 or 2 above, wherein the formaldehyde equivalent is paraformaldehyde or dimethoxymethane.

で示される化合物又はその塩を、等量又は過剰量のアンモニウム塩と水素化ホウ素化合物の存在下反応させ、前記式（４）で示される化合物又はその塩に変換することを含むことを特徴とする、上記１から３のいずれかに記載の製造方法。 4). The following formula (5):

The compound represented by the formula (1) or a salt thereof is reacted in the presence of an equivalent or excess amount of an ammonium salt and a borohydride compound, and converted to the compound represented by the formula (4) or a salt thereof. The manufacturing method according to any one of 1 to 3 above.

で示される化合物又はその塩を還元して、前記式（４）で示される化合物又はその塩に変換することを含むことを特徴とする、上記１から３のいずれかに記載の製造方法。 5). The following formula (6):

The production method according to any one of 1 to 3 above, comprising reducing the compound represented by the formula (1) or a salt thereof to convert the compound represented by the formula (4) or a salt thereof.

で示される１−（３−フルオロフェニル）−３−（４−フルオロフェニル）−プロパン−２−アミン又はその塩と、酸の存在下又は非存在下、ホルムアルデヒド又はホルムアルデヒド等価体を反応させ、次の式（３）：

で示される６−フルオロ−３−（４−フルオロベンジル）−１,２,３,４−テトラヒドロイソキノリン又はその塩を得て、この式（３）で示される化合物又はその塩と次の式（XII）：

（式中、Xは脱離基を示す。）
で表される化合物又はその塩を反応させ、次の式（XIII）：

で示される化合物又はその塩を得て、この式（XIII）で示される化合物又はその塩を還元し、次の式（XIV）：

で示される化合物又はその塩を得て、次いで、この式（XIV）で示される化合物又はその塩と次の式（XV）：

で示される化合物又はその塩を反応させることを特徴とする、次の式（１）：

で示される６−フルオロ−３−（４−フルオロベンジル）−１,２,３,４−テトラヒドロイソキノリン誘導体又はその塩の製造方法。 6). The following formula (4):

1- (3-fluorophenyl) -3- (4-fluorophenyl) -propan-2-amine or a salt thereof represented by the following is reacted with formaldehyde or formaldehyde equivalent in the presence or absence of an acid: Equation (3):

6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline or a salt thereof represented by the following formula (3): XII):

(In the formula, X represents a leaving group.)
Is reacted with a compound represented by the following formula (XIII):

And a compound represented by the formula (XIII) or a salt thereof is reduced, and the following formula (XIV):

Or a salt thereof, and then a compound represented by the formula (XIV) or a salt thereof and the following formula (XV):

A compound represented by the following formula or a salt thereof is reacted:

A method for producing a 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline derivative represented by the formula:

で示される１−（３−フルオロフェニル）−３−（４−フルオロフェニル）−プロパン−２−アミン又はその塩と、酸の存在下又は非存在下、ホルムアルデヒド又はホルムアルデヒド等価体を反応させ、次の式（３）：

で示される６−フルオロ−３−（４−フルオロベンジル）−１,２,３,４−テトラヒドロイソキノリン又はその塩を得て、この式（３）で示される化合物又はその塩と次の式（XVI）：

（式中、Xは脱離基を示す。）
で表される化合物又はその塩を反応させ、次の式（XVII）：

で示される化合物又はその塩を得て、この式（XVII）で示される化合物又はその塩を還元し、次の式（XVIII）：

で示される化合物又はその塩を得て、この式（XVIII）で示される化合物又はその塩とアセトンを反応させ、次の式（XIX）：

で示される化合物又はその塩を得て、次いで、この式（XIX）で示される化合物又はその塩を還元することを特徴とする、次の式（２）：

で示される６−フルオロ−３−（４−フルオロベンジル）−１,２,３,４−テトラヒドロイソキノリン誘導体又はその塩の製造方法。 7). The following formula (4):

1- (3-fluorophenyl) -3- (4-fluorophenyl) -propan-2-amine or a salt thereof represented by the following is reacted with formaldehyde or formaldehyde equivalent in the presence or absence of an acid: Equation (3):

6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline or a salt thereof represented by the following formula (3): XVI):

(In the formula, X represents a leaving group.)
And a compound represented by the following formula (XVII):

And a compound represented by the formula (XVII) or a salt thereof is reduced, and the following formula (XVIII):

And a compound represented by the formula (XVIII) or a salt thereof and acetone are reacted, and the following formula (XIX):

The compound represented by the formula (XIX) or a salt thereof is obtained, and then the compound represented by the formula (XIX) or a salt thereof is reduced.

A method for producing a 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline derivative represented by the formula:

で示される６−フルオロ−３−（４−フルオロベンジル）−１,２,３,４−テトラヒドロイソキノリン若しくはその塩、又はそれらの溶媒和物。
を提供するものである。 8). The following formula (3):

6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline or a salt thereof, or a solvate thereof.
Is to provide.

  According to the present invention, from a relatively inexpensive raw material that is easily available in large quantities, such as 3 or 4-fluorobenzyl halide or 3 or 4-fluorobenzaldehyde, 6-fluoro-3- (4- Fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline can be efficiently produced. The compound represented by the formula (3) is a novel compound useful as an intermediate for producing a tetrahydroisoquinoline compound. When the compound represented by the formula (3) is used, it is not necessary to purify by column chromatography, which is not preferable as an industrial production method in all steps, and is represented by the formulas (1) and (2) useful as a CCR3 antagonist. Can lead to compounds.

  6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline represented by formula (3), which is a novel production intermediate according to the present invention (hereinafter referred to as compound (3)) The same applies to other compounds.) Can be produced, for example, according to the following production method.

（Ｘは脱離基を示す。）

(X represents a leaving group.)

  In the above reaction formula, as the leaving group represented by X, a halogen atom such as chlorine atom, bromine atom or iodine atom, methanesulfonyl group, ethanesulfonyl group, trifluoromethanesulfonyl group, benzenesulfonyl group, p-toluenesulfonyl group A sulfonyl group such as

[Step 1]
Step 1 is a step for producing compound (III). According to a known method (Chem. Lett., 1983, 767-770., Chem. Lett., 1982, 813-814., Etc.), methylthiomethyl p- This is achieved by reacting tolylsulfone (I) with 3-fluorobenzyl halide (II). This reaction can be carried out in a solvent in the presence or absence of a base and in the presence or absence of a quaternary ammonium salt.
As the solvent, for example, toluene, tetrahydrofuran (THF), dioxane, diethyl ether, chloroform, methanol, ethanol, water and the like can be used alone or in combination.
Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride, potassium carbonate and sodium carbonate, and organic bases such as pyridine, triethylamine and diisopropylethylamine.
Examples of the quaternary ammonium salt include trioctylmethylammonium chloride.
3-Fluorobenzyl halide (II) is preferably used in an equivalent amount or twice as much as methylthiomethyl p-tolylsulfone (I), more preferably 1.05-1.35 equivalents.
The reaction conditions are usually -80 to 180 ° C, preferably -30 to 100 ° C, and usually 1 minute to 8 days, preferably 1 hour to 5 days.

