CA1103683A

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Info

Publication number: CA1103683A
Application number: CA285,198A
Authority: CA
Inventors: Charles Malen; Pierre Roger
Original assignee: Science Union et Cie
Current assignee: Science Union et Cie
Priority date: 1976-08-23
Filing date: 1977-08-22
Publication date: 1981-06-23
Also published as: JPS5325571A; OA05744A; NL7709229A; NL190521B; PH16402A; NL190521C; YU40169B; YU176777A; JPS623150B2; HU178104B; ES461758A1; GB1561153A; AR215142A1; CH623818A5; MX5095E; HK8684A; SU880251A3

Abstract

DE DIVULGATION L'invention concerne un nouveau procédé d'obtention des dérivés du thiochromanne répondant à la formule générale I: I dans laquelle A est de l'hydrogène ou un atome d'halogène, R1 est un hydrogène ou un radical alcoyle inférieur, et R2 est un radical alcoyle inférieur ou cycloalcoyle inférieur, dans lequel on fait réagir un hydroxy thiochromanne avec une halohydrine du glycérol, puis soumet le dérivé dihydroxyle ainsi forme à une amination sélective en présence d'un halogénure de triphénylamino phosphonium. Les composes obtenus par ce procédé sont utiles en thérapeutique humaine ou animale comme agents hypotenseurs ou cardiorégulateurs.The invention relates to a new process for obtaining thiochroman derivatives corresponding to the general formula I: I in which A is hydrogen or a halogen atom, R1 is a hydrogen or a lower alkyl radical, and R2 is a lower alkyl or lower cycloalkyl radical, in which a hydroxy thiochroman is reacted with a glycerol halohydrin, then subjects the dihydroxyl derivative thus formed to a selective amination in the presence of a triphenylamino phosphonium halide. The compounds obtained by this process are useful in human or animal therapy as hypotensive or cardio-regulating agents.

Description

~ ~L 33 ~ ~3 3 La presente invention a pour objet un nouveau proc~de d'obtention de derives du thiochromanne.
Elle a plus precisement pour objet l'obtention de derives thiochromanniques repondant à la formule gen~rale I:

A ~ Rl I
O - C~12 C~IOH - CH2 NH R2 dans laquelle A est de l'hydrogene ou un atome d'halogene, Rl est un hydrogene ou un radical alcoyle inferieur ayant de 1 a 5 atomes de carbone en cha~ne droite ou ramifiee, et R2 est un radical alcoyle inferieur ayant de 1 à 7 atomes de carbone ou un radical cycloalcoyle ayant de 3 a 6 atomes de carbone, ainsi que les sels de ces composes avec un acide mineral ou organique, de prefêrence un acide mineral ou organique thera-peutiquement compatible.
Cette classe de composes a deja ete decrite dans le brevet français 2,092,004. Ce brevet d~crit aussi l'obtention .
des composes de formule gênerale I a partir d'un hydroxy thio-chromanne de formule generale II selon un proc~de qui consiste a faire reagir l'hydroxy thiochromanne de formule generale lI:

A ~ ~1 OH
dans laquelle les substituants A et Rl sont definis comme precedemment, avec le l-chloro 2,3-epoxy propane, et a faire reagir le 2,3-epoxy propoxy thiochromanne resultant de formule generale III:

~ 36133 A~--R~ III

~0/
dans laquelle la definition des substituants demeure inchangee, avec une amine primaire de formule generale IV:

dans laquelle R2 est defini comme prêcedemment, pour obtenir un compose de formule generale I. ~ :
Le nouveau procede selon l'invention est caracterise en ce que l'on fait reagir un hydroxy thiochromanne de formule genêrale II:

A ~ - R

' avec une halohydrine du glycerol en milieu fortement basique pour former le derive hydroxy propyl~ de formule generale V: ;

