JPH0119393B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides (±)-4-oxo-1,2,3,
This invention relates to a new and improved production method for 6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline derivatives.

The compound of the present invention is represented by the following general formula.

Here, R ₁ is hydrogen, a lower alkyl group, or R ₄ CO, R ₂ and R ₃ are each independently hydrogen, a lower alkyl group, and an alkoxy group, and R ₄ is hydrogen,
It is a lower alkyl group, a cycloalkyl group, or an allyl group. "Lower alkyl group" as used herein refers to straight chain and branched _C1 - _C6 alkyl groups,
"Alkoxy group" refers to straight chain and branched _C1 - _C6 alkoxy groups. "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 ring carbon atoms (e.g.
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), and "allyl" refers to phenyl or C1 _{- C6} alkyl, halogen, nitro or _C1 - _C6 alkoxy; means a phenyl group optionally substituted with one or more groups.

Certain compounds of the general formula are known compounds and exhibit anthelmintic activity against schistosomes.

Compounds of the general formula described herein have been prepared by various methods known in the prior art.

In the method described in U.S. Pat. No. 3,993,760 (1976), compounds of the general formula 1-(N-acylaminomethyl)-2-halomethylcarboxy-1,
Produced by cyclization of 2,3,4-tetrahydroisoquinoline.

Similar or other processes DOS2457971 (1976)
and 2504250 (1976) and Experientia 33 , 1036
(1977).

The prior art described in the above documents has certain inherent drawbacks. For example, U.S. Patent No. 3993,
760 (1976), the process uses high temperatures to produce the starting material 1-aminomethyl 1,2,3,4-tetrahydroisoquinoline from 1-cyano-2-acyl-1,2-dehydroisoquinoline. Requires high pressure catalytic hydrogenation under (~100°C). Other processes described in DOS 2457971 and 2504250 (1976) and Experientia 33 1036 (1977) are not economically attractive for industrial applications.

It is therefore an object of the present invention to overcome these drawbacks of the prior art.

Another object of the invention is to provide a simple and economical process for preparing compounds of the general formula on a large scale.

We have now found a new method for producing compounds of the general formula. The method is to perform an intramolecular cyclization reaction on each compound represented by the following general formula or.

Here, R ₁ , R ₂ , R ₃ and R ₄ are as defined above, and R ₅ is methyl, or ethyl, or both R ₅ together are a methylene group.

The novelty of this invention is that the isoquinoline ring and the piperazine ring are formed simultaneously or stepwise by an intramolecular cyclization reaction.

According to the invention, compounds of the general formula in which R ₁ is an acyl substituent are converted directly into compounds of the general formula or via intermediates of the general formula which can be isolated under certain reaction conditions if desired. can be transformed.

Compounds of the general formula can also be converted directly or via intermediates of the general formula to compounds of the general formula.

The process of the invention is conveniently carried out in an acidic medium. Excess acid is used as a solvent or the reaction is carried out in an organic solvent.

Suitable acids for use in the process of the invention include sulfuric acid, hydrochloric acid, phosphoric acid, polyphosphoric acid (PPA), formic acid,
Included are acetic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, paratoluenesulfonic acid, and boron trifluoride ether complexes.

Suitable organic solvents include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,
methanol, ethanol, isopropanol,
Includes 1,4-dioxane, tetrahydrofuran (THF), diethyl ether, ethylene glycol, dimethyl ether and acetonitrile.

The one-step conversion of a compound of the general formula or to a compound of the general formula is carried out at 20°C in a strong acid medium without a solvent.
It is desirable to carry out the test at a temperature between 40℃ and 40℃. Concentrated sulfuric acid or methanesulfonic acid are suitable. The reaction is usually completed in about 2 to 8 hours.

When the cyclization reaction of compounds of general formula or is carried out in the organic solvents mentioned above in the presence of a catalytic amount of acid, compounds of general formula are isolated in excellent yields.

Compounds of the general formula are isolated when a compound of the general formula in which R is an acyl substituent is treated with a strong acid at low temperature, preferably from 10°C to 20°C, for about 30 minutes and then added to an aqueous alkaline solution.

The cyclization of compounds of general formula or to compounds of general formula is carried out in a strongly acidic medium as described above for the preparation of compounds of general formula from compounds of general formula or. This reaction is usually carried out without solvent at about room temperature.

The intramolecular cyclization reaction in this invention is described in the literature [Tet.
Let.No.44 4493 (1972) and the same magazine No.11 935 (1977)]
This is theoretically supported by the description of a similar reaction in .

Compounds of the general formula where R ₁ is an acyl substituent are
It is produced by acylating a compound of the general formula in which R ₁ is hydrogen with an acyl chloride or an acid anhydride.

