LU83039A1 - METHODS OF SYNTHESIS OF 1- (4 ISOPROPYLTHIOPHENYL) -2-N OCTYLAMINOPROPANOL - Google Patents

Description

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Patent application for. ? .l décenibre 1980 Designation of the Inventor C) The undersigned Mr. Char! es München, patent attorney in Luxemboi ......................... ................................... place ..... b.ß.u.le.va .rd ...... Pr.in ^ .e .-. He.nri .............................. .................................................. .........................

acting as depositor - agent of the depositor - (2) ...... of ...... la .... soc.i.é.té ..... anonymous ..... .dite ..: ....... '' .. C.ontj '.. ne.nt, al ..... Pharma ", Avenue Loui se, 135, Bruxelles, Belgique (3) de l' invention relating to: "Methods of synthesis of 1 isopropy 11 hiopheny 1) - 2 - n. octylami nopropanol", designated as inventor (s) ·.

l.) Surname and first names Monsieur ..... Georges ..... E ....... LAMBELIN ....................... ....................................

Address .......... 31., ...... Street ...... Cervantes, ....... FQ.re.st .., ...... Belgium ................................................. ......................

'' Mr. Claude GILLET

at. /Last name and first names.............................................. .................................................. .................................................. .................................................. ..................................

Address ........... 1.1 .., ....... B.Ü9 ...... des ...... Lovi ères, B.l.anmo ^ nt ..,. Belgium 3. ilom and first names ........ Ϊ1? .. 9..1.Ϊ.§..9..Γ ...... 1.9 ... 1.IÜ ..... H..B..B111..B..3 ..................................... .................................................. .....................................

Address ......... £ ..9.®.Γ..9 ... 9..1..4.1, Λ ..... 1.8. * ..... W e S pe 1 .δ..δΧ ..., ....... B e 1.0 i.e. ........................... .................................................

^ He affirms the sincerity of the above-mentioned indications and declares to assume full responsibility for them.

Luxembourg) e 31 December 19 80 I tüÔCE lÜ »i« r: eeBfcai, .5 fel f S (Jf y

Received 1p ^ ..... 11 - ”- Ein · ..

The prepcsé, ............................................... ..

• y (signature) ή ^? F _ ('j Last name, first names, firm, address.

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DESCRIPTIVE MEMORY filed in support of an INVENTION PATENT application

on behalf of the public limited company known as: "CONTINENTAL PHARMA" for: "Synthesis processes of 1- (4-isopropylthiophényï) -2-n. o c ty lami n opr opano 1"

Inventors: G. Lambelin C. Gillet J. Herma ns '' /

W

t 2

The present invention relates to processes for the synthesis of 1- (4-isopropylthiophenyl) -2-n.octylamino-propanol (suloctidil) represented by formula I, of its "salts and its esters"

1C3H7-S-OiH-ÇH-MH "C8Hl7 X

- OH CHj

If the derivatives according to formula I are in the form of addition salts with acids, they can be transformed, according to the usual methods, into their free base or into salts with other acids.

The most commonly used salts are acid addition salts, in particular non-toxic acid addition salts, pharmaceutically usable, formed with suitable inorganic acids, for example hydrochloric acid, sulfuric acid or phos-phoric acid or with suitable organic acids, such as aliphatic, cycloaliphatic, aromatic, arali-phatic or heterocyclic, carbocyclic or sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic acids , lactic, malic, tartaric, citric, ascorbic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, hydroxybenzoic, salicylic, phenylacetic, mandelic, embonic, methane-tallow onic, ethanesulfonic, panthotenic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, glucuronic.

Examples of esters commonly used are the acetic, projaonic / cyclohexanecarboxylic, cyclopentanecarboxylic, pivalic, tertiobutylacetic, cyclohexaneacetic, .alkoxyphenylacetic and 2-methyl-propioric acid esters.

In cases where the processes give rise to the production of new intermediate compounds, these new compounds, as well as the processes which serve for their preparation, also form part of the present invention. 3 ê “#” • l

NOT

The present invention relates to processes for the synthesis of 1- (4-isopropylthiophenyl) -2-n.octylaminopropanol (suloctidil) represented by formula I and of its salts.

'iC3H7-s / Q \ cH-CH-NHnC8H17 ^' OH CH3

If the derivatives according to formula I are in the form of addition salts with acids, they can be transformed, according to usual methods, into their free base or into salts with other acids.