A~[3R~ V

O C H 2 2 -`
dans laquelle les substituants A et Rl ont les signi- .
fications fournies anterieurement, -~
que l'on fait reagir avec une amine de formule generale IV:

dans laquelle R2 represente un radical alcoyle inf~-rieur ou un radical cycloalcoyle inferieur, en prêsence d'un halogênure d'amino phosphonium de formule ~
gênerale VI: ~. ~ ~ L 33 ~ ~ 3 3 The present invention relates to a new process ~
for obtaining thiochroman derivatives.
More specifically, it aims to obtain thiochroman derivatives corresponding to the general formula I:

A ~ Rl I
O - C ~ 12 C ~ IOH - CH2 NH R2 in which A is hydrogen or an atom halogen, Rl is a hydrogen or lower alkyl radical having 1 to 5 carbon atoms in a straight or branched chain, and R2 is a lower alkyl radical having from 1 to 7 carbon atoms or a cycloalkyl radical having 3 to 6 carbon atoms, as well as the salts of these compounds with a mineral acid or organic, preferably a mineral or organic acid thera-may be compatible.
This class of compounds has already been described in French patent 2,092,004. This patent also describes obtaining.
compounds of general formula I from a hydroxy thio-chromanne of general formula II according to a process which consists to react the hydroxy thiochroman of general formula III:

A ~ ~ 1 OH
in which the substituents A and R1 are defined like before, with l-chloro 2,3-epoxy propane, and to react 2,3-epoxy propoxy thiochroman resulting from general formula III:

~ 36133 A ~ --R ~ III

~ 0 /
in which the definition of substituents remains unchanged, with a primary amine of general formula IV:

where R2 is defined as before, to obtain a compound of general formula I. ~:
The new process according to the invention is characterized in that we react a hydroxy thiochroman of formula general II:

A ~ - R

'' with a glycerol halohydrin in a strongly basic medium to form the hydroxy propyl derivative of general formula V:;

A ~ [3R ~ V

OCH 2 2 -`
in which the substituents A and R1 have the meanings.
information supplied previously, - ~
that we react with an amine of general formula IV:

in which R2 represents an lower alkyl radical ~ -lower or a lower cycloalkyl radical, in the presence of an amino phosphonium halide of formula ~
General VI: ~.

- 2 -~ ~'33683 \ /
LC6l15 P ~ ~ ~ Vl dans laquelle R'l et R'2, identiques ou differents, -representent un radical alcoyle inferieur ou un radical phenyle, et X est un anion d~rive d'un halogene, pour former un compose de formule generale I, que l'on peut le cas echeant, salifier par addition d'un acide mineral ou orga-nique.
La cha~ne hydroxy propoxylee comporte un atome de carbone asymetrique et il est possible d'effectuer le dedouble-ment de la molecule par salification a l'aide d'un acide opti-quement actif comme l'acide d-tartrique, l'acide di-o.toluyl tartrique ou l'acide d-camphosulfonique ou bien encore par esterification a l'aide d'un acide optiquement actif comme l'acide camphanique.
Le present procede trouve son interêt dans le fait que le procede anterieurement decrit, mettait en oeuvre un exces considerable d'amine de formule generale IV, necessitait pour chaque etape un temps de reaction prolong~ et qu'en outre, chaque fois qu'il etait envisage d'obtenir un compose sous forme optiquement active, il ~tait requis d'avoir recours a une etape supplementaire de dedoublement.
Le present procede par sa simplicite et par sa commo-dit~ d'execution evite chacun de ces inconvenients.
Un autre avantage du proced~, objet de la presente invention, reside dans le fait qu'en employant l'amine de formule gen~rale IV en quantite limitee, il est possible .

