JPS5917097B2 - Method for producing tropolone derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing tropolone derivatives.

The tropolone derivative obtained according to the present invention has the general formula [wherein R1 represents an alkyl group having 1 to 4 carbon atoms and R3 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, respectively].

] It is itself useful as an antibacterial agent, a hair growth promoter, a treatment for alveolar pyorrhea, etc., and is also useful as an intermediate for the synthesis of hinokitiol. The compound in which R1 is a methyl group and R3 is a hydrogen atom in the derivative represented by the general formula (1) is perparogallin carboxylic acid (Pur) obtained by oxidation of a mixture of pyrogallol and gallic acid.
purOgalln-CarbOxylicaCid
、． It is known that it can be obtained by using Cl2H8C7, ) as a starting material, oxidizing it with hydrogen peroxide to give α-mega-carboxyl-β-carboxylmethyltropolone, and then subjecting the compound to a decarboxylation reaction. [JournalOftheChemical
SOciety (1951) Pl325-1327].

However, this reported method is limited to a method for producing tropolone derivatives in which R1 is a methyl group on a laboratory scale, and furthermore, the compound itself as a starting material is difficult to obtain. The present invention provides a new method that can easily produce a series of tropolone derivatives represented by the general formula (1) in large quantities in place of the above-mentioned method. R1 and R2 are the same or different and represent an alkyl group having 1 to 4 carbon atoms.

] is reacted with methyl iodide to form a compound represented by the general formula [where R1 and R2 are the same as above].

] is obtained, and then this compound is decomposed using a basic compound to obtain a quaternary salt derivative represented by the general formula
is the same as above.

[In the formula, R1 is the same as above.

R3 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
] The present invention relates to a method for producing a tropolone derivative represented by:

In the above general formula (1) representing the tropolone derivative obtained by the present invention, the number of carbon atoms represented by R1 and R3 is 1
Specific examples of the alkyl groups of -4 include methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl groups. Further, as representative compounds included in the above general formula (1), the following can be exemplified. 〇Methyl 6-isopropyltropolone-4-carboxylate)
06-isopropyltropolone-4-carboxylic acid 06-
Butyl isopropyltropolone-4-carboxylate 06-
Ethyltropolone-4-carboxylic acid isopropylene.

6-ethyltropolone-4-carboxylic acid 〇6-Butyltropolone-4-carboxylic acid.

Ethyl 6-tert-butyltropolone-4-carboxylate The method of the present invention will be described in detail below with reference to a reaction scheme.

Reaction Scheme-1 [In each formula, R1 and R2 are the same as above.

] In the above reaction scheme-1, the reaction between the compound of general formula (2) and methyl iodide can be carried out without a solvent or in a conventional inert solvent, such as lower alcohols such as methanol and ethanol, ether, dioxane, Ethers such as tetrahydrofuran (THF), ketones such as acetone and methyl ethyl ketone, esters such as ethyl acetate, aromatic hydrocarbons such as benzene and toluene, methylene chloride,
Chloroform etc...number of rogenated hydrocarbons, dimethyl sulfoxide (DMSO), dimethylformamide (DM
The reaction is carried out in a solvent such as F) at usually room temperature to 100°C, preferably room temperature to 50°C, for several hours to three days.

The amount of methyl iodide used in the reaction is:
It is appropriately selected within a wide range without particular limitation, but usually when the compound of general formula (2) is reacted without a solvent, the reaction is carried out in large excess in the presence of a solvent. In this case, the amount may be equimolar to 10 times the molar amount, preferably equimolar to 4 times the molar amount. The decomposition reaction using a basic compound of the quaternary salt derivative of general formula (3) thus obtained can be carried out using a conventional inert solvent such as water, lower alcohols such as methanol or ethanol, ethers such as dioxane or THF, or DM.
S.O. It can be carried out in a solvent such as a D dish.

Examples of basic compounds include alkali metal carbonates such as sodium carbonate potassium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate; alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide; Examples include silver hydroxide.

