KR800000905B1 - Process for preparing 2-substituted-5-alkyl resorcinols - Google Patents

Abstract

The title compds. (I; R1=H, lower alkanoyl; R2=C1-20 straight or side chain alkyl; X=nitrogen or C-methyl), useful as analgesics, were prepd. by reaction of liquid ammonia and isopropenyl derivs. (IV) obtained from dehydration of diacetyl deriv. with thionyl chloride. Diacetyl deriv. was prepared by reaction of anhydrous acetic acid and alcohol(III) obtained from benzopyranone(II) and methyl magnesium bromide in tetrahydrofuran.

Description

[Name of invention]

Method for preparing 2-substituted-5-alkyl resorcinol

Detailed description of the invention

The present invention relates to a process for the preparation of 2-substituted-5-alkyl resorcinols of the following structural formulas useful as analgesics, mental stabilizers, soothing hypnotics and antispasmodics.

In the above structural formula

R ₂ is hydrogen or lower alkanoyl

R ₁ is straight or branched chain alkyl of 1 to 20 carbon atoms

X is nitrogen or C-methyl.

As used herein, "lower alkanoyl" has 2 to 6 carbon atoms in the side chain or linear, saturated monovalent aliphatic groups derived from monocarboxylic acids. Examples include, but are not limited to, acetyl, propionyl, α-methylpropionyl, butyryl, hexanoyl, and the like.

As used herein, “alkyl” refers to a branched or straight chain saturated monovalent aliphatic group having 1 to 20 carbon atoms, for example methyl, n-amyl, n-hexyl, 2-heptyl, n-heptyl, 3-methyl 2-octyl, n-octyl, 2-nonyl, 2-tetradecyl, n-hexadecyl, 2-iconsnilyl and the like.

Resorgar of the present invention is prepared according to the following reaction scheme.

Reaction of benzopyranone (I) with methylmagnesium bromide in tetrahydrofuran yields alcohol (II). When this alcohol (II) is reacted with acetic anhydride in pyridine to give a diacetyl derivative, it is dehydrated with thionylchloride in -10 to 0 ° C. in pyridine to give isopropenyl derivative (III). Treatment of compound (III) with liquid ammonia in a room temperature, high pressure cylinder yields resorcinar (IV). Hydrogenation of isopropenyl derivative (III) with 5% palladium / carbon in ethyl acetate yields isopropyl derivative (V), which is treated with liquid ammonia at room temperature and under high pressure cylinder to deacetylated derivative (VI). Is obtained.

Compounds of the present invention prepared by the above reaction scheme include the following compounds.

(VII) 1,3-diacetyl-2- [4-isopropenyl-3-pyridyl] -5-3-methyl-2-octyl) resorcinol

(VIII) 2- [4-isopropenyl-3-pyridyl] -5- (3-methyl-2-octyl) resorcinol

(IX) 1,3-diacetyl-2- [4-isopropyl-3-pyridyl] -5- (3-methyl-2-octyl) resorcinol

(X) 2- [4-isopropyl-3-pyridyl] -5- (3-methyl-2-octyl) resorcinol

(XI) 1,3-diacetyl-2-[(2-isopropenyl-5-methyl) phenyl] -5- (3-methyl-2-octyl) resorcinol

(XII) 2-[(2-isopropyl-5-methyl) phenyl] -5- (3-methyl-2-octyl) resorcinol

The compounds of the present invention are used in analgesics, mental stabilizers, soothing-hypnotics and antispasmodics. This compound is generally effective at a dose of 1 to 10 mg / kg per day. Analgesia was tested in standard mouse warpage [Whittle, Brit. J. Pharmacol, 22, 296 (1964)] and hotplate testing [Woolfe, G and McDonald, A.J., J. Pharmacol. Exper. Therap. 80, 300 (1944)] and rat tail impulse test.

The following examples further illustrate the present invention.

Example 1

[10-hydroxy-8- (3-methyl-2-octyl) -5-oxo-5H- [1] benzopyrano [4,3-c] pyridine]

3.42 g of 2-benzyl-10-hydroxy-8- (3-methyl-2-octyl) -5-oxo-1,2,3,4-tetrahydro-5H- [1] benzopyrano [4, 3-c] A mixture of pyridine, 10 g 10% palladium / carbon and 120 ml xylene is refluxed with stirring for 23 h. The mixture is filtered, the catalyst is removed and the filtrate is evaporated to dryness in vacuo. Recrystallization of this residue with acetonitrile gives a pure product. Melting point 122-123 °

