CS196345B2 - Method of producing 2,3-cis-1,2,3,4-tetrahydro-5-//2-hydroxy-3-terc.butylamino/propoxy/-2,3-napthalendiole - Google Patents

Description

The present invention provides a process for the preparation of 2,3-cls-1,2,3,4-tetrahydro-5 - [(2-hydroxy-3-tert-butylamino) propoxy] -2,3-naphthalenedol of the formula

According to the state of the art, the compounds whose production forms the subject of the present invention are produced by the methods invented by the applicant. One of these procedures is described in MS. No. 196,346, another in U.S. Pat. No. 3,935,267.

The process according to the invention for the preparation of 2,3-cis-1,2,3,4-tetrahydro-5 - [(2-hydroxy-3-tert-butylamino) propoxy] -2,3-naphthalenediol can be schematically represented as follows:

196343

The core of the invention is the protection of alcoholic hydroxyl groups. This can be accomplished by reacting cis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol with any of the adlehydols having at least two carbon atoms, or with any acetal or enol ether derivative thereof, or any a ketone or any ketal or enol ether derivative thereof. The purpose of the carbonyl reactant or derivative thereof is to protect the alcoholic hydroxyl groups and is therefore immaterial to which aldehyde, ketone, acetal, ketal or enol ether is used. The above schematic representation of the process of the invention assumes that an aldehyde or ketone of the general formula is used

R1-C-R2

II o

or an acetal, ketal or enol ether derivative thereof, wherein the meanings of R 1 and R 2 are given below. It should be noted, however, that any aldehyde, ketone, acetal, ketal or enol ether can be used in the process of the invention. Preferably, aldehydes and ketones of the general formula are used

R1-C-R2

II o

and their acetal, ketal and enol ether derivatives.

In the above general formula means

R 1 is hydrogen, C 1 -C 7 alkyl, C 1 -C 7 monocyclic cycloalkyl, C 1 -C 7 monocarbocyclic aryl or C 1 -C 7 arylalkyl;

R 2 is an alkyl, monocyclic, cycloalkyl, monocarbocyclic aryl or monocarbocyclic arylalkyl radical, all having 1 to 7 C atoms in the alkyl radical.

Process according to the invention for the preparation of the 2,3-cis-1,2,3,4-tetrahydro-5 - [(2-hydroxy-3-tert-butylamino) propoxy] -2,3-naphthalenediol shown in the above reaction scheme, characterized in that cis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol is reacted with a carbonyl compound of the formula

R 1 -CO-R 2, wherein R 1 and R 2 are as defined above, to form a cyclic derivative having a free phenolic hydroxyl group but both alcoholic hydroxyl groups protected, forms a salt of the cyclic derivative which is alkylated with epichlorohydrin to form an epoxide, oxyran the ring of the resulting epoxide is opened with t-butylamine to form an amino alcohol which is hydrolyzed to produce the product.

"Lower alkyl" means hydrocarbon radicals having 1 to 7 C atoms.

