JPS591272B2 - adamantane - Google Patents

Description

[Detailed description of the invention] The present invention relates to a method for producing adamantane derivatives.

In detail, the adamantane derivative that exhibits excellent medicinal efficacy has the formula P(1))-0-(Q)-CH=CHO (where ■ and o are a methylene group or a carbonyl group, and at least ( One of P) and O is a carbonyl group.

) relates to a method for producing an adamantane derivative shown in Adamantane and its derivatives are known to be naturally contained in petroleum, and due to their unique structure, they have high fat solubility and low toxicity to living organisms, making them useful pharmaceuticals and Its realization as an intermediate has been expected.
As a result of the inventors' intensive research from this perspective,
We have succeeded in producing a specific adamantane derivative that is useful as a highly safe cerebral vasodilator with few side effects.
In this research process, are there several species that are useful as precursors for adamantane derivatives that exhibit significant medicinal efficacy? The present invention was completed by studying methods for producing standard adamantane derivatives.

That is, the present invention is based on Shigetsu [7jLP-X (here, (P)
represents a methylene group or a carbonyl group. Moreover, X represents a halogen atom. ) and the formula H? This is a method for producing a novel adamantane derivative represented by the formula, which is characterized by reacting a compound represented by the following formula: -CH=CH→g (where O represents a methylene group or a carbonyl group).

Specifically, the raw material represented by the formula (μm)-X used in the present invention is 1-adamantanoic acid halide and adamantyl methyl halide.

This substance is a known substance. For example, 1-adamantanic acid is synthesized by reacting formic acid and sulfuric acid using adamantane as a raw material, and then halogenation is performed to produce 1-adamantanic acid halide, and after reducing 1-adamantanic acid, It is produced and used by a known method such as halogenation to obtain 1-adamantylmethyl halide. The formula HN used in the present invention is N-cinnamoylbiperazine and N-cinnamylbiperazine.

This substance is also known, and for example, N-cinnamoylbiperazine is produced by the condensation reaction of the known substance cinnamoyl chloride and viperazine, or by the reduction of N-cinnamoylbiperazine or the condensation reaction of cinnamyl chloride and viperazine. to produce N-cinnamylbiperazine,
put to use. The reaction of these raw materials in the present invention is a condensation reaction, and is carried out at nearly equivalent raw material ratios (molar ratio).

However, the reaction will proceed even if either one is in excess. This reaction is preferably carried out in a solvent, in which case it is appropriate to use a cyclic ether such as tetrahydrofuran as the solvent. Moreover, a dehydrohalogenating agent is not necessarily required for this reaction. However, in order to increase the reaction rate or to facilitate post-treatments such as separation of reactants, tertiary amines such as triethylamine or sodium carbonate are effectively used as ordinary dehydrohalogenation agents. In this case, it is preferable to use 1 to 1.5 times the amount (mol) of the target product to be produced. Next, other condensation conditions should be selected depending on the contents of 0)) and O in the above formula.

Each of the three aspects will be explained below. I));O
are both carbonyl groups, that is, N-(1
The reaction to obtain N7-cinnamoylbiperazine is advantageously carried out in the presence of a tertiary amine such as triethylamine as a dehydrohalogenating agent.

Further, this condensation reaction is carried out in a cyclic ether such as tetrahydrofuran, and is completed in about 30 minutes at a reaction temperature of 10° C. or lower. Separation of the target product from the reaction mixture is carried out, for example, by washing the reaction mixture solution with an alkali, then washing with water, separating and drying the ether layer, distilling off the ether, creating a chloroform solution, and using a silica column chromatography method. .

Next, when only 0)) is a carbonyl group, that is, from 1-adamantanoic acid halide and N-cinnamylbiperazine to N
The reaction to obtain -(1-adamantanecarbonyl)-N5-cinnamylbiperazine is carried out in a cyclic ether such as tetrahydrofuran and by dehalogenation, as in the case of the 1-adamantanic acid halide and N-cinnamylbiperazine. It is advantageous to proceed in the presence of triethylamine or the like as a hydrogenating agent.