d'effectuer une amination selective qui porte sur la fonction alcool primaire sans toucher a la fonction alcool secondaire ou sans attaquer les deux fonctions alcools simultanement.
En outre, il est possible de mettre en jeu une amine primaire de formule generale IV dejà sous forme optiquement active, ce qui conduit a un compose de Formule generale I sous forme optiquement active.
Il est possible de citer les amines suivantes opti quement actives qui conviennent pour cette reaction: la see butylamine optiquement active, la (N-ethyl pyrrolidinyl-2) methylamine, la 2-methyl cyclopropylamine, le 3,3-dimethyl 2-aminobutane, le 2-amino 3-methyl hexane, la d-camphylamine etc..
Le procede selon l'invention peut encore être defini par les modes d'execution suivants, actuellement preferes:
1) la reaction entre l'hydroxy thiochromanne de formule generale II et le l-halo 2,3-dihydroxy propane9 est effectuee en presence d'un agent fortement basique comme un hydroxyde de metal alcalin, par exemplP la soude ou la potasse, l'amidure de sodium ou l'hydrure de sodium.
2) la reaction entre l'hydroxy thiochromanne et le l-halo 2,3-dihydroxy propane est effectuee dans un solvant inerte ou dans un solvant polaire comme par exemple~ le di-methyl formamide, le dimethyl acetamide, le dimethyl sulphoxyde ou l'acetonitrile. Le solvant inerte peut être l'acetone, l'êthanol ou le butanol. - 2 -~ ~ '33683 \ /
LC6l15 P ~ ~ ~ Vl in which R'l and R'2, identical or different, -represent a lower alkyl radical or a radical phenyle, and X is an anion derived from a halogen, to form a compound of general formula I, which we can if necessary, salify by adding a mineral or organic acid fuck.
The hydroxypropoxylated chain contains an atom of asymmetric carbon and it is possible to perform the double-ment of the molecule by salification using an optic acid only active like d-tartaric acid, di-o.toluyl acid tartaric or d-camphosulfonic acid or alternatively by esterification using an optically active acid such as camphanic acid.
The present process finds its interest in the fact that the process previously described, implemented a considerable excess of amine of general formula IV, required for each stage a prolonged reaction time ~ and that in addition, whenever he was considering getting a compound under optically active form, it was required to have recourse to a additional step of duplication.
The present procedure by its simplicity and by its said ~ execution avoids each of these drawbacks.
Another advantage of the process ~, object of the present invention resides in the fact that by using the amine of general formula IV in limited quantity, it is possible .

to carry out a selective amination which relates to the function primary alcohol without affecting the secondary alcohol function or without attacking the two alcohol functions simultaneously.
In addition, it is possible to use an amine primary of general formula IV already in optically form active, which leads to a compound of General Formula I under optically active form.
It is possible to cite the following amines opti which are suitable for this reaction: see optically active butylamine (N-ethyl pyrrolidinyl-2) methylamine, 2-methyl cyclopropylamine, 3,3-dimethyl 2-aminobutane, 2-amino 3-methyl hexane, d-camphylamine etc.
The method according to the invention can also be defined by the following modes of execution, currently preferred:
1) the reaction between the hydroxy thiochroman of general formula II and l-halo 2,3-dihydroxy propane9 is performed in the presence of a strongly basic agent such as a alkali metal hydroxide, for example sodium hydroxide or potash, sodium amide or sodium hydride.
2) the reaction between hydroxy thiochroman and l-halo 2,3-dihydroxy propane is carried out in a solvent inert or in a polar solvent such as for example ~ di-methyl formamide, dimethyl acetamide, dimethyl sulphoxide or acetonitrile. The inert solvent can be acetone, ethanol or butanol.

3) la reaction entre l'hydroxy thiochromanne et le l-halo 2,3-dihydroxy propane est effectuee par chauffage ~ une temperature comprise entre 50 et 150, mais de preference entre 75 et 125C. 3) the reaction between hydroxy thiochroman and l-halo 2,3-dihydroxy propane is made by heating ~ a temperature between 50 and 150, but preferably between 75 and 125C.

4) le sel de phosphonium de formule generale VI est .:.~ . .... . . .... .

~3~33-de preference un halogenure de N-methyl N-phenylamino triphenyl phosphonium et par exemple l'iodure de N-methyl N-phenylamino phosphonium. 4) the phosphonium salt of general formula VI is .:. ~. ..... . .....

~ 3 ~ 33-preferably an N-methyl N-phenylamino triphenyl halide phosphonium and for example N-methyl N-phenylamino iodide phosphonium.