[Step 2]
Step 2 is a step of producing compound (V), and is achieved by reacting compound (III) and 4-fluorobenzyl halide (IV) in a solvent using an equivalent amount or an excess amount of a base. The
Examples of the base include butyl lithium, sodium hydride, potassium hydride and the like.
As the solvent, for example, tetrahydrofuran, dioxane, diethyl ether and the like can be used.
4-Fluorobenzyl halide (IV) is preferably used in an amount equivalent to compound (III) or in an excess amount of about 2 times, more preferably 1.05 to 1.5 equivalents.
The reaction conditions are usually −100 to 80 ° C., preferably −40 to 60 ° C. and usually 1 minute to 5 days, preferably 1 hour to 3 days.

[Step 3]
Step 3 is a step of producing compound (5), and is achieved by subjecting compound (V) to solvolysis. This reaction can be carried out in a solvent in the presence or absence of an acid.
Examples of the acid include inorganic acids such as hydrochloric acid, bromic acid, and sulfuric acid.
Examples of the solvent include alcohols such as methanol, ethanol and propanol.
The reaction conditions are usually −80 to 180 ° C., preferably −30 to 100 ° C., usually 1 minute to 5 days, preferably 10 minutes to 3 days.

[Step 4]
Step 4 is a step of producing compound (4), and is achieved by reacting compound (5) in a solvent in the presence of an equivalent amount or an excess amount of an ammonium salt and a borohydride compound.
Examples of ammonium salts include ammonium acetate, ammonium formate, ammonium carbonate, ammonium hydroxide, and ammonium chloride.
Examples of the borohydride compound include sodium borohydride, sodium triacetoxyhydroborate, sodium cyanotrihydroborate and the like.
As the solvent, for example, alcohols such as methanol, ethanol or propanol, ethers such as tetrahydrofuran, toluene, dioxane or diethyl ether can be used alone or in combination.
The ammonium salt is preferably used in the same amount or in excess as the compound (5), more preferably 1 to 10 equivalents.
The reaction conditions are usually -80 to 180 ° C, preferably -30 to 130 ° C, usually 1 minute to 5 days, preferably 10 minutes to 3 days.

[Step 5]
Step 5 is a step of producing compound (3) (6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline), and compound (4) is converted into an ordinary Pictet-Spengler. Achieved by subjecting to reaction. This step is a step for producing a compound (3) by reacting with an equal or excess amount of formaldehyde or formaldehyde equivalent in the presence or absence of an acid. In this reaction, the reaction proceeds with high regioselectivity, and compound (3) is obtained.
Formaldehyde can be used in the form of a formaldehyde solution such as an aqueous formaldehyde solution. Examples of formaldehyde equivalents include paraformaldehyde and dimethoxymethane.
Examples of the acid include trifluoroacetic acid (TFA), sulfuric acid, hydrochloric acid, acetic acid and the like, and it is preferable to use trifluoroacetic acid from the viewpoint of reaction rate.
As the solvent, including solvent-free conditions, for example, toluene, tetrahydrofuran, dioxane, diethyl ether, water and the like can be used alone or in combination.
The formaldehyde or formaldehyde equivalent is preferably used in an equivalent amount or an excess amount, more preferably 1 to 2 equivalents, with the compound (4).
The reaction conditions are usually -80 to 180 ° C, preferably -30 to 130 ° C, usually 1 minute to 5 days, preferably 10 minutes to 3 days.

  In the above series of reactions, the order of introduction of 3-fluorobenzyl halide (II) and 4-fluorobenzyl halide (IV) can be switched.

Moreover, the compound shown by Formula (4) can also be manufactured according to the following manufacturing method.

[Step 6]
Step 6 is a step of obtaining compound (VIII), and reacting nitromethane (VI) with an equivalent amount or an excess amount of 4-fluorobenzaldehyde (VII) in a solvent in the presence or absence of an acid or a base. Achieved by:
Examples of the acid include acetic acid and formic acid.
Examples of the base include butylamine, propylamine, ammonium acetate, ammonium formate, N, N-ethylenediamine, 1-methylpiperazine, piperidine and the like.
As the solvent, for example, toluene, tetrahydrofuran, dioxane, diethyl ether, chloroform and the like can be used alone or in combination.
Nitromethane (VI) is preferably used in an amount equal to or in excess of 4-fluorobenzaldehyde (VII), more preferably 1 to 10 equivalents.
The reaction conditions are usually −30 to 200 ° C., preferably 0 to 150 ° C., usually 1 minute to 5 days, preferably 10 minutes to 3 days.

[Step 7]
Step 7 is a step of obtaining compound (IX), and is achieved by reducing compound (VIII) using a reducing agent such as a borohydride compound in a solvent.
As the solvent, for example, dioxane, tetrahydrofuran, diethyl ether, ethanol, methanol, propanol, toluene, water and the like can be used alone or in combination.
Examples of the borohydride compound include sodium borohydride, sodium triacetoxyhydroborate, sodium cyanotrihydroborate and the like. The reaction conditions are usually -80 to 180 ° C, preferably -30 to 130 ° C, usually 1 minute to 5 days, preferably 10 minutes to 3 days.

[Step 8]
Step 8 is a step for obtaining compound (XI), and reacting compound (IX) with an equivalent amount or an excess amount of 3-fluorobenzaldehyde (X) in a solvent in the presence or absence of an acid or a base. Achieved by:
As the solvent, for example, toluene, tetrahydrofuran, dioxane, diethyl ether, chloroform and the like can be used alone or in combination.
Examples of the base include butylamine, propylamine, ammonium acetate, ammonium formate, N, N-ethylenediamine, 1-methylpiperazine, piperidine and the like.
Examples of the acid include acetic acid and formic acid. 3-Fluorobenzaldehyde (X) is preferably used in an equivalent amount or an excess amount, more preferably 1 to 2 equivalents, with respect to compound (IX).
The reaction conditions are usually -30 to 200 ° C, preferably 0 to 150 ° C and usually 1 minute to 8 days, preferably 1 hour to 5 days.

[Step 9]
Step 9 is a step of obtaining compound (6), and is achieved by reducing compound (XI) in a solvent using a reducing agent such as a borohydride compound.
As the solvent, for example, dioxane, tetrahydrofuran, diethyl ether, ethanol, methanol, propanol, toluene, water and the like can be used alone or in combination.
Examples of the borohydride compound include sodium borohydride, sodium triacetoxyhydroborate, sodium cyanotrihydroborate and the like.
The reaction conditions are usually -80 to 180 ° C, preferably -30 to 130 ° C, usually 1 minute to 5 days, preferably 10 minutes to 3 days.

[Step 10]
Step 10 is a step of obtaining compound (4), and is achieved by reducing compound (6) with a reducing agent in a solvent.
As the solvent, for example, ethanol, methanol, propanol, dioxane, tetrahydrofuran, diethyl ether, water and the like can be used alone or in combination.
As a reducing agent, a combination of zinc, iron, or the like and an acid, or Raney nickel, palladium chloride, palladium black, platinum oxide, rhodium-alumina, or the like can be used in a hydrogen atmosphere.
Hydrochloric acid etc. are mentioned as an acid combined with zinc, iron, etc.
The hydrogen pressure in the catalytic reduction reaction is usually normal pressure to 50 atm, preferably normal pressure to 10 atm.
The reaction conditions are usually -80 to 180 ° C, preferably -30 to 130 ° C, usually 1 minute to 5 days, preferably 1 hour to 3 days.

  In the above series of reactions, the order of introduction of 4-fluorobenzaldehyde (VII) and 3-fluorobenzaldehyde (X) can be switched.

  Furthermore, from 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline represented by the formula (3), N- [3- (methanesulfonylamino] represented by the formula (1) ) Benzyl] -2- [6-fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethanamine can be prepared.

（Ｘは脱離基を示す。）

(X represents a leaving group.)

