JPS5823879B2 - Production method of octahydropyro↓-ro[1,2↓-a]pyrazine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of octahydropyrrolo(1,2-a)pyrazine.

This compound is useful in the synthesis of physiologically active substances, specifically in the coronary expansion preparation 10-(β-(N-1゜4-diazapiclo(4,3,0,1-nonanyl-propionyl, 1)
-2-chlorophenothiazine dichlorohydrate and the neuroleptic γ-(N-(1°4-diazabicyclo-[4,
It is useful as a starting product in the preparation of 3,0]-nonanyl)-furopyruparafluorophenylketone cyclohydrate.

10-(β-(N-(1,4-diazabicyclo-(4+
3. o]-nonanyl)-propionyl])-2-chlorophenothiazine dichlorohydrate and γ-(N-(1
,4-diazabicyclo-[4゜3.0)-nonanyl)]
A known synthesis method for physiologically active compounds such as [propyl-parafluorophenylketone dichlorohydrate] involves the synthesis of hexahydropyrrolo(1,2-a]-pyrazin-1-one with lithium chloride in diethyl ether medium. Using octahydropyrrolo(1,2-a) pyrazine produced by reduction with alumohydride (M.E., Freed, A., Day,
rJ.

Org, Chem, j 25, p. 2109 (1960
);L.

S, Nazarova9A, M, Likhoshers
tov, to, S.

Raevsky, A.P., 5koldinov, [K.
him, Farm, Zh, 11976, No. 1, p. 88).

Starting from this multi-step synthesis from xahydropyrrolo (1,2-a, l-pyrazin-1-one 6-riop valeric acid, e.g. bromination of θ-chlorovaleric acid in the presence of PCl3,
It is produced by esterifying the resulting product and then condensing it with ethylenediamine.

(A, M. Likhosherstov, L, S, Na
zarovatA, P, 5ko-1dinov, IZ
h, Org, KhimJ, Volume V1, page 1729 (
1970) J.

Disadvantages of this process include the need to use lithium almohydride, which has an explosion risk and is rarely available, and the need to use solvents that pose a flame hazard, as well as the need to start from a base of .beta. The difficulty lies in the production of xahydropyrrolo[1,2-a]-pyrazin-1-one.

A method for producing occuhydro CI, 2-al-pyrazine by catalytic dehydration of furandiamine is known in the art.

(A, A, Ponomarev. 1, M, 5kvolt
zov, L) AN 5SSR, Volume 148, No. 4, 860
(see page).

This method suffers from the complex process of dehydrating N-tetrahydrofurfurylethylenediamine over zirconia-activated aluminum oxide in quartz tubes at 300-315°C.

Inadequate for application in commercial large-scale manufacturing.

This method also has the disadvantage of a low yield of the desired product (approximately 30 parts).

The object of the present invention is to produce octahydropyrrolo(1,2-
a) To provide a method for producing pyrazine.

According to this and other objects, the present invention provides
In the process for the preparation of octahydropyrrolo(1,2-a,l pyrazine) comprising reducing a 1,2-al pyrazine derivative according to the invention, 3°4-dihydropyrrolo(1
, 2-a, l pyrazine.
2-a] Pyrazine derivative in the presence of nickel, platinum or palladium catalyst at 100-180 atm, 100-18
The purpose is to reduce by catalytic hydrogenation at 0° G to obtain a reaction mixture containing the desired product, which is subsequently isolated.

3.4-dihydropyrrolo(1,2-a:) pyrazine can be converted to octahydropyrrolo(1,2-a) as shown below.
Reduced (catalytic hydrogenation) to pyrazine; 3,4-dihydropyrrolo (1,2-a,l From the structural formula of pyrazine, it is clear that it has three double bonds, 6,7 and The double bonds at positions 8 and 9 are in the pyrrole configuration of this heterocycle, and the double bond at positions 1 and 2 is conjugated with the pyrrole system and is considered as the double bond of the Schiff base.

It is known that double bonds in Schiff bases are reduced under much milder conditions than double bonds in pyrrole derivatives.

Therefore, the double bond at the 1,2-1 position of 3,4-dihydropyrrolo CI, 2-a, l pyrazine should be reduced under milder conditions than the double bond at the pyrrole portion of the heterocycle.

Based on the results obtained, 3,4-dihydropyrrolo(
1,2-a] During the catalytic reduction of pyrazine, 1.2,3.4
Although mixtures of -tetrahydropyrrolo[1,2-a]pyrazine and octahydropyrrolo[1°2-a]pyrazine were often made, 3,4,6,7,8,9-hexahydropyrrolo It is concluded that no b(1,2-a) pyrazine was formed.

