CS196346B2 - Process for preparing 2,3-cis-1,2,3,4-tetrahydro-5-/2-hydroxy-3-terc.butylamino/propoxy -2,3-naphthalendiole - Google Patents

Description

The above-mentioned pharmacologically active compound is already known. Thus, DOS number 2 258 995 describes the above compound as a substance corresponding to structural formula I.

thanolj to form an alkali metal salt as a compound of formula II,

HIM

HO (b) reacting this alkali metal salt with epichlorohydrin of the formula

O

OF\

C1CH2CH — CH2

ID

This DOS also describes a process for the preparation of the aforementioned compound which comprises reacting (a) cis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol with an alkali metal alkoxide (sodium methoxide) in an alcoholic solvent boiling below 100 ° C (m in a dipolar aprotic solvent (dimethylsulfoxide) under nitrogen with stirring overnight to form the epoxyether of formula III, and

(in) (c) this compound is reacted with tert.butylamine in a pressure vessel for 15 hours at 85-95 ° C to give the final product of formula I.

The present invention provides a simplified process for the preparation of 2,3-cis-1,2,3,4-tetrahydro-5 - [(2-hydroxy-3-tert-butylamino) propoxy] -2,3-naphthalenediol.

The novel process of the invention can be described by the following reaction scheme:

/ ° \

O ~ Ch £ CHCH _from

OH ^{111}

O-CH 2 CH-CH 2 NH-C-CH 3

CH,

The use of this process to produce 2,3-cis-1,2,3,4-tetrahydro-5 - [(2-hydroxy-3-tert-butylamino) propoxy] -2,3-naphthalenediol is associated inter alia with the following advantages :

(1) it is unnecessary to use unpleasant dipolar solvents such as dimethylsulfoxide, (2) the process is essentially carried out in only two stages, (3) crystalline intermediates are formed (not oily intermediates), and (4) the product is obtained in good yields.

The starting material for the process according to the invention is cis-5,6,7,8-tetrahydro-1,6,7-naphthalentrol. This material is known and can be prepared from 1-naphthol by first reducing 1-naphthol to 5,8-dihydro-1-naphthol.

This reduction can be accomplished by lithium in liquid ammonia. The 5,8-dihydro-1-naphthol is converted to its acetate by treatment with acetic anhydride in pyridine, which is then subjected to Woodward cis-hydroxylation with silver acetate and iodine in wet acetic acid. Free triol, i.e. _cis-5) 8,7,8-tetrahydro-8,7-naftalentriol, is released by hydrolysis.

As can be seen from the above scheme, the process of the invention consists essentially of two reaction steps, i.e. the conversion of cis-5,8,7,8-tetrahydro-1,6,7-naphthalentriol to 2,3-cis-1, 2,3,4-tetrahydro-5- [2,3- (epoxy) propoxy] -2,3-naphthalenediol, which is then converted to the desired product, i.e., 2,3-cls-1,2,3, 4-tetrahydro-5 - ((2-hydroxy-3-t-butylamino) propoxy) -2,3-naphthalenediol.

The starting cis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol is alkylated in a mixture containing a large excess of epichlorohydrin in an aprotic solvent (e.g. acetone, dioxane, etc.) containing a small amount of water (e.g. 5-10%). (based on the total volume of the mixture). The alkylation is carried out by adding an aqueous solution of a strong base (e.g. sodium hydroxide, potassium hydroxide, etc.) to the refluxing mixture. The base is consumed as quickly as it is added. The molar ratio of epichlorohydrin to starting naphthalentriol may range, for example, from about 2: 1 to 20: 1.

The intermediate formed in this reaction, i.

2,3-cis-1,2,3,4-tetrahydro-5- [2,3- (epoxy) propoxy] -2,3-naphthalenediol is dissolved in a mixture of tert-butylamine and an alcoholic solvent boiling below about 100 ° C (e.g. methanol). The resulting solution was refluxed under nitrogen for about 3 to 24 hours. Evaporation of the solvent then gave the desired 2,3-cis-1,2,3,4-tetrahydro-5 - [(2-hydroxy-3-tert-butylamino) propoxy] -2,3-naphthalenediol.

In accordance with a specific embodiment of the process according to the invention, the starting cis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol is first reacted with an aldehyde, ketone, acetal, ketal or enol ether, thereby providing alcoholic hydroxyl functions during further reactions. After protection of the hydroxyl functions with an aldehyde, ketone, acetal, ketal or enol ether, the process according to the invention is then carried out as described above. In this case, however, it is necessary to include a further reaction step consisting in hydrolytic cleavage of the protecting groups to give the final product.

