JP4751579B2 - Process for producing optically active tetrahydroisoquinolines - Google Patents

Description

  The present invention relates to a process for producing optically active tetrahydroisoquinolines, and more specifically, optically active 1-phenyl-1,2,3 by asymmetric hydrogenation of 1-phenyl-3,4-dihydroisoquinoline in the presence of a catalyst. , 4-Tetrahydroisoquinoline.

Conventionally, when synthesizing optically active 1-phenyl-1,2,3,4-tetrahydroisoquinoline, racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline is synthesized and optically active carboxylic acid is synthesized. A method of optically dividing using a conventional method was used. However, this method still has the inconvenience that the desired compound cannot exceed the amount existing before the optical resolution even if it is optically resolved. In order to solve these points, synthetic methods by catalytic asymmetric hydrogenation of imines have been actively studied.
As an example thereof, for example, in Patent Document 1, 1-phenyl-3,4-dihydroisoquinoline is hydrogenated in the presence of an iridium complex and an optically active phosphine compound to form optically active 1-phenyl-1,2,3,3. The process for producing 4-tetrahydroisoquinoline is specifically described as an example.
However, this method is not always satisfactory because the iridium complex is expensive and the yield and optical purity of the target product are low.
JP 2001-26580 A

  An object of the present invention is to provide a method capable of producing optically active 1-phenyl-1,2,3,4-tetrahydroisoquinoline having high optical purity or a salt thereof at a low cost and in a high yield.

  As a result of intensive studies to solve the above problems, the present inventors have used a ruthenium-optically active phosphine complex as a catalyst, particularly a ruthenium-phosphine complex represented by the following general formula (5). The present inventors have found that high-purity optically active 1-phenyl-1,2,3,4-tetrahydroisoquinoline or a salt thereof can be obtained at a low cost and in a high yield, and have further studied and completed the present invention.

で表される１−フェニル−３，４−ジヒドロイソキノリンまたはその塩を、触媒の存在下に水素ガスと反応させて一般式（２）

(式中、＊は不斉炭素を意味する)
で表される光学活性１−フェニル−１，２，３，４−テトラヒドロイソキノリンまたはその塩を製造する方法において、触媒として、ルテニウム−光学活性ホスフィン錯体を用いることを特徴とする光学活性１−フェニル−１，２，３，４−テトラヒドロイソキノリンまたはその塩の製造方法。 That is, the present invention includes the following inventions [1] to [3].
[1] The following general formula (1)

1-phenyl-3,4-dihydroisoquinoline or a salt thereof represented by general formula (2) is reacted with hydrogen gas in the presence of a catalyst.

(In the formula, * means an asymmetric carbon)
An optically active 1-phenyl, characterized in that a ruthenium-optically active phosphine complex is used as a catalyst in the process for producing an optically active 1-phenyl-1,2,3,4-tetrahydroisoquinoline represented by the formula: A method for producing -1,2,3,4-tetrahydroisoquinoline or a salt thereof.

（式中、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４はそれぞれ独立して、ハロゲン原子、低級アルキル基および低級アルコキシ基から選ばれる置換基で置換されていてもよいフェニル基を示すか、またはシクロペンチル基もしくはシクロヘキシル基を示す。）
または一般式（４）

（式中、Ｒ^５、Ｒ^６、Ｒ^７およびＲ^８は、それぞれ独立して、ハロゲン原子、低級アルキル基および低級アルコキシ基から選ばれる置換基で置換されていてもよいフェニル基を示すか、またはシクロペンチル基もしくはシクロヘキシル基を示す。）
で表されるホスフィンの光学活性体である前記[１]記載の製造方法。 [2] The optically active phosphine has the general formula (3)

(Wherein R ¹ , R ² , R ³ and R ⁴ each independently represent a phenyl group which may be substituted with a substituent selected from a halogen atom, a lower alkyl group and a lower alkoxy group, or (A cyclopentyl group or a cyclohexyl group is shown.)
Or general formula (4)

(Wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ each independently represent a phenyl group which may be substituted with a substituent selected from a halogen atom, a lower alkyl group and a lower alkoxy group, Or a cyclopentyl group or a cyclohexyl group.)
The production method of the above-mentioned [1], which is an optically active phosphine represented by the formula:

（式中、Ｌは一般式（３）または（４）で表されるホスフィンの光学活性体を示し、ＸはＣｌ、ＢｒまたはＩを示し、ａ、ｂ、ｃ、ｄ、ｅ、ｆ、ｇ、Ｗ、ＹおよびＺは下記ｉ）〜ｖｉ）の組み合わせのいずれかである。）
で表される錯体である前記[２]に記載の製造方法。
ｉ）ａ＝２、ｂ＝０、ｃ＝４、ｄ＝２、ｅ＝１、ｆ＝１、ｇ＝０およびＹ＝Ｎ（ＣＨ_２ＣＨ_３）_３
ｉｉ）ａ＝１、ｂ＝１、ｃ＝１、ｄ＝１、ｅ＝１、ｆ＝１、ｇ＝０、Ｗ＝ベンゼンまたはｐ−シメン、およびＹ＝Ｃｌ、ＢｒまたはＩ
ｉｉｉ）ａ＝１、ｂ＝０、ｃ＝１、ｄ＝１、ｅ＝２、ｆ＝３、ｇ＝１、Ｙ＝（μ−Ｃｌ）、（μ−Ｂｒ）または（μ−Ｉ）、およびＺ＝（ＣＨ_３）_２ＮＨ_２または（ＣＨ_３ＣＨ_２）_２ＮＨ_２
ｉｖ）ａ＝１、ｂ＝２、ｃ＝０、ｄ＝１、ｅ＝１、ｆ＝０、ｇ＝０、およびＷ＝ＣＨ_３ＣＯ_２またはＣＦ_３ＣＯ_２
ｖ）ａ＝１、ｂ＝１、ｃ＝１、ｄ＝２、ｅ＝１、ｆ＝０、ｇ＝０、およびＷ＝Ｈ
ｖｉ）ａ＝３、ｂ＝０、ｃ＝５、ｄ＝３、ｅ＝１、ｆ＝１、ｇ＝０、およびＹ＝Ｃｌ、ＢｒまたはＩ [3] The ruthenium-optically active phosphine complex is isolated from the following general formula (5)

(Wherein L represents an optically active phosphine represented by formula (3) or (4), X represents Cl, Br or I, a, b, c, d, e, f, g , W, Y, and Z are any of the following combinations i) to vi). )
The production method according to [2], wherein the complex is represented by the formula:
i) a = 2, b = 0, c = 4, d = 2, e = 1, f = 1, g = 0 and Y = N (CH ₂ CH ₃ ) ₃
ii) a = 1, b = 1, c = 1, d = 1, e = 1, f = 1, g = 0, W = benzene or p-cymene, and Y = Cl, Br or I
iii) a = 1, b = 0, c = 1, d = 1, e = 2, f = 3, g = 1, Y = (μ-Cl), (μ-Br) or (μ-I), And Z = (CH ₃ ) ₂ NH ₂ or (CH ₃ CH ₂ ) ₂ NH ₂
iv) a = 1, b = 2, c = 0, d = 1, e = 1, f = 0, g = 0, and W = CH ₃ CO ₂ or CF ₃ CO ₂
v) a = 1, b = 1, c = 1, d = 2, e = 1, f = 0, g = 0, and W = H
vi) a = 3, b = 0, c = 5, d = 3, e = 1, f = 1, g = 0, and Y = Cl, Br or I

  According to the method of the present invention, optically active 1-phenyl-1,2,3,4-tetrahydroisoquinoline or a salt thereof having a high optical purity can be obtained at a low yield from 1-phenyl-3,4-dihydroisoquinoline or a salt thereof. Well, it can be manufactured industrially advantageously.

  The present invention will be described below.

