JPS5821904B2 - Sinkinamethano-anthracene - Google Patents

Description

Detailed Description of the Invention The present invention relates to the general formula (I) [wherein A represents a C2-3 saturated or unsaturated aliphatic hydrocarbon chain, and R1 represents a hydrogen atom, a lower alkyl group, a lower R1 and 'B2 represent an alkenyl group, a benzyl group, a cyclopropylmethyl group, or R1 and 'B2 represent an alkylene chain bonded to each other or an alkylene chain via oxygen, and together with the adjacent nitrogen atom, a piperidino group, a pyrrolidino group, or a morpholino group. represent.

The present invention relates to a novel method for producing a novel methano-anthracene derivative represented by the following formula and an acid addition salt thereof.

To describe in detail R and R in the above formula, R and R are the same or different, and are a hydrogen atom or a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a 5ec-butyl group, or an isobutyl group. , or a lower alkenyl group such as an allyl group or a butenyl group, a benzyl group, a cyclopropylmethyl group, or R1
and R2 represents an alkylene chain bonded to each other or an alkylene chain via oxygen, and together with the adjacent nitrogen atom represents a piperidino group, a pyrrolidino group or a morpholino group.

The compound of the present invention represented by general formula (I) has central nervous system,
It has various interesting pharmacological actions on the autonomic nervous system, such as strong antitetrabenazine action, making it a very useful compound as a psychotropic drug, especially as an antidepressant.

That is, it is well known that many bicyclic compounds have been discovered and put to practical use as medicines, especially medicines involving the central nervous system, but the present inventors also He has been actively engaged in research on the synthesis of bicyclic compounds with new carbon skeletons with the aim of creating .

As a result, they synthesized for the first time a compound represented by general formula (I) having a novel bridged carbon skeleton as a bicyclic moiety, found that this compound has strong pharmacological action, and completed the method of the present invention.

Therefore, the gist of the present invention is novel,
The object of the present invention is to provide an advantageous method for producing compounds represented by general formula (I) that have high pharmaceutical value.

The compound group represented by general formula (I) can be produced by various production methods shown below.

■ General formula (I[) [In the formula, A has the same meaning as above.

] and the general formula (III)
[In the formula, R1 and R2 have the same meanings as above.

This is a method for producing a methano-anthracene derivative represented by the general formula (I) by condensing and reducing the amine derivative represented by the formula (I).

Various generally known methods can be used for the condensation and reduction of the aldehyde group and the amine derivative.

For example, in Leuckart-Waltz, the reaction is carried out by adding the aldehyde derivative to a mixture of formic acid and the amine derivative or to an amine formate.
This condensation and reduction method can be achieved by the llach) reaction.

It can also be achieved by catalytically reducing a mixture of the aldehyde derivative and the amine derivative in the presence of a catalyst such as Raney nickel, platinum oxide, palladium, etc., without a solvent or in an inert solvent under low or high pressure.

It is also possible to simultaneously use a condensing agent such as sodium acetate.

Further, reduction can be carried out using methods such as sodium and alcohol, zinc and acid, or zinc and alkali.

Suitable inert solvents include alcoholic solvents such as methanol, ethanol and isopropyl alcohol, dioxane and liquid ammonia, but acetic acid, diethyl ether, diisopropyl ether, tetrahydrofuran and the like can also be used.

It can also be achieved by mixing the aldehyde derivative and the amine derivative to produce a ship base or enamine, followed by catalytic reduction in the presence of a catalyst such as Raney nickel, platinum oxide, palladium, etc. in an inert solvent or without a solvent. be able to.

In addition, reduction can be performed using formic acid, sodium borohydride, lithium borohydride, sodium cyanoborohydride,
This can be achieved by using metal hydride compounds such as lithium aluminum hydride, sodium bis(methoxyethoxy)aluminum hydride, or diborane.

The inert solvent can be selected from among alcoholic solvents such as methanol, ethanol, inglobil alcohol, and butyl alcohol, benzene, toluene, diethyl ether, diisopropyl ether, dioxane, and tetrahydrofuran.

It is desirable to use the reducing agent or catalyst in an amount sufficient to allow the reaction to proceed sufficiently, and the reaction can be suppressed or promoted by appropriately cooling or heating the reaction temperature.

〇 General formula (IV) [In the formula, A has the same meaning as above.