From the above, firstly, octahydropyrrolo [1,2-a]
The manufacturing process of pyrazine is according to the above formula: 1, 2, 3
．． 4-Tetrahydropyrrolo (1,2-a,l is produced in all cases during the production process of pyrazine.

Second, 1,2,3,4-tetrahydropyrrolo[1,
2-a) Under conditions that reduce the double bond in pyrazine,
The three double bonds in 3,4-tetrahydropyrrolo(1,2-a) pyrazine are necessarily reduced.

1.2,3.4-tetrahydropyrrolo [1°2-a]
The proportion of pyrazine to the rubbery products formed during the hydrogenation of octahydropyrrolo[1°2-a]pyrazine and 3,4-dihydropyrrolo(1,2-a)pyrazine depends on the catalyst and treatment used. Depends on conditions.

The selected temperature and pressure ranges are optimal for this method.

1, 2, 3,
The proportion of 4-tetrahydropyrrolo(1,2-a]pyrazine is monitored using gas-liquid chromatography methods.

If there is a substantial amount of 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine in the reaction mixture, an additional amount of the above catalyst should be added and the resulting mixture A further catalytic hydrogenation should be carried out at 100-180 atm and a temperature in the range 100-180 DEG C., and after this the desired product may be isolated.

This modification improves the yield of the desired product.

Nickel, platinum and palladium catalysts made in conventional manner can be used in this process.

Nickel catalysts, which are very readily available and inexpensive, are preferably used.

When using a nickel catalyst, 3,4-dihyls.

Pyrrolo (1,2-a) pyrazine at 150-180°C,
Reduce at 140-180 atmospheres.

When reduced at temperatures and pressures below the aforementioned limits, 1, 2, 3
．． The yield of 4-tetrahydropyrrolo(1,2-a]pyrazine is higher and the yield of the desired product is lower.

Carrying out this process at elevated temperatures results in a substantially rubbery reaction product and reduces the yield of the desired product.

When using platinum or palladium catalysts, 3,4-dihydropyrrolo[1゜2-a]pyrazine is preferably reduced at 140 = 180 °C and 120-160 atm for platinum catalysts, and for palladium catalysts as described above for nickel catalysts. 100-1 for the same reason as shown in
Preferably, the reduction is carried out at 30° C. and 100□-150 atm.

In order to prevent the reaction mixture from becoming gummy and to improve the yield of the desired product, an organic solvent was used to reduce the 3,4-dihydropida-ro(1,2-a]pyrazine. It is preferable to use

N-hebutane and triethylamine are highly preferred solvents as they are readily available.

The obtained octahydropyrrolo(1,2-a:)pyrazine is used for the synthesis of the above-mentioned physiologically active compounds.

The advantage of the process for preparing octahydropyrrolo[1,2□-a]pyrazine according to the present invention is that it uses 3゜4-dihydropyrrolo(1,2-a)pyrazine as the starting material and that this treatment is carried out once. This process can be carried out on a commercial scale.

The preparation of 3.4-dihydropyrrolo(1,2-a,l-pyrazine) is simple as its feedstock is dialkyl acecool or dioxalane dialkoxytetrahydrofurfural made from readily available furfural.

The target product octa)hydropyrrolo(1,2-a,l pyrazine produced by the process according to the invention has a boiling point of 63-65
At °C/7 mm, it is n”81.4980,
And occuhydropyrrolo (1,
2-a,1 matches perfectly with pyrazine.

The yield of this product is 82%.

This process is easy to produce on a large scale for octahydropyrrolo(1,2-a[pyrazine) and is carried out as follows.

; starting product, 3,4-dihydrovirolo[1°2-a
] Pyrazine is present at a temperature of 100 to 150° in a medium of lower fatty acids.
It is prepared in C by reacting a dialkyl acecool or dioxalane 2,5-dialkoxytetrahydrofurfurol with ethylenediamine and subsequent isolation of the desired product in a customary manner.

The reaction is carried out according to the following formula: where R1 is CH3 or C2H6, R2 is CH3, C2H6 or -CH2-CH2-,
and R3 is CH3, C2H5 or -CH2-CH
2-, but when R1 is CH3, R2 and R
3 are both CH3 or -CH2-CH2-, and when R1 is C2H5, R2 and R3 are both C
It is 2H5.

