DE2832488A1 - Tetra:hydro-pyrrolo-pyrazine prepn. - by reducing di:hydro cpd., used as intermediate for drugs esp. coronary vasodilator or neuroleptic - Google Patents

Abstract

Prepn. of 1,2,3,4-tetrahydro-pyrrolo 1,2-a pyrazine (I) comprises reducing 3,4-dihydro-pyrrolo 1,2-a pyrazine (II) in an organic solvent medium. Redn. is effected by hydrogenation in presence of a Pt gp. catalyst or using a complex metal hydride, pref. KBH4 or LiAlH4. (I) is an intermediate for various physiologically active substances, esp. the coronary vasodilator 10-left brace beta- N-(1,4-diazabicycle(4,3,0)nonanyl)-propionyl right brace-2-chlorophenothiazine dihydrochloride and the neuroleptic gamma- N-(1,4-diazabicyclo(4,3,0)nonanyl) -propyl-p-fluorophenyl ketone dihydrochloride. (II) is easily prepd. from furfurol. The process is easily carried out and the double bonds in the pyrrole ring are unaffected. Redn. with KBH4 is pref. effected in a lower aliphatic alcohol at 65-80 degrees C, while redn. with LiAlH4 is pref. in Et2O at 25-36 degrees C. Hydrogenation may be effected using Pt or Pd catalysts.

Description

description

The invention relates to a new compound 1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine and a method for its production.

The said new compound is used as the starting compound for synthesis various physiologically active substances, especially for the synthesis of 0ktahdropyrrolo [1,2-a] -pyrazine used, on the basis of which a coronary dilation Drug 10- {ß- [N- (1,4-Diazabicyclo] 4,3,0] -nonanyl) propionyl]} -2-chlorophenothiazine dihydrochloride and a neuroleptic # - [N- (1,4-diazabicyclo [4,3,0] nonanyl)] -propyl-para-fluorophenylketone dihydrochloride are obtained in known processes for the synthesis of physiologically active Compounds 10- {β- [N- (1,4-diazabicyclo [4,3,0] nonanyl) propiony1]} -2-chlorophenothiazine dihydrochloride and / - 9 - (1,4-diazabicycloS4,3,07nonanyl) 8-propyl-para-fluorophenylketone dihydrochloride Oktahydropyrrolo £ 1,2-ajpyrazine is used, which in turn is obtained by reduction of hexahydropyrrolo [1,2-a] pyrazin-1-one with lithium aluminum hydride in a diethyl ether medium what is obtained is fM.E. Freed, A.K. Day, J. Org. Chem., 25, 2109 (1960); L.S. Nazarova, AT THE. Lichoscherstow, K. S. Rajewski, A.P. Skoldinow, Chim. farm. sh.

(Chem-pharm. Zschr.), 1976, No. 1, p. 88g. The starting hexahydropyrrolo [1,2-a] pyrazin-1-one is produced from i-chlorovaleric acid through the multistage synthesis fiA.M.

Lichoscherstow, L.S. Nasarova, A.P. Skoldinow, Zschr. F.

org. Chem. (USSR), Vol. VI, p. 1729 (1970, which the bromination of # -Chlorvaleric acid in the presence of PCl3, the esterification of the product obtained and the following Includes condensation with ethylenediamine. The disadvantage of the method is the need to be explosive and deficit lithium aluminum hydride, as well as a flammable solvent use, and in the complexity of obtaining the starting hexahydropyrrolo- [1,2-a] pyrazin-1-one.

It is also a process for making Ohtahydropyrro-1011,2-alpyrazine known from catalytic dehydration of furandiamine DA. A. Ponomarew, I. M. Skworzow, DAN SSSR (Lectures of the Academy of Sciences of the USSR), 1963, vol. 148, No. 4, p. 8607. The disadvantage of the method is its complexity the implementation of the dehydration of N-tetrahydrofurfurylethylenediamine, which in the Quan- ° tube at a temperature of 300 to 315 C over zirconium dioxide activated Aluminum oxide is carried out. This process can be divided into large slaves difficult to realize. The disadvantage of the method is also a low one Yield of end product around 30%.

