KR860001393B1 - Process for the preparation of 1-alkyl-2-oxo-4-acyl-1,2,3,4-tetrahydropyrazines - Google Patents

Abstract

1-Alkyl-2-oxo-4-acyl-1,2,3,4-tetrahydropyrazine (I) [R1=C1-7 alkyl, benezene substituted with halogen, hydroxyl, lower alkyl, lower alkoxy; R2=phenyl substituted with lower alkyl, cycloalkyl, hydrogen, benzyl! is prepd. for use as an intermediate of 4-oxo1,3,4,6,7,11b- hexahydro-4H-piperazino[2,1-a!isoquinoline deriv. having a vermicide activity. Compd. (II) [R3=methyl, ethyl, cyclic acetal! is cyclized to give compd. (III), which is alkylized with alkylhalide to give compd. (I).

Description

Method for preparing 1-alkyl-2-oxo-4-acyl-1,2,3,4-tetrahydropyrazine

The present invention relates to 4-oxo-1,3,4,6,7,11b-hexahydro-4H-pyrazino [2,1-a] isoquinoline derivatives exhibiting strong antiparasitic activity against tapeworms and liver and lung repellents. It relates to a new method for preparing 1-alkyl-2-oxo-4-acyl-1,2,3,4-tetrahydropyrazine represented by the following structural formula (I) which can be very usefully used for preparation.

In structural formula (I), R ₁ is a halogen atom, a hydroxyl group, a lower alkyl group having 1-7 carbon atoms, or a lower alkoxy having 1-7 carbon atoms substituted in the lower alkyl group or benzene ring having 1 to 7 carbon atoms. Phenethyl or benzyl group. R ₂ is hydrogen, a lower alkyl group having 1 to 7 carbon atoms, a cycloalkyl group, a nitro group, a hydroxyl group, a lower alkyl group having 1 to 7 carbon atoms or an alkoxy group, or a phenyl group substituted with a halogen atom. .

The method for preparing the compound of formula (I) or the method for preparing praziquantel from the compound of formula (I) is disclosed in the British Patent Publication No. 2,126,212A (1984) and the Republic of Korea Patent Application (83) -2418).

Known or pending methods are those in which the compounds of formula (II) or (III) are cyclized under acidic conditions.

Unlike these methods, the present invention synthesizes a compound of formula (IV), which is a novel compound, and prepares a compound of structure (V), which is a new compound, in high yield by a new cyclization reaction. A new process for preparing compounds of formula (I) by reacting compounds with alkyl halides to alkylate them.

이다. 또한, 구조식(Ⅴ)에서 R₂는 구조식(Ⅰ)의 R₂와 동일한 치환기를 나타낸다.In the above structural formula (Ⅳ), R ₂ represents the same substituent as R ₂ of formula (Ⅰ), R ₃ is clicking, Mr. or represent methyl or ethyl, or both R ₃ groups form a ring methylene acetal

to be. Also, R ₂ in the formula (Ⅴ) represents the same substituent as R ₂ of formula (Ⅰ).

The reaction with the new ring to convert the compound of formula (IV) to the compound of formula (V) takes place in the presence of a catalytic amount of acid using an organic solvent. The organic solvent that can be used at this time may be a lower alcohol having 1-4 carbon atoms, chloro hydrocarbons having 1-2 carbon atoms, nitrile hydrocarbon or ether, the acid is concentrated sulfuric acid, hydrochloric acid, formic acid, methanesulfone, acetic acid, trifluoro acetic acid , Borontrifluoro ether adduct or polyphosphoric acid may be used. The reaction temperature and time are 1-5 hours at 0-80 ° C depending on the acid and organic solvent used. However, the most preferable reaction condition is reflux reaction using concentrated sulfuric acid or hydrochloric acid in nitrile hydrocarbon solvent.

The reaction for preparing the compound of formula (I) by alkylating the compound of formula (V) with an alkyl halide is performed by alkylation in the presence of a base in a polar solvent such as DMF and a quaternary alkyl ammonium salt in a chlorohydrocarbon solvent. There is a method of alkylation in the presence of alkali using a transfer catalyst). Alkaline may be used as alkali earth metal hydroxides or carbonates, and different catalysts may be alkyl quaternary ammonium chloride or bromide or benzyltrialkyl quaternary ammonium chloride or bromide of 1-4 carbon atoms, the reaction temperature is 10-80 ° C is suitable. However, when the alkyl halide is chloride or bromide, the method using a catalyst other than the alkylation reaction in the polar solvent has the advantage of obtaining the structural formula (I) in high yield under mild reaction conditions.

