JPS5811420B2 - Production method of benzobiccycloalkanamines - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for producing benzobiccycloalkanamines.

More specifically, the present invention provides a compound represented by the formula: [wherein R is hydrogen or lower alkyl, R1 is lower alkyl, and Y is hydroxy] or an acid addition salt thereof, =N
The -Y group is reduced to the -NH2 group, and the non-aromatic unsaturated bond is then reduced with or without isolation of the compound, or simultaneously with said reduction, to give the formula [wherein R and R1 is the same as above] 6,7,8,9.10.11-hexahydro-5.10-methano-5H-benzocyclononene-12
- A method for producing an amine or a medically acceptable acid addition salt thereof.

The starting material of formula (1) is a new compound and is produced by the method described below.

In the process of the present invention, the reduction of the -N-Y group is carried out by refluxing in an alkanol such as ethanol or isopropanol with an alkali metal such as soluton, and then the non-aromatic unsaturated bond is removed. Reduce the formula (
2).

However, as described later, by treating the compound of formula (1) with a reducing agent, the -N-Y group and the non-aromatic unsaturated bond are simultaneously reduced in the same reaction system, resulting in the reduction of the compound of formula (2). It is preferable to lead to a compound.

Therefore, the present invention is directed to producing the target compound of formula (2) by reducing the -N-Y group and non-aromatic unsaturated bond of the compound of formula (1) or its acid addition salt. and, if desired, further steps: (a) etherifying the compound where R is hydrogen to obtain a compound where R is lower alkyl; (b) converting the primary amine to a secondary or tertiary amine; (c) A phenolic compound is obtained by cleaving the ether group of a compound in which R is lower alkyl.

(d) splitting a mixture of optical isomers into a pair of diastereomers or individual optical antipodes, (e) formula (3)
) into its pharmaceutically acceptable acid addition salt, or by converting the acid addition salt of formula (3) below into the free amine, the compound of the formula: [wherein R and R1 are Same as above: R2 is hydrogen lower alkyl or phenyl(lower) alkyl; R3 is hydrogen,
means lower alkyl, lower alkenyl, lower alkynyl or phenyl (lower) alkyl] or a pharmaceutically acceptable acid addition salt thereof.

Compounds of formulas (2) and (3) and their pharmaceutically acceptable acid addition salts are useful as analgesics.

These compounds are described in our Belgian Patent No. 776.173 (published June 2, 1972).

Other compounds of formula (2) or (3) can be obtained from the obtained compound of formula (2) or (3) by a conventional method.

For example, a phenolic compound where R is hydrogen is etherified to obtain a compound where R is lower alkyl.

This etherification can be carried out by known methods, for example, the phenolic compound is reacted with dimethyl sulfate or diethyl sulfate in an alkaline aqueous solution to obtain methyl or ethyl ether.

However, it is generally preferred to choose a suitable ether having the desired alkyl group as the starting material for the reduction of formula (1) and to avoid this step.

The primary amine of formula (2) or its acid addition salt can be converted into a secondary or tertiary amine by a conventional method.

This method includes reductive alkylation.

An example of this reductive alkylation of primary amines is the formation of dimethyl tertiary amine derivatives with formaldehyde and formic acid.

Alternatively, primary amines can be expressed using the general formula: % [where Hal is a halogen such as chlorine, bromine or iodine; R2 is hydrogen, R3 is lower alkyl,
It can be converted into a lower alkenyl, lower alkynyl or phenyl(lower)alkyl secondary amine.

Similarly, a secondary amine in which R2 is hydrogen and R3 is lower alkyl, lower alkenyl, lower alkynyl, or phenyl(lower)alkyl is reacted with an appropriate alkyl halide or phenyl(lower)alkyl halide, and R2
is lower alkyl or phenyl(lower) alkyl, R3
can be changed to a tertiary amine of lower alkyl, lower alkenyl, lower alkynyl or phenyl(lower)alkyl.

Similarly, a primary amine can be reacted with a lower alkyl halide or a phenyl(lower)alkyl halide to create a secondary amine.
to obtain a tertiary amine in which R3 is lower alkenyl or lower alkynyl and R2 is lower alkyl or phenyl (lower) alkyl by reacting this with a halogenated lower alkenyl or halogenated lower alkynyl. I can do it.

Alternatively, a secondary amine can be reacted with a haloformic acid ester and then reduced to provide a tertiary amine where R2 or R3 is methyl.