The most commonly used salts are acid addition salts, in particular non-toxic acid addition salts, pharmaceutically usable, formed with suitable inorganic acids, for example hydrochloric acid, sulfuric acid or phosphoric acid or with suitable organic acids, such as aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic, carboxylic or sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic acids . tartaric, citric, ascorbic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, hydroxybenzoic, salicylic, phenylacetic, mandelic, embonic, methanesulphonic, ethanesul fonic, panthotenic, youuenesulfonic, sulfanilonic, sulfanilonic, sulfanilonic.

In cases where the processes give rise to the production of new intermediate compounds, these new compounds, as well as the processes which serve for their preparation, also form part of the present invention. . / /> / (/)! •. The compounds according to the invention are prepared according to the following processes which form part of the present invention and defined as follows: *

Method A.

According to this procedure, an a keto-oxime of formula III is reacted with an aldehyde of formula III and reduced so as to form 1- (4-isopropylthiophenyl) -2-n.octyl-aminopropanol of formula I. The reaction scheme is as follows:

.OH

_ ON7 0 0 iC3H7S ^ n) -C-C-CH3 + C7H15C _y iC3H7S- <y ^ C-CH-N = CH-C7H] j. '- / XH l CH3 i

I II III IV

reduction iC3H7 $ - »^ - CH0HÇHNHnC8H17 ch3

Advantageously, the intermediate iviminoketone IV is not isolated before the reduction to amino alcohol I.

The condensation of oxime II with aldehyde III is conventionally carried out in an inert organic solvent such as chlorinated solvents such as chloroform or dichloromethane or alcohols such as methanol, ethanol, propanol or butanol or aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene or petroleum ether. The reaction takes place in the presence of a hydrogenation catalyst and hydrogen. As hydrogenation catalyst, there may be mentioned, without being exhaustive, platinum oxide ·, Raney nickel, palladium, activated carbon. > / • '5 Oxime II is prepared by treatment of 4-isopropylthiophenyl-propiophenone with an oxidation reagent such as, for example, isoamyl nitrite in the presence of a strong base such as alcoholate.

Process, B.

According to this procedure, 1- (4-thiophenyl) -2-n.octyl-aminopropanol of formula V is alkylated according to the following scheme: HS ^ -CH0HÇHNHnC8H17 + iC3H7X-> iC3H7S - ^) - CH0HÇHNHnC8 H17 ch3 ch3

V VI I

In product VI, X represents a group which easily gives rise to substitution reactions such as, for example, tosyl or mesyl groups or halogens such as chlorine, bromine and iodine.

Conventionally, the reaction takes place in water or in an inert organic solvent such as chlorinated solvents such as' chloroform or dichloromethane, hydrocarbons such as benzene, toluene or petroleum ether, ketones such as acetone or methyl ethyl ketone. Advantageously, an organic or inorganic base is introduced into the reaction mixture. The base can thus be sodium or potassium hydroxide, triethylamine, pyridine or even N-dimethyl-aniline. This reaction can also take place in the presence of a phase transfer catalyst such as, for example, tetra-n.butylammonium hydroxide. Depending on the reagents used, the temperature will be between room temperature and the reflux temperature of the chosen solvent. > / y r) 6

A variant of this process consists in reacting 1- (4-thiophenyl) 2-n.octylaminopropanol V with propene VII according to the scheme: * + HS ^) “CH0HCHNHnC8H17 + CH2 = CH” CH3 —— ”iC3H7S- (g) -CH0HCHNHnC8H17 ch3 ch3

'V VII I

Generally, an excess of olefin is put in the presence of strong acid such as, for example, 75¾ sulfuric acid or concentrated hydrochloric acid, nitric acid or phosphoric acid. Then, with stirring and at a temperature between -20 ° C and 50 ° C, preferably at a temperature close to 0 ° C, the thiophenolic derivative is added. The temperature of the reaction mixture is then allowed to return to normal temperature and the product I is isolated according to conventional methods in organic chemistry.

Thiophenol V can be obtained by diazotization of the corresponding amino derivative and treatment of the diazonium salt with, for example, hydrofluoric acid.

Method C.

This new way of proceeding is illustrated by the following * "diagram: iC3H7S '©" CH0H "CH" NH2 + CH2 ° + CH3-C0- (CH2) 4-CH3 ch3

X

VIII IX

1) condensation 2) reduction iC3H7S '©> “CH0H'CH" NMnC8H17 - / CHq ύ! 7 Amine VIII is placed in the presence of formaldehyde IX and hepta-none-2 X. This reaction is carried out in solvents Inert organic substances such as alcohols, chlorinated solvents or aliphatic or aromatic hydrocarbons and preferably at a temperature above ambient temperature. Advantageously, the reaction will take place under acid catalysis. The acids used for catalytic purposes are mineral or organic such as, for example, hydrochloric acid, sulfuric acid or acetic acid.

