JPS5823399B2 - Phenoxy Amino Probanol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (wherein R represents tetrahydrofurfuryl or furfuryl).

) and a method for producing their acid addition salts.

According to the present invention, the target compound of general formula [1] is as follows:
, manufactured by the method of ■.

Method ■ Reaction of the compound represented by the general formula with 2.2.6.6-titramethylpiperidine.

where Y is -CH-CH2 or -CH(OH)-CH
2-(halogen).

The reaction in method (1) above may be carried out in the presence of a solvent.

Examples of solvents include ethers such as diethyl ether, dioxane, and tetrahydrofuran, alcohols such as methanol, ethanol, furopanol, impropatol, amyl alcohol, and isoamyl alcohol, aromatic hydrocarbons such as benzene, toluene, and xylene, water,
Dimethylformamide, dimethyl sulfoxide, and any other solvent that does not inhibit the reaction may be used.

Among them, methanol, ethanol, etc. are preferred.

When reacting the compound 2.2.6.6-titramethylpiperidine of formula (U) in which Y is -CH(0■()-〇H2-(halogen)), the latter is used in excess as a deoxidizing agent. Also, alkali carbonates such as potassium carbonate and sodium carbonate, caustic alkaline earth metal sodiums such as caustic potash and caustic soda, sodium hydride, sodium amide, etc., or tertiary amines such as triethylamine and pyridine are used as deoxidizing agents. Good too.

Although the reaction generally proceeds at room temperature, it may be heated to about the boiling point of the solvent used.

Compound and general formula represented by A method of reacting with a compound represented by

Here, Z represents a reactive atom or group such as a halogen atom (chlorine, bromine, etc.), aryl- or alkyl-sulfonyloxy (p-tolylsulfonyloxy, methylsulfonyloxy, etc.).

The reaction in method (1) above is usually carried out in a solvent as described in method (2) in the presence of a deoxidizing agent.

Although the reaction proceeds at room temperature, it is preferably carried out under reflux of the solvent used.

The raw material compound is prepared, for example, by the method described below.

(2) Preparation of raw material compound [dish] Preparation example 12 g of pyrocatechol was dissolved in 80 rrLl of acetone, 16 g of potassium carbonate was added, and 14 g of furfuryl chloride was added dropwise at room temperature while stirring.

After the dropwise addition, the temperature was gradually raised and the mixture was stirred and refluxed for 6 hours.

Thereafter, insoluble matter is removed, concentrated under reduced pressure, water is added to the residue, and extracted with benzene 150111.

The benzene layer is extracted with a 5-functional aqueous sodium hydroxide solution.

When the aqueous layer is made acidic with 10% hydrochloric acid water, an oily substance is liberated.

benzene] and extracted with 50 TLl. The benzene layer was washed twice with 100 ml of water and then with 50 ml of an aqueous solution of 5-functional carbon hydrogen sulfur-IJium.

After drying the benzene layer over anhydrous magnesium sulfate, the benzene is distilled off.

1) - When the residual oil is purified by distillation, the boiling point is 105-1120
10 g of 2-(furfuryloxy)phenol of C10, ObnmHg are obtained.

2. Preparation of raw material compound [■] Preparation Example 2 - Dissolve 40 g of (furfuryloxy)phenol in a solution of 13 g of potassium hydroxide in 20,071 L of water, add 21.5 g of epichlorohydrin at room temperature, and stir at room temperature for 8 hours.

After the reaction, the separated oil is extracted with 200 ml of benzene, the benzene layer is washed with water, dried over anhydrous magnesium sulfate, and the benzene is distilled off.

When the residual oil is purified by distillation, it yields 1,2-epoxy with a boiling point of 1522);
5-(2-(furfuryloxy)phenoxy J F0/
21. g is obtained.

Similarly, boiling point 150-162°C 10,5-0.7
mmHg of 1,2-epoxy-3-[2-(tetrahydrofurfuryloxy)phenoxy]propane is obtained.

Preparation Example 2 - (Tetrahydrofurfuryloxy)phenol 5g
1 A mixture of 10 g of epichlorohydrin and 0.1 g of piperidine as a catalyst is heated and stirred at 70 to 80° C. for 3 hours.

After reaction, 0. The reaction solution is concentrated under reduced pressure of 03 mmHg to obtain 7.5 g of 1-chloro-3-[2-(tetrahydrofurfuryloxy)phenoxycou-2-propatol as an oil.

3. Preparation of 2.2.6.6-Titramethylpiperidine This compound is commercially available from Aldrich.

The synthesis method is comparable to Pyleshfin's knot book.

129, with a boiling point of 152°C2n201.
It is 4440.