Structural formula (IV) can be prepared by converting acylglycine, which acylates glycine, into an active anhydride of structural formula (VI), followed by reaction with aminoacetaldehyde dialkylacetal.

R ₂ in formula (Ⅵ) is the same as R ₂ in formula (Ⅰ), R ₄ is a lower alkyl group or a benzyl group having a carbon number of from 1-7.

The following examples will illustrate the technical problems of the present invention in detail, but the present invention is not necessarily limited thereto.

Example 1

Preparation of 2,5-dioxo-3,6-diaza-8,8-dimethoxyoctane (IV; R ₂ = R ₃ = CH ₃ )

29.29 ml of triethylamine and 250 ml of dichloromethane were added to a three necked round bottom flask, and 23.4 g (0.20 mol) of acetylglycine was dissolved therein, and anhydrous calcium chloride tube was attached thereto and maintained at -14 ° C. 27.24 ml (0.21 mol) of isobutyl chloroformate was slowly dropped, and after 22 minutes, 22.88 ml (0.21 mol) of aminoacetaldehyde dimethylacetal was slowly dropped and refluxed for 30 minutes. After cooling the reaction solution to -5 ℃, hydrochloride of triethylamine is filtered off. The organic layer was washed four times with an aqueous saturated potassium carbonate solution and then the solvent was removed and recrystallized with ethyl acetate to obtain 29.60 g (72.5%) of the compound.

Melting Point: 107-108 ° C (Ethyl Acetate)

Hnmr (CDCl ₃ ): δ 2.05 (s, 3H, acetyl hydrogen) 3.40 (s, 6H, dimethoxy hydrogen)

3.98 (d, 2H, -NCH ₂ CH, J = 5,6 Hz), 4.45 (t, 1H, -CH t6

J = 5,6 Hz), 7.24 (b, 2H, amine hydrogen)

i, r. (KBr), cm ^-1 : 3280 (s), 3070 (m), 2940 (w), 1670 (w), 1650 (s), 1630 (s), 1550 (s), 1420 (w), 1370 ( w), 1280 (w), 1240 (m), 1130 (m), 1070 (m), 690 (m)

Example 2

Preparation of 1-cyclohexyl-2,5-diaza-1,4-dioxo-7,7-dimethoxyheptane (IV; R ₂ = C ₆ H ₁₁ , R ₃ = CH ₃ )

The compound was obtained in the yield of 70.5% using hexahydrohydric acid and amino acetaldehyde dimethyl acetal in the same manner as in Example 1.

Melting Point: 112-113 ° C (Ethyl Acetate-hexane)

Hnmr (CDCl ₃ ): δ 1.15-2.40 (m, 11H, cyclohexyl hydrogen), 3.45 (s, 6H, dimethoxy hydrogen)

3.44 (s, 2H, -NHCH ₂ CO-), 4.00 (d, 2H, -NHCH ₂ CH-, J = 5.2 Hz), 4.45 (t, 1H, -CH t6-1 J = 5.2 Hz), 6.80 ( s, 2H, amine hydrogen)

i, r, (KBr), cm ^-1 : 3,300 (s), 3,100 (w), 2,950 (m), 1,680 (w), 1630 (s), 1,570 (m), 1,550 (m), 1,530 (w ), 1,440 (w), 1,130 (w), 1,060 (w)

Example 3

Preparation of 4-acetyl-1H-3,4-dihydropyrazin-2-one (V; R ₂ = CH ₃ )

17.41 g (0.085 mol) of 2,5-dioxo-3,6-diaza-8,8-dimethoxyoctane (IV; R ₂ = R ₃ = CH ₃ ) and 500 ml of acetonitrile were placed in a 1 l round bottom flask. After adding 0.5 ml of concentrated sulfuric acid, the reaction was slowly refluxed for 2 and a half hours. After cooling, 16 g of anhydrous K ₂ CO ₃ was ground into a powder, put into a container, stirred well for 2-3 hours, filtered, the solids were discarded, and the solution was concentrated to give 8.03 g (67.2%) of crystals.