The aim of the present invention is to produce one new substance - I, 23,4-tetrahydropyrrolo- [1,2-a] pyrazine, its use as a starting raw material would allow the above-mentioned physiologically active compounds after a to obtain simpler and more convenient procedures.

According to the invention, a new compound not described in the literature - 1,27394-tetrahydropyrrolo-1,2-aJpyrazine of the structural formula suggested.

1,2,3,4-Tetrahydropyrrolo [1,2-a] pyrazine is a colorless liquid with an amine odor, 100 to 1010C / 7 torr 20 bp and n20 1.5530. The structure the obtained compound was determined by the data of the elemental analysis of the base and Salts as well as by spectra of proton magnetic resonance (to) and by the mass spectrum confirmed. In the PMR spectrum there is a singlet at 1.56 ppm (6 scale, inner Standard according to tetramethylsilane), which corresponds to a proton in the NH group, two triplets centered at 2.86 ppm and 3.63 ppm, the 4 protons on the carbon atoms C3 and C4 correspond; a singlet at 3.8 ppm that has two protons on the carbon atom C1 corresponds to and three multiples in the intervals from 5.56 to 5.7 ppm, from 5.86 to 6.0 ppm, from 6, 23 to 6.37 ppm, the 3 protons on the carbon atoms C6, C7 and C8 correspond. The integral curve corresponds to a total of 10 protons and their appearance corresponds to the formula offered for the compound. The individuality the compound was also proven by the gas chromatographic method and their Molecular weight was determined from the mass spectrum data, according to which M m / e of 122 has.

According to the present invention, there is the process for the preparation of 1,2,3,4-tetrahydropyrrolo , 2-ajpyrazine in that 3,4-dihydropyrrolor1,2-avpyrazine in the medium of an organic Solvent of the reduction by its hydrogenation with hydrogen or complexes Metal hydrides with subsequent isolation of the end product from the one obtained Reaction mixture is subjected; thereby the hydrogenation in the case of use made of hydrogen in the presence of a platinum group catalyst and then the end product is isolated from the reaction mixture obtained.

Various complex metal hydrides can be used as complex metal hydrides which have the C = N double bond in the Schiff'schen Reduce bases. Preferably are accessible and broad for such types of reactions usable lithium aluminum hydride and sodium and potassium borohydrides to use.

When carrying out the reduction by catalytic hydrogenation or the reduction with potassium borohydride is recommended as an organic solvent to use lower aliphatic alcohols. Here are preferably methyl and Use ethyl alcohol. When carrying out the reduction with lithium aluminum hydride aliphatic ethers or cyclic ethers can be used. It is preferred To use diethyl ether.

In the process according to the invention, platinum group catalysts can be used used in the hydrogenation of the -C = N double bond in the Schiff's Bases are applied. Above all, you can use the most accessible platinum and palladium catalysts following ordinary Methods are prepared, or platinum and palladium catalysts are used, which are produced on supports (for example the platinum catalyst produced by Adams or palladium catalyst on barium sulfate).

When carrying out the process under the proposed conditions the reduction of the double bond in the 1, 2-position of 3, 4-dihydropyrroloL; i , 2-a7pyrazine with the formation of 1,2,3,4-tetrahydropyrroloL1,2-ajpyrazine.

The synthesis of 1,2,3,4-tetrahydropyrrolo (1,2-a] pyrazine proceeds in accordance with the following equation: As can be seen from the structural formula of 3,4-dihydropyrrolotI2-aJ-pyrazine, it contains three double bonds, two of which belong to the pyrrole part of the heterocycle and the third double bond is coupled to the pyrrole system and can be used as a double bond in the Schiff's bases to be viewed as. Under the conditions offered, the reduction of only one double bond in the 1,2-position of the heterocycle takes place without the double bond in the pyrrole part of the heterocycle being attacked.

When reducing with lithium aluminum hydride are used as a solvent usually ether used.

The process described above uses lithium aluminum hydride good in diethyl ether, which is most widely used for these purposes. In connection This means that the temperature range up to the boiling point of diethyl ether (25 up to 360C) is most preferable.

When reducing with potassium or sodium borohydrides are used as solvents generally lower aliphatic alcohols are used. As it is recommended to use as such alcohols to use the most accessible methyl and ethyl alcohols, in these cases, the reduction process is preferably at the boiling point Solvent (65 to 800C).