で表される１−フェニル−３，４−ジヒドロイソキノリンは、公知の方法により製造することができ、例えば、ベンゾイルクロリドと２−フェニルエチルアミンとから得られるアミド化合物を五酸化リンを用いて環化させる方法（Ｊ．Ｍｅｄ．Ｃｈｅｍ．，（１９８９）、３２（６）、１２４２−１２４８）等により得ることができる。 General formula (1) used as a raw material

1-phenyl-3,4-dihydroisoquinoline represented by the formula can be produced by a known method, for example, an amide compound obtained from benzoyl chloride and 2-phenylethylamine is cyclized with phosphorus pentoxide. (J. Med. Chem., (1989), 32 (6), 1242-1248) and the like.

  Moreover, the salt of 1-phenyl-3,4-dihydroisoquinoline can be easily obtained by stirring a pair of acidic compound and 1-phenyl-3,4-dihydroisoquinoline in a solvent. Furthermore, an asymmetric hydrogenation reaction can be carried out in the presence of an acidic compound without taking out a salt from a mixed solution of 1-phenyl-3,4-dihydroisoquinoline and an acidic compound. Examples of the acidic compound to be paired include inorganic acid, organic acid or Lewis acid, specifically hydrogen chloride, hydrogen bromide, hydrogen iodide, hypochlorous acid, chlorous acid, chloric acid, perchloric acid, Phosphoric acid, boric acid, acetic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, bromoacetic acid, trifluoroacetic acid, formic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, benzoic acid, sulphur Examples include acid, tartaric acid, citric acid, succinic acid, malic acid, malonic acid, salicylic acid, picric acid, fumaric acid and the like.

Examples of the ruthenium-optically active phosphine complex used in the present invention include a complex composed of a ruthenium compound, an optically active phosphine compound, and, if desired, a neutral organic coordination compound and an amine compound.
The ruthenium compound may be any ruthenium compound usually used in this field. For example, ruthenium halides such as RuCl ₃ , RuBr ₃ and RuI ₃ and hydrates thereof, [RuCl ₂ (benzene)] ₂ , [RuBr ₂ (benzene)] ₂ , [RuI ₂ (benzene)] ₂ , [RuCl ₂ (p-cymene)] ₂ , [RuBr ₂ (p-cymene)] ₂ , [RuI ₂ (p-cymene)] ₂ , [ And a complex such as RuCl ₂ (cod)], [RuBr ₂ (cod)], RuI ₂ (cod)] (the above “cod” represents 1,5-cyclooctadiene; the same shall apply hereinafter).

（式中、記号は前記と同一意味を有する）
または一般式（４）

（式中、記号は前記と同一意味を有する）
で表されるホスフィンの光学活性体などが挙げられる。 The optically active phosphine compound may be an optically active phosphine compound usually used in this field, and examples thereof include a bidentate phosphine compound, and more preferably an optically active phosphine compound having axial asymmetry. .
Specific examples of the optically active phosphine compound include, for example, the general formula (3)

(Wherein the symbols have the same meaning as above)
Or general formula (4)

(Wherein the symbols have the same meaning as above)
The optically active substance of the phosphine represented by these, etc. are mentioned.

Hereinafter, each substituent in the general formulas (3) and (4) will be described.
In the general formulas (3) and (4), “from halogen atom, lower alkyl group and lower alkoxy group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ ” The “phenyl group optionally substituted with a selected substituent” is a phenyl group or a phenyl group substituted with a substituent selected from a halogen atom, a lower alkyl group and a lower alkoxy group.
A phenyl group substituted with a substituent selected from a halogen atom, a lower alkyl group and a lower alkoxy group is a substitution in which one or more hydrogen atoms of the phenyl group are selected from a halogen atom, a lower alkyl group and a lower alkoxy group And a phenyl group substituted with a group. When two or more substituents are used, they may be the same or different.