The starting material, which is a compound of the general formula, is simply N-
It is produced by reacting (2-phenyl)ethyl monochloroacetamide [J ACS 55 2555 (1933)] with an N-substituted or unsubstituted aminoacetaldehyde dialkyl acetal.

Compounds of the general formula are prepared by treating N-(2,2-dialkoxy)ethylphenethylamine (made from phenethylamine and chloro or bromoacetaldehyde dialkyl acetal) with N-acylglycine.

The following examples further illustrate the invention without limiting it.

Example 1 (±)-4-oxo-1,2,3,6,7,
11b-hexahydro-4H-pyrazino [2,1-
a] Isoquinoline (:R ₁ = R ₂ = R ₃ = H) N-(2-phenyl)ethyl-α-N-(2,
2-dimethoxy)ethylglycinamide (:
22.6 g of R ₁ = R ₂ = R ₃ = H, R ₅ = CH ₃ ) was added to 40 ml of concentrated sulfuric acid while cooling, and the mixture was stirred at room temperature for 30 minutes.
Stir and react for some time. After the reaction is completed, the resulting mixture is poured into ice water and then reduced to about 20% while cooling.
Neutralize with aqueous caustic soda solution. The neutralized solution was extracted with diethyl ether and the ether extract was concentrated to give 12.3 g (61
%) was obtained.

Example 2 (±)-4-oxo-1,2,3,6,7,
11b-hexahydro-4H-pyrazino [2,1-
a] Isoquinoline (: R ₁ = R ₂ = R ₃ = H) N-(2-phenyl)ethyl-α-N-(2,2
-dimethoxy)ethylglycinamide (:R ₁
=R ₂ =R ₃ =H, R ₅ =CH ₃ ) 2.7 g are added and the resulting mixture is stirred at room temperature for 5 hours. When the reaction mixture was operated in the same manner as in Example 1, 1.8 g of product was obtained.
(89%).

The reaction gives the same product when diethyl ether is used as the solvent instead of acetonitrile.

Example 3 (±)-2-cyclohexanecarbonyl-4-
Oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline (: R ₁ : cyclohexane carbonyl,
R ₂ = R ₃ = H] N-(2-phenyl)ethyl-α-[N-
(2,2-dimethoxy)ethyl-N-cyclohexanecarbonyl)glycinamide (: R ₁ = cyclohexane carbonyl, R ₂ = R ₃ = H, R ₅ = methyl) 3.76 g (0.01 mol) was mixed with methanesulfonic acid 20
ml and the resulting mixture is stirred at room temperature for 8 hours. The reaction mixture is concentrated under vacuum, then the residue is diluted with water and neutralized with 10% aqueous sodium hydroxide solution. The neutralized solution is extracted with dichloromethane and the extract is concentrated. When the residue is recrystallized from ethyl acetate, m.
1.9 g (61%) of product with p 133-134° C. are obtained.

Example 4 (±)-2-benzoyl-4-oxo-1,
2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline (: R ₁ = benzoyl, R ₂ = R ₃ = H) diethyl ether 5 ml
N-(2-phenyl)ethyl-α-[N-
(2,2-dimethoxy)ethyl-N-benzoyl]
A solution of 3.7 g of glycinamide is slowly added to 10 ml of concentrated sulfuric acid. The mixture is stirred at room temperature for 7 hours. After the reaction is complete, the resulting mixture is poured into ice water and neutralized with aqueous alkaline solution. The resulting solution is extracted with diethyl ether and then the ether extract is concentrated. When the residue is recrystallized from ethyl acetate,
1.8 g (68%) of product with m.p 162-163°C are obtained.

Example 5 1-(2-phenyl)ethyl-4-acetyl-
2-Hydroxypiperazin-6-one (:
R ₁ = acetyl, R ₂ = R ₃ = H) N-(2-phenyl)ethyl-α in 5 ml of concentrated sulfuric acid
-[N-(2,2-dimethoxy)ethyl-N-acetyl]glycinamide (: R ₁ = acetyl,
3.08 g of R ₂ = R ₃ = H, R ₅ = methyl) are added.
Stir the mixture for 30 minutes at room temperature. The reaction mixture is slowly added to an approximately 10% aqueous solution of caustic soda while cooling. The resulting mixture is extracted with dichloromethane and the extract is concentrated. When the residue was recrystallized from a mixed solvent of ethyl acetate and hexane, 2.4 g (92%) of the product was obtained.
get. This product has a melting point of 128-129℃, nmr
(CDCl ₃ ) = 2.05 (S, 3COCH ₃ ), 2.65-4.80 (m,
10, CH ₂ , CH), 7.20 (S, 5, phenyl ring proton), IR (KBr) cm ^-1 ; 3350 (S, OH), 2930
(m, CH), 1650 (S, CO), 1420-1480 (S),
1170(S).

