KR850001227B1 - Process for preparing 2-acyl-4-oxo-1,3,4,6,7,11b-hexahydro-4h-pyrazino(2,1-a)isoquinoline derivatives - Google Patents

Abstract

The title compounds I (R1 = H, lower alkyl, phenyl; R2=R3=H, hydroxy, C1-6 alkoxy, C1-6 aliphatic group) and their derivatives, used in the extermination of insects especially distoma, were prepared using a novel method. Thus, 1-phenyl-6-acetyl-8,8-dimethoxy3,6-diazooctane-4- on was cyclized under an acid catalyst to give 92% 1-(2-phenyl)ethyl- 4-acetyl-6-hydroxy piperazine-2-on without using a difficult process. Acids used in the reaction were selected from H2SO4, HCl, methan sulfonic acid, formic acid and p-toluene sulfonic acid, etc.

Description

Method for preparing 2-acyl-4-oxo-1,3,4,6,7,11b-hexahydro-4H-pyrazino [2,1-a] isoquinoline derivative

The present invention provides a novel novel compound of 2-acyl-4-oxo-1,3,4,6,7,11b-hexahydro-4H-pyrazino [2,1-a] isoquinoline derivative represented by the following structural formula (I): Also related to advanced methods of preparation, these compounds exhibit potent activity against antiparasitic activity, in particular against dystomosis and reptiles.

In addition, some of these derivatives are biologically active in the central nervous system and have an effect on blood pressure.

In formula (I), R ₁ is hydrogen, lower alkyl group, or phenyl group. The lower alkyl group is an aliphatic hydrocarbon having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, and the phenyl group is an aliphatic lower alkyl having 1 to 6 carbon atoms and a phenyl group substituted with 2-3 halogen atoms in the benzene ring.

R ₂ and R ₃ are hydrogen, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or an aliphatic hydrocarbon having 1 to 6 carbon atoms.

Known methods for preparing compounds of formula (I) include various preparation methods described in Korean Patent Publications (Publication Nos. 80-31 and 80-89), US Patent Nos. 3,993,760 (1976) or Experientia 33, 1036 (1977). Described.

A common major disadvantage of the methods described in the above documents is that all of these preparation methods have to go through the process of preparing the heavy-weight compounds of the following structural formulas (II), (III) and (IV) which are difficult to industrially mass-produce. Is that.

That is, the compound of formula (II) is known as a reaction of Resert's compound obtained by reacting isoquinoline with acyl chloride and alkali metal cyanide at high temperature (100 ° C.) and high pressure (100 atmospheres) in the presence of a catalyst. In the patent (US Pat. No. 3,993,760), it can be produced by hydrogen reduction, so the safety due to the high temperature, high pressure and hydrogen reduction is a problem. Compounds of formula (III) also have to start with phenylglyoxal and undergo several stages of reaction (6-8) as described in known patents (Korean Patent Publication No. 80-30). Yields are not good, it is not an industrial recipe.

Finally, Experientia 33, 1036 (1977) states that compounds of formula (I) can be prepared starting from compounds of formula (IV), but the synthesis method of formula (IV) or the reaction intermediate of each reaction intermediate Since no data on structural identification have been described, it is not a practical synthesis process.

The present invention is an economical and advanced new method that is completely different from the known methods described above, and does not require a difficult reaction process. The compounds of the structural formulas (V) and (VI), which are the starting materials of the present invention, are used in a simple synthesis method. It is a method for preparing a compound of formula (I) by the cyclization reaction in the presence of an acid catalyst prepared in high yield. The present invention also provides compounds of formula (I) which can be prepared directly from the starting materials of formula (I) or (VI), depending on the reaction conditions, and which are intermediates of the cyclization reaction (VII) or (VIII). The compounds of formula (I) may also be prepared separately.

R ₄ in the compounds of formula (V) or (VI) represents methyl, ethyl or acetyl in which two R ₄ groups form a ring as methylene group.

Acid catalysts used in the preparation of compounds of formulas (I), (VII) and (VIII) from compounds of formula (V) or (VI) include sulfuric acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, formic acid, acetic acid, methanesulfonic acid , Trifluoroacetic acid, trichloroacetic acid, borontrifluoroether adduct, p-toluene sulfonic acid are used as a reaction solvent and catalyst, or C ₁ -C ₂ hydrocarbon chlorides (methylenedichloride, dichloroethane, chloroform These acids can be used as catalysts, such as solvents such as carbon tetrachloride, nitrile (acetonitrile) and ethers (diethyl ether, tetrahydrobutane, dioxane, etc.).