Suitable aldehydes and ketones used in the process of the invention include lower alkanals with at least two carbon atoms such as paraldehyde, propanal and hexanal, di196343 (lower alkyl Jketones such as acetone, diethylketone, dibutylketone, methylethylketone and methylsobutylketone, cycloalkanols such as cyclobutanone, cyclopentanone, cyclohexanone, suberone and cyclohexanone, mono- and dicycloalkyliketones such as cyclohexylmethylketone and dicyclopropylketone, halogen (lower alkanals such as chloral hydrate, trifluoroacetaldehyde hemiacetal and heptafluorobutanethylhemiacetal, halogen (lower) alkanecyclones such as 1,1,1-carbocyclones, aromatic aldehydes such as benzaldehyde, halobenzaldehydes, e.g. p-chlorobenzaldehyde and p-fluorobenzaldehyde, lower alkoxybenzaldehydes, e.g. o-anisaldehyde, di (lower alkoxy) benzaldehydes, e.g. veratraldehyde, hydroxybenzaldehydes, e.g. n-alkylbenzaldehydes, e.g. m-tolualdehyde and p-eithylbenzaldehyde, dl (lower alkyl) benzaldehydes, e.g. o, p-dimethylbenzaldehyde, nitrobenzaldehydes, acylamidobenzaldehydes, e.g. ,. [beta] -phenylpropionaldehyde, N-phenylbutyraldehyde, and their aromatic substituted halogen, lower alkoxy, hydroxyl and lower alkyl derivatives, nitroderivatives, acylamidoderivatives and cyanoderivatives, monocyclic heterocyclic aldehydes such as picolinaldehydes, furfural, thiophenecarbonals and their halogen, lower-alkoxy, lower-alkoxy, lower alkyl derivatives, nitroderivatives and cyanoderivatives, monocyclic heterocyclic lower alkanals, 1- (monocyclic carbocyclic aromatic) substituted lower alkanals such as acetophenone, α, α, α-trifluoroacetophenone, propiophenone, butyrophenone, valerophenone, iso-ketophenone, halo-phenylphenyl -chloroacetophenone and p-chloropropiophenone, (lower alkoxy) phenyl (lower alkyl alkyl ketones, for example p-anisylmethylkeitone, di (lower alkoxy) phenyl (lower) alkyl ketones, hydroxyphenyl (lower) alkyl ketones, dihydroxyphenyl (lower J alkyl ketones, for example res acetophenone, (lower alkyl) lower alkyl alkyl ketones such as methyl-p-tolyl ketone, di (lower alkyl) phenyl (lower) alkyl ketones such as o, p-xylyl methyl ketone, nitrophenyl lower alkyl ketones such as p-nitroacetethenenone, acylamidopheniyl (lower J alkyl ketones such as acetylanilines, and cyanophenyl ( lower alkyl alkyl ketones, benzophenones and their mono- and bis-substituted halogen, lower alkoxy, hydroxyl and lower alkyl derivatives, nitroderivatives, acylamide and cyanoderivatives, monocyclic carbocyclic aromatic lower alkanones such as 1-phenyl-3-butanone and 1-phenyl- 4-pentanone, and aromatic substituted derivatives thereof,

1- (monocyclic heterocyclic J substituted lower alkanals such as 2-acetylfuran, 2-benzoylfuran and 2-acelyl thiefite, oxosubstituted monocyclic helerocycles such as alloxane, monocyclic heterocyclic lower alkanones, and oxo (lower glycanoic acids such as pyruvic, acetacetic, (3-ketopropionic, α-ketobutyric, levulin, β-keto-caproic and (3-keto-caprylic), and esters thereof, such as lower alkyl esters such as methyl and ethyl esters.

The formation of acetals, ketals, and enol ethers from the above aldehydes and ketones is carried out by known methods and will not be described in detail herein. As mentioned above, aldehydes, ketones, acetals, ketals and enol ethers are used to protect the alcoholic hydroxyl groups of the starting compound, i.e., eis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol, in other reactions; the chemical nature of these reactants is not critical and their choice will depend on availability, price, etc.

According to the above schematic diagram, in step 1, the free triol of formula I is converted to the cyclic derivative of formula II. In Step 2, a salt of the cyclic derivative is prepared which is then alkylated with epichlorohydrin to give the epoxide of formula III. In step 3 ', the oxyran ring is opened with t-butylamine to give the amino alcohol of formula IV. In step 4, the amino alcohol of formula IV is hydrolyzed to produce 2,3-cis-1,2,3,4-tetrahydro-5 - ((2-hydroxy-3-tert-butylamino) propoxy) -2,3- of naphthalenediol of formula V.

The starting compound in the process of the invention is cis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol. This compound is known; it can be prepared from 1-naphthol. The 1-naphthol is first reduced to 5,8-dihydro-1-naphthol by lithium in liquid ammonia. 5,8-dihydro-1-naiftol is then converted to its acetate derivative with acetic anhydride in pyridine; this derivative is then subjected to Woodword cis-hydroxylation using silver acetate and iodine in aqueous acetic acid. The free triol, i.e. cis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol, is then released by hydrolysis.