Similarly, primary amines can be reacted with haloformic acid esters to provide N-methyl secondary amines.

Acylation of a secondary amine yields a compound where R2 is acyl, and then reduction of this acylated amine yields other tertiary amines.

If desired, R is a lower alkyl group of formula (2) or (3).
) or its acid addition salt can be cleaved to obtain a phenolic compound in which R is hydrogen.

Reagents used to cleave ether bonds include Lewis acids such as aluminum chloride or boron tribromide and /'% hydrologonic acids such as hydrobromic acid.

The compounds of formulas (2) and (3) are optically active, and mixtures of optical isomers can be separated into optically active forms.

Alternatively, the optically active form of the compound of formula (1) can be reduced to obtain the optically active form of the compound of formula (2) or its acid addition salt.

The compounds of formula (2) or (3) can be isolated as such or in the form of their acid addition salts.

This acid addition salt is obtained by adding an acid to the compound.

The acids used to derive acid addition salts are hydrochloric acid, maleic acid, citric acid, acetic acid, benzoic acid or other pharmaceutically acceptable acids.

The acid addition is preferably carried out in an alcoholic solution.

Compounds of formula (2) or (3) or pharmaceutically acceptable salts thereof, which can be converted into their amines by adding a strong base to their amines, are toxic acid addition salts of compounds of formula (1). It can also be obtained by removing its toxic components during the manufacturing process.

The compounds of the present invention and their pharmaceutically acceptable acid addition salts can be obtained by directly reducing the compound of formula (1), preferably without separating the reduced compound of the -N=Y group.

Accordingly, the compound of chain formula (2) can be added to the compound of the chain formula (2) as desired.
The compound of formula (3) or a pharmaceutically acceptable acid addition salt thereof can be obtained by subjecting it to one or more of the steps a) to (e).

Reduction of the compound of formula (1) can preferably be carried out by catalytic hydrogenation, for example using Raney nickel as catalyst, thereby reducing the =N-Y group and the non-aromatic ring double bond to form the formula (2 ) is obtained.

The compound of formula (1) is a compound represented by the formula: [wherein R and R1 are the same as the above formula (1)] or a compound represented by the formula H2NY (wherein Y is the same as above) It can be manufactured by processing.

The compound of formula (4) has the formula: [wherein R is lower alkyl;
1 is a lower alkyl such as methyl or ethyl; ) and optionally cleave the ether bond to obtain a phenolic compound in which R is hydrogen.

The strong base used in the reaction with the compound of formula (5) is preferably used in an excess amount in a suitable solvent.

For example, potassium t-butoxide in t-butanol,
Sodium hydride or sodium amide in dimethylformamide.

The ether bond can be cleaved by a known method using, for example, a Lewis acid.

The compound of formula (5) is prepared by adding a compound represented by the formula: [In the formula, R is lower alkyl; R1 means lower alkyl such as methyl or ethyl] to a strong base, preferably an alkali metal alkoxide or hydride. Alternatively, it is produced by treatment with a cis-compound represented by the formula: [wherein X means chlorine or bromine] in the presence of an amide.

Strong bases are preferably used in excess in a suitable solvent.

The product (5) obtained is used directly to form the tricyclic ketone (4) without separation.

The starting materials used for the production of the compound of formula (5) are known and can be obtained by known methods.

In particular, cis-1,4-dichloro-2-butene and cis-1,4-dibromo-2-butene are known.

The compound of formula (6), ie, 1-alkyl-tetralone, is produced by the method described below.

For example, the synthesis method of the present invention is as follows.

The compound of the formula: [wherein R is lower alkyl; R1 means lower alkyl such as methyl or ethyl] is synthesized as follows: (a) The compound of the formula [wherein R and R1 are the same as above] ] is treated with cis-1,4-dichloro or 1,4-dibromo-2-butene in the presence of excess alkali metal alkoxide, hydride or amide to form , R and R1 are the same as above; X means monomine or bromine] to obtain a compound represented by the following.

(b) The compound of formula (9) is treated with a second excess alkali metal alkoxide, hydride or amide to form a tricyclic compound of the formula: [wherein R and R1 are as defined above] To obtain a ketone, (c) the tricyclic ketone of formula (4) is treated with a compound of the formula: 2NY1 [wherein Yl means hydrogen, hydroxy], and the tricyclic ketone of formula (4) is treated with a compound of the formula: [wherein R, R1 and (d) selectively reducing the imino group of the imino compound of formula (10) to obtain an imino compound represented by the formula: [wherein R and R1 are the same as above] A compound represented by ] is obtained, and then the non-aromatic double bond is reduced.