The most suitable reaction condition for preparing the compound of formula (I) directly from the compound of formula (V) or (VI) is 3-5 hours at room temperature using sulfuric acid or methanesulfonic acid as a solvent. The compound of intermediate (VII) is obtained by adding a reactant reacted for a short time (within 1 hour) from the compound of formula V under the above conditions to an aqueous alkaline solution. The intermediate of formula (VIII) is obtained by reacting a compound of formula (V) or (VI) in the presence of a solvent with the acid listed above as a catalyst.

Most preferred conditions are to react in 20% hydrochloric acid or to add the above-mentioned acids in a 10% molar ratio and reflux in a solvent.

The rationale that compounds of formula (VII) or (VIII) can be obtained from compounds of formula (V) or (VI) and that formula (I) can be prepared from these intermediates are also described in Tet. Letters, No. 44, 44493 (1972) and ibid, No. 11, 935 (1977). However, the reaction used in the present invention is a new reaction that is not known until the fund for simultaneously forming the pyrazino ring and the isoquinoline ring of the compound of formula (I), and can be applied to the synthesis of the attached ring-based compound of isoquinoline. It's a progressive way.

Compounds of formula (V) or (VI) can be synthesized from four starting materials centered on nitrogen atoms. That is, in the case of the compound of formula (V), the phenethylamine derivative and the monochloroacetyl chloride are reacted by the method of the known method [JACS, 55, 2555 (1983)] to synthesize an intermediate of the formula (IX), and the compound is aminoacetaldehyde. The compound of formula (V) can be obtained by reaction with alkylacetyl to give a compound of formula (X) and then the corresponding carboxylic acid chloride.

In addition, a compound of formula (XI) obtained by reacting glycine with bromoacetaldehyde dialkyl acetal is reacted with a corresponding carboxylic acid chloride to obtain a compound of formula (XII), and then reacted with a phenethylamine derivative to give a formula (V ) Compound can also be obtained.

The compound of formula (V) can also be obtained by reacting N- (2,3-dialkoxy) ethylacylamide (XIII) with a compound of formula (IX) in the presence of a base (alkali metal alkoxide).

The compound of formula (VI) is obtained by the reaction of N- (2,2-dialkoxy) ethyl phenethylamine derivative (XIV: easily obtained by reaction of phenethylamine derivative with haloacetaldehydealkyl acetal) with N-acylglycine. It is made by reaction.

In addition, the compound of formula (VI) can be obtained by reacting carboxylic acid amide with the compound of formula (XV) obtained by reacting mono chloroacetyl chloride with the compound of formula (XIV).

As such, the compounds of formula (V) or (VI), which are the starting materials of the present invention, can be synthesized by the methods described above using various starting materials. There is an advantage of the invention.

The following examples will illustrate the technical problem of the present invention in detail, but the present invention is not necessarily limited to this range.

Example 1

1- (2-phenyl) ethyl-4-acetyl-6-hydroxypiperazin-2-one

(VII: R ₁ = methyl, R ₂ = R ₃ = hydrogen)

3.08 g (0.01 mol) of 1-phenyl-6-acetyl-8,8-dimethoxy-3,6-diazooctan-4-one was added to 5 ml of concentrated sulfuric acid, stirred at room temperature for 30 minutes, and then 10% caustic. It is slowly added to the aqueous solution of soda while cooling.

The neutralized solution was extracted with dichloromethane, dried, the solvent was removed, and the residue was recrystallized with ethyl acetate-hexane to obtain 2.4 g (92%) of a white solid.

mp: 128-129 ° C., nmr (CDCl ₃ ) δ: 2.05 (S, 3, COCH ₃ ), 2.65-4.80 (m, 10, CH ₂ , CH), 7.20 (S, 5, benzene cyclic hydrogen), IR (KBr) cm ^-1 : 3350 (S, OH), 2930 (m, CH), 1650 (S, CO), 1420-1480 (S), 1170 (S)