Step 1 according to the invention involves the formation of a hydroxyl protecting group on. cis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol of formula 1. This is achieved by reacting cis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol of formula I with an aldehyde or a ketone of formula

Rt - Cl - R2,

II o

wherein R 1 and R 2 are as defined above, or with an acetal, ketal or enol ether derivative thereof. The reaction is preferably carried out by adding an acid catalyst, such as perchloric acid, to a suspension or solution of cis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol of formula I in the carbonyl reactant or derivative thereof, p-toluenesulfonic acid, hydrochloric acid, etc., the acid is neutralized and the resulting cyclic acetal is formed. The metal derivative of formula II is isolated. If the carbonyloxy19455 reactant or derivative thereof is a solid, an organic solvent is also used. The reaction is carried out at a temperature in the range of 20 to 120 ° C, preferably in the range of 20 to 50 ° C, and takes about 0.5 to 24 hours.

Step 2 of the process of the invention first involves the formation of a salt of the cyclic derivative formed in step 1, followed by its alkylation with epichlorohydrin to form the epoxide of formula III. The cyclic derivative of formula (II) is reacted with an alkali metal alkoxide, preferably sodium or potassium alkoxide, in an alcoholic solvent boiling below 100 ° C, for example methanol, under an inert atmosphere such as nitrogen to give the salt. The salt formation reaction is carried out at a temperature in the range of 15 to 75 ° C, preferably 25 to 40 ° C. The resulting salt is stirred with epichlorohydrin in a dipolar aprotic solvent such as dimethylsulfoxide, hexamethylphosphoramide or dimethylformamide under an inert atmosphere to form the epoxide of formula III. In addition to the above process, the salt may be prepared directly in a dipolar aprotic solvent.

The alkylation of said salt with epichlorohydrin is carried out at a temperature in the range of 10 to 60 ° C, preferably 20 to 40 ° C, and lasts for about 2 to 24 hours.

Step 3 involves opening the oxyran ring of the epoxide of formula III with tert-butylamine. The epoxide of formula III, which is an oily liquid, is dissolved in a mixture of tert-butylamine and an alcoholic solvent boiling below 100 ° C, for example in methanol. The solution was heated to reflux under a nitrogen atmosphere. The reflux is carried out for about 3 to 24 hours. Removal of the solvent left a compound of formula IV.

The final step is the hydrolysis of the amine of formula IV to 2,3-cis-1,2,3,4-tetrahydro-5 - [(2-hydroxy-3-tert-butylamino) propoxy] -2,3-naphthalenediol. The amine is hydrolyzed by dissolving in water and an acid, for example hydrochloric acid, followed by stirring until the ketal groups are no longer present. One way to detect the presence of ketal groups is by n and thin layer chromatography. It is preferred that chloroform is added to the water / acid mixture to ensure mixing efficiency.

The compound produced by the process of the invention is useful as a softening agent and for preventing corrosion of machine lubricants. It is also useful as an anti-fibrillating agent by counteracting cardiac arrhythmia in mammals, for example by inhibiting the .alpha.-adrenergic myocardium receptors. For this purpose, the compound produced by the process of the invention or a physiologically acceptable salt thereof may be used in conventional dosage forms such as tablets, capsules, elixirs, injectable solutions and the like, together with the necessary carriers, lubricants, buffers and the like.

The following examples illustrate the invention.

Example 1

a) 5-hydroxy-3α, 9α-cis-3α, 4,9,9α-tetrahydro-2,2-dimethyl-2H-naphtho [2,3-d] -1,3-dloxol

A suspension of 90.0 g (0.50 mol) of cis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol in 900 ml of acetone dimethyl ketal is stirred with 0.5 g of p-toluenesulfonic acid monohydrate (dissolution is achieved about 15 minutes). After 2 hours, the clear solution is diluted with an equal volume of ether and washed with a mixture of 900 ml of saturated aqueous sodium chloride solution and 100 ml of saturated aqueous sodium bicarbonate solution. Drying with sodium sulfate followed by removal of the solvent gave a solid. After comminution and drying at 50 DEG C. under a reduced pressure of 26.66 Pa, 112.4 g are obtained

5-hydroxy-3α, 9α-cis-3α, 4,9,9α-tetrahydro-2,2-dimethyl-2H-naphtho [2,3-d] -1,3-dioxole as a tan solid using chromatography Silica gel thin layer, hexane / chloroform solvent system (1: 1). The title compound is obtained in about 100% yield.

b) 5- (2,3- (epoxy) propoxy] -3a, 4,9,9atetrahydro-2,2-dimethyl-2H-naphtho [2,3-d] -1,3-dloxol