The 1,2,3,4-tetrahydropyrroloC1, 2-appyrazine obtained can be used as an intermediate be used for the synthesis of physiologically active compounds.

The advantage of using 1,2,3,4-tetrahydropyrrolo-1,2-adpyrazine As an intermediate there is the possibility of the production of Oktahydropyrrolor1,2-avpyrazine to be carried out on an industrial scale. In addition, the process of making 1,2,3,4-Tetrahydropyrrolof1,2-aJ-pyrazine itself technologically simple because as Starting raw material used for its production 3,4-Dihydropyrrolo [1,2-a] -pyrazine which in turn is obtained from the available furfural.

The process for the preparation of 1, 2,3,4-tetrahydropyrrolo-1,2-ajpyrazine is technologically simple and is carried out as follows.

The starting product - 3,4-DihydropyrroloD, 2-aJpyrazine is through Implementation of 2, 5-Dialkoxytetrahydrofurfuroldialkylacetalen or -dioxalan with Ethylenediamine in the medium of lower aliphatic acids at a temperature of 100 obtained up to 1500C and then isolated the end product in a conventional manner.

The reaction proceeds according to the scheme: where: R1 = R2 = R3 = CH3 or R1 = R2 = R3 = C2H5 or R1 = CH3, R2, R3 = -CH2-CH2-.

The 3,4-dihydropyrrolo [1,2-a] pyrazine obtained is in an organic Solvent dissolved and reduced by one of the following methods.

In the case of using the method of catalytic hydrogenation was the reduction at room temperature and atmospheric pressure in the presence of the catalysts performed by the platinum group. The procedure is closed with stirring System in the solution of a lower aliphatic alcohol in the hydrogen atmosphere carried out.

The speed of the process depends on the nature of the applicable Catalyst. After the theoretical amount of hydrogen has been absorbed, the The catalyst is filtered off and the solvent is driven off from the filtrate the end product is purified by vacuum distillation.

In the case of reduction with potassium borohydride, the process is preferred with stirring at a temperature of 65 to 80 0C in solutions of lower aliphatic Alcohols carried out.

The speed of the process depends on the temperature at which the process is performed. The isolation of the final product is done by the addition of water to the reaction mixture and its subsequent extraction with Benzene running. After the solvent has been stripped off, the product is vacuum distilled cleaned.

In the case of reduction with lithium aluminum hydride, the process is preferred carried out with stirring at a temperature of 25 to 36 0C in diethyl ether solution. The speed of the process depends on the temperature at which the process takes place is carried out. The isolation of the end product is achieved by the decomposition of the Reaction mixture with water and / or aqueous alkali with the separation Pre-standardize the essential solution by decanting. After stripping off the solvent the end product is purified by vacuum distillation.

For a better understanding of the present invention, the following are made concrete examples are given.

Example 1 In a single-neck flask equipped with a magnetic stirrer from 0.5 1 content one brings 36 g of 3,4-dihydropyrrolor [1,2-a] pyrazine in 250 ml of absolute Methanol and 1 g of 10% Pd / BaS04. The system for supplying hydrogen becomes the piston connected. The reaction mass is blown through with hydrogen to remove air and afterwards in a hydrogen atmosphere with stirring until the theoretical one is absorbed Amount of hydrogen left to stand. The theoretical amount of hydrogen was during 3 hours absorbed. The result is the reaction mixture from which the Catalyst is removed by filtration. The filtrate becomes the solvent driven off and the residue is distilled off under vacuum by removing the fraction with a bp of 100-101 ° C / 7 torr. The yield of 1,2,3,4-tetrahydropyrrolo [ , 2-ajpyrazine is 20-34 g (95% of theory), nD 1.553 °.

Found in%: C 68.49; H 8.15. C7H10N2.

Calculated in%: C 68.82; H 8.25.

The illeate is obtained by mixing the solutions of the product and IIaleic acid (molar ratio 1 or

1.1) obtained in ethyl alcohol. Mp. 151 to 1520C (from aqueous Alcohol).