  In the above reaction formula, as the leaving group represented by X, a halogen atom such as chlorine atom, bromine atom or iodine atom, methanesulfonyl group, ethanesulfonyl group, trifluoromethanesulfonyl group, benzenesulfonyl group, p-toluenesulfonyl group A sulfonyl group such as

[Step 11]
Step 11 is a step of obtaining compound (XIII), and 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline represented by the formula (3) in the presence of a base or It is achieved by reacting with an equal or excess amount of compound (XII) in a solvent in the absence.
Examples of the base include potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, pyridine, triethylamine, diisopropylethylamine and the like.
As the solvent, for example, acetonitrile, toluene, tetrahydrofuran, dioxane, diethyl ether, chloroform and the like can be used alone or in combination.
Compound (XII) is preferably used in an equivalent amount or an excess amount of 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline (3), more preferably 1 to 2 equivalents. is there.
The reaction conditions are usually −30 to 200 ° C., preferably 0 to 150 ° C., usually 1 minute to 5 days, preferably 10 minutes to 3 days.

[Step 12]
Step 12 is a step of obtaining compound (XIV), and is achieved by reducing compound (XIII) with a reducing agent in a solvent.
As the solvent, for example, tetrahydrofuran, diethyl ether, dioxane, methanol, ethanol, propanol and the like can be used alone or in combination.
As the reducing agent, a reducing agent such as lithium aluminum hydride, sodium borohydride, borane-dimethylsulfide complex, borane-THF complex, diborane alone, or a reducing agent such as sodium borohydride is equivalent or excessive. In combination with nickel chloride, cobalt chloride or the like, or Raney nickel, palladium chloride, palladium black, platinum oxide, rhodium-alumina in a hydrogen atmosphere.
The hydrogen pressure in the catalytic reduction reaction is usually normal pressure to 50 atm, preferably normal pressure to 10 atm.
The reaction conditions are usually −80 to 180 ° C., preferably −50 to 80 ° C., usually 1 minute to 5 days, preferably 10 minutes to 3 days.

[Step 13]
Step 13 includes N- [3- (methanesulfonylamino) benzyl] -2- [6-fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinoline-2 (1H) represented by the formula (1). ) -Yl] ethanamine in the presence or absence of a base, in the presence or absence of an acid, in the presence or absence of a desiccant, in an equal or excess amount. This is achieved by reacting the aldehyde form (XV) with a solvent.
Examples of the desiccant include MS (molecular sieve).
In the reaction, compound (1) is obtained by using Raney nickel, palladium chloride, palladium black, platinum oxide, rhodium-alumina, etc. in a hydrogen atmosphere.
Alternatively, compound (1) can also be obtained by using sodium borohydride, sodium triacetoxyhydroborate, sodium cyanotrihydroborate or the like as the reducing agent.
As the solvent, for example, toluene, tetrahydrofuran, dioxane, methanol, ethanol and the like can be used alone or in combination.
Examples of the base include sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and the like.
An acetic acid etc. are mentioned as an acid.
The aldehyde (XV) is preferably used in the same amount or in excess as the compound (XIV), more preferably 1 to 2 equivalents.
The reaction conditions are usually −80 to 150 ° C., preferably 0 to 100 ° C., usually 1 minute to 5 days, preferably 15 minutes to 3 days.

  Further, from 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline represented by the formula (3), 4-[[2- [6- Fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethylamino] methyl] -N-isopropylaniline can be prepared.

（Ｘは脱離基を示す。）

(X represents a leaving group.)

  In the above reaction formula, as the leaving group represented by X, a halogen atom such as chlorine atom, bromine atom or iodine atom, methanesulfonyl group, ethanesulfonyl group, trifluoromethanesulfonyl group, benzenesulfonyl group, p-toluenesulfonyl group A sulfonyl group such as

[Step 14]
Step 14 is a step of obtaining compound (XVII), and 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline represented by the formula (3) in the presence of a base or It is achieved by reacting with an equal or excess amount of compound (XVI) in a solvent in the absence.
As the solvent, for example, acetonitrile, toluene, tetrahydrofuran, dioxane, diethyl ether, chloroform and the like can be used alone or in combination.
Examples of the base include inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and lithium hydroxide, and organic bases such as pyridine, triethylamine and diisopropylethylamine.
Compound (XVI) is preferably used in an equivalent amount or an excess amount of 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline (3), more preferably 1-2 equivalents. is there.
The reaction conditions are usually −30 to 200 ° C., preferably 0 to 150 ° C., usually 1 minute to 5 days, preferably 10 minutes to 3 days.

[Step 15]
Step 15 is a step of obtaining compound (XVIII), and is achieved by reducing compound (XVII) with an equal amount or an excess amount of a reducing agent in the presence or absence of a metal catalyst.
As the metal catalyst, nickel chloride, copper chloride, palladium chloride, cobalt chloride, tin chloride, rhodium chloride and the like can be used.
As the reducing agent, reducing agents such as sodium borohydride, lithium borohydride, lithium aluminum hydride, or a combination of these with a metal catalyst such as nickel chloride, or Raney nickel, palladium chloride, palladium black, platinum oxide in a hydrogen atmosphere. And rhodium-alumina.
As the solvent, for example, methanol, ethanol, propanol or the like can be used alone or in combination.
The hydrogen pressure in the catalytic reduction reaction is usually normal pressure to 50 atm, preferably normal pressure to 10 atm.
The reaction conditions are usually -80 to 180 ° C, preferably -30 to 130 ° C, and usually 1 minute to 5 days, preferably 15 minutes to 3 days.

[Step 16]
Step 16 is a step of obtaining compound (XIX), and compound (XVIII) is present in the presence or absence of an acid, in the presence or absence of a desiccant such as MS (molecular sieve), in an equal amount or in excess. This is achieved by reacting with acetone in a solvent.
Examples of the reaction reagent include sodium borohydride, sodium triacetoxyhydroborate, sodium cyanotrihydroborate and the like.
Alternatively, compound (XIX) can also be obtained by reduction with Raney nickel, palladium chloride, palladium black, platinum oxide, rhodium-alumina or the like in a hydrogen atmosphere.
As the solvent, for example, toluene, tetrahydrofuran, dioxane, methanol, ethanol and the like can be used alone or in combination.
An acetic acid etc. are mentioned as an acid.
Acetone is preferably used in the same amount or in excess as compound (XVIII), more preferably 1 to 2 equivalents.
The reaction conditions are usually −80 to 150 ° C., preferably 0 to 100 ° C., usually 1 minute to 5 days, preferably 15 minutes to 3 days.

[Step 17]
Step 17 represents 4-[[2- [6- [6-fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethylamino] methyl] represented by the formula (2). A step of obtaining -N-isopropylaniline, which is achieved by subjecting compound (XIX) to a reduction reaction using a reducing agent in a solvent in the presence or absence of a Lewis acid.
Examples of the reducing agent include borane-dimethylsulfide complex, borane-THF complex, diborane, lithium aluminum hydride, lithium borohydride, diisobutylaluminum hydride and the like.
Examples of Lewis acids include BF ₃ · diethyl ether and titanium dichloride.
As the solvent, for example, tetrahydrofuran, DME, dioxane, toluene, methanol, ethanol and the like can be used alone or in combination.
The reducing agent is preferably used in an equivalent amount or an excess amount, more preferably 1 to 10 equivalents, with respect to compound (XIX).
The Lewis acid is preferably used in an equivalent amount or an excess amount, more preferably 1 to 10 equivalents, with respect to the compound (XIX).
The reaction conditions are usually −80 to 150 ° C., preferably 0 to 130 ° C. and usually 1 minute to 8 days, preferably 1 hour to 5 days.