R3 is a hydrogen atom, a lower alkyl group, a lower alkenyl group,
Means a phenyl group or a cyclopropyl group.

R4 is a hydrogen atom-lower alkyl group, lower alkenyl group,
Represents a benzyl group or a cyclopropylmethyl group.

] By reducing the amide group of the amide derivative represented by formula (V) to a methylene chain or a methyl group, R3 and R4 are the same as described above.

] This is a method for producing a methano-anthracene derivative represented by:

As the reduction method, various reducing agents and various embodiments that are generally used when reducing an acid amide or urethane to an amine are possible.

First, suitable reducing agents include metal hydride compounds such as lithium aluminum hydride and sodium bis(methoxyethoxy)aluminum hydride.

These metal hydride compounds are achieved by reacting with acid amide derivatives in an inert solvent, examples of which include diethyl ether diisopropyl ether and tetrahydrofuran.

Particularly preferred solvents include dioxane and ethylene glycol dimethyl ether, but heftane, hexane, cyclohexane, benzene, toluene, and the like can also be used.

It is desirable to use the reducing agent in an amount sufficient to allow the reaction to proceed sufficiently, and the reaction can be suppressed or accelerated by appropriately cooling or heating the reaction temperature.

Other practical methods for reducing the acid amide include methods using boron metal hydride, diborane, and the like.

Sodium borohydride is a reducing agent that is easy to use because it is easily available or an alcoholic solvent can be used, but its ability to reduce acid amide groups is weak, so aluminum chloride is not suitable for the purpose of the method of the present invention. A method in which the acid amide moiety is used in the coexistence with salts such as triethyloxonium fluoroborate ((C2R5) 3 ”
A method can be used in which activation is performed with O.BF, -) or the like, followed by reduction with sodium borohydride.

1. Diborane can also be used as a reducing agent for the acid amide group.

After the reaction is completed, the resultant can be taken out using conventional organic chemistry techniques.

■ By hydrolyzing the amide derivative represented by the above general formula (IV), the general formula (VI) [wherein A,
R4 has the same meaning as above.

] This is a method for producing a methano-anthracene derivative represented by:

As the hydrolysis method, various known conditions that are generally used when hydrolyzing acid amides to produce amines can be used.

First, the preferred conditions are alkaline conditions such as potassium hydroxide, sodium hydroxide, etc., which can easily achieve the purpose directly or in an inert solvent.

Alternatively, a method of hydrolysis directly under mineral acidity such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc. or in an inert solvent can be used.

As the inert solvent, preferably alcoholic solvents such as methanol, ethanol, flobyl alcohol, butyl alcohol are suitable, but ether, tetrahydrofuran, dioxane, ethylene lycol dimethyl ether, benzene, toluene, dimethyl sulfoxide, etc. are also suitable. Can be used together.

It is desirable to use an alkali or acid at a concentration that allows the reaction to proceed sufficiently, and the reaction can be suppressed or accelerated by appropriately cooling or heating the reaction temperature.

Furthermore, a method using a hydrazine derivative such as hydroresin or methylhydrazine can also be used.

After the reaction is complete, the resultant can be taken out using conventional organic chemistry techniques.

■ Amine derivatives represented by general formula (VI) and general formula [In the formula, R3 has the same meaning as above.

] by condensation and reduction with an aldehyde derivative represented by [In the formula, A has the same meaning as above.

R/l is the same as R4 or R3CH2.

] This is a method for producing a methano-anthracene derivative represented by:

This can be achieved by treating the amine derivative (VI) and the aldehyde derivative (■) in the same manner as described in section 0.

For reductive methylation with formaldehyde, E.
Particularly effective is methylation with formaldehyde and formic acid, known as the reaction known as ::1arke).

When R4=H in the general formula (VI), general formula (■)
The general formula (
V can also be used to form a methano-anthracene derivative, where =R3CH2.

■ General formula (■) [In the formula, A has the same meaning as above.

R5 is a nitrile group -C3N or an oxime group -CH=NOH.

] By reducing the nitrile group or oxime group of the nitrile derivative or oxime derivative represented by the general formula (IX) [wherein A has the same meaning as above.

] This is a method for producing a methano-anthracene derivative represented by:

As the reduction method, various modes generally used when reducing a nitrile group or an oxime group to an amine are possible.

This can be achieved by a reduction method similar to that described in section 0 or a catalytic reduction method similar to that described in section 0.