Example 6 1-(2-phenyl)ethyl-4-cyclohexanecarbonyl-2,3-dehydropiperazin-6-one (V: R ₄ = cyclohexyl, R ₂ =
R ₃ = H) N-(2-phenyl) in 10 ml of dichloromethane
Ethyl-N-(2,2-diethoxy)ethyl-α
-N-cyclohexanecarbonylglycinamide (: R ₄ = cyclohexyl, R ₂ = R ₃ = H, R ₅ =
1 ml of methanesulfonic acid is added to a solution of 4.0 g (ethyl) and the mixture is stirred at room temperature for 3 hours. After washing the reaction mixture with an aqueous alkali solution, the organic layer is concentrated. When the residue was recrystallized from a mixed solvent of ethyl acetate and hexane, 2.8 g (90%) of product with m.p 128-130°C was obtained.
get. This product has nmr( _CDCl3 )〓,0.85~2.0
(m, 10, cyclohexane ring proton), 2.90 (t,
2, CH ₂ ), 3.70 (t, 2, CH ₂ ), 4.20 (S, 2,
CH ₂ ), 5.30 (d, l, vinyl proton), 600 (d,
l, vinyl proton), 7,10 (S, t, phenyl ring proton), IR (KBr) cm ^-1 :2930 (m, CH),
1660 (S, CO), 1450, 1400 (m), 1300 (m),
1000 (m), 700 (w).

Example 7 (±)-2-cyclohexane carbonyl-4-
Oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline (: R ₁ = cyclohexane carbonyl,
R ₂ = R ₃ = H) 1-(2-phenyl)ethyl-4-cyclohexanecarbonyl-2-hydroxypiperazine-6
3.3 g of -on (: R ₂ = R ₃ = H, R ₁ = cyclohexane carbonyl) are slowly added to 5 ml of concentrated sulfuric acid. The mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into ice water and neutralized with aqueous alkaline solution. After extracting the resulting mixture with dichloromethane, the extract is concentrated. Recrystallization of the residue from ethyl acetate yields 3.0 g (95%) of product with m.p 132-134°C.

Example 8 (±)-2-(acetyl-4-oxo-1,
2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline (:R ₁
= Acetyl, R ₂ = R ₃ = H) N-(2-phenyl)ethyl-N-(2,2-
To a solution of 3.4 g of diethoxy)ethyl-α-N-acetylglycinamide (: R ₂ = R ₃ = H, R ₄ = methyl) dissolved in 10 ml of 1,2-dichloroethane, 3 ml of methanesulfonic acid was added. 8 of the mixture
Time circulates. After the reaction is completed, the product is washed with aqueous alkaline solution, and then the organic layer is concentrated. When the residue is recrystallized from ethyl acetate, the product mp144-145℃
Obtain 2.1g (86%).

Example 9 1-(2-phenyl)ethyl-4-cyclohexanecarbonyl-2,3-dehydropyrazine-
6-one (:R ₂ = R ₃ = H, R ₄ = cyclohexyl) N-(2-phenyl)ethyl-α-[N-
Obtained by adding 3.8 g of (2,2-dimethoxy)ethyl-N-cyclohexanecarbonyl]glycinamide (: R ₁ = cyclohexane carbonyl, R ₂ = R ₃ = H, R ₅ = methyl) to 5 ml of 20% hydrochloric acid. The mixture is stirred at room temperature for 3 hours. When the solid produced after the reaction is completed is collected by filtration, mp129°~
2.9 g (93%) of product are obtained at 131°C.

Example 10 (±)-4-oxo-9,10-dimethoxy-
1,2,3,6,7,11b-hexahydro-4H
-Pyrazino[2,1-a]isoquinoline (:
R ₁ = H, R ₂ = R ₃ = OCH ₃ ) N-[2-(3,4-dimethoxyphenyl)ethyl]-α-N-(2,2-dimethoxy)ethyl glycinamide (:R ₁ = H, R ₂ = R ₃ = OCH ₃ ,
2.16 g of R ₅ =CH ₃ ) are added with 2 ml of concentrated sulfuric acid at 0° C. and the mixture is stirred for 1.5 hours at room temperature. The resulting mixture is poured into ice water and neutralized to approximately PH=8 with an aqueous alkaline solution. Extract the neutralized solution with dichloromethane,
Concentrate the extract. Recrystallization of the residue from ethyl acetate yields 1.5 g (96%) of product with mp 136-137°C. This product is nmr (CDCl ₃ ) = 2.0 (S, l,
NH), 2.30-3.10 (m, 4, _CH2 ) 3.30-4.00 (m,
3, CH ₂ and CH), 3.8 (S, 6, OCH ₃ ), 4.40 ~
5.00 (m, 2, CH ₂ ), 6.5 (S, 2, phenyl ring proton).