The amount to be used is appropriately selected from a wide range without particular limitation, but it is usually an equimolar to excess amount, preferably an equimolar to twice the molar amount of the compound of general formula (3). The above decomposition reaction is usually carried out at room temperature to 50°C, preferably at room temperature for several hours to about 8 hours.
) can be obtained. The hydrolysis reaction of the tropone derivative (4) obtained above is carried out by a conventional method. For example, according to a method using an acid, the compound of general formula (1-a) is produced as shown in the reaction scheme-1 above. The obtained compound (1-a) is further hydrolyzed in the presence of a basic compound to obtain the compound (1-b)
It can be a compound of

The hydrolysis reaction using the above acid can be carried out using water or lower alcohols such as methanol and ethanol containing water, dioxane,
In a mixed solvent such as ethers such as T', DMSO, m', etc.
It is usually carried out at 40 to 100°C, preferably 50 to 70°C, for about 1 to 6 hours.

As the acid used in the above reaction, known ones,
Specifically, inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid and trichloroacetic acid can be used. The amount of the acid to be used is not particularly limited and can be appropriately selected within a wide range, but it is usually sufficient to use an excess amount relative to the compound of general formula (4). The hydrolysis reaction of the compound of general formula (1-a) thus obtained in the presence of a basic compound can be carried out using water, lower alcohols such as methanol and ethanol, the above-mentioned ethers, DIV
In a mixed solvent of water and a solvent such as ISO, DMF, usually 40
1 hour at ~150°C, preferably 50-100°C ~10
It takes about time to complete.

Basic compounds used in this reaction include known ones, such as alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, sodium carbonate, potassium carbonate, and sodium hydrogen carbonate. Alkali metal carbonates such as can be widely used.
The amount of the basic compound to be used is not particularly limited and is appropriately selected within a wide range, but it is usually sufficient to use a large excess amount relative to the compound of general formula (1-a). The compound of general formula (1-b) can also be produced by hydrolyzing the compound of general formula (4) under appropriate reaction conditions in the presence of an acid catalyst.

In the method of the present invention shown in Reaction Scheme-1 above, the compound of general formula (2) used as a starting material is a new compound, and is produced, for example, by the method shown in Reaction Scheme-2 below.

Reaction formula-2 [In each formula, R1 and R2 are the same as above.

] That is, the general formula (7) obtained by reacting the Grignard reagent represented by the general formula (6) with the known 5-methoxy-1-methyl-1-6-dihythro-3(2) pyridone (5)
) is aromatized using a peroxide compound to obtain a betaine derivative represented by general formula (8), and then an acrylate represented by general formula (9) is added to the betaine derivative (8). A compound represented by the general formula (2) is produced by an addition reaction.

More specifically, the reaction between compound (5) and compound (6) is
It is carried out under normal Grignard reaction conditions.

The reaction is usually carried out in a conventional inert solvent such as ethers such as ether, dioxane and THF, and saturated hydrocarbons such as n-hexane and cyclohexane at a temperature of 0 to 80°C.
, preferably at room temperature to 50° C. for about 30 minutes to several hours. The mixing ratio of compound (5) and compound (6) may generally be from equimolar to 1.5 times the molar ratio of the latter to the former. The reaction between compound (7) and the peroxide compound can be carried out using a commonly used inert solvent, such as chloroform, methylene chloride, halogenated hydrocarbons such as 1,2-dichloroethane, aromatic hydrocarbons such as benzene, n-hexane, etc. , in a saturated hydrocarbon solvent such as cyclohexane, usually from 0 to
It may be carried out at 50°C, preferably at room temperature, for about 10 minutes to several hours.