5~ la reaction d'amination est effectu~e dans un solvant inerte mais de preference dans un solvant polaire. Les solvants utilisables sont par exemple un hydrocarbure aroma-tique comme le benzene ou le tolu~ne, un solvant polaire comme le dimethyl formamide, le dimethyl sulfoxyde ou l'hexamethyl phosphorotriamide. 5 ~ the amination reaction is carried out in a inert solvent but preferably in a polar solvent. The solvents which can be used are, for example, an aromatic hydrocarbon tick like benzene or tolu ~ ne, a polar solvent like dimethyl formamide, dimethyl sulfoxide or hexamethyl phosphorotriamide.

6) la salification des composes de formule generale I est effectuee par addition d'un acide mineral ou organique tel que l'acide chlorhydrique, l'acide sul~urique, l'acide nitrique, l'acide phosphorique, l'acide formique, l'acide butyrique, l'acide salicylique, l'acide thiazol carboxylique, l'acide pyrrolidone carboxylique ou l'acide isethionique.
Les composes de formule generale I ainsi que leurs sels d'addition sont connus pour leurs proprietes pharmacologi-ques interessantes. Ce sont des agents ~-bloqueurs puissants.
Ils trouvent leur utilisation en therapeutique humaine ou animale dans le traitement des troubles du rythme cardiaque, de l'hypertension et de certains etats psychotiques.
A ces fins, ils sont utilis~s sous forme de composi-tions pharmaceutiques en association avec un excipient ou vehi-cule inerte, non-toxique, pharmaceutiquement acceptable conve-nant pour l'administration par voie buccale, parenterale ou rectale.
Les hydroxythiochromannes de formule generale II qui sont utilises comme composes de depart peuvent être obtenus selon le procedë decrit dans le brevet français 2,042,374.
Les halogenures d'amino phosphonium de formule gene-rale VI sont decrits dans la litterature notamment par Tanigawa ., . ~ . . ,- . . . ~ , . ~ . .

(Tetrahedron Letters 1975, 471-472).
Les exemples suivants illustrent l'invention. Ils ne la limitent en aucune façon.
EXEMPLE _ dl 8-(3-terbutylamino 2-hydroxypropoxy) thiochromanne ______ ____ _ __ __ ___ ______ ________ _ __ . _ _ Stade A
On introduit dans un ballon a 3 tubulures successive-ment 4 9 de soude en pastilles, 20 ml d'eau puis apres disso-lution 16.6 g de 8-hydroxy thiochromanne prealablement dissout dans 200 ml d'ethanol. Le melange est chauffe a 50 pendant 15 minutes sous agitation et tout en maintenant l'agitation, on ajoute goutte a goutte 12.1 9 de l-chloro 2,3-dihydroxy propane. On maintient le melange reactionnel a 50 pendant 3 heures, en ajoutant toutes les heures une quantite supplemen-taire de l-chloro 2,3-dihydroxy propane.
On chauffe au total pendant 5 heures a 50, laisse refroidir le melange reactionnel à temperature ordinaire puis evapore ~ sec sous vide, le solvant. Le residu sec est repris par l'eau et agite vigoureusement. L'insoluble est separe par filtration, lave a l'eau jusqu'~ neutralite des eaux de lavage et seche sous vide phosphorique. Le produit brut ainsi obtenu pèse 16 9, soit un rendement de 66%. Le 8-(2,3-dihydroxy propoxy) thiochromanne brut fond ~ 115-120. Apres recristal-lisation de l'acetate d'ethyle, il fond a 118-120.
Stade B
On met 2 g 4 de 8-(2,3-dihydroxy propoxy) thiochro-manne dans 10 ml de dimethyl formamide. On ajoute a la solu-tion O 9 24 d'hydrure de sodium et on chauffe le melange à 80 pendant 30 mn. On introduit alors une solution de 4 9 25 d'iodure de N-methyl N-phenylamino triphenyl phosphonium dans 40 ml de dim~thyl formamide puis une solution de 1 9 46 de 3~