Found in, 6c: C, 55.50; H 6.04; N 11.87. C11H14N204.

Calculated in%: C 55.46; H 5.92; N 11.760 Example 2 In one with the magnetic stirrer equipped single-necked flask with a capacity of 50 ml is placed in 2.4 g of 3,4-dihydropyrrolotl, 2-ajpyrazine in 20 ml of ethyl alcohol and 0.2 g of platinum. Next is the reduction and isolation of the end product carried out according to the methodology described in Example 1. the theoretical amount of hydrogen was absorbed in 1 hour. the The yield of the end product is 2.2 g (92% of theory). The constants and the Analysis results of the obtained substance are the constants and the analysis results identical to the substance described in Example 1.

Example n In one provided with the magnetic stirrer and air cooler Bring 6 g of 3,4-dihydropyrrolo £ 1,2-ajpyrazine into a two-necked flask of 100 ml in 50 ml of ethyl alcohol and 5.4 g of potassium borohydride. The reaction mixture is under Stirred for 6 hours at room temperature. The reaction mass will Poured into water and extracted the end product with benzene. The solvent is driven off and the residue is distilled off under vacuum by removing the fraction with a bp of 100-1010C / 7 torr.

20 The yield is 5.2 g (85 °, ó of theory), nD 1.5525.

The analysis results of the obtained substance are the analysis results identical to the substance described in Example 1.

Example 4 The end product is made according to the methodology of Example 3, however, while heating the reaction mixture at a temperature of 78 0C 2 hours received. The yield is 79 50 of theory. The constants and the Analysis results of the obtained substance are the constants and the analysis results identical to the substance described in Example 1.

Example 5 In one with the stirrer, reflux condenser and dropping funnel Provided three-necked flask with a volume of 250 ml one brings 2.28 g of lithium aluminum hydride in 50 ml of absolute diethyl ether and gives afterwards drop by drop 3.6 g of 5,4-dihydropyrrolo-L1,2-appyrazine in 50 ml of absolute diethyl ether are added. That The reaction mixture is mixed for 4 hours at room temperature and then mixed add 2.3 ml of running water and 1.7 ml of 40% sodium hydroxide solution in a certain order and 8 ml of water were added. The ethereal solution is separated by decanting. Ether is driven off, the residue is evaporated with benzene and under vacuum distilled off by collecting the fraction with a boiling point of 100 to 101 0C / 7 Torr will.

The yield is 3.2 g (87 c, b 'of theory), 20 1.5522.

nD The analysis results of the obtained substance are the analysis results identical to the substance described in Example 1.

Example 6 The end product is made using the methodology of Example 5, however, while boiling the reaction mixture at a temperature of 36 0C 1 hour received. The yield is 83 cj6 of theory. The constants and the Analysis results of the obtained substance are the constants and the analysis results identical to the substance described in Example 1.

Claims (1)

i, 2,3,4-TETRAHYDROPYRROLO [1,, 2-a] PYRAZINE UTD PROCESS FOR THE PRODUCTION THEREOF Patent Claims 1. 1,2,3,4-Tetrahydropyrrolo [1,2-a] pyrazine of the structural formula: 2. A process for the preparation of 1,2,3,4-tetrahydropyrrolo- £ 1,2-ajpyrazine according to claim 1, characterized in that one 3,4-dihydropyrrolo [1,2-a] pyrazine in the medium of an organic The reduction solvent is reduced by hydrogenating it with hydrogen or complex metal hydrides, the hydrogenation being carried out in the presence of a platinum group catalyst in the case of the use of hydrogen and then the end product being isolated from the reaction mixture obtained. 3. The method according to claim 2, d a d u r c h g e -k e n n z e i c h n e t that as complex metal hydrides I aluminum borohydride or lithium aluminum hydride be used. 4. The method according to claim 2 and 3, d a d u r c h g e -k e n n z e i c h n e t that in the case of the use of potassium borohydride the reduction in the medium Lower aliphatic alcohols carried out at a temperature of 65 to 80 0C will. 5. The method according to claim 2 and 3, d a d u r c h g e -k e n n z e i c h n e t that in the case of using the lithium aluminum hydride the reduction is carried out in diethyl ether at a temperature of 25 to 360C.