  In the production method of the present invention, the isolation / purification operation in each step can be performed by a simple method capable of handling a large-scale synthesis, such as extraction, concentration, distillation, crystallization, filtration, and recrystallization. A purification method such as graphy may be used.

Furthermore, this invention also includes the substance which has various hydrates and solvates, and a crystal polymorph of compound (3) or its pharmaceutically acceptable acid addition salt.
A pharmaceutically acceptable acid addition salt of the tetrahydroisoquinoline compound represented by the formula (3) is also encompassed in the present invention. Specific examples of the pharmaceutically acceptable acid addition salt of the tetrahydroisoquinoline compound represented by the formula (3) include inorganic acids (for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, Phosphoric acid etc.) and organic acids (for example, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, and acid addition salts with p-toluenesulfonic acid, aspartic acid, glutamic acid and the like.
Examples of the solvate of the tetrahydroisoquinoline compound represented by the formula (3) or a pharmaceutically acceptable salt thereof include various hydrates and solvates (for example, solvates with alcohols such as ethanol). Can be mentioned.
In addition, as a salt of the compound represented by the formulas (1), (2), (4), (5) and (6) and other compounds used in the production method of the present invention, the above formula (3) What was illustrated as a salt of the tetrahydroisoquinoline compound shown by these is mentioned.

  If compound (3) which is a novel intermediate is used, compound (1) or (2) can be advantageously produced industrially by the production method described above. These compounds (1) and (2) have CCR3 antagonistic activity as shown in the test examples described below, and diseases involving CCR3 (particularly asthma, allergic rhinitis, sinusitis, allergic conjunctivitis, atopic) Dermatitis, ulcerative colitis, Crohn's disease, rheumatoid arthritis and other allergies or autoimmune diseases, and HIV infection and its associated encephalitis and dementia).

  Hereinafter, although an example is given and explained in detail, the present invention is not limited to these.

Example 1 Preparation of 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline
a) Preparation of 4-methylphenyl [1- (methylthio) -2- (3-fluorophenyl) ethyl] sulfone

350 g of methylthiomethyl p-tolylsulfone was dissolved in 500 mL of toluene and stirred at room temperature. To this, 352 g of 3-fluorobenzyl bromide and 26 g of trioctylmethylammonium chloride were sequentially added. Next, 500 g of a 50% aqueous sodium hydroxide solution was added, and stirring was continued for 2 days at room temperature.
After completion of the reaction, 500 ml of water was added to the reaction solution, and the organic layer was separated. The mixture was further extracted with ethyl acetate, and the organic layers were combined and washed successively with 1N aqueous hydrochloric acid and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 732 g of a crude product as a pale yellow solid.
The resulting crude product was stirred with 500 mL of diethyl ether: hexane = 1: 4 mixed solution, and the suspension was collected by filtration and washed with hexane to obtain 429 g (yield 82%) of the title compound as a pale yellow solid. .
¹ H-NMR (CDCl ₃ ) δ: 2.14 (3H, s), 2.48 (3H, s), 2.63 (1H, dd, J = 11.7, 14.4 Hz), 3.59 (1H, dd, J = 2.8, 14.4 Hz ), 3.84 (1H, dd, J = 2.8, 11.7 Hz), 6.88-6.99 (3H, m), 7.39 (2H, d, J = 8.1 Hz), 7.88 (2H, d, J = 8.1 Hz).
Elemental analysis (C ₁₆ H ₁₇ O ₂ S ₂ F ₁ )
Theoretical C, 59.23; H, 5.28; F, 5.86
Found C, 59.42; H, 5.31; F, 5.69

b) Preparation of 4-methylphenyl [1- (4-fluorobenzyl) -1- (methylthio) -2- (3-fluorophenyl) ethyl] sulfone

  400 g of 4-methylphenyl [1- (methylthio) -2- (3-fluorophenyl) ethyl] sulfone was dissolved in 1.2 L of anhydrous THF and stirred at room temperature under an argon atmosphere. The reaction solution was cooled to −10 to −12 ° C., and 404 mL (2.62 mol / L) of n-butyllithium / hexane solution was slowly added thereto over 50 minutes. Next, 279 g of 4-fluorobenzyl bromide dissolved in 400 mL of anhydrous THF was slowly added over 20 minutes, and stirring was continued for 2 hours. The reaction solution was changed to ice cooling and stirred for 2 hours, and then stirred overnight at room temperature.

After completion of the reaction, 500 ml of water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, 1N aqueous hydrochloric acid and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 532 g of a yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 2.31 (3H, s), 2.46 (3H, s), 3.33 (1H, d, J = 15.1 Hz), 3.35 (1H, d, J = 15.1 Hz), 3.39 ( 1H, d, J = 15.1 Hz), 3.40 (1H, d, J = 15.1 Hz), 6.78-6.91 (5H, m), 7.02-7.08 (2H, m), 7.11 (1H, ddd, J = 6.1, 8.1, 8.3 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.77 (2H, d, J = 8.2 Hz).

c) Preparation of 1- (3-fluorophenyl) -3- (4-fluorophenyl) -propan-2-one

4-Methylphenyl [1- (4-fluorobenzyl) -1- (methylthio) -2- (3-fluorophenyl) ethyl] sulfone (532 g) was dissolved in methanol (550 mL) and stirred. 275 mL of 9N hydrochloric acid was added to the reaction solution, and stirring was continued for 3 hours under reflux.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, added with 500 ml of water, and extracted with chloroform. The organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 495 g of a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 3.71 (2H, s), 3.72 (2H, s), 6.84-6.88 (1H, m), 6.91 (1H, d, J = 7.6 Hz), 6.95 (1H, dd , J = 2.4, 8.6 Hz), 7.01 (2H, ddd, J = 2.2, 6.4, 8.6 Hz), 7.09-7.13 (2H, m), 7.26-7.31 (1H, m).

d) Preparation of 1- (3-fluorophenyl) -3- (4-fluorophenyl) -propan-2-amine

To 490 g of 1- (3-fluorophenyl) -3- (4-fluorophenyl) -propan-2-one and 764 g of ammonium acetate, 2.6 L of methanol was added and dissolved. Next, 85 g of sodium cyanotrihydroborate was added to the reaction solution, and the mixture was stirred for 30 minutes under reflux.
After completion of the reaction, the reaction solution was cooled to room temperature and 200 mL of saturated aqueous sodium bicarbonate was slowly added. Thereafter, the mixture was concentrated under reduced pressure, aqueous sodium hydroxide was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with aqueous sodium hydroxide and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 484 g of an orange oil.

This crude product was dissolved in methanol, and 143 g of fumaric acid was added and dissolved by heating. Thereafter, diethyl ether was added at room temperature, and crystals were precipitated while stirring at room temperature. The resulting crystals were collected by filtration and washed with hexane to obtain 320 g of crude crystals of monofumarate.
The crude crystals were dissolved again by heating in methanol, and diethyl ether was added at room temperature and stirred overnight to precipitate crystals. The obtained crystals were collected by filtration and washed with hexane to give the 1 fumarate salt as a slightly yellow solid.