Regarding the reaction temperature and time, about 2 hours at around room temperature is sufficient.

The target product is separated from the reaction mixture in the same manner as in the case of N-(1-adamantanecarbonino(ha)-N5-cinnamoylbiperazine).

◎ Only the carbonyl group, that is, the reaction to obtain N-(1-adamantylmethyl)-N'-cinnamoylbiperazine from 1-adamantylmethyl halide and N-cinnamoylbiperazine proceeds satisfactorily even without solvent. .

However, the reaction temperature is preferably 150 to 300°C. In this case, sodium carbonate is suitable as the dehydrohalogenating agent, and since 1-adamantylmethyl halide has sublimation properties, it is generally preferable to carry out the reaction in a sealed tube or in a sealed system. In the case of this condensation reaction, an effective yield of the desired product is reached in about 10 hours.

N-(1-adamantylmethyl)-N7 from the reaction mixture
- Separation of cinnamoylbiperazine is carried out in the same manner as described above, with the reaction mixture being dissolved in chloroform.

Novel adamantane derivatives obtained by the method of the present invention [N-(1-adamantanecarbonyl)-N'-cinnamoylbiperazine, N-(1-adamantylmethyl)]
-N'-cinnamylbiperazine and N-(1-adamantanecarbonyl-N'-cinnamylbiperazine)
By applying a reducing agent such as lithium aluminum hydride and converting the carbonyl group into a methylene group, all the same substances N-(1-adamantylmethino(c)
-N'-cinnamylbiperazine is provided.

N-(1-adamantylmethino(c)-N'-cinnamylbiperazine) has few side effects such as excessive hypotensive action, low toxicity, and exhibits excellent medicinal efficacy as a cerebral vasodilator. , in the production of the substance, the present invention
This method is extremely useful as a method for providing precursors.

The method of the present invention will be explained in more detail below along with examples.

Note that a method for preparing raw materials used in Examples is shown as a reference example.

Reference example 1 (1) 98 of 23509 (24 mol) in 30 flasks of 1-adamantanoic acid production method 101
(f) Concentrated sulfuric acid and 500 ml of carbon tetrachloride and 689 (
0.5 mol) of adamantane was added thereto and stirred well, and 5 ml of 98(:f) formic acid was added thereto while cooling to 17-19°C with ice.

Next, 98-100(f) formic acid 2759 (6 mono(c)
A solution of t-butyl alcohol 1489 (190ml, 112 mol) was added dropwise to the solution. The dropping time was 2 hours, and the temperature was maintained at 17-25°C. Furthermore, after stirring for 30 minutes, crushed ice was added to separate the organic layer.
The resulting aqueous layer was extracted three times with 500 ml of carbon tetrachloride.
Collect the carbon tetrachloride layer and add 550ml of 15N ammonia water.
The ammonium salt of 1-adamantanate was filtered through a Buchner funnel. Cool the obtained solid with acetone 1
Wash with 00ml of water, suspend in 1250ml of water, add 1
125 ml of 2N hydrochloric acid was added and extracted with 500 ml of chloroform. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain about 809 grams of crude 1-adamantanoic acid. This was reconsolidated from a methanol/water (3:1) solution, and 1-adamantanoic acid 68
I got a 9. When the melting point of the obtained 1-adamantanic acid was measured, it was 175-177°C, and the yield was 7501)
It is. (2) Method for producing 1-adamantanic acid chloride 1-adamantanic acid 1 obtained by the method in (1) above
50 ml of thionyl chloride was added to 8f1 with cooling, and the mixture was heated under reflux for 30 minutes, and then excess thionyl chloride was removed under reduced pressure.

Next, 30 ml of dry benzene was added twice to remove traces of thionyl chloride, and then 30 ml of anhydrous ether was added and distilled off.

As a result, 1-adamantanoic acid chloride 19.29 was obtained as a brownish white solid. The melting point of the product was 46-47°C.
The yield was about 92%. Reference Example 2 Production of N-cinnamoylbiperazine Anhydrous Viperazine 2069 was dissolved in 500ml of chloroform, and 66.39ml of cinnamoyl chloride was gradually added over 3 hours while stirring at 0°C.