Further, the synthesis of a compound represented by the formula: [wherein R1 means lower alkyl such as ethyl or methyl] is as follows: (a) Formula: [wherein R is lower alkyl; R1 is the above-mentioned ] is treated with cis-1,4-dichloro or 1,4-dibromo-2-butene in the presence of excess alkali metal alkoxide, hydride or amide to give the formula: [In the formula, R and R1 are the same as above; , a hydride or an amide to obtain a tricyclic ketone of formula: [wherein R and R1 are as defined above] (c) converting the tricyclic ketone of formula (4) to formula: 2NY1 [In the formula, Yl means hydrogen or hydroxyl] is treated with a compound represented by the formula: [In the formula, R, R1 and NYl are the same as above] to obtain an imide compound represented by the formula: (d) Selectively reduces imide groups.

(e) After cleavage, the formula: [In the formula, R1 is the same as above] Obtain the compound shown by, then (f) reducing non-aromatic double bonds;

Next, the manufacturing method of the present invention will be described in more detail using the accompanying drawings.

In the drawings, each compound is shown using Roman numerals, and the drawing shows a specific compound in which only the -N=Y group of formula (1) is reduced, that is, 12-amino-5-ethyl-6,9, 1
0,11-tetrahydro-5,10-methano-(5H)
-benzocyclononen-3-ol (X) and formula (2
), i.e. 5-ethyl-6,9,10,11
-tetrahydro-3-methoxy-5,10-methano-
5H]-benzocyclononen-12-amine (■) and the specific compound of formula (4), i.e., 5-
This is a flow sheet showing ethyl-6,7,10°11-tetrahydro-3-methoxy-5,10-methane-(5H)-benzocyclononen-12-one (■).

In addition, the drawings show specific examples of the manufacturing method of the present invention.
,10.11-hexahydro-5,10-methano-[5
H]-benzocyclononen-12-amine,
5-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methane-[5H]-benzocyclononen-12-amine (■) and 12-amino-5-ethyl It is a flow sheet showing an example used in the production of -6,7,8,9,10,11-hexahydro-5,10-methane-[5H]-benzocyclononen-3-ol (XI).

■-Ethyl-7-medoxy-2-tetralone (III)
and excess cis-1,4,-dichloro-2-butene (
IV) preferably with a slight excess of 1 equivalent of strong base (preferably potassium t-butoxide) under an inert atmosphere at room temperature for about 12 to about 24 hours (preferably about 18 hours).
Processing yields a compound of formula (V).

Separation of the compound of formula (■) is not necessary; the reaction mixture containing it is further treated with an excess of strong base and then heated (
Preferably, a solvent is used at reflux temperature for 6 hours) followed by further reaction (preferably about 16 hours at room temperature).

The reaction time and temperature are not particularly limited.

The strong base and suitable solvent used are also not particularly limited, and there are many suitable combinations such as commonly used potassium t-butoxide and t-butanol and sodium hydride or sodium amide and dimethylformamide. .

When using potassium t-butoxide as a strong base,
T-butanol is a particularly preferred solvent.

Then, the obtained compound (■) is separated by a conventional method.

Compound (■) is then treated with a hydroxyamine in an inert solvent (preferably methanol), initially for a short time at elevated temperature (preferably 6 hours at the reflux temperature of the solvent used) and then for a longer time. Treatment at room temperature (preferably for 18 hours) yields the oxime (■).

Compound (■) is recovered by a conventional method. If desired, compound (■) may be directly reduced to compound (■).

Catalytic hydrogenation is a particularly preferred method for this transformation.

If desired, the compound (
(2) can be cleaved to obtain compound (XI).

Alternatively, the oximino group of the compound (■) can be selectively reduced, particularly preferably by Bouveaul
Compound (IX) is obtained by the tBlanc method.

Compound (VII) can be obtained by reducing compound (■).

Catalytic hydrogenation is particularly preferred for carrying out this reduction.

Compound (IX) is preferably cleaved with a Lewis acid such as boron tribromide to obtain compound (X).

Compound (X) is reduced, preferably by catalytic hydrogenation, to obtain compound (XI).

Compounds (■), (IX), (X) and (XI) are separated in a conventional manner.