This solid was dissolved in chloroform and washed with aqueous sodium hydroxide. The aqueous layer was extracted again with chloroform, and the organic layer was washed with aqueous sodium hydroxide and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain 226 g (yield 74%, III → V → (5) → (4): 3 steps) was obtained as a yellow oil.
1 fumarate
¹ H-NMR (DMSO-d ₆ ) δ: 3.10-3.70 (4H, m), 3.64 (1H, m), 6.57 (2H, s), 7.03-7.18 (6H, m), 7.24-7.36 (2H, m).
Elemental analysis (C ₁₉ H ₁₉ N ₁ O ₄ F ₂ )
Theoretical C, 62.80; H, 5.27; N, 3.85; F, 10.46
Found C, 62.84; H, 5.31; N, 3.83; F, 10.73
Free base
¹ H-NMR (CDCl ₃ ) δ: 2.64 (1H, dd, J = 4.2, 8.1 Hz), 2.67 (1H, dd, J = 3.9, 8.1 Hz), 2.76-2.85 (2H, m), 3.24-3.32 (1H, m), 3.38-3.52 (2H, br), 6.87-7.01 (4H, m), 7.12-7.16 (2H, m), 7.23-7.28 (2H, m).

e) Preparation of 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline

84 g of 1- (3-fluorophenyl) -3- (4-fluorophenyl) -propan-2-amine was dissolved in 672 mL of TFA, 53.9 g of an aqueous formaldehyde solution was added, and the mixture was stirred at 70 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 84 g of a crude product as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 2.80 (1H, dd, J = 4.2, 16.8 Hz), 2.92 (1H, dd, J = 10.0, 16.8 Hz), 2.95 (1H, dd, J = 9.2, 13.2 Hz ), 3.33 (1H, dd, J = 5.1, 13.2 Hz), 3.34-3.44 (1H, m), 4.19 (1H, m), 4.31 (1H, m), 6.76 (1H, dd, J = 2.4, 9.3 Hz), 6.88 (1H, ddd, J = 2.4, 8.5, 8.5 Hz), 6.98-7.07 (3H, m), 7.18-7.24 (2H, m).

Example 2 Preparation of 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline
a) Preparation of 4-fluoro-β-nitrostyrene

155 g of nitromethane and 63 g of 4-fluorobenzaldehyde were dissolved in 300 mL of toluene, 1.83 g of butylamine and 1.52 g of acetic acid were added, and the mixture was stirred at 75 ° C. for 12 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off. The resulting orange solid was suspended in hexane and collected by filtration to obtain 84 g (yield 99%) of the desired product as a yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 7.16 (2H, ddd, J = 2.1, 6.5, 8.6 Hz), 7.54 (1H, d, J = 13.6 Hz), 7.56 (2H, ddd, J = 2.1, 5.4, 8.6 Hz), 7.98 (1H, d, J = 13.6 Hz).

b) Production of 1-nitro-2- (4-fluorophenyl) ethane

Sodium borohydride (22 g) was dissolved in ethanol (440 mL) and stirred. The reaction solution was cooled with ice, and 440 mL of 1,4-dioxane solution of 44 g of 4-fluoro-β-nitrostyrene was added dropwise over 1 hour. After the dropwise addition, the reaction solution was stirred at room temperature for 15 minutes. After completion of the reaction, the reaction solution was cooled with ice and saturated aqueous sodium bicarbonate was added. The reaction solution was concentrated under reduced pressure, the solvent was distilled off, the residue was dissolved in ethyl acetate, and washed with dilute hydrochloric acid and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 44 g (yield 99%) of the desired product as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 3.29 (2H, t, J = 7.2 Hz), 4.59 (2H, t, J = 7.2 Hz), 7.01 (2H, dd, J = 8.5, 8.5 Hz), 7.17 ( (2H, dd, J = 5.6, 8.5 Hz).

c) Preparation of 1- (3-fluorophenyl) -3- (4-fluorophenyl) -2-nitro-1-propene

58 g of 1-nitro-2- (4-fluorophenyl) ethane and 51 g of 3-fluorobenzaldehyde are dissolved in 290 mL of toluene, 6.0 g of N, N-dimethylethylenediamine and 20.6 g of acetic acid are added, and the mixture is refluxed for 40 hours. Stir. The reaction solution was washed with dilute hydrochloric acid and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 89 g (yield 94%) of the desired product as a yellow oil.
_{^{1 H-NMR (CDCl 3)}} δ: 4.21 (2H, brs), 7.02 (2H, ddd, J = 2.2, 6.4, 8.6 Hz), 7.11-7.19 (4H, m), 7.19-7.23 (1H, m) , 7.42 (1H, ddd, J = 5.9, 8.0, 8.0 Hz), 8.22 (1H, s).

d) Preparation of 1- (3-fluorophenyl) -3- (4-fluorophenyl) -2-nitropropane

Dissolve sodium borohydride (27 g) in ethanol (890 mL) and stir with ice cooling. To this, 89 g of 1- (3-fluorophenyl) -3- (4-fluorophenyl) -2-nitro-1-propene dissolved in 890 mL of 1,4-dioxane was added dropwise over 30 minutes. The reaction was warmed to room temperature and stirred for 15 minutes. After completion of the reaction, the reaction solution was cooled with ice and 100 mL of saturated ammonium chloride was slowly added. The reaction solution was concentrated under reduced pressure, and the organic solvent was distilled off. The residue was dissolved in ethyl acetate and washed with dilute hydrochloric acid, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 89 g (yield 99%) of the desired product as a black-brown solidified product.
¹ H-NMR (CDCl ₃ ) δ: 3.05 (1H, dd, J = 1.8, 5.1 Hz), 3.09 (1H, dd, J = 1.8, 5.1 Hz), 3.27 (1H, dd, J = 9.0, 14.4 Hz ), 3.29 (1H, dd, J = 9.0, 14.4 Hz), 4.83-4.92 (1H, m), 6.87 (1H, dd, J = 2.1, 9.4 Hz), 6.93 (1H, brd, J = 7.8 Hz) , 6.96-7.03 (3H, m), 7.12 (2H, ddd, J = 2.2, 5.2, 8.6 Hz), 7.28 (1H, ddd, J = 5.9, 7.8, 8.0 Hz).

e) Preparation of 1- (3-fluorophenyl) -3- (4-fluorophenyl) -propan-2-amine

89 g of 1- (3-fluorophenyl) -3- (4-fluorophenyl) -2-nitropropane was dissolved in 890 mL of methanol and stirred at room temperature. To the reaction solution, 105 g of zinc was added little by little, and the reaction solution was heated to 65 ° C. To the reaction solution, 890 mL of 4N hydrochloric acid was slowly added over 15 minutes, and stirring was further continued for 30 minutes.
After completion of the reaction, the reaction solution was suction filtered and the mother liquor was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, neutralized with aqueous sodium hydroxide, separated, and further washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain 80 g (yield 99%) of the desired product as an orange oil.
The crude product was purified in the same manner as in Example 1.