Analysis: C ₂₁ H ₂₅ NO ₃

Calculated: C, 74.31; H, 7.42; N, 4.13

Found: C, 74.08; H, 7.36; N, 3.98

Example 2

[2- {4-[(1-hydroxy-1-methyl) ethyl] -3-pyridyl} -5- (3-methyl-2-octyl) resorcinol]

16.97 g (0.05 mole) of 10-hydroxy-8- (3-methyl-2-octyl) -5-oxo-5H- [1] benzopyrano [4,3-c] pyridine into 125 ml tetrahydrofuran The dissolved solution is slowly refluxed by dissolving 3M methyl magnesium bromide in 125 ml of ether and 125 ml of tetrahydrofuran in small portions to the stirred solution. After the addition, the reaction mixture is heated at reflux for 1 to 1/2 hour, cooled, decomposed with 200 ml of saturated ammonium chloride and extracted twice with tetrahydrofuran. The tetrahydrofuran extract is dehydrated over anhydrous sodium sulfate and evaporated in vacuo to give the product.

Melting Point 82 ~ 87 °

Example 3

[1,3-diacetyl-2- {4-[(1-hydroxy-1-methyl) ethyl] -3-pyridyl} -5- (methyl-2-octyl) resorcinol]

9.73 g of 2- {4 [(1-hydroxy-1-methyl) ethyl] -3-pyridyl} -5- (3-methyl-2-octyl) resorcinol dissolved in 40 ml of anhydrous pyridine Cool in an ice bath and add 7.65 g of acetic anhydride. The mixture is stirred for 1 hour at an ice bath temperature, overnight at room temperature and then concentrated in vacuo. The residue is poured into 300 ml of ice water and the rubbery substance is taken up in ether. The ether solution is washed twice with water, dehydrated over anhydrous sodium sulfate and then evaporated in vacuo to give the product. It is used in the next step without the need for purification.

Example 4

[1,3-Diacetyl-2- [4-isopropenyl-3-pyridyl] -5- (3-methyl-2-octyl) resorcinol]

컬럼(60내지 100메쉬)상에 크로마토그라피하면 생성물이 수득된다.40 ml of 1.27 g of 1,3-diacetyl-2- {4- [1-hydroxy-1-methyl) ethyl] -3-pyridyl} -5- (3-methyl-2-octyl) resorcinol The solution dissolved in pyridine was cooled to -10 ° C. in an ice salt bath and 5 ml of thionyl chloride was added dropwise. The mixture is stirred and the temperature is raised to 0 ° C. in 1-1 / 2 hours. This mixture is poured into ice water and extracted with ether. The ether extract is washed with water, dehydrated on anhydrous magnesium sulfate and evaporated in vacuo. Florisil using residue as pure methanol / benzene as solvent

Chromatography on column (60-100 mesh) yields the product.

Analysis: C ₂₇ H ₃₅ NO ₄

Calculated: C, 74.11; H, 8.06; N, 3.20

Found: C, 74.19; H, 8.02; N, 3.23

Example 5

[2- [4-isopropenyl-3-pyridyl] -5- (3-methyl-2-octyl) resorcinol]

40 ml of a solution obtained by dissolving 4.37 g of 1,3-diacetyl-2- [4-isopropenyl-3-pyridyl] -5- (3-methyl-2-octyl) resorcinol in 50 ml of toluene Place in a high pressure cylinder with ammonia. This mixture is shaken overnight at room temperature. Excess ammonia is blown off and the residue is treated with water and extracted with chloroform. This chloroform extract is washed twice with water, dehydrated on magnesium sulfate and evaporated in vacuo. The residue is recrystallized from ether-petroleum ether to give the pure product. Melting Point: 128 to 129 °

Analysis: C ₂₃ H ₃₁ NO ₂

Calculated: C, 78.14; H, 8.84; N, 3.97

Found: C, 78.43; H, 8.98; N, 3.99

Example 6

[1,3-diacetyl-2- [4-isopropyl-3-pyridyl] -5- (3-methyl-2-octyl) resorcinol]

1.2 g of a solution of 6.0 g of 1,3-diacetyl-2- [4-isopropenyl-3-pyridyl] -5- (3-methyl-2-octyl) resorcinol dissolved in 200 ml of ethyl acetate 5% Palladium / Carbon is hydrogenated for 1-1 / 2 hours in a Parr apparatus. The solution is filtered and 1.2 g of 5% palladium / carbon are added and the mixture is hydrogenated for 4 hours. After removal of the catalyst, the filtrate is evaporated in vacuo to give pure product.

