JPH06211798A - Tetrahydroisoquinoline derivative and its production - Google Patents

Abstract

PURPOSE:To obtain the subject novel compound derivative useful as an organic intermediate for producing medicines, agricultural chemicals, etc., by reacting a specific 1,2,3,4-tetrahydroquinolin-1-one derivative with a mineral acid, an organic acid, a metal halide, etc. CONSTITUTION:An isoquinoline derivative of formula I (R<1> is 1-6C alkyl; R<2> is H, 1-6C alkyl, halogen; R<4> is 1-4C alkyl) [e.g. 3-(4-t-butylphenyl)-7-methoxy-2- methyl-1,2,3,4-tetrahydroquinolin-1-one] is reacted with a mineral acid (e.g. hydrobromic acid), an organic acid (e.g. acetic acid), or a metal halide (e.g. aluminum chloride) under heating for a whole day and night to provide a novel tetrahydroisoquinoline derivative of formula II [e.g. 3-(4-t-butylphenyl)-7- hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-one] useful as an organic intermediate for producing medicines, agricultural chemicals, etc.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an organic intermediate useful for the production of medicines and agricultural chemicals. More specifically, it relates to novel hydroxytetrahydroisoquinolinone derivatives and tetrahydroisoquinolinone derivatives, and methods for producing them.

[0002]

2. Description of the Related Art Tetrahydroisoquinoline skeleton is contained in benzophenanthridine alkaloids and is known to have various physiological activities such as anticancer action and antiviral action [eg J. Am. Chem. Soc. , 1983, 10
5,2873; Org. Chem. , 1977, 4
2, 1111; ibid. , 1978, 43, 286;
ibid. , 1987, 52, 907; ibid. , 1
987, 52, 5378; Chem. Soc.
(C), 1970, 2578; Tetrahedro.
n, 1977, 33, 331; EP-A-0 025.
598 etc.]. However, among known tetrahydroisoquinoline derivatives, only those having a specific substituent at a specific position are known, and those found in the present invention are not known.

[0003]

The present invention provides a novel hydroxytetrahydroisoquinolinone derivative and tetrahydroisoquinolinone derivative which are organic intermediates which play important roles as medicines and agricultural chemicals, and a method for producing the same.

[0004]

Means for Solving the Problems The present inventors have completed the present invention by earnestly researching a novel tetrahydroisoquinolinone derivative which is important as an intermediate for medical and agricultural chemicals.

That is, the present invention has the general formula [I]

[0006]

[Chemical 4]

(R ¹ represents a C _{1 to} C ₆ linear or branched alkyl group, and R ² represents a hydrogen atom, a C _{1 to} C ₆ linear or branched alkyl group, or a halogen atom). Hydroxytetrahydroisoquinolinone derivative represented and general formula [II]

[0008]

[Chemical 5]

(R ¹ and R ² are the same as above, and R ³ is a phenyl group, a C ₁ -C ₆ lower alkyl group, a phenyl group substituted with a halogen atom, nitrogen, oxygen and sulfur, either alone or at the same time. A tetrahydroisoquinolinone represented by a phenyl group substituted with a 5- or 6-membered heterocyclic aromatic group or a 5- or 6-membered heterocyclic aromatic group containing nitrogen, oxygen, or sulfur alone or simultaneously. A derivative and a method for producing the same are provided. Hereinafter, the present invention will be described in detail.

The compound of the present invention will be described in detail. R ¹ in the hydroxyisoquinolinone derivative represented by the general formula [I] is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or ter.
t-butyl, pentyl, isopentyl, neopentyl,
Mention may be made of C ₁ -C ₆ linear or branched alkyl groups such as tert-pentyl. Preferred are methyl and ethyl. R ² is a hydrogen atom, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec
Examples thereof include C _{1 to} C ₆ linear or branched alkyl groups such as -butyl, tert-butyl, pentyl, isopentyl, neopentyl, and tert-pentyl, and halogen atoms such as chlorine, bromine, and fluorine.