Example 3 Preparation of N- [3- (methanesulfonylamino) benzyl] -2- [6-fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethanamine
a) Preparation of 2-cyanomethyl-6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline

2.1 g of 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline obtained in Example 1 was dissolved in 12 mL of acetonitrile. To the reaction solution, 1.7 g of potassium carbonate and 1.1 g of bromoacetonitrile were added and heated to 60 ° C. and stirred for 12 hours. After completion of the reaction, the reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. To this were added ethyl acetate and water, and the mixture was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Then, 5 mL of ethyl acetate was added and dissolved by heating at 50 ° C., 15 mL of hexane was added and the mixture was stirred at room temperature for 6 hours. The precipitate was collected by filtration to obtain 2.1 g (yield 90%) of a pale yellow solid as the pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 2.45 (1H, dd, J = 11.1, 14.3 Hz), 2.56 (1H, dd, J = 7.1, 16.6 Hz), 2.67 (1H, dd, J = 4.4, 16.6 Hz) ), 3.04-3.14 (2H, m), 3.62 (1H, J = 17.3 Hz), 3.87 (1H, J = 16.4 Hz), 3.91 (1H, J = 17.3 Hz), 3.92 (1H, J = 16.4 Hz) , 6.71 (1H, dd, J = 2.2, 9.5 Hz), 6.85 (1H, ddd, J = 2.4, 8.6, 8.6 Hz), 6.96-7.04 (3H, m), 7.11-7.17 (2H, m).

b) Preparation of 2- [6-fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethanamine

  Under an argon atmosphere, 0.3 g of LAH was dissolved in 1.5 mL of anhydrous THF and stirred under cooling with ice. 2-Cyanomethyl-6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline (2.1 g) in anhydrous THF (2.5 mL) was slowly added to the reaction solution, and stirring was continued for 1 hour. After completion of the reaction, saturated aqueous ammonium chloride was slowly added to the reaction solution, and then ethyl acetate was added. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was dissolved in ethanol, 6.1 g of fumaric acid was added and dissolved by heating, and the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration, and 1.9 g of 2- [6-fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethanamine monofumarate (yield 89%) ) Was obtained as a pale yellow solid.

1 fumarate
¹ H-NMR (CD ₃ OD) δ: 2.52 (1H, dd, J = 10.0, 13.2 Hz), 2.57 (1H, dd, J = 3.9, 16.6 Hz), 2.84 (1H, dd, J = 5.1, 13.8 Hz), 2.88 (1H, dd, J = 10.5, 13.5 Hz), 2.94 (1H, dd, J = 5.0, 13.5 Hz), 2.98 (1H, dd, J = 5.1, 13.8 Hz), 3.06-3.11 (2H , m), 3.23-3.31 (1H, m), 3.85 (1H, d, J = 15.8 Hz), 3.92 (1H, d, J = 15.8 Hz), 6.68 (2H, s), 6.81 (1H, dd, J = 2.7, 9.6 Hz), 6.90 (1H, ddd, J = 2.7, 8.5, 8.5 Hz), 7.02 (2H, ddd, J = 2.2, 6.6, 8.8 Hz), 7.12 (1H, dd, J = 5.9, 8.5 Hz), 7.13 (2H, ddd, J = 2.2, 5.4, 8.8 Hz).
Free base
¹ H-NMR (CDCl ₃ ) δ: 2.40-2.62 (4H, m), 2.66-2.96 (6H, m), 3.16-3.28 (1H, m), 3.80 (2H, s), 6.76 (1H, dd, J = 2.0, 9.5 Hz), 6.86 (1H, ddd, J = 2.0, 8.3, 8.3 Hz), 6.94-7.04 (3H, m), 7.08 (2H, dd, J = 5.9, 8.0 Hz).

c) Preparation of N- [3- (methanesulfonylamino) benzyl] -2- [6-fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethanamine

  2- [6-Fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethanamine monofumarate 10 g, 3- (methanesulfonylamino) under argon atmosphere Benzaldehyde (4.8 g) and sodium hydrogen carbonate (4.0 g) were dissolved in methanol (100 mL), and the mixture was stirred at 60 ° C. for 5 hours. The reaction solution was brought to room temperature, 10% Pd-C 300 mg was added, and the mixture was stirred overnight under a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered through celite and concentrated under reduced pressure. The filtrate was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was dissolved in 3 mL of methanol, 4.6 g of citric acid was added and dissolved by heating, 9 mL of ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration and converted from 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline to N- [3- (methanesulfonylamino) benzyl] -2- [6-fluoro. 11.2 g (yield 96%) of citrate salt of -3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethanamine was obtained as a colorless crystalline powder.

1 citrate
¹ H-NMR (CD ₃ OD) δ: 2.50 (1H, dd, J = 10.0, 13.4 Hz), 2.55 (1H, dd, J = 3.4, 16.1 Hz), 2.72 (2H, d, J = 15.4 Hz) , 2.85 (2H, d, J = 15.4 Hz), 2.85-2.95 (3H, m), 3.02 (3H, s), 3.03-3.12 (1H, m), 3.15-3.20 (2H, m), 3.22-3.30 (1H, m), 3.82 (1H, d, J = 16.4 Hz), 3.87 (1H, d, J = 16.4 Hz), 4.19 (2H, s), 6.81 (1H, dd, J = 2.4, 9.5 Hz) , 6.90 (1H, ddd, J = 2.4, 8.5, 8.5 Hz), 7.00 (2H, dd, J = 8.6, 8.6 Hz), 7.09 (1H, dd, J = 5.8, 8.5 Hz), 7.14 (2H, dd , J = 5.4, 8.6 Hz), 7.21-7.35 (2H, m), 7.39 (1H, d, J = 7.8 Hz), 7.42 (1H, brs).
Elemental analysis (C ₃₂ H ₃₇ N ₃ O ₉ F ₂ S)
Theoretical C, 56.71; H, 5.50; N, 6.20; F, 5.61
Found C, 56.65; H, 5.58; N, 6.10; F, 5.43
Free base
¹ H-NMR (CDCl ₃ ) δ: 2.44 (1H, dd, J = 9.8, 13.4 Hz), 2.50 (1H, dd, J = 3.9, 16.6 Hz), 2.72-2.90 (6H, m), 2.95 (3H , s), 3.14-3.22 (1H, m), 3.76 (2H, s), 3.77 (2H, s), 6.75 (1H, dd, J = 2.4, 9.5 Hz), 6.86 (1H, ddd, J = 2.4 , 8.5, 8.5 Hz), 6.94 (2H, ddd, J = 2.0, 6.6, 8.6 Hz), 6.99 (1H, dd, J = 5.7, 8.5 Hz), 7.02-7.15 (4H, m), 7.26-7.31 ( 2H, m).

Example 4 Preparation of 4-[[2- [6-Fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethylamino] methyl] -N-isopropylaniline
a) Preparation of N- (4-nitrobenzyl) -2-bromoacetamide

10 g of 4-nitrobenzylamine monohydrochloride was stirred in 50 mL of acetonitrile. The reaction solution was cooled with ice, and 13.1 g of dimethylaniline was slowly added. Slowly add 12 g of bromoacetyl bromide to the reaction mixture and continue stirring for 15 minutes. After completion of the reaction, water was added to the reaction mixture, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was precipitated from an ethyl acetate-toluene mixture and collected by filtration to obtain 14.4 g (99%) of the desired product as a slightly yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 3.98 (2H, s), 4.59 (2H, d, J = 6.1 Hz), 6.94 (1H, brs), 7.46 (2H, d, J = 8.1 Hz), 8.21 ( (2H, d, J = 8.1 Hz).

b) Preparation of N- (4-nitrobenzyl)-[6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -yl] acetamide

60.0 g of 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline obtained in Example 1 was dissolved in 360 mL of acetonitrile. To the reaction solution, 69.6 g of N- (4-nitrobenzyl) -2-bromoacetamide and 95.7 g of potassium carbonate were sequentially added at room temperature, followed by stirring at 60 ° C. overnight. The reaction solution was suction filtered, and the filtrate was concentrated under reduced pressure. The concentrated solution was dissolved in ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in ethyl acetate, 4N hydrochloric acid / ethyl acetate was added under ice cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue and dissolved by heating, and hexane was added with stirring at room temperature. The precipitate was collected by filtration and washed with hexane to obtain 105.8 g (yield 95%) of the target hydrochloride as a pale yellow solid.
The obtained hydrochloride was dissolved in chloroform, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. Methanol was added to the residue for dissolution, hexane was added, and the mixture was stirred at room temperature for 2 hours. The precipitate was collected by filtration and washed with hexane to obtain 100.9 g (yield 85%) of the target product as a pale yellow solid.