Melting Point: 150-151 ° C (acetonitrile)

Hnmr (DMSO): δ 2.10, 2.13 (s, 3H, acetal); 4.22, 4.32 (s, 2H, -COCH ₂ N-); 5.74, 5.84 (d, 1H, vinyl hydrogen, J = 5.0 Hz); 6.39, 6.54 (d, 1H, J = 5.0 Hz); 9.72 (b, 1H, amine hydrogen)

ir (KBr), cm ^-1 : 3200 (w), 3070 (s), 2930 (m), 1690 (s), 1660 (s), 1600 (s), 1410 (m), 1380 (m), 1340 (w), 1090 (w), 960 (w), 930 (w), 810 (m), 700 (w)

Example 4

Preparation of 4-cyclohexylcarbonyl-1H-3,4-dihydropyrazin-2-one (V; R ₂ = C ₆ H ₁₁ )

12.12 g (0.0445 mol) of 1-cyclohexyl-2,5-diaza-1,4-dioxo-7,7-dimethoxyheptane (IV; R ₂ = C ₆ H ₁₁ , R ₃ = CH ₃ ) Place in a 2 l round bottom flask, add 1.5 l of acetonitrile, add 0.8 ml of concentrated sulfuric acid, and slowly reflux for 1 hour. 5.36 g of anhydrous K ₂ CO ₃ was added, followed by stirring for 2-3 hours. Filtration removes the solid and concentrates to yield 7.14 g (77%) of the compound.

Melting Point: 168.5-170.5 ° C (Ethyl Acetate-hexane)

Hnmr (CDCl ₃ ): δ1.0-2.1 (b, 10H, cyclohexyl hydrogen), 2.2-2.9 (b, 1H, cyclohexyl carbonyl α-hydrogen), 4.38 (s, 2H, -COCH ₂ N- ), 5.80 (dd, 1H, vinyl J _1-6 = 5.0 Hz, J _5-6 = 5.8 Hz), 6.30 (d, 1H, vinyl J _5-6 = 5.8), 9.15 (b, 1H, hydrogen of amine )

ir (KBr), cm ^-1 : 3230 (s), 3100 (m), 2900 (m), 2830 (w), 1680 (s), 1610 (s), 1395 (m), 1310 (w), 1270 (w), 1170 (m), 1070 (w), 980 (w), 920 (w), 770 (m)

Example 5

1-phenylethyl-2-oxo-4-cyclohexylcarbonyl-1,2,3,4-tetrahydropyrazine (I; R ₁ = C ₆ H ₅ CH ₂ CH ₂ , R ₂ = C ₆ H ₁₁ )synthesis

1.96 g (0.01 mol) of 4-cyclohexylcarbonyl-1H-3,4-dihydropyrazin-2-one (V; R ₂ = C ₆ H ₁₁ ) was dissolved in 2.41 g (0.013 mol) of phenethylbromide and dichloromethane. 20 ml, caustic soda 1.40 g, anhydrous K ₂ CO _{3 and} 2.80 g were added to a round bottom flask, followed by 0.31 g (0.1 molar equivalent) of benzyl tri (n-butyl) ammonium chloride, followed by reflux for 4 hours and 40 minutes. Cool to to filter the solids. 100 ml of dichloromethane is added to the organic layer, and then washed twice with 10 ml of saturated potassium carbonate solution. The organic layer is dried and concentrated. The concentrate is combined with ethyl acetate to recrystallize to yield 1.5 g (48.1%) of the compound.

Melting Point: 131 ° C (Ethyl Acetate)

ir (KBr), cm ^-1 : 2900 (m), 2830 (w), 1650 (s), 1630 (sh), 1440 (m), 1390 (m), 1280 (m), 980 (w)

Example 6

Synthesis of 1-benzyl-2-oxo-4-acetyl-1,2,3,4-tetrahydropyrazine (I; R ₁ = C ₆ H ₅ CH ₂ , R ₂ = CH ₃ )

1.27 g (9.06 × 10 ⁻³ mol) of 4-acetyl-1H-3,4-dihydropyrazin-2-one (V; R ₂ = CH ₃ ), 1.25 g of anhydrous K ₂ CO ₃ , 1.38 g of benzylchloride ( 0.010 mole) and 25 ml of n-propyl alcohol are placed in a 50 ml round bottom flask, and the mixture is refluxed at 6:20 for cooling. After filtering off the solids, the solvent was blown off under reduced pressure, 200 ml of dichloromethane was added and washed twice with 50 ml of water. Drying the organic layer and recrystallization with ethyl acetate and hexane yielded 1.53 g (73.2%) of the compound.