In general, the reaction mixture is refluxed for several hours. The product can then be isolated and purified or immediately undergo reduction of the carbonyl group.

This reduction can be carried out in the usual way, for example, by hydrogenation in the presence of a catalyst, such as palladium on carbon, Raney nickel or platinum, in the presence of a solvent, such as methanol or ethanol. , and that at ordinary pressure or at high pressure, or by the action of alkali metal hydrides such as sodium borohydride, in a solvent such as methanol or ethanol preferably at low temperature or aluminum hydride and lithium in ether or tetrahydrofuran, preferably at low temperature, or by the action of an aluminum alcoholate, such as aluminum isopropylate, and this in a solvent, such as isopropanol, most advantageously at reflux thereof, or alternatively by the action of hydrazine hydrate under the conditions required for the reduction of Wolff-Kishner c *> of Huang-Mi ni on.

.. * The product is then isolated by crystallization and purified. / • · fl 7 /.

8

Method D.

According to this way of proceeding, l- (4-aminophenyl) -2-n.octyl aminopropanol XI is transformed into l- (4-isopropyl thiophenyl) -2- n.octylaminopropanol I via the diazonium salt XII according to the • scheme. : H2N- (2) "CH0HCHNHnC8H17 - N2 - @ - CH0HCH ~ NHnC8Hi7 CH3 HCl / NaN02 CH3

XI XII

iC ^ HySH / base

XIII

> r i C3H7S - ^) - CH0HCHNHnC8H17 CH3

The diazonium salt XII is conventionally formed by the addition at low temperature, that is to say at a temperature between -20 ° C. and 10 ° C., of an aqueous solution of sodium nitrite to an aqueous solution of amine. and hydrochloric acid. The diazonium salt thus obtained is neither isolated nor purified, it is opposed to an aqueous solution of isopropylmercaptan XIII in basic medium. The base can be mineral like sodium or potassium hydroxide or organic like triethylamine or pine ridine. This second reaction occurs first at low temperature as explained above, but it may be advantageous at the end of the reaction to increase the temperature to approximately!

50-100 ° C, preferably 70 ° C. X

.. / i (t É I 9! EXAMPLE 1.

! . '- -! | 11.8 g of 1- (4-thiophenyl) -2-n.octylaminopropanol and 14.7 g (0.05 mole) of isopropyl tosylate are dissolved in 25 ml of a 15% aqueous hydroxide solution of sodium and heated at 75 ° C for 2 hours, with stirring.

. After cooling, add 50 ml of water and filter. Recrystallize from n.heptane at -20 ° C and filter. Recri stalliser optionally in n.heptane or in acetone.

Yield: 11.4 g (68%).

Melting point: 61-64 ° C.

EXAMPLE 2.

A mixture of 14.7 g (0.05 M) of 1- (4-thiophenyl) -2-octyl-aminopropanol and 2.2 g of sodium hydroxide in 50 ml of isopro-panol is heated to 60 ° C then treated slowly with 7.38 g (0.06M) of isopropyl bromide. Return for 4 hours. Evaporate to dryness. take up the residue in 30 ml of water and 50 ml of toluene. After complete dissolution, separate the organic phase, wash it, treat it with animal black and filter it hot on celite. Evaporate the solvent in vacuo, recrystallize from n.heptane and filter at -20 ° C. Recrystallize from acetone.

Yield: 10.6 g (63%).

Melting point: 63.4 ° C.

EXAMPLE 3.

.. a) Formatior of the diazonium salt XII.

In a 250 ml ball, a mixture of 17 g (0.06 mole) l- (4-aminophé-nyl) -2-n. octyl-ami nopropanol XI and 67.5 ml 4N HCl is cooled with stirring to -5 ° C. Then, a solution of 9.3 g (0.135 mole) of sodium nitrite in 70 ml of water is added keeping the temperature between -5 ° C and 0 ° C and the mixture obtained (cloudy yellowish solution) is stirred for 2 hours at low temperature.

The product thus obtained (intermediate XII) is not isolated and the reaction mixture is used as it is in the following stage.

, / y i. ‘10 b) Thioalkylation of the diazonium salt.

Under a nitrogen atmosphere, a solution of 11 g of sodium hydroxide and 5.2 g (0.068 mole) of isopropylmercaptan in 100 ml of water is prepared and cooled to -5 ° C. Then, under a nitrogen atmosphere and with stirring, the intermediate product obtained above is added thereto in approximately 2 hours at a temperature between -5 ° C. and 0 ° C.