Free base
¹ H-NMR (CDCl ₃ ) δ: 2.55 (1H, dd, J = 3.9, 16.4 Hz), 2.62 (1H, dd, J = 7.6, 13.2 Hz), 2.70-2.90 (2H, m), 3.20 (1H , d, J = 16.8 Hz), 3.22-3.28 (1H, m), 3.38 (1H, d, J = 16.8 Hz), 3.78 (1H, d, J = 16.4 Hz), 3.90 (1H, d, J = 16.4 Hz), 4.42 (1H, d, J = 7.2 Hz), 4.45 (1H, d, J = 7.2 Hz), 6.80 (1H, dd, J = 2.4, 9.5 Hz), 6.92 (1H, ddd, J = 2.4, 8.5, 8.5 Hz), 6.95-7.11 (4H, m), 7.35 (2H, dd, J = 1.9, 7.0 Hz), 7.40-7.46 (1H, m), 8.18 (2H, dd, J = 1.9, 7.0 Hz).

c) Preparation of N- (4-aminobenzyl)-[6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -yl] acetamide

N- (4-nitrobenzyl)-[6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -yl] acetamide 87.5 g was suspended in methanol, 4.5 g of 10% Pd-C (wet.) Was added. The reaction system was purged with hydrogen, and the reaction was continued at room temperature for 2 hours. After completion of the reaction, the reaction solution was filtered through Celite, and the filtrate was concentrated to quantitatively obtain the target product as a white foamy solid.
¹ H-NMR (CDCl ₃ ) δ: 2.52-2.54 (2H, m), 2.72-2.86 (2H, m), 3.13 (1H, d, J = 16.4 Hz), 3.13-3.22 (1H, m), 3.33 (1H, d, J = 16.4 Hz), 3.74 (1H, d, J = 16.2 Hz), 3.80 (1H, d, J = 16.2 Hz), 4.20-4.32 (2H, m), 6.63 (2H, d, J = 8.5 Hz), 6.81 (1H, dd, J = 2.4, 9.2 Hz), 6.88 (1H, ddd, J = 2.4, 8.5, 8.5 Hz), 6.90 (2H, dd, J = 8.5, 8.5 Hz), 6.98 (1H, dd, J = 5.9, 8.5 Hz), 6.98-7.20 (5H, m).

d) Preparation of N- (4-isopropylaminobenzyl)-[6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -yl] acetamide

67.0 g of N- (4-aminobenzyl)-[6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -yl] acetamide was dissolved in 670 mL of toluene. . To this was added 10.2 g of anhydrous acetone. Under ice cooling, 47.3 g of sodium triacetoxyhydroborate and 13 mL of acetic acid were sequentially added, and the mixture was stirred overnight at room temperature. After completion of the reaction, saturated aqueous sodium hydrogen carbonate and ethyl acetate were added to the reaction solution. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. Methanol was added to the residue and dissolved by heating. A methanol solution of 18.5 g of maleic acid was added and stirred at room temperature. Further, ethyl acetate and hexane were added and stirred. The precipitate was collected by filtration to obtain 81.8 g (yield: 88.8%) of the target product as a slightly yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.1 Hz), 2.54 (1H, dd, J = 8.3, 13.9 Hz), 2.55 (1H, dd, J = 5.4, 14.5 Hz), 2.74-2.86 (2H, m), 3.15 (1H, d, J = 16.6 Hz), 3.14-3.22 (1H, m), 3.35 (1H, d, J = 16.6 Hz), 3.47 (1H, brs), 3.56 -3.66 (1H, m), 3.76 (1H, d, J = 16.4 Hz), 3.82 (1H, d, J = 16.4 Hz), 4.22 (1H, dd, J = 5.6, 14.4 Hz), 4.31 (1H, dd, J = 5.6, 14.4 Hz), 6.53 (2H, d, J = 8.5 Hz), 6.80 (1H, dd, J = 2.2, 9.3 Hz), 6.86 (1H, ddd, J = 2.7, 8.5, 8.5 Hz) ), 6.92 (2H, dd, J = 8.6, 8.6 Hz), 6.97 (1H, dd, J = 5.9, 8.5 Hz), 7.00-7.06 (4H, m), 7.20-7.30 (1H, m).

e) Preparation of N- [4-Isopropylamino) benzyl] -2- [6-fluoro-3- (4-fluorobenzyl) -3,4-dihydroisoquinolin-2 (1H) -yl] ethanamine

  The maleate of N- (4-isopropylaminobenzyl)-[6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -yl] acetamide was converted to ethyl acetate. The extract was washed with 100 mL of 2N aqueous sodium hydroxide solution twice and then with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was azeotroped with toluene to give N- (4-isopropylaminobenzyl)-[6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -yl] acetamide. Collected quantitatively.

10.4 g of the recovered N- (4-isopropylaminobenzyl)-[6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -yl] acetamide was added to anhydrous THF. Dissolved in 83 mL. Under an argon gas atmosphere and ice cooling, 9.5 g of BF ₃ · diethyl ether was added to the reaction solution, and the mixture was stirred at 60 ° C. for 1 hour. Thereafter, 8.5 g of borane-dimethyl sulfide complex, 112 mM was added, and the mixture was stirred for 6 hours. After completion of the reaction, 44 mL of 5N hydrochloric acid was added little by little to the reaction solution under ice cooling, and the mixture was stirred at 60 ° C. for 10 hours. Thereafter, 2N aqueous sodium hydroxide solution was added under ice-cooling to make it weakly basic, and the organic layer was separated with ethyl acetate. The organic layer was washed successively with 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated.

The crude product was dissolved in a small amount of methanol, a methanol solution of fumaric acid was added, and the mixture was concentrated under reduced pressure to obtain a white amorphous.
This white amorphous was dissolved in THF by heating, hexane was added, and the mixture was suspended by heating at 40 ° C. for 2 hours, and further stirred overnight at room temperature. This was collected by filtration to obtain 10.5 g (yield 80%) of the desired product as colorless crystals.
1 fumarate
¹ H-NMR (CD ₃ OD) δ: 1.18 (6H, dd, J = 1.3, 6.2 Hz), 2.47 (1H, dd, J = 10.0, 13.4 Hz), 2.53 (1H, dd, J = 3.4, 16.8 Hz), 2.78-2.86 (1H, m), 2.87 (2H, dd, J = 4.9, 14.9 Hz), 2.94-3.02 (1H, m), 3.08-3.20 (3H, m), 3.56-3.64 (1H, m), 3.79 (2H, s), 4.03 (2H, s), 6.62 (2H, dd, J = 2.0, 6.6 Hz), 6.68 (2H, s), 6.80 (1H, dd, J = 2.6, 9.6 Hz ), 6.89 (1H, ddd, J = 2.6, 8.5, 8.5 Hz), 7.00 (2H, dd, J = 8.6, 8.6 Hz), 7.07 (1H, dd, J = 5.9, 8.5 Hz), 7.10 (2H, dd, J = 5.5, 8.6 Hz), 7.15 (2H, dd, J = 2.0, 6.6 Hz).
Elemental analysis _{(C 32 H 37 N 3 O} 4 F 2)
Theoretical C, 67.95; H, 6.59; N, 7.43; F, 6.72
Found C, 67.91; H, 6.66; N, 7.40; F, 6.80
Free base
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.1 Hz), 2.40 (1H, dd, J = 10.0, 13.4 Hz), 2.48 (1H, dd, J = 3.7, 16.6 Hz), 2.73-2.88 (6H, m), 3.13 (1H, m), 3.56-3.68 (1H, m), 3.67 (2H, s), 3.73 (2H, s), 6.53 (2H, d, J = 8.3 Hz) , 6.74 (1H, dd, J = 2.4, 9.5 Hz), 6.85 (1H, ddd, J = 2.4, 8.5, 8.5 Hz), 6.94 (2H, dd, J = 8.6, 8.6 Hz), 6.98 (1H, dd , J = 5.6, 8.5 Hz), 7.03 (2H, dd, J = 5.6, 8.6 Hz), 7.07 (2H, d, J = 8.3 Hz).