R ¹ and R ² in the tetrahydroisoquinolinone derivative represented by the general formula [II] are the same as above, and R ³ is phenyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. - butyl, tert- butyl, pentyl, isopentyl, neopentyl, tert- linear or branched alkyl group or a chlorine C ₁ -C ₆ of pentyl, bromine, halogen atom or a furyl group such as fluorine, a phenyl group, pyrrolyl group, A phenyl group substituted with an aromatic substituent such as a thienyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, a pyrazolyl group, an isoxazolyl group, an isothiazolyl group, a pyridyl group; or a furyl group, a phenyl group, a pyrrolyl group, a thienyl group, an oxazolyl group. Group, thiazolyl group, imidazolyl group, pyrazoly Group, isoxazolyl group, isothiazolyl group, furyl group substituted with an aromatic substituent such as pyridyl group, pyrrolyl group, thienyl group, oxazolyl group, thiazolyl group, imidazolyl group, pyrazolyl group, isoxazolyl group, isothiazolyl group, pyridyl group, etc. The heteroaromatic substituents can be mentioned.

As the substitution position of the R ³ CH ₂ O group, 5-position, 6-position
The seventh, the eighth and the eighth can be mentioned.

The present invention also provides a method for producing a hydroxytetrahydroisoquinolinone derivative represented by the general formula [I] and a tetrahydroisoquinolinone derivative represented by the general formula [II].

The method for producing the compound of the present invention will be specifically described.

The hydroxytetrahydroisoquinolinone derivative represented by the general formula [I] is represented by the general formula [III]

[0016]

[Chemical 6]

(R ¹ and R ² are the same as above, and R ⁴ is C ₁
~C represents a linear or branched alkyl group of _4. ) In the presence of a mineral acid such as hydrobromic acid, hydrochloric acid or sulfuric acid, an organic acid such as acetic acid or trifluoroacetic acid, or a dealkylating agent such as a metal halide such as aluminum chloride or boron tribromide. It can be produced by reacting in the presence or absence of a solvent such as water, acetic acid or alcohol.

The reaction temperature is 0 ° C to 200 ° C, preferably 5 ° C.
The reaction time is 5 minutes to 200 hours, preferably 30 minutes to 60 hours, and the amount of the reagent used in the reaction is 0.degree. It is 1 to 100 equivalents.

As the solvent used in the reaction, alcohols such as methanol, ethanol, propanol and isopropanol, organic acids such as acetic acid and trifluoroacetic acid, ethers such as ether, tetrahydrofuran and dioxane can be used. .

A hydroxytetrahydroisoquinolinone derivative represented by the general formula [I] and a general formula [IV] R ⁵ CH ₂ X [IV] (wherein R ⁵ is a phenyl group, a C ₁ -C ₆ lower alkyl group) A phenyl group substituted with a halogen atom, a phenyl group substituted with a 5- or 6-membered heterocyclic aromatic group containing nitrogen, oxygen, or sulfur alone or simultaneously or 5-6 containing nitrogen, oxygen, or sulfur alone or simultaneously A membered ring heterocyclic aromatic group, and X represents a halogen atom.) Is represented by the general formula [II] by reacting a halogen compound represented by the formula (II) with or without a solvent in the presence of a base. A tetrahydroisoquinolinone derivative can be produced. As R ⁵ of the halogen compound represented by the general formula [IV], those similar to R ³ of the general formula [II] can be mentioned. Examples of the halogen atom include chlorine, bromine, iodine and the like.

Preferred bases used in the reaction include alkali metal carbonates and alkali metal hydroxides such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

Preferred examples of the solvent used in the reaction include ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and dioxane, dichloromethane, chloroform and chlorobenzene. Halogenated hydrocarbons such as pyridine, triethylamine, tertiary amines such as N, N-dimethylaniline, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, phosphorus Examples thereof include polar solvents such as acid hexamethyltriamide.

The reaction temperature is 0 ° C to 200 ° C, preferably 5 ° C.
The reaction time is 5 minutes to 200 hours, preferably 30 minutes to 60 hours, and the amount of the reagent used in the reaction is 1 to 1 equivalent of the compound represented by the general formula [I]. ] The compound shown by] is 0.1 equivalent to 1
0 equivalent and the base are 0.1 to 20 equivalents.

[0024]

Industrial Applicability According to the present invention, it is possible to provide a compound which is highly useful as an intermediate for medicines and agricultural chemicals and a method for producing the same.