Example 11 (±)-2-(p-chlorobenzoyl)-4-
Oxo-9.10-dimethoxy-1,2,3,6,
7,11b-hexahydro-4H-pyrazino [2,
1-a] Isoquinoline (: R ₁ = p-chlorobenzoyl R ₂ = R ₃ = OCH ₃ ) (±)-4-oxo-9,10-dimethoxy-
1,2,3,6,7,11b-hexahydro-4H-
Pyrazino[2,1-a]isoquinoline (:R ₁
= H, R ₂ = R ₃ = OCH ₃ ) 2.62 g in dichloromethane
After adding 2 ml of triethylamine to a solution dissolved in 10 ml, 1.9 g of p-chlorobenzoyl chloride was added to
Add slowly at 5℃. The resulting mixture was heated at 10°C.
Stir for 1.5 hours. Water was added to the reaction mixture, the organic layer was separated, the organic extract was concentrated, and the residue was triturated with ethyl acetate-ether mixture to obtain 4.0 g (100%) of the product, mp 139-140°C.

Example 12 N-[2-(3,4-dimethoxyphenyl)ethyl]-α-N-(2,2-dimethoxy)ethylglycinamide (: R ₁ = H, R ₂ = R ₃ =
OCH ₃ ) 12.86 g of N-(3,4-dimethoxyphenyl)ethyl monochloroacetamide and 11.6 g of aminoacetaldehyde dimethyl acetal were mixed with 10 g of toluene.
ml and the mixture is refluxed for 40 minutes. After cooling the reaction mixture, the solid formed is filtered off. After washing the filtrate with water, the toluene solution was concentrated to obtain a viscous oil (11.19 g, 99.3%), the hydrochloride of which had a melting point of 98-99°C.

Claims (1)

[Scope of Claims] 1. A compound having the general formula in an acid medium containing an organic solvent or an acid medium not containing an organic solvent or a compound having the general formula The following general formula consists of performing an intramolecular cyclization reaction of (±)-4-oxo-1,2,3,
A method for producing a 6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline derivative. However, in the general formula and, R ₁ represents hydrogen, a lower alkyl group, or R ₄ CO, and R ₂
and R ₃ each independently represent hydrogen, a lower alkyl group, or an alkoxy group, R ₄ represents hydrogen, a lower alkyl group, a cycloalkyl group, or an allyl group, and R ₅ represents a methyl group, an ethyl group, or both R ₅ together represent a methylene group, 2. The acids mentioned above are sulfuric acid, hydrochloric acid, phosphoric acid, polyphosphoric acid (PPA), formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, para-toluenesulfonic acid and trifluoride. A method for producing the compound according to claim 1, which is an acid selected from the group consisting of boron ether complex compounds. 3 When an organic solvent is present, the organic solvent is dichloromethane, chloroform, carbon tetrachloride, 1,2-
The compound according to claim 1, which is an organic solvent selected from the group consisting of dichloroethane, methanol, ethanol, isopropanol, 1,4-dioxane, tetrahydrofuran (THF), diethyl ether, ethylene glycol, dimethyl ether, and acetonitrile. manufacturing method. 4 The cyclization reaction of a compound in which R ₁ is R ₄ CO in the above general formula is carried out in the presence of an acid and an organic solvent to form an intermediate compound having the following general formula. A method for producing the compound according to claim 1, which is carried out in a two-stage reaction via. However, R ₁ represents R ₄ CO, R ₂ and R ₃ each independently represent hydrogen, a lower alkyl group, or an alkoxy group, and R ₄ represents hydrogen, a lower alkyl group, a cycloalkyl group, or an allyl group. 5 The cyclization reaction of the compound having the above general formula or the intermediate compound having the following general formula in the presence of an acid and an organic solvent A method for producing the compound according to claim 1, which is carried out in a two-stage reaction via. However, R ₂ and R ₃ each independently represent hydrogen, a lower alkyl group, or an alkoxy group, and R ₄ represents hydrogen, a lower alkyl group, a cycloalkyl group, or an allyl group. 6. A process for producing compound I according to claim 1, wherein the conversion is carried out at a temperature of 20°C to 40°C. 7. The manufacturing method according to claim 4, wherein the acid treatment is carried out at a temperature of 10°C to 20°C.