After further stirring at room temperature for 2 hours, the generated precipitate was separated, and the chloroform layer was extracted with 50% sodium hydroxide solution.
After washing with 50 ml of water and 50 ml of water, the solvent was distilled off under reduced pressure, and the residue was subjected to silica column chromatography (developing solution: chloroform-methanol) to obtain crystals of N-cinnamoylbiperazine. The melting point of the product is 30~
It was hygroscopic at 40°C and the yield was 30%. Example 1 N-cinnamoylbiperazine 19 obtained in Reference Example 2 and triethylamine 0.479 were dissolved in 15 ml of tetrahydrofuran, and 15 ml of a tetrahydrofuran solution of 0.99 of 1-adamantanoic acid chloride obtained in Reference Example 1 was dissolved.
was dripped.

Furthermore, after stirring for 2 hours, the generated precipitate was separated. Next, the slurry was washed with 50 ml of 5(f) aqueous sodium hydroxide solution and 50 ml of water, and after drying, the solvent was distilled off under reduced pressure. The obtained solid was reconsolidated from methanol and N-
Pale yellow crystals of (1-adamantanecarbonyl)-N'-cinnamoylbiperazine were obtained. The melting point of the product is 220
℃, the yield was about 100 Cf). The analysis results of N-(1-adamantanecarbonyl)-N'-cinnamoylbiperazine are as follows. Note that FIG. 1 shows the mass spectrum of the compound, FIG. 2 shows the infrared absorption spectrum, and FIG. 3 shows the nuclear magnetic resonance spectrum. Analysis results of N-(1-adamantanecarbonino(c)-N'-cinnamoylbiperazine) (1) Elemental analysis value calculation value (C24H3ON2O2) Carbon 76.15 (I
) Hydrogen 7.99% Nitrogen 7.40% Actual value Carbon 74.9
(!I) Hydrogen 8.5#) Nitrogen 7.201) (2) Mass spectrometry results (3) Absorption range by infrared absorption spectrum (KBr tablet method) 4) Nuclear magnetic resonance (solvent: deuterium chloroform CD
Absorption region by C/3) 5) Structural formula From the above experimental results, it can be seen that the structural formula of the compound is as follows.

Winter example 3 1) Production method of 1-adamantyl methyl alcohol 500
159 lithium aluminum hydride was placed in 1 ml of dry ether and stirred, and 500 ml of 1-adamantanoic acid 54,09 (0.3 mol) obtained by the method in Reference Section 1) was added to the mixture. The solution in dry ether was added dropwise at a rate sufficient to maintain mild reflux (approximately 2.5 hours).

After the dropwise addition, the mixture was further refluxed for 2 hours, cooled to room temperature, and 75 ml of distilled water was carefully added thereto. followed by 300
ml of 5N monosulfuric acid and 500 d of ether were added.
Next, this ether layer was separated and the aqueous layer was further separated for 300 m
After extracting once with ether of 1, the ether layers were combined, washed successively with water, saturated aqueous sodium bicarbonate solution, water, and dried over anhydrous magnesium sulfate. When this ether layer was evaporated and the resulting solid was reconsolidated with methanol-water, 1-adamantylmethyl alcohol was
79 was obtained. The melting point of the obtained 1-adamantylmethyl alcohol was 114-116°C, and the yield was 94%.
It was hot. ). ) Preparation method of 1-adamantylmethylbromide 399 (0.17 mol) of zinc bromide and 29 of hydrobromic acid
．． After adding 11.59 (0.069 mol) of 1-adamantyl methyl alcohol obtained by the method (1) above to the solution containing 8 ml (about 479, 0.17 mol),
It was refluxed for 1 hour. After cooling to room temperature, add 200ml of water to this
ml and extracted twice with 300 ml of ether. 5
100 d of aqueous sodium bicarbonate solution of 01) and 10 d of water
After washing with 0ml, drying with anhydrous magnesium sulfate,
I passed a lot.