Test Example 1 CCR3 Antagonism Test Guinea pig eosinophils were adjusted with reference to the method of the literature (Pinkus, Blood. 52 (1978) 127-134). Specifically, polymyxin B (SIGMA) diluted with PBS (−) was injected once a week into a 6-week-old Hartley male guinea pig (n = 3, Japan SLC) peritoneal cavity at 2 mg per animal. 24 hours after performing the same operation four times, 50 mL of PBS (-) containing 6 U / mL heparin and 1 mM EDTA per individual was injected into the abdominal cavity under diethyl ether anesthesia, and the same solution was recovered. After washing with PBS (−) containing 1 mM EDTA, cells suspended in a Percoll solution having a specific gravity of 1.070 were centrifuged using a discontinuous Percoll gradient solution to obtain a crude eosinophil fraction. After washing with PBS (−), the suspension was suspended in RPMI-1640 medium (SIGMA) containing 1% FCS and cultured overnight in a CO ₂ incubator.

The cells were collected the next day, and the test compound was added to eosinophils suspended in RPMI-1640 medium containing 0.1% BSA (Bovine Serum Albumin, bovine serum albumin, SIGMA) and allowed to stand at 37 ° C. for 30 minutes. Was pretreated. A mixed solution of guinea pig eotaxin (Chemical Synthesis Services) prepared to a final concentration of 100 ng / mL and a test compound is added to the lower chamber of a 96-well chemotaxis chamber (Neuroprobe), and a pore size of 5 μm treated with polyvinylpyrrolidone (PVP) is added. 12.0 × 10 ⁵ eosinophils per well and a mixture of test compounds were placed in the upper chamber in this order in the upper chamber, and reacted in a CO ₂ incubator for 1 hour.
After completion of the reaction, the filter was taken out, cell staining was performed with a Diff-Quik staining kit (international reagent), and eosinophils migrated under a microscope were counted. The number of migratory fields was counted per well, the average value was taken as the number of migrating eosinophils, the inhibition rate was calculated when the reaction of eotaxin alone was taken as 100%, and the concentration (inhibition rate curve showing 50% inhibition) ( IC50 value) was calculated. The results are shown in Table 1.

Test Example 2 Inhibition of eosinophil infiltration into the lung in an ovalbumin-induced guinea pig eosinophil infiltration model Male Std / Hartley guinea pig (n = 8) with 10 μg ovalbumin (OVA, Sigma) and 100 mg aluminum hydroxide (Wako Pure Chemical) And the suspension was administered intraperitoneally, and sensitization was performed again under the same conditions two days later.
Sixteen days after the first sensitization, 0.5% by mass OVA was inhaled for 30 minutes, and 30 minutes before and 4 hours later, Compound (1) suspended in 0.5% aqueous methylcellulose was administered at a dose of 10 mg / kg. In addition, only a solvent (0.5% methylcellulose aqueous solution) was administered to the control group, and untreated animals were used for the normal group.
17 days after the first sensitization, the alveoli were washed with PBS containing 0.1% BSA (10 mL × 5 reciprocations × 2 times) to collect the alveolar lavage fluid.
The collected alveolar lavage fluid was measured for the number of eosinophils using a multi-item automatic blood cell analyzer XT-2000i (Sysmex). The results are shown in FIG.

  From the above, it was shown that the compound (1) and the compound (2) produced using the compound (3) according to the present invention have a CCR3 antagonistic action superior to that of Test Example 1, and It is also effective as a preventive and / or therapeutic agent for diseases involving CCR3, particularly asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, etc. It is suggested that the effect is demonstrated. These compounds have been confirmed to have almost no toxicity and are useful as pharmaceuticals.

It is a graph which shows the eosinophil infiltration inhibitory effect to a lung in a guinea pig eosinophil infiltration model by a compound (1).

Claims (8)

The following formula (4):

Reacting 1- (3-fluorophenyl) -3- (4-fluorophenyl) -propan-2-amine or a salt thereof represented by the above with formaldehyde or formaldehyde equivalent in the presence or absence of an acid. Characteristic, the following formula (3):

A method for producing 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline or a salt thereof represented by the formula:   The production method according to claim 1, wherein the acid is trifluoroacetic acid (TFA).   The method according to claim 1 or 2, wherein the formaldehyde equivalent is paraformaldehyde or dimethoxymethane. The following formula (5):

The compound represented by the formula (1) or a salt thereof is reacted in the presence of an equivalent or excess amount of an ammonium salt and a borohydride compound, and converted to the compound represented by the formula (4) or a salt thereof. The manufacturing method according to any one of claims 1 to 3. The following formula (6):

The production method according to any one of claims 1 to 3, comprising reducing the compound represented by the formula (1) or a salt thereof to convert the compound represented by the formula (4) or a salt thereof. The following formula (4):

1- (3-fluorophenyl) -3- (4-fluorophenyl) -propan-2-amine or a salt thereof represented by the following is reacted with formaldehyde or formaldehyde equivalent in the presence or absence of an acid: Equation (3):

6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline or a salt thereof represented by the following formula (3): XII):

(In the formula, X represents a leaving group.)
And a compound represented by the following formula (XIII):

And a compound represented by the formula (XIII) or a salt thereof is reduced, and the following formula (XIV):

Or a salt thereof, and then a compound represented by the formula (XIV) or a salt thereof and the following formula (XV):

A compound represented by the following formula or a salt thereof is reacted:

A method for producing a 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline derivative represented by the formula: The following formula (4):

1- (3-fluorophenyl) -3- (4-fluorophenyl) -propan-2-amine or a salt thereof represented by the following is reacted with formaldehyde or formaldehyde equivalent in the presence or absence of an acid: Equation (3):

6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline or a salt thereof represented by the following formula (3): XVI):

(In the formula, X represents a leaving group.)
And a compound represented by the following formula (XVII):

And a compound represented by the formula (XVII) or a salt thereof is reduced, and the following formula (XVIII):

And a compound represented by the formula (XVIII) or a salt thereof and acetone are reacted, and the following formula (XIX):

The compound represented by the formula (XIX) or a salt thereof is obtained, and then the compound represented by the formula (XIX) or a salt thereof is reduced.

A method for producing a 6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline derivative represented by the formula: The following formula (3):

6-fluoro-3- (4-fluorobenzyl) -1,2,3,4-tetrahydroisoquinoline or a salt thereof, or a solvate thereof.

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