112.4 g (0.50 mol) of the crude product from a) of this example are dissolved in 1.2 liters of dimethylsulfoxide, dried by molecular sieving, 27.5 g (0.51 mol) of sodium methoxide are added thereto at Approximately 100 ml of solvent was distilled off at 40 ° C under a reduced pressure of 26.66 Pa. The solution was then cooled to ambient temperature, 50 ml (60 g, 0.64 mol) of epichlorohydrin (distilled and dried with molecular sieves) were added and the resulting solution was stirred at ambient temperature under nitrogen atmosphere for about 15 hours (overnight). Approximately 100 ml of solvent is distilled off under reduced pressure of 26.66 Pa and the remaining solution is poured into 9 l of water. The resulting solution was extracted with a total of 4 L of ether (a total of 3 extractions were carried out using 2 L, 1 L and 1 L respectively), washed with water (4 washes, 1.5 L each) and saturated aqueous sodium chloride solution. and then dried over sodium sulphate. Removal of the solvent yielded 136.5 g (89% yield).

5- [2,3- (epoxy) -propoxy] -3a, 4,9,9a-tetrahydro-2,2-dimethyl-2H-naphthol [2,3-d] -1,3-dioxole, in the form of oil liquids.

c) 5- (3-tert-butylamino-2-hydroxypropoxy) -3a, 4,9,9a-tetrahydro-2,2-dimethyl-2H-naphtho [2,3-d] -1,3-dioxole

The oily liquid obtained in (b) is dissolved in a solution of 1 liter of tert-butylamine196345 n and 0.5 liters of methanol, and the solution obtained is refluxed overnight under a nitrogen atmosphere. The solvents were removed under reduced pressure (benzene was added twice to remove t-butylamine residues and evaporated) to give 179.6 g of 5 (3-tert-butylamino-2-hydroxypropoxy) -3a, 4,9,9 α-tetrahydro-2,2-dimethyl-2H-naphtho [2,3-d] -1,3-dioxole as an oil.

d) 2,3-cis-1,2,3,4-tetrahydro-5- (2-hydroxy-3-tert-butylaminopropoxy) -2,3-naphthalenediol

179.6 g of the crude amine of (c) are dissolved in 320 ml of chloroform and stirred for 4 hours with a solution of 100 ml of concentrated hydrochloric acid in 1600 ml of water. The resulting viruses were separated and the aqueous solution was extracted twice with 0.5 L of chloroform again. The aqueous layer was concentrated under reduced pressure on a rotary evaporator to remove acetone (approximately 100 mL of aqueous distillate was obtained). To the aqueous layer were added 65 g of sodium hydroxide, 100 ml of water and 200 ml of ice, and the solution was then extracted with chloroform, 3 extractions, each with 1 liter. The combined chloroform extracts were washed with 0.5 L of saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated to give 128.6 g of an oily liquid which solidified. Recrystallization from 1400 mL of 4: 1 benzene / acetonitrile gave 106 g of solid which was washed with 300 mL of 4: 1 benzene: acetonitrile and 300 mL of ether. Recrystallization of this solid from the same solvent yielded 80.6 g of solid, which was washed with 300 ml of 4: 1 acetonitrile and 300 ml of ether, and then dried under reduced pressure for about 15 hours. The melting point is in the range

126.5 to 139 ° C. The sample for analysis is dried at 78 ° C under reduced pressure.

Analysis for C17H27NO4:

calculated:

H, 8.80; N, 4.53. Found:

66.09 θ / ο C, 9.05 θ / ο H, 4.50% N. Example 2

a) 5-hydroxy-3α, 4,9,9α-tetrahydro-2-phenyl-2H-naphtho [2,3-d] -1,3-dioxole

A suspension of 0.50 moles of cis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol in 900 ml of benzaldehyde is stirred with 0.5 g of p-toluenesulfonic acid monohydrate. After 2 hours, the clear solution is diluted with an equal volume of ether and washed with a mixture of 900 ml of saturated aqueous sodium chloride solution and 100 ml of saturated aqueous sodium bicarbonate solution. Drying over sodium sulfate followed by removal of the solvent gave a solid which was pulverized and dried at 50 ° C under reduced pressure to give a solid. to give 5-hydroxy-3a, 4,9,9a-tetrahydro-2-phenyl-2H-naphtho [2,3-d] -1,3-dioxole.