4. Preparation of raw material compound (IV) Preparation example 2, 2.6.6-Titramethylpiperidine 1.41 g ether 1 om1. Add 0.9 of epichlorohydrin to the solution.
Add 3g under water cooling.

After a while, the ether was distilled off under reduced pressure to obtain 2.35 g of -chloro-3-(2,2,6,6-titramethylpiperidino)-2-propatol as an oil.

Since Motoichi is unstable, it will be used as is for the next reaction.

Compound [1] produced by the above method can be converted into an acid addition salt by a conventional method.

Acids used to produce acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and hydrobromic acid, oxalic acid, maleic acid, fumaric acid, malic acid, and o-(p-hydroxybenzoyl). Examples include organic acids such as benzoic acid and phenolphthalin.

Since the compound represented by the general formula [■] has an asymmetric carbon, it can be an optically active form or a racemic form.

A racemate with two asymmetric carbon atoms in the molecule can be divided into two racemic streomers.

Furthermore, racemates can be usually separated into optically active enantiomers and diastereomers by well-known methods.

Phenoxy amine propatool derivatives of general formula [1] and acid addition salts thereof are useful compounds as local anesthetics and antiarrhythmic agents.

Example 1 ■, 5.0 g of 2-epoxy 5-(:2-(tetrahydrofurfuryloxy)phenoxy)propane was dissolved in butanol 357711, 3.1 g of 2.2.6.6-titramethylpiperidine, and 1 drop of water. and heated under reflux for 9 hours.

The butanol was distilled off, and the residue was extracted with 150 mK of benzea and 10,077 L of hydrochloric acid.

After neutralizing the aqueous layer with potassium carbonate, it is further made alkaline with potassium hydroxide, and the liberated oil is mixed with benzene 200TI.
Extract with Ll.

After washing the benzene extract with water, it is dried over anhydrous magnesium sulfate.

When benzene is distilled off and the residue is purified by distillation, the boiling point is 20
1-(2,2,6
, 6-titramethylpiperidino)-3-(2-(tetrahydrofurfuryloxy)phenoxy-2-propatool) is obtained.

The fumarate salt of Motoichi has a melting point of 140-142.5°C (recrystallized from ethanol-isopropyl ether).

Example 2 5.7 g of 1-chloro-3-[2-(tetrahydrofurfuryloxy)phenoxy-2-propatol was dissolved in 55 ml of ethanol, and 6.2 g of 2.2.6.6-titramethylpiperidine was added. Heat under reflux on a water bath for 20 hours.

Ethanol is distilled off, the residue is dissolved in ether, and extracted with 150 ml of 5% hydrochloric acid.

The aqueous layer is made alkaline with thorium hydroxide and the liberated oil is extracted twice with ether.

After drying the ether layer over anhydrous potassium carbonate, the ether is distilled off and the residue is purified by distillation, resulting in a boiling point of 200-2270.
C/0.7 mmHg 1-(2,2,6,6-titramethylpiperidino)-3-[2-(tetrahydrofurfuryloxy)phenoxyio2-p0/Knorr 6
65g is obtained.

Example 3 2-(TeI-lahydrofurfuryloxy)phenol 3
9g 1 anhydrous potassium carbonate 2.8g, acetone 75TLl
1-chloro-5-(2,2
, 6,6-titramethylpiperidino)-2=5.2 g of propatool was added, and the mixture was heated under reflux with stirring for 20 hours.

After the reaction, insoluble materials are removed from the furnace and the P solution is concentrated under reduced pressure.

Dissolve the remaining residue in ether and 15 oml of 5 polyhydrochloric acid! Extract with

The aqueous layer is made alkaline with sodium hydroxide and the liberated oil is extracted twice with ether.

After drying the ether layer over anhydrous potassium carbonate, the ether is distilled off and the residue is purified by distillation, resulting in a boiling point of 200-227°.
5.8 g of 1-(2,2,6,6-titramethylpiperidino)-3-[2-(tetrahydrofurfuryloxy)phenoxy-2-propatol at C10.7 mmHg
can get.

1- (2, 2, 6,
6-titramethylpiperidine)-3-1: :2-(furfuryloxy)phenoxy-2-propatur is obtained, the fumarate salt of which exhibits a melting point of 170-172°C.

Claims (1)

[Claims] 1 General formula (wherein R is tetrahydrofurfuryl or furfuryl, Y is -CH-CH2 or -CH(OH)-CH2
- (halogen). ) and 2.2.6.6. -Tetramethylpiperidine. A compound represented by the general formula (wherein R represents tetrahydrofurfuryl or furfuryl) is reacted with a compound represented by the general formula (wherein Z represents a reactive atom or group). and
A method for producing a compound represented by the general formula (wherein R has the same meaning as above).