Since the compound of general formula (I) obtained by the method of the present invention is an amine derivative, various physiologically harmless inorganic and organic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, oxalic acid, citric acid, malic acid, tartaric acid,
Acid salts can be formed with fumaric acid, conolic acid, etc.

The raw material compounds of the present invention were synthesized via a series of new compounds synthesized for the first time by the present inventors, as shown in the synthetic route below.

[In the reaction formula, R represents a hydrogen atom or a general protecting group for alcohol.

R' represents a hydrogen atom or a lower alkyl group.

] That is, the present inventors obtained an amino derivative (XI) from the carboxylic acid derivative (X) of ethano-anthracene and succeeded in transferring it to a new methano-anthracene derivative (■), which is normally The carbon chain can be elongated by a method, for example, to form a carboxylic acid derivative (xm).

Further, each raw material compound can be obtained by general methods such as reduction and oxidation.

Next, the present invention will be explained in more detail with reference to Examples, but the present invention is of course not limited to these in any way.

Reference example 1 12-acetoxy-9,10-dihydro-9,10-ethano-anthracene-9-carboxylic acid (i,oy) was dissolved in benzene (10,0ml), and thionyl chloride (4,0ml) was added. It was refluxed for 4 hours.

By distilling off benzene and excess thionyl chloride, 12-acetoxy-9,10-dihydro-9
-10-ethano-anthracene-9-carboxylic acid chloride was obtained.

This carboxylic acid chloride derivative was dissolved in dry acetone (25
Sodium nitride (o, 6
An aqueous solution (1,3rrLl) of 3P) was added and stirred for 2 hours.

Water was added, and the mixture was extracted with benzene. The benzene layer was washed with water, dried with sodium sulfate, and refluxed for 2 hours. 12-acetoxy-9.10-dihydro-9.10=ethano-anthracene-9-isocyanate was obtained by distilling off the benzene.

Add this directly to a 20% aqueous sodium hydroxide solution (15,
0ml) and ethanol (12,0ml) for 6 hours.

After most of the ethanol was distilled off, water was added and the mixture was extracted with ethyl acetate.

The ethyl acetate layer was washed with water, dried with sodium sulfate, and the solvent was distilled off to obtain the desired crystal of 9-amino-12-hydroxy-9,10-dihydro-9,10-ethano-anthracene.
I got ft.

m, p, 181-181.5°C Reference example 2 9-amino-12-hydroxy-9,10-dihydro-
9,10-ethano-anthracene (3,01) was dissolved in acetic acid (
240rrLl), an aqueous solution (120ml) of sodium nitrite (6,71) was added dropwise at 2-5°C, and the mixture was stirred for 1 hour.

After stirring at 95-105°C for 5 hours, water was added and extracted with benzene. The benzene layer was washed with water, dried with sodium sulfate, and the solvent was distilled off to obtain 9-formyl-9,10-dihydro-9,10-methano-anthracene. A crude crystal of (2,8S') was obtained.

White crystals were obtained by recrystallization. m, p,
99-100℃ Reference Example 3 Triethylphosphonoacetate (2,651
) in 50% sodium hydride (0,661) and dry benzene (10,0ml) was treated with 9-formyl
9,10-dihydro-9,10-methano-anthracene (2,Of) was dissolved in dry benzene (20,0 ml) and added dropwise at room temperature.

After stirring at room temperature for 5 hours, the mixture was heated to 70° C. for 1 hour.

After adding water and extracting with ethyl acetate, washing the organic layer with water, drying with sodium sulfate and removing the solvent, β-[9,10-dihydro-9,1
0-methano-9-anthryloxyacrylic acid ethyl ester was obtained.

This ethyl ester derivative was mixed with methanol (53.0ml
) and refluxed for 4 hours in a 10% aqueous sodium hydroxide solution (12, oml).

β-[9,10-dihydro-9,10-methanol-
9-Anthryl teracrylic acid was obtained.

m, p, 219-224°C Reference example 4 9-γ-hydroxygloby-9,10-dihydro-9
- 10-methano-anthracene (100~) was stirred with chromium trioxide-pyridine in dichloromethane (4 ml) at room temperature for about 5 minutes according to the method of Collins.

Benzene was added and the precipitate was removed by filtration.