*

Then the mixture is stirred for 16 hours at room temperature, then carefully heated to 70 ° C and cooled again to 0 ° C.

Acidify (pH = 0) with 25 ml of concentrated hydrochloric acid, bubbling a stream of nitrogen for 30 minutes to remove the excess of isopropylmercaptan. Then add in 15 minutes, 12.5 g of cuprous chloride (CuCl) dissolved in 75 ml of concentrated HCl and stir for 30 minutes at room temperature, in order to transform the nîtrosamine again and secondary amine. Then 250 ml of toluene are added and the reaction mixture is brought to pH = 14 with 250 ml of sodium hydroxide at 15¾.

The mixture obtained is filtered, the filtrate is decanted and the organic phase is evaporated under reduced pressure. The residue is redissolved in 250 ml of ethyl acetate and this solution is filtered through a bed of silica gel and evaporated under reduced pressure. Recreate twice in n.heptane at -15 ° C. Optionally, treat with activated carbon and recrystallize.

11.6 g are obtained, ie 56% of product I.

Melting point 62 ° C.

EXAMPLE 4.

a) A mixture composed of 6.4 g (24.5 mmol) of 1- (4-isopropyl-thiophenyl-2-aminopropanol) hydrochloride, 1.33 g (44.5 mmol) of paraformaldehyde and 10, 15 g (89 mmol) of hepta-none-2 in 25 ml of ethanol is heated at reflux for 2 hours.

Remove the solvent in vacuo and add 40 ml of ether to the residue. Filter the precipitate obtained and add 100 ml of ether to the filtrate. After several hours, a precipitate is deposited. Filter. / Combine the 2 fractions: 3 grams of the produvt / / I · 11% ketone are obtained, characterized by IR and NMR spectroscopy.

b) Dissolve 2.2 g (55 mmol) of sodium hydroxide in 25 ml of ethylene glycol at 110 ° C. Cool to 90 ° C and add 3 g (7.8 mmol) of ketone obtained above and 2 ml (40 mmol) of hydrazine hydrate at 80J. Gradually heat up to 195 ° C while collecting the distillate (3 ml) and reflux for 2 hours. Cool, pour into 50 ml of water and extract with ether. Dry and evaporate the ether under vacuum. Take up the residue with pentane, cool to -20 ° C and filter. Recrystallize from n-heptane.

This gives 1- (4-isopropylthiophenyl) -2-n.octylamino-propanol EXAMPLE 5.

Suspend 5.3 g of platinum oxide in 15 ml of dry ethanol in a hydrogenation reactor and introduce a slight hydrogen pressure.

Then add at room temperature a solution of 7 g (24.5 mmol) of compound II and 3.75 g (29.3 mmol) of octanal in 75 ml of dry ethanol. Stir under a hydrogen atmosphere until the reagents disappear. Remove the solvent in vacuo and purify the product by column chromatography and recrystallization from n.pentane.

Claims (7)

1. Process for the synthesis of 1- (4-i $ opropylthiophenyl) -2-n.octyl-aminopropanol, its esters and its salts, characterized in that compound II is reacted with octanol and that 1. α-irninoketone thus obtained is reduced to amino alcohol OH * / 0 N 1 C3H7s <^^ - C-C-CH3 II 2. Process for the synthesis of l- (4-isopropylthiophenyl) -2-n-octyl ami i propanol, its esters and its salts, characterized in that l- (4-thiophenyl) -2-n is subjected -octylaminopropanol to alkylation " 3. Method according to claim 2, characterized in that l- (4-thiophenyl) -2-n-octylaminopropanol is reacted with an alkylating agent iCgH ^ X where X represents an easily removable group 4.. Next process claim 2, characterized in that 1- (4-thiophenyl) -2-n-octylaminopropanol is reacted with propene in an acid medium. 5. Process for the synthesis of l- {4-isopropylthiophenyl) -2-n.octyl-aminopropanol, its esters and its salts, characterized in that the l- (4-isopropylthiophenyl) -2- is reacted aminopropanol with formaldehyde and heptanone-2 and that the product obtained is reduced to amino alcohol. 6. Process for the synthesis of l- (4-isopropylthiophenyl) -2-n.octyl-aminopropanol, its esters and its salts, characterized in that the diazonium salt of l- (4-friend nophenyl) -2- not. octyl ami nopropanol is treated with isopropylmercaptan and is finally hydrolyzed in basic medium to give the abovementioned amino alcohol. 'JL · c't-n; ...... Λ-- P- - i: ... OJ i - · “......... A; - vs; .cr.c'Cé .: or '........ A ..... c. :: · ί · Λ |. > * \ & Λ