  As said halogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom etc. are mentioned, for example, Especially a fluorine atom is preferable. Examples of the lower alkyl group include linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples of the lower alkoxy group include linear, branched or cyclic alkoxy groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

  Specific examples of the optically active phosphine compound represented by the general formula (3) include, for example, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (hereinafter referred to as BINAP), 2,2′-bis. [Di (p-tolyl) phosphino] -1,1′-binaphthyl (hereinafter referred to as T-BINAP), 2,2′-bis [di (m-tolyl) phosphino] -1,1′-binaphthyl, 2, 2'-bis [di (3,5-xylyl) phosphino] -1,1'-binaphthyl (hereinafter referred to as DM-BINAP), 2,2'-bis [di (p-tert-butylphenyl) phosphino]- 1,1′-binaphthyl, 2,2′-bis [di (p-methoxyphenyl) phosphino] -1,1′-binaphthyl, 2,2′-bis [di (3,5-di-tert-butyl- 4-methoxyphenyl) Sufino] -1,1′-binaphthyl, 2,2′-bis [di (cyclopentyl) phosphino] -1,1′-binaphthyl (hereinafter referred to as Cp-BINAP), 2,2′-bis [di (cyclohexyl) Phosphino] -1,1′-binaphthyl (hereinafter referred to as Cy-BINAP) and the like. Of these, BINAP or T-BINAP is more preferred.

  Specific examples of the optically active phosphine represented by the general formula (4) include (4,4′-bi-1,3-benzodioxole) -5,5′-diyl-bis (diphenylphosphine). (SEGPHOS), (4,4′-bi-1,3-benzodioxole) -5,5′-diyl-bis [di (3,5-dimethylphenyl) phosphine] (DM-SEGPHOS), (4 , 4′-bi-1,3-benzodioxole) -5,5′-diyl-bis [bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphine] (DTBM-SEGPHOS), (4,4′-bi-1,3-benzodioxole) -5,5′-diyl-bis [di (4-methoxyphenyl) phosphine], (4,4′-di-1,3-benzo Dioxole) -5,5'-diyl-bis (disi Rohexylphosphine) (Cy-SEGPHOS), (4,4′-bi-1,3-benzodioxole) -5,5′-diyl-bis [bis (3,5-di-tert-butylphenyl) Phosphine] and the like.

  Furthermore, examples of the neutral organic coordination compound include N, N-dimethylformamide and acetonitrile, and examples of the amine compound include tri-lower alkylamine (eg, trimethylamine, triethylamine) and di-lower alkylamine (eg, , Dimethylamine, diethylamine, etc.), pyridine and the like.

Examples of the ruthenium-optically active phosphine complex include the following, but the present invention is not limited thereto.
Ru (OAc) ₂ (L), Ru (OCOCF ₃ ) (L), Ru ₂ Cl ₄ (L) ₂ NEt ₃ , [{RuCl (L)} ₂ (μ-Cl) ₃ ] [Me ₂ NH ₂ ] , [{RuCl (L)} ₂ (μ-Cl) ₃ ] [Et ₂ NH ₂ ], RuCl ₂ (L), RuBr ₂ (L), RuI ₂ (L), RuCl ₂ (L) (pyridine) ₂ , RuBr ₂ (L) (pyridine) ₂ , RuI ₂ (L) (pyridine) ₂ , [RuCl (benzene) (L)] Cl, [RuBr (benzene) (L)] Br, [RuI (benzene) (L )] I, [RuCl (p-cymene) (L)] Cl, RuBr (p-cymene) (L)] Br, [RuI (p-cymene) (L)] I, [Ru (L)] (OTf ) ₂ , [Ru (L)] (BF ₄ ) ₂ , [Ru (L)] (ClO ₄ ) ₂ , [Ru (L)] (SbF ₆ ) ₂ , [Ru (L)] (BF ₄ ) ₂ , Ru ₃ Cl ₅ (L) ₃ , RuHCl (L) ₂
(In the above, L represents an optically active phosphine compound, Ac represents an acetyl group, Et represents an ethyl group, Me represents a methyl group, and Tf represents a trifluoromethanesulfonyl group. The same shall apply hereinafter.)