After concentrating solution F, water was added, extracted, washed with water, dried with mirabilite, and the solvent was distilled off to obtain β-[9,10-dihydro-9,10-methanol-
9-Anthrylcupropionaldehyde was obtained.

m, p, 135.5-138°C Reference example 5 9-γ-aminopropyl-9,10-dihydro = 9,1
0-methano-anthracene (2301v) and acetic anhydride (
9-γ-acetylaminopropyl-9,10-dihydro- Crystals of 9,10-methano-anthracene were obtained.

m, p, 172-176°C Reference Example 6 β-[9,10-dihydro-9,10-methano-9-anthryl]-propionic acid amide (250 ml) was mixed with thionyl chloride (0,5 ml) in dry toluene (3 ml). )
and refluxed for 4 hours.

By distilling off excess thionyl chloride and the solvent, β-[9,10-dihydro-9,10-methano-9-7
7tolyl]-propionitrile crystals were obtained.

m, p, 147-148.5°C Reference example 7 9-γ-acetylaminopropyl-9,10-dihydro-9,10-methano-anthracene (1007n9) and ″50% sodium hydride (32■) was stirred in dry dioxane (12 ml) at 80°C for 1 hour.

Allyl bromide (62 .mu.) was added and the mixture was refluxed for 7 hours.

9-γ
-Acetylallylaminopropyl-9-10-dihydro-9,10-methano-anthracene crystals were obtained.

m, p, 88-91°C Example 1 Morpholine (870-) and formic acid (460my) at 60°C
β-[9,10-dihydro-9,10-methano-9-anthrylcupropionaldehyde (50~
) and stirred at 60°C for 30 minutes and at 80°C for 1.5 hours.

9-
γ-morpholinopropyl-9,10-dihydro-9,1
0-methano-anthracene was obtained.

The hydrochloride salt of this product melted at 173-176.5°C.

Example 2 β-[9,10-dihydro-9,10-methano-9-anthrylcupropionaldehyde (150m9) and 5
ee-butylamine (1007Q) at -5℃-0℃
The mixture was stirred in methanol for 0 minutes.

Add sodium borohydride (50~) and leave for 2 hours~0
Stir at ℃.

After adding water and extracting, the basic part was separated using hydrochloric acid, neutralized, extracted, washed with water, dried with sodium sulfate, and the solvent was distilled off to give 9-γ-5ec-butylaminoglobil-9, 10-dihydro-9, 10.
-methano-anthracene was obtained.

The hydrochloride salt of this product melted at 216-219°C.

Example 3 9-γ-acetylaminopropyl-9,10-dihydro-9,10-methano-anthracene (70~) and lithium aluminum hydride (35) in dry dioxane (2
After reacting for 9 hours at 40-50°C in 77Ll), water was added to decompose excess lithium aluminum hydride, ethyl acetate was added, and the mixture was dried with sodium sulfate.

By evaporating the solvent, 9-γ-ethylaminopropyl-9.
10-dihydro-9.10-methano-anthracene was obtained.

The hydrochloride salt of this product melted at 182-186°C.

Example 4 9-γ-acetylallylaminopropyl-9,10-dihydro-9,10-methano-anthracene (1001n
9) was refluxed in ethanol-25% NaOH aqueous solution (3 ml) for about 10 hours.

9-γ
-allylaminopropyl-9,10-dihydro-9,1
0-methano-anthracene was obtained.

The hydrochloride salt of this product melted at 227-228°C.

Example 5 9-r-7 Minoprobyl-9,10-dihydro-9,1
0-methano-anthracene (125~) and 90% formic acid (
A mixture of 300 ml) and 37% formalin (0.25 ml) was stirred at 90°C to 100°C for 8 hours.

Thereafter, 4N hydrochloric acid was added and the mixture was dried under reduced pressure. After adding water to the residue and making it basic with aqueous ammonia, extraction, washing with water, drying of sodium sulfate, and distillation of the solvent were carried out to give 9-r-dimethylaminoglobil-
9,10-dihydro-9,10-methano-anthracene was obtained.

The hydrochloride salt of this product melted at 244-247°C.

Example 6 β-[9,10-dihydro-9,10-methano-9-anthrylcupropionitrile (250m9) and lithium aluminum hydride (100rv) were mixed in dry dioxane (12ml) at 60°C for 5 hours. After the reaction, water was added to decompose excess lithium aluminum hydride, and ethyl acetate was added to dry the sodium sulfate.