If the process according to the invention is carried out without protecting the alcoholic hydroxyl groups, only the two-step process is fully realized. Intermediate 2,3-cis-1,2,3,4-tetrahydro-5- [2,3- (epoxy) propoxy] -2,3-naphthalenediol cannot be easily purified by distillation, but when alcoholic hydroxyl groups in the With the material as described above, the intermediate epoxyether can be easily purified by distillation.

The compound produced by the novel method of the invention is useful as an antifibrillating agent, for example, for arresting cardiac arrhythmia in mammals (e.g., by inhibiting adrenergic β-receptors in the myocardium). a dosage form such as a tablet, capsule, elixir, injectable, etc., together with the necessary carrier material, excipient, glidant, buffer and the like.

Using the dosage forms described above, single or sub-doses may be administered in an amount of about 5 to 25 mg / kg, preferably about 4 to 10 mg / kg, two to four times daily.

The invention is illustrated by the following non-limiting example.

Example {a) 2,3-cis-1,2,3,4-tetrahydro-5- [2,3- (epoxy) propoxy] -2,3-naphthalenediol

7.26 g (0.04 mol) of cis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol in a mixture of 37.4 ml of acetone, 37.4 ml of epichlorohydrin and 4.9 ml of water are added under a solution of 1.6 g (0.04 mol) of sodium hydroxide in 9 ml of water (about 1.5 ml every 5 minutes) was added over 30 minutes. The resulting mixture was stirred at reflux for 3.5 hours and then stirred at room temperature for about 15 hours (overnight).

The reaction mixture was evaporated in vacuo to a residue which was partially solid and partially oily, partitioned between 100 ml of water and 100 ml of chloroform. The aqueous layer was extracted twice with 100 ml of chloroform each time, the chloroform phase was dried over magnesium sulfate, and evaporated in vacuo. Yield: 8.75 g

92.8%) of a white solid, m.p. 72-112 ° C.

(b) 2,3-cis-1,2,3,4-tetrahydro-5 - [(2-hydroxy-3-tert-butylamino) propoxy] -2,3-naphthalenediol

8.13 g (0.0344 mol) of the epoxy ether obtained in (a) are dissolved in 80 ml of tert-butylamine and 40 ml of methanol and the solution is stirred at room temperature under nitrogen for about 15 hours (overnight). Evaporation of the resulting mixture in vacuo yielded

10.4 g (yield of crude product 98%) of a foamy residue which was dissolved in boiling benzene (150 ml) and filtered through diatomaceous earth. The filtrate was heated for 4 hours and then allowed to stand at room temperature for about 15 hours (overnight). The solid material was filtered off, washed with ether and dried in vacuo. 8.54 g (80.4% yield) of a white solid are obtained, m.p. 115-133 ° C.

Analysis for C17H27NO4:

calculated:

% C, 65.99;% H, 8.80;% N, 4.53.

% C, 66.04;% H, 8.76;% N, 4.79

Claims (4)

P R E D HAVE THE INVENTION A process for the preparation of 2,3-cis-1,2,3,4-tetrahydro-5 - [(2-hydroxy-3-tert-butylamino) propoxy] -2,3-naphthalenediol of formula I, with the addition of an aqueous base under reflux, and to the thus obtained epoxyether of formula III HIM HOO-CH-CH-CH 2 HH-CCHL I * ³³ Ol- ^H, characterized in that the cis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol of the formula IIIa, in which the cis-6,7-hydroxyl groups are optionally in protected form, is reacted in a mixture of excess epichlorohydrin, in a molar ratio of epichlorohydrin to cis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol from 2: 1 to 20: 1, and an aprotic solvent in the presence is treated with tert-butylamine. 2. A process according to claim 1, wherein the water is present in the reaction mixture in an amount of 5 to 10% by volume, based on the total volume of the mixture. 3. The process according to claim 1, wherein the cis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol of formula IIIa in a mixture of acetone and epichlorohydrin is heated to reflux in the presence of water. Aqueous sodium hydroxide is added under reflux, and the thus obtained epoxy ether of the above formula III is treated with tert-butylamine. 4. The process according to claim 1, wherein the starting material is cis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol of the formula IIIa in which the cis-6,7-hydroxy groups are protected form obtained by treatment with an aldehyde, ketone, acetal, ketal or enol ether.