Then, the ether was distilled off under reduced pressure. The obtained solid was purified by recrystallization or sublimation (1 mmHg, 75 meC) with methanol, and 13 g of 1-adamantylmethylbromide was obtained. The melting point of the product is 37-39
The yield was 8401). (3) Manufacturing method of 1-adamantylmethyl chloride Using 1-adamantyl methyl alcohol obtained in the same manner as in Reference Example 3 (1), using zinc chloride instead of zinc bromide in Reference Example 3 (2). The chlorination reaction was carried out under the same conditions as the bromination reaction, except that hydrochloric acid was used instead of hydrobromic acid.

Tamashi purification was performed by methanol reconsolidation. The melting point of the obtained 1-adamantylmethyl chloride was 32 to 34°C, and the yield was 91 (Ff). Example 2 N-cinnamoylbiperazine obtained according to Reference Example 2 0.59 (0
．． 0023 mol), 1- obtained by Reference Example 3 (2)
Adamantylmethylbromide 0.529 (0.0023
mol) and anhydrous sodium carbonate 0.249 (0.00
(23 mol) in a 10 ml autoclave, the atmosphere was replaced with argon, and the reaction was carried out at 2000C for 24 hours.

After the temperature was returned to room temperature, 20 ml of chloroform was added for washing, and the chloroform was further distilled off under reduced pressure. The residue was subjected to silica column chromatography (developing solution: chloroform-methanol), and the obtained N-(1-adamantylmethyl)-N'-cinnamoylbiperazine was reconsolidated with ethanol. Furthermore, 29% of 1-adamantylmethylbromide was recovered. The melting point of the product is 123-125
℃, yield was 5101). Example 3 The same method as in Example 2 was carried out except that the same mole of 1-adamantylmethyl chloride obtained in Reference Example 3 (3) was used instead of 1-adamantylmethyl bromide in Example 2. But N1 (1-adamantylmethino(c)-
N'-cinnamoylbiperazine was obtained in a yield of 18(f).

In addition, as unreacted 1-adamantylmethyl chloride, 7
0% recovered. N-( obtained in Examples 2 and 3)
The analysis results of 1-adamantylmethyl)-N'-cinnamoylbiperazine are as follows.

Incidentally, FIG. 4 shows the mass spectrum of the compound, FIG. 5 shows the infrared absorption spectrum, and FIG. 6 shows the nuclear magnetic resonance spectrum.

Analysis results of N-(1-adamantylmethino(c)-N'-cinnamoylbiperazine (1) Calculated elemental analysis value (C24H32OlN2) Carbon 79.08#)
Hydrogen 8.85% Nitrogen 7.69% Actual value Carbon 79.3 (
f) Hydrogen 9.5 (!) Nitrogen 7.6 Cf) (2) Mass spectrometry results (3) Absorption range by infrared absorption spectrum (KBr tablet method) (4) Nuclear magnetic resonance (solvent: deuterium chloroform CD
Absorption region (5) Structural formula due to Cl3) From the above experimental results, it can be seen that the structural formula of the compound is as follows.

Reference Example 4 Production method of N-cinnamylbiperazine Anhydrous Viperazine 2179 (2.5 mol) was dissolved in isopropanol of 11, and 72.6 g (0.5 mol) of cinnamyl chloride was gently added dropwise while standing at room temperature. .

After dropping, the mixture was heated to 70° C. for 3 hours while stirring. After distilling off the solvent under reduced pressure, the reaction mixture was dissolved in 500 ml of chloroform and washed with an aqueous sodium hydroxide solution and water, respectively. After drying with potassium carbonate, a lot of chloroform was collected and chloroform was distilled off under reduced pressure. The resulting mixture was sublimated to remove biperazine, and the residue was further distilled to obtain N-cinnamylbiperazine. This material was crystallized and recrystallized from n-hexane. The boiling point of the product is 162-165℃ (4mmHg)
The melting point was 31-33°C, and the yield was 5601). Example 4 17 g of N-cinnamylbiperazine obtained in Reference Example 4 (
0.084 mol) and triethylamine 10.3f1 (
0.101 mol) was dissolved in 500 ml of tetrahydrofuran, and 200 ml of a tetrahydrofuran solution of 1-adamantanyl chloride 209 (0.101 mol) obtained by the method of Reference Example 1 was added dropwise while stirring at 0°C.