Subsequently, the obtained 3,4-dihydropyrrolo[1,2-
a.] Catalytic hydrogenation of pipyran in an organic solvent or without the use of an organic solvent.

The process is carried out at 100-180 atmospheres and 100-180 DEG C. in a Stijl autoclave with stirring.

Preferred conditions for this process depend on the type of catalyst used.

The hydrogenation treatment was monitored by gas-liquid chromatography.

If reduction does not occur completely, additional amounts of catalyst are added to the reaction mixture and the resulting mixture is left under stirring under the conditions described above to absorb the stoichiometric amount of hydrogen.

If the process is carried out without a solvent, an organic solvent is added to the reaction mass, the catalyst is filtered off, the solvent is distilled off, and the residue is removed in order to isolate the desired product. Distill in vacuo.

If this treatment is carried out in an organic solvent medium, there is no need to add fresh organic solvent and the treatment is repeated.

Octahydropyrrolo (1,
2-a) An example of the production of pyrazine will be given below.

Example 1 3.4-dihydropyrrolo(1,2-a,l pyrazine 2
4.9 and skeletal nickel catalyst 12I were loaded into a 0.251 rotating steel autoclave.

The autoclave was purged with hydrogen and the hydrogen pressure was then increased to 150 atmospheres.

The autoclave was gradually heated to 150-180°C under stirring and heated at the same temperature for 3 hours.

After cooling, the reaction mass was removed and the autoclave was washed with methanol.

The catalyst was stripped off, the solvent was distilled off, and the resulting residue was distilled in vacuo, yielding 16! 17 (section 70) of octahydropyrrolo[1°2-a]pyrazine (boiling point 6
3-65 °C/7 mvt nDl, 4980) and 4 g of 1,2,3,4-tetrahydropyrrolo (1,2
-a] Pyrazine (boiling point: 100-103°C, 77mm) was obtained.

Example 2 3.4-dihydropyrrolo(1,2-a]pyrazine 24
g of skeletal nickel catalyst and 12F were loaded into a 0.254 rotary steel autoclave and processed as described in Example 1, then 4 g of skeletal nickel catalyst was added to the reaction mass to yield 160 g of skeletal nickel catalyst. Hydrogenation treatment was carried out for 2 hours under stirring at -170°C and 140 atm.

After cooling, add 30 ml of absolute alcohol to the reaction mass;
Then, this reaction mass was taken out.

The catalyst was filtered off, the solvent was distilled off, and the resulting residue was distilled in vacuo.

211 (Theory 83) Octahydropyrrolo (1,2
=a) Pyrazine (boiling point 63-65°C/7mln￥, 1
．． 4980) was obtained.

Example 3 3.4-dihydropyrrolo(1,2-a,l pyrazine 3
1', t') 20 g of ethylamine-washed skeletal nickel catalyst and 40 ml of triethylamine were loaded into a 0.57 rotary steel autoclave.

The autoclave was purged with hydrogen and then the pressure was increased to 152 atmospheres.

The autoclave was gradually heated to 150°C while stirring.
The mixture was then left at the same temperature for 2 and a half hours with stirring.

After cooling, the reaction mass was removed, the catalyst was stripped off, the solvent was distilled off, and the resulting residue was distilled in vacuo.

31 g (82%) of octahydropyrrolo (1,2-a
l pyrazine (boiling point 63-65 °C / 7 mm nL'
1.4972 ) and 2 g (7) 1,2°3,4-tetrahydropyrrolo(1,2-a,l pyrazine (boiling point 1
00-103°C/7 mm).

Example 4 3.4-dihydropyrrolo(1,2-a'J pyrazine 1
2 g of heptane washed framework nickel catalyst and 20 ml of heptane were charged into a 0.251 rotary steel autoclave.

The autoclave was purged with hydrogen and then the pressure was increased to 144 atmospheres.

This autoclave was heated slowly to 150°C while stirring.
and left for 3 hours with stirring at a temperature of 150-160°C.

After cooling, the reaction mass was removed, the autoclave was washed twice with benzene, the catalyst was filtered off, the solvent was distilled off and the residue obtained was distilled in vacuo.

9 g (75% of theory) of octahydropyrrolo (1,2
-a] Pyrazine was obtained.

The hydrogenated product obtained corresponded to the corresponding product described in Example 1.

Example 5 3,4-dihydropyrrolo(1,2-a,l pyrazine 1
2 g and 0.7 I of the platinum catalyst prepared by Adams.
A 57 rotating tail autoclave was loaded.