Examples of the peroxide compound used in the reaction include known ones, such as m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, pertrifluoroacetic acid, etc., preferably m-chloroperbenzoic acid. can. The amount of the peroxide compound to be used is not particularly limited and may be appropriately selected from a wide range, but it may be from equimolar to 1.5 times the molar amount of the compound of general formula (4). The addition reaction between compound (8) obtained above and compound (9) can be carried out using a commonly used inert solvent, such as lower alcohols such as methanol and ethanol, ether, THF. Ethers such as dioxane, aromatic hydrocarbons such as benzene and toluene, hydrocarbons such as methylene chloride, chloroform, and 1,2-dichloroethane, ketones such as acetone and methyl ethyl ketone, and esters such as ethyl acetate. Class, DMSO, . In a solvent such as DMF or hexamethylphosphoric acid triamide (HMPA), usually at 40 to 150°C, preferably at 50 to 100°C, for several hours to
It is enough if you can do it for about 15 hours.

In this reaction, the blending ratio of compound (8) and compound (9) is not particularly limited and is appropriately selected within a wide range, but usually the latter is from 1 to 5 times the former by mole, preferably from 1 to 5 times the mole of the former. It is sufficient to use 1.5 times the molar amount.a The compounds obtained by each reaction shown in the above reaction schemes -1 and -2 can be isolated from the reaction mixture according to a conventional method after the reaction is completed.

This is carried out, for example, by distilling off the solvent from the reaction mixture. Further, each of the obtained compounds can be further purified, if necessary, using commonly used methods such as recrystallization, column chromatography, preparative thin layer chromatography, solvent extraction, and precipitation. Tropolone derivative (1) obtained according to the present invention can easily form a salt with a pharmacologically acceptable basic compound.

As such a basic compound, a wide variety of commonly used basic compounds can be used, and specifically, hydroxides of alkali metals or alkaline earth metals such as potassium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, etc. ,
Inorganic basic compounds such as alkali metal carbonates such as potassium carbonate and potassium hydrogen carbonate, N-ethylamine, N-N
Examples include organic basic compounds such as -dimethylamine, piperazine, piperidine, and morpholine. Moreover, the tropolone derivative (1-b) obtained by the present invention can be induced to hinokitiol (10) by the method shown in the following reaction scheme-3.

Reaction formula-3 [In the formula, R1 is the same as above.

] For this decarboxylation reaction, a wide range of conditions can be applied to ordinary decarboxylation reactions of aromatic carboxylic acids.

For example, in the presence of a conventional decarboxylation catalyst such as copper powder or copper chromite, in a conventional inert solvent with a boiling point of 200°C or higher, such as quinoline, the temperature is usually 200 to 300°C, preferably 200 to 250°C. The reaction may be carried out at a temperature of about several hours to about 10 hours. Reference Examples and Examples are given below to further explain the present invention, but the present invention is not limited thereto.

Reference example 1 Synthesis of sarcosine ethyl ester hydrochloride Narcosine (1007) water ethanol (500ml
) solution was refluxed with thionyl chloride (100 m
) was added dropwise in 30 minutes.

The mixture was further stirred and refluxed for 5 hours, and after standing overnight, the solvent was distilled off under reduced pressure to obtain sarcosine ethyl ester hydrochloride as colorless crystals. This is recrystallized from acetone. Reference Example Synthesis of 2N-acetonyl sacosine ethyl ester A solution of sarcosine ethyl ester hydrochloride (75y) and sodium bicarbonate (557 in aqueous tetrahydrofuran (tetrahydrofuran:water - 350ml:20ml))
While stirring at ~60°C, chloroacetone (60y) was added dropwise over 1 hour.

The mixture was further stirred at 50 to 55°C for 3 hours, and after being left overnight, the precipitated salt (NaCl) was removed and the solvent was distilled off under reduced pressure. The residue is distilled off under reduced pressure to obtain N-acetonylsarcosine ethyl ester. Reference Example 3 Synthesis of 1-methylpiperidine-3,5-dione Anhydrous t-
Potassium (10.1
7) was completely dissolved, anhydrous ether (350 mO) was added, and N-acetonylsarcosine ethyl ester (387) was added dropwise over 1 hour at 0°C while stirring.

