JPH0529355B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention is based on the general formula () This is an invention of a catechol derivative represented by [wherein R ₁ is the same as above]. The catechol derivative provided by the present invention and represented by the general formula () is a compound itself that has pharmacological activity and has applications in various agricultural medicines, particularly as an agent for preventing and treating the progression of central nervous system degenerative diseases and as an intermediate in the production thereof. It is useful for the body. [Prior Art] Conventionally, as related derivatives of the compound of general formula (), compounds in which R ₁ is a hydrogen atom [Recl.
Trav.Chim.Pays−Bas, 54 volumes, 995 pages (1935
)] and compounds in which R ₁ is a methyl group are known. However, except for the above-mentioned compounds, the compounds of the present invention and their closely related derivatives are completely unknown. Therefore, nothing is known about the usefulness of these compounds. [Problems to be solved by the present invention] We have discovered that the compound represented by the general formula (), which was previously unknown, has pharmacological activity and is useful as various agricultural medicines and intermediates for their production. As a result of intensive study, we have completed the present invention. [Means for Solving the Problems] The catechol derivative represented by the general formula () in the present invention can be produced by the method shown below. (a) When R ₁ is a methyl group (1) Homocatechol and acetone in the absence of a solvent or in the presence of an inert organic solvent (alicyclic solvents such as cyclopentane and cyclohexane, xylene, toluene, benzene, and chlorobenzene) , aromatic solvents such as nitrobenzene, etc.), acid catalysts (mineral acids such as sulfuric acid, phosphoric acid, hydrohalic acid, anhydrous aluminum chloride, zinc chloride, iron chloride, titanium tetrachloride, tin tetrachloride, Lewis catalysts such as BF ₃ , etc.) Acids, organic sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid, and laurylsulfonic acid, organotin compounds such as dibutyltin oxide, dibutyltin dilaurate, and dimethyltin dichloride, metal alkoxides such as titanium isopropoxide, and cation exchange. A method of reacting in the presence of resins, etc.) while removing secondary water. (2) Homocatechol and 2,2-dihalogenopropane (2,2-dichloropropane, 2,2-
dibromopropane, etc.) in an inert organic solvent (alcoholic solvents such as ethanol, propanol, butanol, dimethylformamide, dimethyl sulfoxide, etc.) and a base (alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, hydroxide, etc.). Alkaline earth metal hydroxides such as magnesium and calcium hydroxide, sodium carbonate, sodium hydrogen carbonate,
Alkali metal oxides such as potassium carbonate and potassium hydrogen carbonate, alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate, alkaline earth metal oxides such as magnesium oxide and calcium oxide, tertiary amines such as triethylamine and pyridine. etc.). (b) When R ₁ is other than methyl group (1) General formula () [In the formula, n is 1 to 2, R ₂ is a hydrogen atom or a C ₁ to C ₄ alkyl group, and R ₃ is a hydrogen atom or a C ₁ to C ₃ alkyl group]. By hydrogenating using as a catalyst, the general formula () [where n,
R ₂ and R ₃ are the same as above] A compound represented by is obtained, and this is mixed with hydroiodic acid, hydrobromic acid, hydrobromic acid, etc. in a solvent such as acetic acid or acetic anhydride.