terbutylamine dans 15 ml de dimethyl formamide.
Le melange reactionnel est chauffe à nouveau à 80 pendant 2 heures puis laisse à refroidir à temperature ordi- ;
naire. Le solvant est evapor~ par distillation sous pression reduite et le residu est repris dans le chloroforme. La solu-tion organique est extraite à 3 reprises avec de l'acide chlorhydrique decinormal. On reunit les solutions acides, les alcalinise franchement par addition de soude puis epuise nouveau ~ l'ether.
Les solutions etherees sont lavees à l'eau, puis sechees sur sulfate de magnesium, filtrees et evaporees à sec.
On recueille ainsi un residu huileux pesant 2 g 4. On le puri-fie par chromatographie sur colonne de silice et elution par un melange de benzene et de methanol à parties egales. L'evapo-ration du solvant de l'eluat permet d'obtenir le dl 8-(3-ter-butylamino 2-hydroxy propoxy) thiochromanne avec un rendement de 60%. Il fond à 70-72.
Le dl 8-(3-terbutylamino 2-hydroxy propoxy) thiochro-manne peut être transforme en sel par mise en solution dans le methanol et addition d'acide chlorhydrique pour former le chlorhydrate, d'acide methane sulfonique pour former le methane sulfonate ou d'acide maleïque pour former le maleate.
EXEMPLE II
8-(3-sec-butylamino 2-hydroxy eroeoxy) thiochromanne En ut-ilisant le mode op~ratoire de l'exemple I stade B, au depart du 8-(2,3-dihydroxy propoxy) thiochromanne et de (+) sec.butylam-ine, on obtient le 8-(3-sec.butyl'amino 2-hydroxy propoxy) thiochromanne (isomère dextrogyre) avec un rendement de 55%-6!33 Point de fusion: 80-88 ~578 = ~ 4 1 (c - 1% methanol) ~365 ~ ~ 1l (c = 1% methanol) EXEMPLE III
8-(3-sec.butylamino 2-hydroxy eropoxy) thiochromanne ________ _ _ ________ ___ _ __ __ ______ ___ _ _ En operant comme a l'exemple I stade B, au depart du 8-(2,3-dihydroxy propoxy) thiochromanne et (-) sec.butylamine, on obtient avec un rendement de 55% lé 8-(3-sec.butyl 2-hydroxy propoxy) thiochromanne (isomere levogyre). ;
~ ~5378 - - 4.1 (c - 1% méthanol) ~ ~365 11 (c ~ 1% methanol) Preparation du 8-hydroxy thiochromanne de depart On chauffe a 40 300 9 d'acide polyphosphonique au bain d'eau et on y ajoute en 90 minutes 30 9 d'acide (o.
methoxyphenyl) thio propionique. On maintient le melange sous agitation pendant 2 heures ~ 40. On coule alors sur de la glace pilee. Après hydrolyse totale du melange reactionnel, le produit est separê par filtration, essor~, lave ~ l'eau et seche en etuve. On obtient ainsi 21 g 9 de 8-methoxy thiochro-20 mannone sous forme d'une poudre jaune-clair oxydable a l'air. ~
Le produit pur fond a 98-100 (Rendement 80%). ;
On introduit dans un ballon 23 9 96 de 8-methoxy thiochromannone dans un melange de 27.4 ml d'hydrate d'hydra-zine et 112 ml de glycol. On porte au reflux pendant 2 heures puis on refroidit le melange reactionnel a temperature ordi-naire et ajoute sous forte agitation 15 9 8 de potasse en pas-tilles. On porte au reflux apres dissolution de la potasse tout en eliminant l'eau par distillation. On porte progressi-vement a 205-210 puis laisse 6 heures a cette temperature. Au 30 bout de ce laps de temps, on ajoute 10 ml d'hydrate d'hydrazine ~
' ~;: ;