[0025]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

Example 1 [3- (4-tert-butylphenyl) -7-hydroxy-2-methyl-1,2,3,3]
Production of 4-tetrahydroisoquinolin-1-one (Compound No. 1) (1)] 3- (4-tert-Butylphenyl) -7-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1 -ON: To a solution of 10.82 g dissolved in 10 ml of acetic acid was added 30 ml of 47% hydrobromic acid aqueous solution, and the temperature was 120 ° C.
I reacted all day and night. After completion of the reaction, the solvent was distilled off from the reaction mixture under reduced pressure, the residue was dissolved in a 1N sodium hydroxide aqueous solution and washed with diethyl ether. Hydrochloric acid was added to the aqueous layer to neutralize it, and the mixture was extracted with ethyl acetate (200 ml × 3). The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 3- (4-tert.
-Butylphenyl) -7-hydroxy-2-methyl-
1,2,3,4-tetrahydroquinolin-1-one;
9.15 g was obtained (yield 86%).

¹ H-NMR (δppm / CDCl ₃ , 300 MHz) 8.19 (1H, s), 7.38 (1H, s), 7.26 (2H, d, J = 7.5), 6.88 to 7.04
(4H, m), 4.73 (1H, dd, J = 6.7,2.5), 3.58 (1H, dd, J = 15.8,6.
7), 3.98 (1H, dd, J = 15.8,2.5), 1.27 (9H, s) IR (cm ⁻¹ / KBr) 3310,2960,1640,1600,1490,1275,1230 m. p. From 247 to 248 ° C. Elemental analysis (%) Found C as _{C 20 H 23 NO 2; 77.80} , H; 7.38, N; 4.58 Calculated C; 77.64, H; 7.49, N; 4.53 Example 2 [3- (4 -Tert-butylphenyl) -7
-Hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-one (Compound No. 1) (2)] 3- (4-tert-Butylphenyl) -7-methoxy-2-methyl Aluminum chloride (0.75 g) was added to a solution prepared by dissolving 1.01 g of -1,2,3,4-tetrahydroquinolin-1-one (1.01 g) in benzene (10 ml), and the mixture was reacted overnight with heating under reflux. After completion of the reaction, 50 ml of 1N hydrochloric acid was added to the reaction mixture and extracted with ethyl acetate (100 ml).
× 3). The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 3-
(4-tert-butylphenyl) -7-hydroxy-
2-methyl-1,2,3,4-tetrahydroquinoline-
1-one; 0.87 g was obtained (yield 90%).

Example 3 [3- (4-tert-butylphenyl) -7-hydroxy-2-methyl-1,2,3,3]
Production of 4-tetrahydroisoquinolin-1-one (Compound No. 1) (3)] 3- (4-tert-Butylphenyl) -7-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1 -ON; 1.00 g is dissolved in 10 ml of benzene,
By performing the same reaction as in Example 2 by using 1.62 g of boron tribromide in place of aluminum chloride, 3- (4
-Tert-butylphenyl) -7-hydroxy-2-
Methyl-1,2,3,4-tetrahydroquinoline-1-
On; 0.79 g was obtained (yield 83%).

Example 4 [3- (4-tert-butylphenyl) -7-hydroxy-2-methyl-1,2,3,3]
Preparation of 4-tetrahydroisoquinolin-1-one (Compound No. 1) (4)] 3- (4-tert-Butylphenyl) -7-tert
-Butoxy-2-methyl-1,2,3,4-tetrahydroquinolin-1-one; 1.02 g was dissolved in 10 ml of trifluoroacetic acid and reacted overnight at room temperature. After the reaction,
The reaction mixture was dried under reduced pressure, the residue was dissolved in a 1N aqueous sodium hydroxide solution and washed with diethyl ether. Hydrochloric acid was added to the aqueous layer for neutralization, and the mixture was extracted with ethyl acetate (100 ml
× 3). The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 3-
(4-tert-butylphenyl) -7-hydroxy-
2-methyl-1,2,3,4-tetrahydroquinoline-
0.63 g of 1-one was obtained (yield 73%).