The mixture was stirred for 1 hour under ice cooling, and further stirred at room temperature for 10 hours.

After completely distilling off the solvent under reduced pressure, ether (50 m
Add e), crush well with a glass rod, and collect the precipitate.
This precipitate was quickly poured into glacial acetic acid (30 ml), and the precipitated crystals were recrystallized from methanol and water to obtain 1-methylpiperidine-3,5-dione. Reference example 4 5-methoxy-1-methyl-1,6-dihythro 3(2
H)-Synthesis of pyridone 1-methylpiperidine-3.5-
To a solution of dione (117) in anhydrous methanol (150Tn0) was added sulfuric acid (2 ml) under ice cooling and refluxed for 10 hours.

After making the mixture alkaline by adding aqueous ammonia, the precipitated salts are removed, and methanol is distilled off under reduced pressure. Chloroform (30
The extract was extracted with m1×6), washed with saturated brine, and dried with MgSO4. The crude crystals obtained by distilling off the solvent under reduced pressure were recrystallized from n-hexane to synthesize colorless needle-like crystals of 55-isopropyl-1-methyl-1,6-dihydro-3(2H)-pyridone isopropylmagnesium bromide ( Isopropylbromide 1,977 and magnesium 0.39f
) was added dropwise to a solution of 5-methoxy-1-methyl-1,6-dihythro-3(2H)-pyridone (2,37) in anhydrous ether (500 ml) under a nitrogen atmosphere, and the mixture was stirred for 1 hour. Stir under reflux.

The reaction solution was poured into ice water, made acidic with 10% hydrochloric acid, and stirred for 30 minutes. After making alkaline with aqueous ammonia, extract with chloroform. After washing with saturated brine and drying with MgSO4, the solvent was distilled off under reduced pressure to obtain 5-isopropyl-1
-Methyl-1,6-dihydro-3(2H)-pyridone is obtained as an oil. Since this product is unstable at room temperature, it is used in the next reaction without purification. UV (ethanol): 2
Maximum absorption was observed at 28 nm.

The picrate salt of the compound obtained (recrystallized from ethanol) exhibits a melting point of 143-145°C.

Reference example Synthesis of 65-isopropyl-1-methyl-3-oxidepyridinium 5-isopropyl-1-methyl-
1,6-dihythro-3(2H)-pyridone (1.627
m-chloroperbenzoic acid (1.907) was added little by little to a solution of ) in methylene chloride (20 ml) while stirring under ice cooling.

After stirring at room temperature for 20 minutes, the solvent was distilled off under reduced pressure and the residue was purified using ion exchange resin 1RA-4 using methanol as a solvent.
Multiply by 10.

When the solvent was distilled off, 5-isopropyl-1-methyl-3
-Pyridinium oxide is obtained in syrup form. Since this product is unstable in air, it is immediately subjected to the next reaction. Yield 1.62yNMR (DMSO-D6): δ1.15[d, 6H, CH(
CH3) 2, J = 7Hz] 2.55 to 3.02 [m
) IH, CH(CH3)2, J= 7Hz] 3.98
[s, 3H, NCH3] 6.88 [Bs, IH, H-
4] 7.27 [m) IH) H-2] 7.33 [s)
IH,. H-6] Nail (ethanol): 224, 25
Maximum absorption was observed at 6,332 nm.

Reference example 7 4-isopropyl-8-methyl-8-asabicyclo[3
・2.1] Synthesis of methyl octan-3-en-2-one-6-exo-carboxylate Add methyl acrylate to a solution of 5-isopropyl-1-methyl-3-oxidepyridinium (1.62V) in tetrahydrofuran (30ml). (1.13V) and reflux for 7 hours.