After stirring at room temperature for 2 hours, the precipitate was separated, and the resulting solution was diluted with 300% water.
m11501) After washing with 300 ml of an aqueous sodium hydroxide solution and 300 ml of water, drying, and filtration, the solvent was removed under reduced pressure. The obtained solid N-(1-adamantanecarbonyl)-N/-cinnamylbiperazine was reconsolidated with ethanol. The melting point of the product was 108-109°C, and the yield was 950/). The analysis results of N-(1-adamantanecarbonyl)-N'-cinnamylbiperazine are as follows.

Note that FIG. 7 shows the mass spectrum of the compound, FIG. 8 shows the infrared absorption spectrum, and FIG. 9 shows the nuclear magnetic resonance spectrum. Analysis results of N-(1-adamantanecarbonyl)-N'-cinnamylbiperazine (1) Calculated elemental analysis values Carbon 79.08% Hydrogen 8.85% Nitrogen (2)
Mass spectrometry results (3) Absorption range by infrared absorption spectrum (KBr tablet method) (4) Nuclear magnetic resonance (solvent: deuterated chloroform CDCl
3) Absorption region (5) Structural formula From the above experimental results, it can be seen that the structural formula of the compound is as follows.

(6) Melting point application example 1 N-(1-adamantanecarbonino(ha)-N-cinnamoylbiperazine 19 obtained in Example 1) was dissolved in 20 ml of tetrahydrofuran, and lithium aluminum hydride was added to the solution at 0°C. 0.249 of the powder was added slowly.

Next, the reaction was carried out under reflux for 4 hours, and then cooled to 0°C. Water was carefully added at 0° C., the organic layer was separated, and the solvent was distilled off under reduced pressure.

The residue was dissolved in chloroform, washed with water, dried, and then chloroform was distilled off under reduced pressure. When the residue was subjected to silica column chromatography (developing solution: chloroform-methanol), N-(1-adamantylmethyl)-N'-
Cinnamylbiperazine was obtained. The melting point of the product is 85
The temperature was 87° C. and the yield was 20(f). Application Example 2 2 g (0.00
5 mol) was dissolved in 20 ml of tetrahydrofuran, and 0.319 (0.008 mol) of lithium aluminum hydride powder was gradually added thereto while stirring at 0°C.

Next, the reaction was carried out under reflux for 3 hours, and then the temperature was raised to 0° C., 10 ml of water was added, and the organic layer was separated. After washing with water and drying, the solvent was distilled off under reduced pressure. The residue was subjected to silica column chromatography (developing solution: chloroform-methanol).
N-(1-adamantylmethino(
c) -N'-cinnamylbiperazine was reconsolidated with ethanol. The melting point of the product is 85-87 taC1 yield 40 (:
i) It was. Application example 3 0.99 (0.0
025 mol) was dissolved in 157 n1 of tetrahydrofuran, and 0.025 mol of lithium aluminum hydride powder was added to the solution at 0°C.
149 (0.0037 mol) was added.

Next, the reaction was carried out under reflux for 9 hours, then cooled to 0°C, and 10 d of water was gradually added thereto to form an organic layer! After separation and drying, the solvent was distilled off under reduced pressure. The residue was subjected to silica column chromatography (developing solution: chloroform-methanol (c)), and the obtained N-(1-adamantylmethino(c)-N1-cinnamylbiperazine) was reconsolidated with ethanol. The product had a melting point of 85-87°C and a yield of 55 (:f).
The analysis results and medicinal efficacy of -(1-adamantylmethyl)-N'-cinnamylbiperazine are shown below. In addition, Figure 10
11 shows the mass spectrum of the compound, FIG. 11 shows the infrared absorption spectrum, and FIG. 12 shows the nuclear magnetic resonance spectrum.