Analysis: C ₂₇ H ₃₇ NO ₄

Calculated: C, 73.78; H, 8.52; N, 3.20

Found: C, 73.47; H, 8.59; N, 3.01

Example 7

[2- [4-isopropyl-3-pyridyl] -5- (3-methyl-2-octyl) resorgar]

By the method of Example 5, 1,3-diacetyl-2- [4-isopropyl-3-pyridyl] -5- (3-methyl-2-octyl) resorcinol was treated with ammonia to give 2- [ 4-Isopropyl-3-pyridyl] -5- (3-methyl-2-octyl) -resorcinol is prepared.

Example 8

[1-hydroxy-9-methyl-3- (3-methyl-2-octyl) -6-oxo-6H-dibenzo [b] [d] pyran]

8.4 g of 1-hydroxy-9-methyl-3- (3-methyl-2-octyl) -6-oxo-7,8,9,10-tetrahydro-6H-dibenzo [b] [d] pyran And a mixture of 2.4 g of sulfur are heated in an oil bath at 255 to 260 ° C. for ½ hour.

After cooling, 100 ml of ether is added to the residue and the ether solution is filtered to remove insoluble matters. The filtrate was concentrated in vacuo to yield 7.9 g of an amorphous solid. Melting Point 80 to 85 °

Example 9

[2- {2-[(1-hydroxy-1-methyl) ethyl] -5-methylphenyl} -5- (3-methyl-2-octyl) resorcinol]

Reaction with 1-hydroxy-9-methyl-3- (3-methyl-2-octyl) -6-oxo-6H-dibenzo [b] [d] -pyranol methyl magnesium bromide by the method of Example 2 The complex was decomposed with an aqueous sodium carbonate solution to prepare 2- {2-[(1-hydroxy-1-methyl) ethyl] -5-methylphenyl} -5- (3-methyl-2-octyl) resorcinol.

Example 10

[1, 3-Diacetyl-2- {2-[(1-hydroxy-1-methyl) ethyl] -5-methylphenyl} -5- (3-methyl-2-octyl) resorcinol]

2- {2-[(1-hydroxy-1-methyl) ethyl] -5-methylphenyl} -5- (3-methyl-2-octyl) resorcinol to pyridine by acetic anhydride by the method of Example 3 Was dissolved in a solution of 1,3-diacetyl-2- {2-[(1-hydroxy 1-methyl) ethyl] -5-methylphenyl} -5- (3-methyl-2-octyl) resorcinol To prepare.

Example 11

[1,3-diacetyl-2-[(2-isopropenyl-5-methyl) phenyl] -5- (3-methyl-2-octyl) resorcinol]

1,3-Diacetyl-2- {2-[(1-hydroxy-1-methyl) ethyl] -5-methylphenyl} -5- (3-methyl-2-octyl) rezo by the method of Example 4 Resinol was reacted with thionyl chloride and pyridine to prepare 1,3-diacetyl-2 [(2-isopropenyl-5-methyl) phenyl] -5- (3-methyl-2-octyl) resorcinol do.

Analysis: C ₂₉ H ₃₈ O ₄

Calculated: C, 77.30; H, 8.50; O, 14.20

Found: C, 76.82; H, 8.60; O, 13.67

Example 12

[1,3-diacetyl-2-[(2-isopropyl-5-methyl) phenyl] -5- (3-methyl-2-octyl) resorcinol]

컬럼을 통과시켜 촉매를 제거한다. 용출액을 진공 농축시키면 생성물이 수득된다.2.5 g of 1,3-diacetyl-2-[(2-isopropenyl-5-methyl) phenyl] -5- (3-methyl-2-octyl) resorcinol dissolved in 100 ml of deoxygenated benzene and 1.0 g of tristriphenyl phosphine rhodium chloride is hydrogenated overnight at room temperature under 3 atmospheres. The solution is concentrated in vacuo to dryness: the residue is dissolved in ether and the ether solution is florisil.

Pass the column to remove the catalyst. Concentration of the eluate in vacuo affords a product.

Example 13

[2-[(2-isopropyne-5-methyl) phenyl] -5- (3-methyl-2-octyl) resorcinol]

컬럼(60내지 100메쉬)에 크로마토그라피하여 정제한다.The 1,3-diacetyl-2-[(2-isopropyl-5-methyl) phenyl] -5- (3-methyl-2-octyl) resorcinol was treated with ammonia by the method of Example 7 -[(2-Isopropyl-5-methyl) phenyl] -5- (3-methyl-2-octyl) resorcinol was prepared using a pure ether / petroleum ether (30-60 °) solvent mixture room

Purify by chromatography on column (60-100 mesh).