（式中、Ｌは一般式（３）または（４）で表されるホスフィンの光学活性体を示し、ＸはＣｌ、ＢｒまたはＩを示し、ａ、ｂ、ｃ、ｄ、ｅ、ｆ、ｇ、Ｗ、ＹおよびＺは下記ｉ）〜ｖｉ）の組み合わせのいずれかである。）で表される錯体であるのが好ましい。
ｉ）ａ＝２、ｂ＝０、ｃ＝４、ｄ＝２、ｅ＝１、ｆ＝１、ｇ＝０およびＹ＝Ｎ（ＣＨ_２ＣＨ_３）_３
ｉｉ）ａ＝１、ｂ＝１、ｃ＝１、ｄ＝１、ｅ＝１、ｆ＝１、ｇ＝０、Ｗ＝ベンゼンまたはｐ−シメン、およびＹ＝Ｃｌ、ＢｒまたはＩ
ｉｉｉ）ａ＝１、ｂ＝０、ｃ＝１、ｄ＝１、ｅ＝２、ｆ＝３、ｇ＝１、Ｙ＝（μ−Ｃｌ）、（μ−Ｂｒ）または（μ−Ｉ）、およびＺ＝（ＣＨ_３）_２ＮＨ_２または（ＣＨ_３ＣＨ_２）_２ＮＨ_２
ｉｖ）ａ＝１、ｂ＝２、ｃ＝０、ｄ＝１、ｅ＝１、ｆ＝０、ｇ＝０、およびＷ＝ＣＨ_３ＣＯ_２またはＣＦ_３ＣＯ_２
ｖ）ａ＝１、ｂ＝１、ｃ＝１、ｄ＝２、ｅ＝１、ｆ＝０、ｇ＝０、およびＷ＝Ｈ
ｖｉ）ａ＝３、ｂ＝０、ｃ＝５、ｄ＝３、ｅ＝１、ｆ＝１、ｇ＝０、およびＹ＝Ｃｌ、ＢｒまたはＩ The ruthenium-optically active phosphine complex used in the present invention is isolated from the following general formula (5)

(Wherein L represents an optically active phosphine represented by formula (3) or (4), X represents Cl, Br or I, a, b, c, d, e, f, g , W, Y, and Z are any of the following combinations i) to vi). ) Is preferable.
i) a = 2, b = 0, c = 4, d = 2, e = 1, f = 1, g = 0 and Y = N (CH ₂ CH ₃ ) ₃
ii) a = 1, b = 1, c = 1, d = 1, e = 1, f = 1, g = 0, W = benzene or p-cymene, and Y = Cl, Br or I
iii) a = 1, b = 0, c = 1, d = 1, e = 2, f = 3, g = 1, Y = (μ-Cl), (μ-Br) or (μ-I), And Z = (CH ₃ ) ₂ NH ₂ or (CH ₃ CH ₂ ) ₂ NH ₂
iv) a = 1, b = 2, c = 0, d = 1, e = 1, f = 0, g = 0, and W = CH ₃ CO ₂ or CF ₃ CO ₂
v) a = 1, b = 1, c = 1, d = 2, e = 1, f = 0, g = 0, and W = H
vi) a = 3, b = 0, c = 5, d = 3, e = 1, f = 1, g = 0, and Y = Cl, Br or I

Among the ruthenium-optically active phosphine complexes represented by the general formula (5), a = 2, b = 0, c = 4, d = 2, e = 1, f = 1, g = 0 and Y = N (CH ₂ CH ₃ ) ₃ and a complex in which L is an optically active substance of the compound represented by the general formula (3) is preferable, and a = 2, b = 0, c = 4, d = 2, e = 1, f = 1, g = 0 and Y = N (CH ₂ CH ₃ ) ₃ and L is more preferably an optically active BINAP.