Analysis results of N-(1-adamantylmethyl)-N'-cinnamylbiperazine (1) Calculated elemental analysis value (C24H34N2) Carbon 82.2301) Hydrogen (2) Mass spectrometry results (3) Infrared absorption spectrum ( (4) Nuclear magnetic resonance (solvent: deuterated chloroform CDC')
3) Absorption region (5) Structural formula From the above experimental results, it can be seen that the structural formula of the compound is as follows.

(6) The medicinal efficacy of melting point N-(1-adamantylmethino-N'-cinnamylbiperazine) was investigated in comparison with cinnarizine (Cinnarizine), which is commercially available as a cerebral vasodilator.

The comparative pharmacology results are as follows.

(1) The LD5O values of acutely toxic mice measured by μp&Down method are as follows.

(2) Effect on contraction of isolated smooth muscle The extent to which the contraction effect of contractile substances such as adrenaline on isolated smooth muscle is suppressed by the administration of N-(1-adamantylmethyl)-N'-cinnamylpiperazine and cinnarizine was investigated. Examined.

The results are as follows. As a result of the experiment, the smooth muscle relaxing effect of N-(1-adamantylmethyl)-N'-cinnamylbiperazine was observed.

(3) Effect on blood flow The effect on cerebral blood flow and muscle blood flow was investigated using a cat weighing approximately 3k9.

As a result, N-(1-adamantylmethyl)-N'-cinnamylbiperazine 1 g/11 g clearly increased cerebral cortical blood flow, which was superior to the effect of cinnarizine 1 to 1/kg. On the other hand, N-(1-adamantylmethyl)-N'-cinnamylbiperazine also showed a clear increasing effect on muscle blood flow (gastrocnemius muscle blood flow and deep head muscle blood flow), which was stronger than the effect of cinnarizine. It was remarkable. (
4) Blood pressure lowering effect Cinnarizine already showed a clear decrease in blood pressure at 0.5~/kg, but N-(1-adamantylmethyl)-N'-cinnamylbiperazine lowered blood pressure at 5~/kg or more. It showed a descending effect for the first time.

Therefore, this substance is presumed to be safer than cinnarizine because it has a clearly weaker antihypertensive effect.

[Brief explanation of drawings]

Figure 1 shows N-(1-adamantanecarbonyl)-N'-
FIG. 2 shows the mass spectrum of cinnamoylbiperazine, FIG. 2 shows the infrared absorption spectrum of the compound, and FIG. 3 shows the nuclear magnetic resonance spectrum of the compound. Figure 4 shows N-(1-adamantylmethyl)-N'-
FIG. 5 shows the mass spectrum of cinnamoylbiperazine, FIG. 5 shows the infrared absorption spectrum of the compound, and FIG. 6 shows the nuclear magnetic resonance spectrum of the compound. Figure 7
shows the mass spectrum of N-(1-adamantanecarbonyl)-N'-cinnamylbiperazine, FIG. 8 shows the infrared absorption spectrum of the compound, and FIG. 9 shows the nuclear magnetic resonance spectrum. Furthermore, FIG. 10 shows N −(1−
11 shows the infrared absorption spectrum of the compound, and FIG. 12 shows the nuclear magnetic resonance spectrum of the compound (adamantylmethyl)-N'-cinnamylbiperazine.

Claims (1)

[Claims] 1 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (here, (
P) represents a methylene group or a carbonyl group. Moreover, X represents a halogen atom. ) and the compound shown by
Formulas▲There are mathematical formulas, chemical formulas, tables, etc.▼(Here, (Q)
represents a methylene group or a carbonyl group. ) A formula ▲ characterized by reacting a compound represented by
There are mathematical formulas, chemical formulas, tables, etc. (where (P) and (Q) are as defined above. However, at least one of (P) and (Q) is a carbonyl group.) A method for producing adamantane derivatives.