Example 2

1- (2-phenyl) ethyl-4-cyclohexanecarbonyl-1,2,3,4-tetrahydropyrazin-2-one

(VIII: R ₁ = cyclohexyl, R ₂ = R ₃ = hydrogen)

4.0 g (0.01 mol) of 1-phenyl-3- (2,2-diethoxy) ethyl-7-cyclohexyl-3,6-diazaheptan-4,7-dione was dissolved in 10 ml of dichloromethane and After adding ㎖ and stirred at room temperature for 3 hours. After the reaction solution was washed with an aqueous alkali solution, the organic layer was dried, the solvent was removed, and the residue was recrystallized with etaacetate-hexane to obtain 2.8 g (90%) of a white solid.

mp: 128-130 ° C., nmr (CDCl ₃ ) δ: 0.85-2.0 (m, 10, cyclohexanecyclohydrogen), 2.90 (t, 2, CH ₂ ), 3.70 (t, 2, CH ₂ ), 4.20 ( S, 2, CH ₂ ) 5.30 (d, 1, vinyl hydrogen), 6.00 (d, 1, vinyl hydrogen), 7.10 (s, t, benzenebenzenehydrogen), IR (KBr) cm ^-1 : 2930 (m, CH), 1660 (S, CO), 1450, 1400 (m), 1300 (m), 1000 (m), 700 (w)

Example 3

2-cyclohexanecarbonyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino [2, 1-a] isoquinoline (I: R ₁ -cyclohexanecarbonyl, R ₂ = R ₃ = hydrogen)

3.3 g (0.01 mol) of 1- (2-phenyl) ethyl-4-cyclohexanecarbonyl-6-hydroxypiperazine-2-silver (produced by the same method as in Example 1) was added to 5 ml of concentrated sulfuric acid. Stir at room temperature for 3 hours. The reaction solution is added to ice water, neutralized with alkali and extracted with dichloromethane.

The extract was dried, the solvent was removed and the residue was recrystallized from ethyl acetate to give a white solid 3.0 (95%). m.p. : 132-134 ℃

Example 4

2-acetyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino [2, 1-a] isoquinoline (I: R ₁ -methyl R ₂ = R ₃ = hydrogen )

2.4 g (0.01 mol) of 1- (2-phenyl) ethyl-4-acetyl-1,2,3,4-tetrahydropyrazin-2-one (prepared by the same method as Example 2) was added to dichloroethane 10 The solution was dissolved in ㎖, and 3 ml of methanesulfonic acid was added, followed by refluxing for 3 hours. The reaction solution was washed with alkali, the organic layer was dried and the solvent was removed to obtain 2.1 g (86%) of the crude product. Recrystallization with ethyl acetate gives a pure product with a melting point of 144-145 ° C.

nmr (CDCl ₃ ) δ: 2.20 (S, 3, COCH ₃ ), 2.50-5.30 (m, 9, CH ₂ , CH), 7.10 (S, 4, benzenebenzene)

Example 5

1- (2-phenyl) ethyl-4-cyclohexanecarbonyl-1,2,3,4-tetrahydroparazin-2-one,

(VIII: R ₁ = cyclohexyl, R ₂ = R ₃ = hydrogen)

3.8 g (0.01 mol) of 1-phenyl-6-cyclohexanecarbonyl-8,8-dimethoxy-3,6-diazaoctan-4-one was added to 5 ml of 20% hydrochloric acid and stirred at room temperature for 3 hours. Let

The resulting solid was filtered, washed several times with water and dried to yield 2.9 g (93%) of a white solid.

m.p: 129-131 ℃

Example 6

2-d-chlorobenzoyl-4-oxo-9,10-dimethoxy-1,2,3,6,7,11b-hexahydro-4H-pyrazino [2,1-a] isoquinoline (I: R ₁ = p-chlorobenzoyl, R ₂ = R ₃ = methoxy)

4.9 g (0.01) of 1- (3,4-dimethoxy) phenyl-3- (2,2-diethoxy) ethyl-7- (4-chloro) phenyl-3,6-diazaheptan-4,7-dione Mole) is dissolved in 10 ml of chloroform, 1 ml of boron trifluoroether adduct is added, and the mixture is refluxed for 3 hours.