The solvent is distilled off and the residue is applied to an alumina column using methylene chloride as a solvent to obtain a viscous oil.
Yield 1.94VN MR (CDCl3): δ1.17 [d, 6H, CH (
CH3)2, J-7Hz] 1.70-2.15
[m, IH, H-7 ego 2.38 [s.3H,. N
CH3] 2.50 to 2.95 [m, 3H, -7 E
ndO,. H-6end0,. qU(CH3)2]3.
51 [same, IH, H-1, J-6Hz] 3.98. s)
IH,. H-5] 5.79 [Bs) IH,. H-
3] IJV (ethanol): maximum absorption was observed at 233 nm.

Example 1 (1) 4-isopropyl-8-8-dimethyl-8-azoniabicyclo[3.2.1]octane-3
Synthesis of -en-2-one-6-exo-carboxylic acid methyl iodide 4-isopropyl-8-methyl-
Methyl 8-azabicyclo[3.2.1]octan-3-en-2-one-6-oxocarboxylate (1.9
Add methyl iodide (4V) to a solution of ethyl acetate (5ml)
3.63V) and left at room temperature for 3 days, the title compound is obtained in a yield of 76% (2.35V).

M. p. 165-167℃ (recrystallized from methanol) (
2) Synthesis of methyl 2-(N-N-dimethylamino)-6-isopropyltropone-4-carboxylate 0.1
Quaternary salt 4-isopropyl-8, 8-dimethyl-8 in 6N sodium bicarbonate solution (25 ml)
-azoniabicyclo[3.2.1]octan-3-en-2-one-6-exo-carboxylic acid methyl iodide (1.0 IV) is dissolved and stirred at room temperature for 5 hours.

The reaction solution was extracted with chloroform, dried over MgSO4, and the solvent was distilled off to obtain dimethylaminotropone as a yellow viscous oil. B. p. l7O~180℃ (0.
3mmHg) Yield 508W1f7NMR (CDCl3
): δ1.25 [d, 6H, CH(CH3)2, J
= 7Hz] 2.80 [m, IH, . CH (CH3)
2, J = 7Hz] 3.11 [s) 6H, N(CH3
)2] 3.91 [s, 3H, 0CH3] 6.90 [B
s, IH, 7-H] 7.12 [BsJH, H-3] 7
．． 38 [Bs, IH, H-5] (3) Synthesis of methyl 6-isopropyltropolone-4-carboxylate 2 -(
5% of methyl N-N-dimethylamino)-6-isopropyltropone-4-carboxylate (227~)
Heat the HCI (6 ml) solution at 60-70<0>C for 2 hours.

After cooling, the precipitated crystals are collected and recrystallized from methanol-water to obtain methyl 6-isopropyltropolone-4-carboxylate. Yield 199Tf19m. p. 82-83℃ Elemental analysis value Calculated value (%) as C, 2H, 4O4 C: 64.85H: 6.35 Actual value (%)
) C:64.69H:6.30 Example Synthesis of 26-isopropyltropolone-4-carboxylic acid Methyl 6-isopropyltropolone-4-carboxylate (10
0~) IN-KOH (10ml) solution at 60~70℃
After heating for 6 hours and acidifying the reaction solution with concentrated hydrochloric acid, the precipitated crystals are collected and recrystallized from acetone to obtain 6-isopropyltropolone-4-carboxylic acid.

Reference example 8 Synthesis of hinokitiol 6-isopropyltropolone-4-carboxylic acid (70η
) and copper chromite (140 my) in quinone (10 w) solution are heated at 225-230°C for 3 hours.

After removing the solvent, the residue was poured into water, extracted with chloroform, washed with 10% hydrochloric acid and saturated brine, and dried over MgSO4. After distilling off the solvent, the residue is extracted from n-hexane and the solvent is removed to obtain hinokitiol. Yield 25w

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 and R_2 are the same or different and have a carbon number of 1
~4 alkyl group is shown. ] By reacting the compound represented by methyl iodide, the general formula ▲ has mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 and R_2 are the same as above. ] A quaternary salt derivative represented by is obtained, and then the compound is decomposed using a basic compound to obtain the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 and R_2 are the same as above. ] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 is the same as above. R_3 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. ] A method for producing a tropolone derivative.