The ruthenium-optically active phosphine complex according to the present invention is produced using a known method or a method known per se. For example, J. et al. Chem. Soc. , Chem. Commun. 922 (1985), [Ru (cod) Cl ₂ ] _n and an optically active phosphine compound can be prepared by heating to reflux in a toluene solvent in the presence of a trialkylamine. Further, it can be prepared by heating and refluxing [Ru (benzene) Cl ₂ ] ₂ and an optically active phosphine compound in tetrahydrofuran in the presence of a dialkylamine by the method described in JP-A-11-269185. In addition, J.H. Chem. Soc. , Chem. commun. 1208 (1989), [Ru (p-cymene) I ₂ ] ₂ and an optically active phosphine compound can be prepared by heating and stirring in methylene chloride and ethanol.

  The reaction of the present invention is a hydrogenation reaction and can be carried out by reacting 1-phenyl-3,4-dihydroisoquinoline or a salt thereof with hydrogen gas in the presence of a ruthenium-optically active phosphine complex. The amount of the ruthenium-optically active phosphine complex used varies depending on the reaction conditions, the type of ruthenium-optically active phosphine complex, etc., but is usually 1/50 to 1 / phenyl-3,4-dihydroisoquinoline or a salt thereof. It is 1/5000, preferably in the range of 1/200 to 1/2000.

Moreover, the hydrogenation reaction of this invention can be implemented suitably in a solvent. As the solvent, those capable of dissolving the substrate and the catalyst are preferable. Specifically, aromatic hydrocarbons such as toluene and xylene, aliphatic hydrocarbons such as hexane and heptane, halogenated hydrocarbons such as methylene chloride and chlorobenzene, diethyl Ethers such as ether, tetrahydrofuran and 1,4-dioxane, alcohols such as methanol, ethanol, isopropanol and n-butanol, esters such as ethyl acetate and butyl acetate, nitriles such as acetonitrile, N, N-dimethylformamide Amides such as N-methylpyrrolidone, and amines such as pyridine and triethylamine. The amount of the solvent used can be appropriately selected depending on the reaction conditions and the like.
The hydrogen pressure in the hydrogenation reaction of the present invention is usually 1 to 10 MPa, preferably 3 to 6 MPa. The reaction temperature naturally varies depending on the type of the catalyst and the like, but is usually 5 to 150 ° C, preferably 50 to 100 ° C. The reaction time varies depending on the reaction conditions, but is usually 5 to 30 hours.

(式中、＊は不斉炭素を意味する)
で表される光学活性１−フェニル−１，２，３，４−テトラヒドロイソキノリンまたはその塩が得られるが、該化合物の立体配位は使用するルテニウム−光学活性ホスフィン錯体の立体配位を適宜選択することにより、Ｒ体またはＳ体を製造することができる。 As described above, the general formula (2)

(In the formula, * means an asymmetric carbon)
An optically active 1-phenyl-1,2,3,4-tetrahydroisoquinoline or a salt thereof represented by the following formula is obtained, and the configuration of the compound is appropriately selected from the configuration of the ruthenium-optically active phosphine complex to be used. By doing so, R body or S body can be manufactured.

  EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. In the examples, the conversion rate was determined by gas chromatograph (NEUTRA BOND-1 30 m × 0.25 mm ID 0.4 μm), and the optical purity (% ee) was determined by liquid chromatograph (Daicel CHIRALCEL OD-H). Asked.

Example 1
In a 100 mL autoclave containing a stir bar, 1-phenyl-3,4-dihydroisoquinoline (1 g, 4.82 mmol) and Ru ₂ Cl ₄ {(R) -T-BINAP} ₂ .NEt ₃ (21.9 mg, 0 .0121 mmol) was charged. After purging with nitrogen, 5 mL of toluene was added. Subsequently, after purging with hydrogen, the mixture was stirred at 90 ° C. for 15 hours at a hydrogen pressure of 6 MPa. When the reaction solution was analyzed, (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline was produced with an optical purity of 88.9% ee and a conversion rate of 56.9%.