et on renouvelle le chauffage. A la fin de cette deuxième periode de chauffage, on verse le m~lange reactionnel sur de l'eau froide. On acidifie le melange par addition d'acide chlorhydrique puis on epuise à 3 reprises au chloroforme.
Les phases chloroformiques reunies sont lavees ~ 3 reprises par 200 ml d'eau, puis sechees et evaporees à sec. Le residu sec est purifie par distillation fractionnee. On recueille une fraction pure distillant à 104-106 sous 0.1 mm Hg. Le rendement est de 13 g 61 soit 67%~
Le 8-hydroxy thiochromanne fond ~ 86-88. Par ailleurs, les distillats eau ~ glycol sont recuperes, dilues à
l'eau, epuises au chloroforme. Les solutions chloroformiques sont lavees ~ l'acide chlorhydrique dilue, lavees a l'eau, sechees sur sulfate de sodium et amenees a sec. On obtient 3 g 11 de 8-methoxy thiochromanne sous forme d'un liquide epais.
Ebo 06 ~ 115-118 n23 - 1.6110 Le 8-methoxy thiochromanne est ensuite demethyle par action du complexe trifluorure de Bore^acide acetique dans le chlorure de methylene.
On obtient ainsi une deuxieme fraction de 8-hydroxy thiochromanne.

" 6) the salification of the compounds of general formula I is carried out by adding a mineral or organic acid such as hydrochloric acid, sul ~ uric acid, acid nitric, phosphoric acid, formic acid, acid butyric acid, salicylic acid, thiazol carboxylic acid, pyrrolidone carboxylic acid or isethionic acid.
The compounds of general formula I and their addition salts are known for their pharmacological properties.
what are interesting. They are powerful ~ blockers.
They find their use in human therapy or animal in the treatment of heart rhythm disorders, hypertension and certain psychotic states.
For these purposes, they are used in the form of a compound.
pharmaceuticals in combination with an excipient or vehicle inert, non-toxic, pharmaceutically acceptable formula suitable for administration by the oral, parenteral or rectal.
The hydroxythiochromans of general formula II which are used as starting compounds can be obtained according to the method described in French patent 2,042,374.
The amino phosphonium halides of formula gene-rale VI are described in the literature notably by Tanigawa .,. ~. . , -. . . ~,. ~. .

(Tetrahedron Letters 1975, 471-472).
The following examples illustrate the invention. They don't limit it in any way.
EXAMPLE _ dl 8- (3-terbutylamino 2-hydroxypropoxy) thiochroman ______ ____ _ __ __ ___ ______ ________ _ __. _ _ Stage A
We introduce into a balloon with 3 successive tubes-4 4 soda in pellets, 20 ml of water then after dissolving 16.6 g of previously dissolved 8-hydroxy thiochroman in 200 ml of ethanol. The mixture is heated to 50 during 15 minutes with stirring and while maintaining stirring, 12.1 9 of l-chloro 2,3-dihydroxy are added dropwise propane. Maintaining the reaction mixture at 50 for 3 hours, adding an additional amount every hour shut up with l-chloro 2,3-dihydroxy propane.
We heat in total for 5 hours at 50, leave cool the reaction mixture to room temperature then evaporated ~ dry under vacuum, the solvent. The dry residue is taken up by water and shakes vigorously. The insoluble matter is separated by filtration, washing with water until the washing water is neutral and dries under phosphoric vacuum. The gross product thus obtained weighs 16 9, ie a yield of 66%. 8- (2,3-dihydroxy propoxy) crude thiochroman background ~ 115-120. After recrystal-lization of ethyl acetate, it melts at 118-120.
Stage B
We put 2 g 4 of 8- (2,3-dihydroxy propoxy) thiochro-manna in 10 ml of dimethyl formamide. We add to the solu-tion O 9 24 of sodium hydride and the mixture is heated to 80 for 30 min. A solution of 4 9 25 is then introduced.
N-methyl N-phenylamino triphenyl phosphonium iodide in 40 ml of dim ~ thyl formamide then a solution of 1 9 46 of 3 ~