Heat treatment with hydrochloric acid etc. and dealkylation yields 4-alkylcatechols. The compound of the present invention represented by the general formula () is obtained by various methods shown in (a). (2) Veratrols and fatty acid anhydrides and fatty acid halides (fatty acid chloride, fatty acid bromide, etc.) in the presence of iodine, anhydrous aluminum chloride, zinc chloride, iron chloride, titanium tetrachloride, tin tetrachloride, BF ₃ , etc. React with the corresponding 4-acylveratrols () [In the formula, R ₄ is a C ₁ - _{C 5} alkyl group, R ₃ is the same as above], and this is converted into LiAlH ₄ , NaBH ₄ ,
4-Alkylberatores () corresponding to methods such as hydrogen reduction and dehydration in the presence of metal catalysts such as Pd/C and Raney nickel, or Clemmensen reduction and Wolfxyuner reduction, etc. [wherein R ₁ and R ₃ are the same as above] is obtained. This is dealkylated by heat treatment with hydroiodic acid, hydrobromic acid, hydrochloric acid, etc. in a solvent such as acetic acid or acetic anhydride to obtain 4-alkylcatechols. The compound of the present invention represented by the general formula () is obtained by various methods shown in (a). (3) Catechol and fatty acid anhydride or fatty acid halide (fatty acid chloride, fatty acid bromide, etc.) in the presence of a Lewis acid such as anhydrous aluminum chloride, zinc chloride, iron chloride, titanium tetrachloride, tin tetrachloride, BF ₃ , etc. react,
The corresponding 4-acylcatechol () is obtained, and this is reduced by the method shown in (2) to obtain the corresponding 4-alkylcatechol (). The compound of the present invention represented by the general formula () is obtained by various methods shown in (a). By the above method, the compound of the present invention represented by the general formula () can be easily obtained. [Function] The compound represented by the general formula () in the present invention is
The present invention is useful as a variety of pharmacologically active agricultural and pharmaceutical drugs themselves and intermediates for their production, particularly as agents for preventing and treating central nervous system degenerative diseases. The present invention will be specifically explained below with reference to Examples, but it is not limited thereto. Reference Example 1 Production of 5,2,2-trimethyl-1,3-benzodioxole Homocatechol (reagent special grade commercial product) 6.21 g (50
A mixture of 15 ml of acetone, 30 mg of p-toluenesulfonic acid hydrate, and 15 ml of benzene was heated and stirred under reflux for 48 hours. At this time, only the by-product water was removed by passing the ternary azeotropic mixture of acetone, benzene, and by-product water through a tower packed with molecular sieves, and the mixture of acetone and benzene was returned to the reaction system. By distilling this under reduced pressure, 5,
2,2-trimethyl-1,3-benzoxole
7.88g (48mM) was obtained as a light brown liquid with a bp of 79-80°C/9mmHg. IR spectrum ν ^neat _nax cm ^-1 2990, 2920, 2870, 1500, 1440, 1380, 1350 1255, 1230, 1155, 1120, 1070, 1040, 980 930, 880, 840, 825, 795, 745 NMR spectrum (CDCl ₃ ) δ: 1.68 (6H, s), 2.27 (3H, s), 6.60 (3H) Elemental analysis value (%) C H Calculated value [C ₁₀ H ₁₂ O ₂ ]: 73.15 7.37 Actual value: 72.87 7.13 Example 1 Production of 5-ethyl-2,2-dimethyl-1,3-benzoxole 4-ethylcatechol 6.91g (50mM), 90%
NaOH4.43g (105mM) and 1-butanol
In a 200ml mixture, heat and stir at an internal temperature of 70℃, 2.
6.55 g (55 mM) of 2-dichloropropane was added dropwise over 2 hours. After aging at this temperature for 1 hour,
The mixture was further heated and stirred under reflux for 3 hours. generated
After filtering and washing NaCl, 5-ethyl-2,2-dimethyl-1,3-benzoxole was removed by distillation under reduced pressure to remove 1-butanol.
5.08g (29mM) was obtained as a light brown liquid with a bp of 103-105°C/12mmHg. The starting material 4-ethylcatechol is
3,4-dimethoxystyrene in methanol
4 by hydrogenation using Pd/C catalyst.