Example 5 [3- (4-tert-Butylphenyl) -7- (2-methylbenzyloxy) -2-methyl-1,2,3,4-tetrahydroisoquinoline-1
Preparation of 3-one (Compound No. 6)] 3- (4-tert-Butylphenyl) -7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-one; 1.501 g of acetonitrile 70
2-methylbenzyl bromide in a solution dissolved in ml;
918 mg and potassium carbonate (1.009 g) were added, and the mixture was reacted by heating under reflux for 16 hours. After completion of the reaction, the reaction mixture was poured into diethyl ether and this solution was washed with water. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane / ethyl acetate =
4/1), 3- (4-tert-butylphenyl) -7- (2-methylbenzyloxy) -2-methyl-1,2,3,4-tetrahydroquinolin-1-one;
1.871 g was obtained (yield 93%).

¹ H-NMR (δppm / CDCl ₃ , 300 MHz) 7.85 (1H, d, J = 2.4Hz), 7.45 (1H, d, J = 7.2Hz), 7.29 (2H, d, J =
8.1Hz), 7.25 (3H, m), 7.03 (2H, d, J = 8.2Hz), 7.01 (1H, dd, J =
8.4,2.4), 6.95 (1H, dd, J = 8.4), 5.11 (1H, dd, J = 15.9,3.0),
2.41 (3H, s), 1.29 (9H, s) IR (cm ^-1 / KBr) Viscous oil Elemental analysis (%) Actual value as C ₂₈ H ₃₃ NO C; 83.93, H; 8.60, N; 3.38 Calculation Value C; 84.17, H; 8.32, N; 3.51 Examples 6 to 13 Tetrahydroisoquinolinone derivatives of compound numbers 2 to 5 and 8 to 11 shown in Table 1 were prepared according to the method of Example 5. Physical properties of the obtained compound are shown in Tables 2 to 6.

Example 14 The tetrahydroisoquinolinone derivative of Compound No. 7 shown in Table 1 was produced according to the method of Example 1. Table 4 shows the physical properties of the obtained compound.

[0033]

[Table 1]

[0034]

[Table 2]

[0035]

[Table 3]

[0036]

[Table 4]

[0037]

[Table 5]

[0038]

[Table 6]

Claims (4)

[Claims] 1. A compound represented by the general formula [I]: (R ¹ represents a C _{1 to} C ₆ linear or branched alkyl group, and R ² represents a hydrogen atom, a C _{1 to} C ₆ linear or branched alkyl group, or a halogen atom.). Hydroxytetrahydroisoquinolinone derivative. 2. A compound represented by the general formula [II]: (R ¹ represents a C ₁ -C ₆ linear or branched alkyl group. R ² represents a C ₁ -C ₆ linear or branched alkyl group,
Represents a halogen atom, R ³ is a phenyl group, a C _{1 to} C ₆ lower alkyl group, a phenyl group substituted with a halogen atom,
It represents a phenyl group substituted with a 5- or 6-membered heterocyclic aromatic group containing nitrogen, oxygen, or sulfur alone or simultaneously, or a 5- or 6-membered heterocyclic aromatic group containing nitrogen, oxygen, or sulfur alone or simultaneously. ) A tetrahydroisoquinolinone derivative represented by: 3. A compound represented by the general formula [III]: (R ¹ represents a C _{1 to} C ₆ linear or branched alkyl group, R ² represents a C _{1 to} C ₆ linear or branched alkyl group,
It represents a halogen atom, and R ⁴ represents a C _{1 to} C ₄ linear or branched alkyl group. The method for producing a hydroxytetrahydroisoquinolinone derivative according to claim 1, wherein the isoquinolinone derivative represented by (4) is reacted with a mineral acid, a triorganoic acid or a metal halide. 4. The isoquinolinone derivative according to claim 1 and the general formula [IV] R ₅ CH ₂ X [IV] (wherein R ₅ is substituted with a phenyl group, a C ₁ -C ₆ lower alkyl group, or a halogen atom). A phenyl group, a phenyl group substituted with a 5- or 6-membered heterocyclic aromatic group containing nitrogen, oxygen, or sulfur alone or simultaneously, or a 5- or 6-membered heterocyclic aromatic group containing nitrogen, oxygen, or sulfur alone or simultaneously Group is represented and X represents a halogen atom.) The method for producing a tetrahydroisoquinolinone derivative according to claim 2, wherein the halogen compound represented by the formula (1) is reacted in the presence of a base.