b j 5- [2,3- (Epoxy) propoxy] -3a, 4,9,9a-tetrahydro-2-phenyl-2H-naphthol [2,3-d] -1,3-dioxole

The crude product from (a) of this example was dissolved in 1.2 L of molecular sieves dried with molecular sieve, 0.51 mol of sodium ethoxide was added and about 100 mL of solvent was distilled off at 40 ° C under reduced pressure. The solution is cooled to ambient temperature, 50 ml of epichlorohydrin distilled and dried with molecular sieves are added, and the resulting solution is stirred for about 15 hours at ambient temperature under a nitrogen atmosphere. Approximately 100 ml of solvent are then distilled off under reduced pressure of 26.66 Pa and the remaining solution is poured into 9 liters of water. The resulting solution was extracted with ether, washed with water and saturated aqueous sodium chloride solution and dried over sodium sulfate. Removal of the solvent gave 5- [2,3- (epoxy) propoxy] -3a, 4,9,9a-tetrahydro-2-phenyl-H-naphtho [2,3-d] -1,3-dioxole.

c j 5- (3-tert-Butylamino-o-2-hydroxypropoxy) -3a, 4,9,9a-tetrahydro-2-phenyl-2-naphthol [2,3-d] -1,3-dioxole

The oily liquid obtained according to paragraph bj of this example was dissolved in a solution of 1 liter of tert-butylamine and methanol and heated at reflux overnight under a nitrogen atmosphere. The solvents were removed under reduced pressure (benzene was added twice and evaporated to remove tert-butylamine residues) to give 5- (3-tert-butylamino-2-hydroxypropoxy) -3a, 4,9,9a-tetrahydro-2. -phenyl-2H-naphtho [2,3-d] -1,3-dioxole.

d) 2,3-cis-1,2,3,4-tetrahydro-5- (2-hydroxy-3-tert-butylaminopropoxy) -2,3-naphthalenediol

The crude amine from step c) of this example was dissolved in 320 ml of chloroform and stirred for 4 hours with a solution of 100 ml of concentrated hydrochloric acid in 1600 ml of water. The resulting layers were separated and the aqueous layer was extracted twice with chloroform. The aqueous layer was then concentrated under reduced pressure on a rotary evaporator. 65 g of sodium hydroxide, 100 ml of water and 200 g of ice were added to the aqueous layer, and the solution was extracted with chloroform. The chloroform extract was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to give 2,3-cis-1,2,3,4-tetrahydro-5- (2-hydroxy-3-tert-butylaminopropoxy) - 2,3-naphthalenediol. The product obtained is recrystallized from a 4: 1 mixture of benzene and acetonitrile.

Claims (3)

SUBJECT Process for the preparation of 2,3-cls-1,2,3,4-tetrahydro-5 - [(2-hydroxy-3-tert-butylamino) propoxy] -2,3-naphthalenediol, characterized in that cis -5,6,7,8-tetrahydro-1,6,7-naphthalentriol is reacted with a carbonyl compound of the formula R 1 -CO-R 2, where is R 1 is hydrogen, (C 1 -C 7) alkyl, (C 1 -C 7) monocyclic cycloalkyl, (C 1 -C 7) monocarbocyclic aryl or (C 1 -C 7) aryl radical; and R 2 is C 1 -C 7 alkyl, C 1 -C 7 monocyclic cycloalkyl, C 1 -C 7 monocarbocyclic aryl or C 1 -C 7 arylalkyl; OF THE INVENTION with an acetal, ketal or enol ether derivative to form a cyclic derivative having a free phenolic hydroxyl group, but both alcoholic hydroxyl groups are protected, forming a salt of the cyclic derivative which is alkylated with epichlorohydrin to form an epoxide, the oxirane ring of the resulting epoxide opens. butylamine to form an amino alcohol which is hydrolyzed to produce the product. 2. The method of item. 1, characterized in that cis-5,6,7,8-tetrahydro-1,6,7-naphthalentriol is reacted with an aldehyde, acetal, ketone, ketal or enolether to protect alcoholic hydroxyl groups in subsequent reactions to obtain the product compounds. 3. The process of claim 2 wherein the ketal is acetone dimethyl ketal.