By evaporation of the solvent, 9-γ-aminoprohypre 9 and 10
-dihydro-9,10-methano-anthracene was obtained.

The hydrochloride of this product decomposed at 275°C.

The following compounds were obtained by the method described above.

9-γ-methylaminopropyl-9,10-dihydro-
9,10-methano-anthracene hydrochloride m, p, 247
~249°C 9-r-pyrrolidinoglovir-9,10-dihydro-9
・10-methano-anthracene hydrochloride m, p, 244~
248℃ 9-γ-hyhelicinoglopyru-9・lo-dihydro-9
・10-methano-anthracene hydrochloride m, p, 272~
279°C 9-r-1 Noglovir aminoglovir-9,10-dihydro-9,10-methano-anthracene hydrochloride m, p
, 255-256°C 9-r-inobutylaminopropyl-9,1°-dihydro-9,10-methano-anthracene hydrochloride m, p,
247-251.5°C 9-γ-pendylaminoglobin-9,10-dihydro-9,10-methano-anthracene hydrochloride m, p, 19
6-201°C 9-γ-benzylcyclopropyl methylamine/propyl-9, 10-dihydro-9, 10-methano-anthracene hydrochloride m, p, 207-209°C 9-δ-dimethylaminobutyl-9. 10-dihydro-
9,10-methano-anthracene hydrochloride m, p, 20
1 to 202.5°C 9-δ-dimethylamino-α-butenyl-9,10-dihydro-9,IO-methano-anthracene hydrochloride m,
p, 154.5-155°C 9-γ-methylamino-α-propenyl-9·IO-methano-anthracene hydrochloride m, p.

244-246℃ 9-r-ethylmethylaminopropyl-9,10-dihydro-9,10-methano-anthracene oxalate m, p
, 168-169℃

Claims (1)

[Claims] 1 General formula [wherein A represents a C2-3 saturated or unsaturated aliphatic hydrocarbon chain. ] and the general formula [where R1 and R2 represent a hydrogen atom, a lower alkyl group, a lower alkenyl group, a benzyl group, a cyclopropylmethyl group, or R1 and R2 represent an alkylene chain or It represents an alkylene chain via oxygen and together with the adjacent nitrogen atom represents a piperidino, pyrrolidino or morpholino group. [In the formula, A, R1, and R2 have the same meanings as above. ] A method for producing a novel methano-anthracene derivative and its acid addition salt. 2 General Formula [In the formula, A represents a C2-3 saturated or unsaturated aliphatic hydrocarbon chain, and R3 means a hydrogen atom, a lower alkyl group, a lower alkenyl group, a phenyl group or a cyclopropyl group. R4 is a hydrogen atom, a lower alkyl group, a lower alkenyl group,
Represents a benzyl group or a cyclopropylmethyl group. A general formula characterized by reducing the amide group of an amide derivative represented by the formula [wherein A, R3 and R4 have the same meanings as above. ] A method for producing a methanol anthothecene derivative and its acid addition salt. 3 General formula [wherein A represents a C2-3 saturated or unsaturated aliphatic hydrocarbon chain, and R3 means a hydrogen atom, a lower alkyl group, a lower alkenyl group, a phenyl group or a cyclopropyl group. R4 is a hydrogen atom, a lower alkyl group, a lower alkenyl group,
Represents a benzyl group or a cyclopropylmethyl group. [In the formula, A and R4 have the same meanings as above. ] A method for producing a methano-anthracene derivative and its acid addition salt. 4 General formula [wherein A represents a C2-3 saturated or unsaturated aliphatic hydrocarbon chain, R4 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a benzyl group, or a cyclopropylmethyl group . ] and the general formula [wherein R3 means a hydrogen atom, a lower alkyl group, a lower alkenyl group, a phenyl group or a cyclopropyl group. [In the formula, A and R3 have the same meanings as above, R4
has the same meaning as the above-mentioned R4 or R3CH2. ] A method for producing a methano-anthracene derivative and its acid addition salt. 5 General Formula [In the formula, A represents a C2-3 saturated or unsaturated aliphatic hydrocarbon chain. R5 is a nitrile group -C3N or an oxime group -CH=N
It means OH. [In the formula, A has the same meaning as above. ] A method for producing a methano-anthracene derivative and its acid addition salt.