The autoclave was purged with hydrogen and then the pressure was increased to 150 atmospheres.

While stirring, gradually heat this autoclave to 14
0°C and left for 3 hours at a temperature of 150-160°C and under stirring.

After cooling, the reaction mass was taken out and the autoclave was heated for 2 hours.
Washed twice with benzene, the catalyst was filtered, the solvent was distilled off, and the residue was distilled in vacuo.

Octahydropyrrolo (1,2-a,l pyrazine 4.2
g (33% of theory) and 5.9 g of 1,2,3,4-tetrahydro(1,2-a]pyrazine.

The hydrogenated products obtained are in each case the same as those described in Example 1.

Ta.

Example 6 3.4-dihydropyrrolo (1,2-33199212
g and 0.7 g of platinum catalyst manufactured by Adams.
A rotating tail autoclave was loaded.

The autoclave was purged with hydrogen and the pressure was then increased to 140 atmospheres.

While stirring, gradually heat this autoclave to 13
0°C and left for 3 hours at a temperature of 135-150°C and under stirring.

After cooling, an additional 0.11' of platinum catalyst was added to the reaction mass, the reaction mass was removed, the catalyst was filtered off, the solvent was distilled off, and the residue was vacuum distilled.

9 g (71% of theory) of octahydropyrrolo(1,2-a]pyrazine were obtained.

The hydrogenated product obtained was identical to the corresponding material described in Example 1.

Example 7 3.4-dihydropyrrolo (1,2-33199212
g and 10% palladium catalyst 29 supported on a charcoal support were loaded into a 0.25 A rotating steel autoclave.

The autoclave was purged with hydrogen and then the pressure was increased to 100 atmospheres.

The autoclave was gradually heated to 100-130° C. with stirring and left at the same temperature for 3 hours with stirring.

After cooling, the reaction mass was removed, the autoclave was washed twice with absolute alcohol, the catalyst was evaporated, the solvent was distilled off and the residue was distilled in vacuo.

Octahydropyrrolo(1,2-al pyrazine 8.i(
70 section of theory) was obtained.

The hydrogenated product obtained was identical to the corresponding material described in Example 1.

Example 8 3.4-dihydropyrrolo [1,2-33199212
g, 25 ml of heptane, and 2 g of a 10-group palladium catalyst supported on a charcoal carrier were loaded into a 0.25 A rotating steel autoclave.

The autoclave was purged with hydrogen and then the pressure was increased to 130 atmospheres.

This autoclave was gradually heated to 130°C while stirring.
and 130 to 140°C for 3 hours with stirring.
It was left at a temperature of

After cooling, the reaction mass was removed, the autoclave was washed twice with benzene, the catalyst was evaporated, the solvent was distilled off and the residue was distilled in vacuo.

Octahydropyrrolo(1,2-a)pyrazine 9.9g
(78% of theory), but the material obtained was identical to the octahydropyrrolo(1,2-a]pyrazine described in Example 1.

Claims (1)

[Claims] 1. In the presence of a nickel, platinum or palladium catalyst, 3, at 100-180 atm and 100-180°C.
4-dihydropyrrolo(1,2-a)pyrazine is reduced by catalytic hydrogenation to give the desired product octahydropyrrolo(1,2-a)pyrazine
1,2-a) Octahydropyrrolo(1,2-a) consisting of obtaining a reaction mixture containing pyrazine and then isolating it.
2-a') Method for producing pyrazine. 2. Before isolating the desired product, the reaction mixture is heated at 100-1 in the presence of a nickel, platinum or palladium catalyst.
The method according to claim 1, wherein catalytic hydrogenation is carried out again at 80 atm and 100-180°C. 3 Using a nickel catalyst, the reduction was carried out to 140-180
The manufacturing method according to claim 1, which is carried out at atmospheric pressure and 150-180°C. 74. The method according to claim 1, wherein the reduction is carried out at 120-160 atm and 140-180°C using a platinum catalyst. 5 Using a palladium catalyst, the reduction was carried out at 100-150
The process according to claim 1, carried out at atmospheric pressure and 100-130°C. 6 3,4-dihydropyrrolo(1) in the presence of an organic solvent
, 2-a) The production method according to any one of claims 1 to 4, wherein pyrazine is reduced. 7. The method according to claim 6, wherein the organic solvent comprises an aliphatic hydrocarbon. 8. The method according to claim 6, wherein the organic solvent comprises a tertiary aliphatic amine.