The manufacturing method of the present invention shown in the drawings is a method for manufacturing 1-ethyl-7-medoxy-2-tetralone, but this method is the same for other tetralones having various substituents at the 1- and 7-positions within the scope of the present invention. It can be used like this.

Similarly, various substituted secondary and tertiary amines within the scope of the present invention can be prepared by conventional methods.

For example, dimethyl tertiary amine derivatives can be prepared using formic acid and formaldehyde via the Leuchart-Wallach reaction.

Cleavage of the ether bond in compound (■) is carried out in the same manner as the cleavage of the ether bond in compound (IX), and the obtained phenolic compound can also be converted in the same manner as compound (■).

Other 3 having an ether at the 3-position of formula (4) within the scope of the present invention
Cyclic ketones can likewise be cleaved to the corresponding phenolic compounds and can likewise be further reacted.

The starting materials used in the practice of this invention, namely 1-alkyl-2-tetralone, are obtained from Stork and Schulenberg [5tork and Schulenberg].

J, ArT1. It can be easily produced from 2-tetralone by the known alkylation reaction described in Chem, Soc, Vol. 84, p. 284 (1,962).

The tetralone is treated with pyrrolidine in an inert solvent such as benzene and then with a suitable lower alkyl halide in an inert solvent such as benzene or dioxane at elevated temperature (preferably less than the solvent used). Reflux temperature)
Make it react.

They are also described by Howell and Taylor (Howell and Taylor J, Chem, s.
oc, p. 1249 (1958)] by reacting the appropriate commercially available 1-tetralone with a Grignard reagent prepared from the appropriate lower alkyl halide to produce the resulting 1-monosubstituted dihydronafucrene. Obtained by oxidation with peracid.

Many tetralones are commercially available, and even those that are not commercially available can be easily synthesized based on literature.

For example, the synthesis of α-tetralone is described in Organic Synthesis, Vol.
The synthesis of β-tetralone is described on page 98, and the synthesis of β-tetralone is described on page 903.
The general synthesis method for tetralone is from Nagata.
Dutch Patent No. 67.0953 of et al.
No. 4 (January 10, 1968).

The ketone of formula (4) is obtained as a racemic mixture, and upon reduction of the oxime, the amine of formula (1) is obtained as a diastereomer.

Separation of a pair of diastereomers and optical antipodes can be performed by known methods.

Useful raw products obtained by various production methods of the present invention, 6
,7,8,9,10.11-hexahydro-5,10-
Methanol-5H-benzocyclononen-12-amine exhibits analgesic effects on warm-blooded animals and is disclosed in Belgian Patent No. 776.173 (June 2, 1972).

As used herein, the term "lower alkyl" refers to methyl,
It means a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms such as propyl and isobutyl.

The term "lower alkenyl" includes allyl, 2-butenyl,
It means a straight or branched chain unsaturated hydrocarbon group having 3 to 5 carbon atoms such as 3-methyl-2-butenyl and 2-pentenyl.

The term "phenyl(lower)alkyl" refers to lower alkyl groups such as benzyl, phenethyl, o-1m-1p-anisyl, veratryl and o-1m-1p-xylyl in which said lower alkyl group terminates in a phenyl group or lower alkyl or lower alkyloxy. means substituted with a phenyl group substituted with a group.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples.

Reference example 1 6.9,10.11-tetrahydro-3-methoxy-5
-Methyl-5,10-methano-5H-benzocyclononen-12-one Under a nitrogen atmosphere, 40 g (0.21 mol) of 1-methyl-7-medoxy-2-tetralone was added to 100 ml of t-butanol.
1 and freshly prepared potassium t-butoxide solution [9.8 g of potassium in 400 ml of t-butanol ('
0.25 mol)].

After the addition was complete, the mixture was stirred at room temperature for 1 hour, transferred to a dropping funnel under a nitrogen atmosphere, and while stirring under a nitrogen atmosphere.
cis-1,4-dichloro-2 dissolved in t-butanol
-butene, 53. g (0.42 mol).

After adding 1 g of potassium iodide, stirring is continued at room temperature for about 18 hours.

Furthermore, freshly prepared potassium t-butoxide solution [t
- in 400 ml of butanol, 15 g of potassium (0,38
mol)] dropwise and after the addition is complete, the mixture is refluxed for 6 hours.

After refluxing, stirring is continued for about 16 hours at room temperature.