Analysis: C ₂₅ H ₃₆ O ₂

Calculated: C, 81.47; H, 9.85; O, 8.68

Found: C, 80.91; H, 9.85; O, 8.99

Example 14

The following several experiments were conducted to determine the usefulness and effectiveness of the compounds of the present invention as antipsychotics, analgesics and anticonvulsants. Experiments using the compounds of the invention are described below and the results of the experiments are shown in Table (I).

Experimental Example 1

[Psychopathic Action (Deathoxin Antagonism in Rats)]

Psychotherapeutic action (desoxin antagonism) is measured by a motor activity chamber with photocells attached. A group of nine rats were orally administered with the compound one hour before the experiment and then 3 mg / kg of methamphetamine (desoxin) was injected subcutaneously into the device. Changes in motor capacity are recorded as counts from photovoltaic cells and compared with the deoxoxin control controls.

[Test Example 2]

Pain Relief

To test the analgesic activity of this compound [BA Whittle. Brit. Acetic acid twist test was performed by the method described in J. Pharmacol 22, 246 (1964). Drugs or control carriers are orally administered to a group of Swiss-Webster rats. Intravenous dye use is omitted. After 1 hour, 0.4 ml of 0.5% HOAc is administered intraperitoneally. Count the number of twists that occur 20 minutes after 5 minutes of HOAc injection. Analgesic is reported as% inhibition of distortion or ED ₅₀ compared to control.

FE D'Amour and DL Smith J. Pharmacol. Exp. Ther. 72, 74 (1941)] to test the analgesic action by the rat tail impulse method described in the following modifications. Sprague-Dawley rat groups weighing 140-170 g are blackened with Indian ink. The radiant heat is focused on their tails so that the normal pain threshold (time to escape or tail fry) is 8 to 10 seconds. This test proceeds after administration of the test compound and measures the pain threshold of the animals hourly. Analgesic effects are listed in Table I as% of initial pain threshold or ED ₅₀ after 2 hours of administration.

Experimental Example 3

[Audiogenic Seizure Test (Rat)]

O'Grady male rats (14-16 g), who were tamed to be sensitive to petty seizures, were used as test subjects. The petitioner consists of a wooden box containing a metal container with two doorbells on top. After drug administration, the animal is placed in a petitioner and the doorbell is operated for one minute and then observed for convulsions. [Reference: N.P. Plotnikoff and D.M. Green, J. Pharmacol. Exp. Ther. 119 294 (1957)

TABLE I

W (PO): Twisting test RTF: Rat tail impulse test

A pharmaceutical composition may be prepared by mixing the compound of the present invention as an active ingredient and a pharmaceutically nontoxic carrier or diluent. The compounds of the present invention can be formulated to be suitable for oral, parenteral and rectal administration since they show activity during oral or parenteral administration.

Solid form for oral administration include capsules, tablets, pills, powders, and granules. Such solids are made by mixing the active ingredient with at least one of an inert diluent such as sucrose, lactose or starch. Such agents generally contain, in addition to inert diluents, adducts such as lubricants such as magnesium stearate, sweeteners and flavoring agents. Tablets and pills can be prepared as enteric coatings.

Liquid preparations for oral administration include emulsions, liquids, suspensions, syrups, and elixirs, including inert diluents commonly used in the art, such as water. Such compositions may include, in addition to inert diluents, auxiliaries such as wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents and fragrances.

Formulations of the present invention for parenteral administration include sterile water-soluble or non-aqueous solutions, suspensions, emulsions. Non-aqueous solvents or excipients include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as oleic acid esters. Such formulations may contain preservatives, wetting agents, emulsifiers and dispersants. These are filtered through a bacterial filter or sterilized by mixing, irradiating or heating the composition with a fungicide. They can also be used in the form of sterile solids which can be dissolved in sterile water or other sterile injectable medium immediately before use.

Compositions for rectal administration include suppositories which include, in addition to the active ingredient, excipients such as cocoa butter or suppository waxes.

The active ingredient content of the present invention in the composition varies.

The amount of active ingredient depends on the suitable dosage form. Dosage depends on the desired therapeutic effect, route of administration and duration of treatment.

Claims (1)

The benzopyranone of formula (II) is then reacted with methyl magnesium bromide to form an alcohol of formula (III), which is then reacted with acetic anhydride to produce the corresponding diacetyl derivative, followed by dehydration with thionyl chloride. A method of producing 2-substituted-5-alkyl resorcinol of the following formula (I) by producing isopropenyl derivative of (IV) and then treating with liquid ammonia.

Wherein R ₁ is hydrogen or lower alkanoyl, R ₂ is straight or branched chain alkyl of 1 to 20 carbon atoms and X represents nitrogen or C-methyl.