Melting Point: 80-82 ° C (Ethyl Acetate)

Hnmr (CDCl ₃ ): δ 2.10 (s, 3H, acetyl), 4.32 (s, 2H, -NCOCH ₂ N-), 4.65 (s, 2H, hydrogen at benzyl), 5.52 (d, 1H, vinyl J = 6.0 Hz), 6.05 (d, 1H, vinyl J = 6.0 Hz), 7.22 (s, 5H phenylcyclic hydrogen)

i, r. (KBr), cm ^-1 : 3120 (w), 1670 (s), 1650 (sh), 1460 (m), 1440 (m), 1420 (s), 1400 (m), 1350 (m), 1300 ( m), 1170 (w), 1090 (w), 950 (w), 900 (w), 720 (m), 700 (w)

Example 7

Synthesis of 1-methyl-2-oxo-4-acetyl-1,2,3,4-tetrahydropyrazine (I; R ₁ = R ₂ = CH ₃ )

4-acetyl-1H-3,4-dihydropyrazin-2-one (V: R ₂ = CH ₃ ) 1.32 g (9.42 x 10 ^-3 ) mol), anhydrous K ₂ CO ₃ 1.69 g, dimethylformamide 20 ml Into a 50ml round bottom flask and filtered after about 45 hours to remove the solids. Distillation under reduced pressure to remove dimethylformamide and recrystallization of ethanol yields about 1.18 g (81.3%) of product.

Melting Point: 141-144 ° C (Ethyl Alcohol)

Hnmr (D ₂ O): δ 2.10 (s, 3H, acetyl); 3.00 (s, 3H, N-methyl); 4.20, 4.30 (s, 2H, -N-CH ₂ -CO-); 5.76, 5.80 (d, 1H, vinyl hydrogen J = 6.0 Hz); 6.37, 6.51 (d, 1H, vinyl hydrogen J = 6.0 Hz)

i. r. (KBr): 3060 (w), 2925 (w), 1660 (s, broad), 1475 (m), 1400 (s), 1360 (m), 1300 (m), 1040 (m), 930 (w) , 750 (w)

Claims (7)

In preparing the compound of formula (I), the compound of formula (IV) is cyclized in an organic solvent in the presence of an acid catalyst to prepare a compound of formula (V), and alkylated with an alkyl halide of R ₁ X to form a compound of formula (I). Method for preparing the compound.

In structural formula (I), R ₁ is a lower alkyl group having ₁ to 7 carbon atoms or a benzene ring substituted with a halogen atom, a hydroxyl group, a lower alkyl group having 1 to 7 carbon atoms, and a lower alkoxy group having 1 to 7 carbon atoms. Phenethyl or benzyl, X is halogen, and in formula (I) (IV) (V), R ₂ is hydrogen, a lower alkyl group having 1-7 carbon atoms, a cycloalkyl group, a benzene ring nitro group, a hydroxyl group Cyclic acetals having up to 1 to 7 carbon atoms, an alkoxy group or a phenyl group substituted with a halogen atom, R ₃ represents methyl or ethyl, or two R ₃ rings in a methylene group

to be. The process of claim 1 wherein the acid catalyst is selected from the group consisting of sulfurous acid, hydrochloric acid, formic acid, metalsulfonic acid, acetic acid, trifluoroacetic acid, borontrifluoroether ether adduct or polyphosphoric acid. The organic solvent of claim 1 is selected from the group consisting of lower alcohols having 1-4 carbon atoms, chlorohydrocarbons having 1-2 carbon atoms, nitrile hydrocarbons, or ethers, and reacting at reflux temperatures of these solvents, or 0-80 ° C. How to react in The process of claim 1, wherein the alkylation is carried out in the presence of a base in a polar solvent or the quaternary alkylammonium salt in a chlorohydrocarbon solvent in the presence of a base using a phase transfer catalyst. The method of claim 4 wherein the base is selected from among hydrates or carbonates of alkaline earth metals. The quaternary alkyl ammonium salt is selected from the group consisting of lower alkyl quaternary ammonium chloride or bromide having 1 to 4 carbon atoms or trialkylbenzyl ammonium chloride or bromide having up to 1 to 4 carbon atoms, and having 1 to 2 chlorohydrocarbons. Reaction in a solvent. A process for preparing Structural Formula (IV) characterized by reacting acylglycine active ester of Structural Formula (VI) with aminoacetaldehyde dialkyl acetyl.

In the structural formula (Ⅵ), R ₂ is the same as R ₂ in formula (Ⅰ), (Ⅳ), (Ⅴ), R 4 is a lower alkyl group or a benzyl group having a carbon number of from 1-7.