The reaction mixture was then poured into water (approx.

The benzene solution was washed twice with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 57 g of an oily crude product.

This crude product is distilled to obtain 36 g of product.

Boiling point 155-165°C (0.5mmHg): Melting point 79
~81°C (crystallized from hot heptane) Reference example 2 6.9,10.11-tetrahydro-3-methoxy-5
-Methyl-5,10-methano-5H-benzocyclononen-12-one, oxime A clear solution of 23 g of sodium acetate in 15 ml of methanol is mixed with a clear solution of 19.5 g of hydroxyamine hydrochloride in 200 ml of methanol, The resulting precipitate of sulfur chloride is separated by filtration.

6,9,1 dissolved in 50ml of methanol was added to this mixture.
0.11-tetrahydro-3-methoxy-5-methyl-
5,10-methano-5H-benzocyclononene-12-
Add 13.5g of onion.

After the addition was complete, the reaction mixture was refluxed for about 4 hours, then for about 1 hour.
Stir for 6 hours.

The solvent was distilled off under reduced pressure, and water was added to the residue to make a slurry.
A solid is obtained, separated by filtration, washed thoroughly with water and dried, yielding 14.2 g of product (melting point 122-125 °C).
.

117g of the title compound was recrystallized from isopropanol.
get.

Melting point 124-126°C Example 1 6.7. s,c+,io,11-hexahydro-3-methoxy-5α-methyl-5,10-nucuno5H-benzocyclononene-12β-amine6.9,10.11-tetrahydro-3-methoxy-5
-Methyl-5,10-methane-5H-benzocyclononen-12-one, oxime 5g, ethanol 150ml
．． 30 ml of concentrated ammonium hydroxide and 2 tablespoons of Raney nickel are shaken with hydrogen at room temperature and 40 psi pressure for 5 hours.

The catalyst is separated by filtration and the solvent is removed under reduced pressure.

The oily residue is partitioned between ether and water.

Separate the ether layer, dry over magnesium sulfate and remove the solvent under reduced pressure to obtain 4.5 g of crude product.

The ethereal solution of the crude product is treated with anhydrous hydrogen chloride to obtain 3.5 g of precipitate (melting point 265-272°C).

Recrystallization from hot water gives 1.6 g of the hydrochloride salt of the title compound.

Melting point 301-303°C Reference example 3 5-ethyl-6,9,10,11-tetrahydro-3-
Methoxy-5,10-methano-5H-benzocyclononen-12-one 20.4 g of 1-ethyl-7-medoxy-2-tetralone and cis-1,4
- From 25 g of dichloro-2-butene, the title compound 17.
Obtain 8g.

Boiling point 150-185°C (0.4 mmHg) Reference example 4 5-ethyl-6,9,10,11-tetrahydro-3-
Methoxy-5,10-nucuno-5H-benzocyclononen-12-one, oxime 5-ethyl-6,9
,10,11-tetrahydro-3-methoxy-5,10
-methano-5H-benzocyclononen-12-one 16
．． 10.3 g of the title compound are obtained from a clear solution of 25.5 g of sodium acetate and 22 g of hydroxyamine hydrochloride dissolved in 200 ml of Og and methanol.

Melting point 150-153°C Example 2 5α-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12β-amine Previous example In the same manner as in method 1, 5-ethyl-6,9
,10,11-tetrahydro-3-methoxy-5,10
1.4 g of the hydrochloride of the title compound are obtained from 3.0 g of -methano-5H-benzocyclononen-12-one, oxime.

Melting point 247-250°C Example 3 6°9.1 obtained in the same manner as Reference Examples 1 and 2 above
0.11-tetrahydro-3-methoxy-5-propyl-5,10-methano-5H-benzocyclononene-12
-one, oxime, 6,
7,8,9,10.11-hexahydro-3-methoxy-5-propyl-5,10-methano-5H-benzocyclononen-12-amine is obtained.

Melting point 226-227°C

[Brief explanation of drawings]

The drawing is a flow sheet showing a specific example of the manufacturing method of the present invention.

Claims (1)

[Scope of Claims] 1 Formula: [In the formula, R and R1 are the same as below; Y means hydroxy] Reducing the -N-Y group and non-aromatic ring double bond of the compound threaded by the formula: A method for producing benzobiccycloalkanamines or acid addition salts thereof, characterized by the formula: [In the formula, R means hydrogen or lower alkyl, and R1 means lower alkyl].