The reaction solution was washed with water, the organic layer was dried, the solvent was removed, and the residue was recrystallized with ethyl acetate-ether to obtain 3.3 g (82%) of a white solid.

mp: 138-140 ° C, IR (KBr) cm ^-1 : 2920,2850 (m, CH), 1640,1660 (S, C = O), 1510, 1420, 1230, 1170 (S), 840, 750 ( m)

Example 7

2-acetyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino [2, 1-a] isoquinoline (I: R ₁ -methyl, R ₂ = R ₃ = Hydrogen)

3.1 g (0.01 mol) of 1-phenyl-6-acetyl-8,8-dimethoxy-3,6-diazaoctan-4-one is added to 10 ml of polyphosphoric acid, and stirred at room temperature for 3 hours, and then diluted with ice water. To the diluent, saturated sodium carbonate demand is added until the carbonic acid gas is no longer generated, neutralized, extracted with dichloromethane and removed. Recrystallization of the residue as in Example 6 yielded 1.9 g (78%) of a white solid.

Example 8

2-cyclohexanecarbonyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino [2,1-a] isoquinoline (I: R ₁ = cyclohexanecarbonyl, R ₂ = R ₃ = hydrogen)

Dissolve 3.8 g (0.01 g mol) of 1-phenyl-6-cyclohexanecarbonyl-8,8-dimethoxy-3,6-diazaoctane in 10 ml of dichloromethane, add 0.5 ml of formic acid, and reflux for 3 hours. Let The solvent in the reaction solution is removed under reduced pressure, 5 ml of concentrated sulfuric acid is added to the residue, and the mixture is stirred at room temperature for 4 hours. The reaction was added to iced water, saturated aqueous sodium carbonate solution was added until neutral carbonic acid was no longer generated, neutralized, extracted with dichloromethane, dried and the solvent was removed. .

Claims (6)

2-acyl-4-oxo-1,3,4,6,7,11b-hexahydro-4H-pyrazino of formula (I), wherein the compound of formula (V) is cyclized in the presence of an acid alone or in the presence of an organic solvent. 2,1-a] Method for preparing isoquinoline derivative

In the compounds of formulas (I) and (V), R ₁ is hydrogen, an aliphatic hydrocarbon having 1-6 carbon atoms, a cycloalkyl group having 3-7 carbon atoms, or an aliphatic alkyl group having 1-6 carbon atoms in the benzene ring, and having 2 to 3 halogen atoms. Is a substituted phenyl group. R ₂ and R ₃ are hydrogen, a hydroxy group, or alkoxy having 1 to 6 carbon atoms or aliphatic hydrocarbon having 1 to 6 carbon atoms. R ₄ is methyl, ethyl. The compound of claim 1, wherein the compound of formula (V) is cyclized in the presence of an acid alone or in the presence of an acid and an organic solvent to prepare a compound of formula (VII) or (VIII), and then to a compound of formula (VII) or a formula (VIII). A process for preparing 2-acyl-4-oxo-1,3,4,6,7,11b-hexahydro-4H-pyrazino [2,1-a] isoquinoline derivative of formula (I).

R ₁ , R ₂ , R ₃ , R ₄ in formula (I) (V) (VII) (VIII) are as described above. 2-acyl-4-oxo-1,3,4,6,7,11b-hexahydro-4H-pyrazino [1] of formula (I), wherein the compound of formula (VI) is cyclized in the presence of an acid alone or in the presence of an organic solvent. 2,1-a] Method for preparing isoquinoline derivative

R ₁ , R ₂ , R ₃ , R ₄ in formula (I) (VI) are as described above. The compound of claim 3, wherein the compound of formula (VI) is cyclized in the presence of an acid alone or in an organic solvent to prepare a compound of formula (VIII), and then 2-acyl-4- of formula (I) to cyclize the compound of formula (VIII). Method for preparing oxo-1,3,4,6,7,11b-hexahydro-4H-pyrazino [2,1-a] isoquinoline derivative.

R ₁ , R ₂ , R ₃ , R ₄ in formula (I) (VI) (VII) are as described above. The acid used in claim 1 or 3 may be sulfuric acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, methanesulfonic acid, formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, borontrifluoroether, adduct, p-toluene sulfonic acid. Claims The method of selecting the organic solvent used in Claim 1 or 3 from dichloromethane, chloroform, carbon tetrachloride, dichloroethane, acetonitrile, diethyl ether, dioxane, tetrahydrofuran.