(Example 2)
In a 100 mL autoclave containing a stir bar, 1-phenyl-3,4-dihydroisoquinoline hydrochloride (1 g, 4.10 mmol) and Ru ₂ Cl ₄ {(R) -T-BINAP} ₂ .NEt ₃ (18.7 mg , 0.0103 mmol). After purging with nitrogen, 5 mL of methanol was added. After purging with hydrogen, the mixture was stirred at 90 ° C. for 19 hours at a hydrogen pressure of 3 MPa. Toluene and a 1 mol / L sodium hydroxide aqueous solution were added to the reaction mixture and stirred, and then the reaction solution was analyzed. As a result, (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline was produced with an optical purity of 59.7% ee and a conversion rate of 89.3%.

(Example 3)
In a 100 mL autoclave containing a stir bar, 1-phenyl-3,4-dihydroisoquinoline (1 g, 4.82 mmol) and Ru ₂ Cl ₄ {(R) -BINAP} ₂ .NEt ₃ (8.2 mg, 0.00485 mmol) ). After purging with nitrogen, 5.96 mL of toluene and formic acid (182 μL, 4.82 mmol) were added. After purging with hydrogen, the mixture was stirred at 90 ° C. for 15 hours at a hydrogen pressure of 3 MPa. Toluene and a 1 mol / L sodium hydroxide aqueous solution were added to the reaction solution and stirred, and then the reaction solution was analyzed. As a result, (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline was produced with an optical purity of 66.7% ee and a conversion rate of 91.4%.

Example 4
1-phenyl-3,4-dihydroisoquinoline hydrochloride (500 mg, 2.05 mmol) and Ru (OAc) ₂ {(R) -BINAP} (8.6 mg, 0.0102 mmol) were added to a 100 mL autoclave containing a stir bar. Prepared. After purging with nitrogen, 2.5 mL of methanol and methyl salicylate (10.6 μL, 0.0818 mmol) were added. After purging with hydrogen, the mixture was stirred at 90 ° C. for 19 hours at a hydrogen pressure of 3 MPa. Toluene and a 1 mol / L sodium hydroxide aqueous solution were added to the reaction solution and stirred, and then the reaction solution was analyzed. As a result, (R) -1-phenyl-1,2,3,4-tetrahydroisoquinoline was produced with an optical purity of 65.4% ee and a conversion rate of 83.1%.

The optically active 1-phenyl-1,2,3,4-tetrahydroisoquinoline or a salt thereof obtained by the production method of the present invention is useful as a pharmaceutical agrochemical intermediate and useful for optical resolution of chiral carboxylic acids. .

Claims (1)

The following general formula (1)

1-phenyl-3,4-dihydroisoquinoline or a salt thereof represented by general formula (2) is reacted with hydrogen gas in the presence of a catalyst.

(In the formula, * means an asymmetric carbon)
In the method for producing optically active 1-phenyl-1,2,3,4-tetrahydroisoquinoline or a salt thereof represented by the following, using a ruthenium-optically active phosphine complex as a catalyst, the ruthenium- optically active phosphine complex is: The following general formula (5)

(Wherein R ¹ , R ² , R ³ and R ⁴ each independently represent a phenyl group which may be substituted with a substituent selected from a halogen atom, a lower alkyl group and a lower alkoxy group, or (A cyclopentyl group or a cyclohexyl group is shown.)
X represents Cl, Br or I, a, b, c, d, e, f, g, W, Y and Z are combinations of i) to ii) below One of them. )
The process for producing an optically active 1-phenyl-1,2,3,4-tetrahydroisoquinoline or a salt thereof, wherein optically active substance der Rukoto phosphine represented in.
i) a = 2, b = 0, c = 4, d = 2, e = 1, f = 1, g = 0 and Y = N (CH ₂ CH ₃ ) ₃
ii) a = 1, b = 2, c = 0, d = 1, e = 1, f = 0, g = 0, and W = CH ₃ CO ₂ or CF ₃ CO ₂