-Ethylveratrol was derived and further demethylated with acetic acid and hydrogen bromide. IR spectrum ν ^neat _nax cm ^-1 3030, 2985, 2960, 2935, 2880, 1500, 1450,
1385, 138, 1365, 1320, 1275, 1260, 1230,
1160, 1120, 1060, 980, 920, 835, 805, 785 NMR spectrum ( _CDCl3 ) δ: 1.20 (3H, t), 1.69 (6H, s), 2.58 (2H,
q) Elemental analysis value (%) C H Calculated value [C ₁₁ H ₁₄ O ₂ ]: 74.13 7.92 Actual value: 73.89 7.86 Example 2 5-n-propyl-2,2-dimethyl-1,3
- Production of benzodioxole 4-n-propylcatechol 7.61g (50mM),
15 ml of acetone, p-toluenesulfonic acid monohydrate
Reference example 1 using a mixture of 30 mg and 15 ml of benzene
The reaction was carried out in the same manner as described above to obtain 9.13 g (47 mM) of 5-n-propyl-2,2-dimethyl-1,3-benzoxole as a colorless transparent liquid with a bp of 82-87°C/3 mmHg. In addition, 4-n-propylcatechol used as a starting material was reduced from 1,2-dimethoxy-4-n-propynylbenzene in the presence of methanol to lead to 4-n-propylveratrol, which was then treated with acetic acid. The one obtained by demethylation with hydrogen bromide was used. IR spectrum ν ^neat _nax cm ^-1 3060, 3015, 2970, 2940, 2920, 2860, 1600,
1490, 1440, 1370, 1330, 1260, 1245, 1220,
1210, 1145, 1115, 1070, 975, 925, 860, 825,
795, 780, 755 NMR spectrum (CDCl ₃ ) δ: 0.92 (3H, t), 1.65 (6H, s) 1.57 (2H,
sex) 2.48 (2H, t), 6.38-6.72 (3H) Elemental analysis value (%) C H Calculated value [C ₁₂ H ₁₆ O ₂ ]: 74.97 8.39 Actual value: 74.81 8.43 Example 3 5-n-butyl- 2,2-dimethyl-1,3-
Production of benzodioxole 4-n-butylcatechol 4.16g (25mM),
15 ml of acetone, p-toluenesulfonic acid monohydrate
Using a mixture of 30 mg and 7 ml of benzene, 5-n-butyl-2,
2-dimethyl-1,3-benzodioxole 4.74
g (23mM) was obtained as a colorless transparent medium with a bp of 74-78°C/1 mmHg. Note that 4-n-butylcatechol can be obtained by reacting veratrol with anhydrous n-butyric acid in the presence of iodine to obtain 4-n-butylcatechol, which is then reduced in diethylene glycol using hydrazine hydrate and caustic potassium. The product obtained by demethylating 4-n-butylveratrol with acetic acid and hydrogen bromide was used. IR spectrum ν ^neat _nax cm ^-1 3060, 3010, 2975, 2940, 2920, 2860, 2845,
1600, 1495, 1440, 1380, 1370, 1265, 1250,
1225, 1210, 1150, 1115, 1075, 975, 935, 830,
795, 780, 760, 745 NMR spectrum ( _CDCl3 ) δ: 0.92 (3H, t), 1.08-1.80 (4H, m), 1.64
(6H, s), 2.50 (2H, t), 6.4-6.68 (3H) Elemental analysis value (%) C H Calculated value [C ₁₃ H ₁₈ O ₂ ]: 75.69 8.80 Actual value: 75.42 9.05 Example 4 5- Isobutyl-2,2-dimethyl-1,3-
Production of benzodioxole 4-isobutylcatechol 4.16g (25mM),
15 ml of acetone, p-toluenesulfonic acid monohydrate
5-isobutyl-2,
2-dimethyl-1,3-benzodioxole 4.69
g (23mM) was obtained as a colorless transparent liquid with a bp of 79-83°C/2mmHg. The starting material in this case, 4-isobutylcatechol, was obtained by using isobutyric anhydride instead of n-butyric anhydride used to obtain the starting material in Example 3. IR spectrum ν ^neat _nax cm ^-1 3060, 3025, 2980, 2950, 2920, 2870, 2845,
1605, 1495, 1465, 1450, 1440, 1380, 1375,
1365, 1330, 1285, 1270, 1255, 1235, 1220,
1165, 1155, 1120, 1085, 1070, 980, 930, 920,
875, 860, 840, 795, 765 NMR spectrum ( _CDCl3 ) δ: 0.85 (6H, d), 1.4-2.0 (1H, m), 1.65
(6H, s), 2.37 (2H, d), 6.3-6.7 (3H) Elemental analysis value (%) C H Calculated value [C ₁₃ H ₁₈ O ₂ ]: 75.69 8.80 Actual value: 75.46 9.04

[Claims]

1 formula: [In the formula, R is the following formula:

[Formula] (R ₁ is hydrogen, C ₁ - _{C 4} alkoxycarbonyl, C _1
-C4 alkylcarbonyl, _C1 - _C4 alkylsulfonyl, _C1 - _C4 alkylaminocarbonyl); _R2 is hydrogen or is an ester-forming group that is hydrolyzable in vivo or a pharmaceutically acceptable compound.