terbutylamine in 15 ml of dimethyl formamide.
The reaction mixture is again heated to 80 for 2 hours then leaves to cool to room temperature;
nary. The solvent is evaporated by pressure distillation reduced and the residue is taken up in chloroform. The solu-organic tion is extracted 3 times with acid hydrochloric decinormal. We bring together the acid solutions, alkalinizes frankly by adding sodium hydroxide then exhausts new to ether.
The ethereal solutions are washed with water, then dried over magnesium sulfate, filtered and evaporated to dryness.
An oily residue weighing 2 g 4 is thus collected. It is purified fi by chromatography on a silica column and elution with a mixture of benzene and methanol in equal parts. The evapo-ration of the eluate solvent makes it possible to obtain the dl 8- (3-ter-butylamino 2-hydroxy propoxy) thiochroman with a yield 60%. It melts at 70-72.
Dl 8- (3-terbutylamino 2-hydroxy propoxy) thiochro-manna can be transformed into salt by solution in the methanol and addition of hydrochloric acid to form the hydrochloride, methane sulfonic acid to form methane sulfonate or maleic acid to form the maleate.
EXAMPLE II
8- (3-sec-butylamino 2-hydroxy eroeoxy) thiochroman Using the operating mode of Example I stage B, departing from 8- (2,3-dihydroxy propoxy) thiochroman and (+) sec.butylam-ine, we get 8- (3-sec.butyl'amino 2-hydroxy propoxy) thiochroman (dextrorotatory isomer) with a yield 55% -6! 33 Melting point: 80-88 ~ 578 = ~ 4 1 (c - 1% methanol) ~ 365 ~ ~ 1l (c = 1% methanol) EXAMPLE III
8- (3-sec.butylamino 2-hydroxy eropoxy) thiochroman ________ _ _ ________ ___ _ __ __ ______ ___ _ _ By operating as in example I stage B, from the 8- (2,3-dihydroxy propoxy) thiochroman and (-) sec.butylamine, we obtain with a yield of 55% le 8- (3-sec.butyl 2-hydroxy propoxy) thiochroman (levorotatory isomer). ;
~ ~ 5378 - - 4.1 (c - 1% methanol) ~ ~ 365 11 (c ~ 1% methanol) Preparation of the starting 8-hydroxy thiochroman 40,300 9 of polyphosphonic acid are heated to water bath and 30 ml of acid (o.
methoxyphenyl) thio propionic. We keep the mixture under stirring for 2 hours ~ 40. We then run on crushed ice. After complete hydrolysis of the reaction mixture, the product is separated by filtration, drying ~, washing ~ water and dry in an oven. 21 g 9 of 8-methoxy thiochro- are thus obtained.
20 mannone in the form of a light yellow, air-oxidizable powder. ~
The pure product melts at 98-100 (Yield 80%). ;
23 9 96 of 8-methoxy are introduced into a flask thiochromannone in a mixture of 27.4 ml of hydrate hydrate zine and 112 ml of glycol. We bring to reflux for 2 hours then the reaction mixture is cooled to normal temperature and add 15 9 8 of potash in vigorous stirring tilles. It is brought to reflux after dissolution of the potash while removing water by distillation. We wear progressi-at 205-210 then leave 6 hours at this temperature. At 30 end of this period of time, 10 ml of hydrazine hydrate are added ~
'~ ;:;

and the heating is renewed. At the end of this second heating period, pour the reaction mixture on cold water. The mixture is acidified by adding acid hydrochloric then exhausted 3 times with chloroform.
The combined chloroform phases are washed 3 times with 200 ml of water, then dried and evaporated to dryness. The residue dry is purified by fractional distillation. We collect a pure fraction distilling at 104-106 at 0.1 mm Hg.
yield is 13 g 61 or 67% ~
8-hydroxy thiochroman melts ~ 86-88. By elsewhere, the water ~ glycol distillates are recovered, diluted to water, exhausted with chloroform. Chloroform solutions are washed ~ dilute hydrochloric acid, washed with water, dried over sodium sulfate and brought to dry. We get 3 g 11 of 8-methoxy thiochroman in the form of a thick liquid.
Ebo 06 ~ 115-118 n23 - 1.6110 The 8-methoxy thiochroman is then demethylated by action of the boron trifluoride complex ^ acetic acid in the methylene chloride.
A second fraction of 8-hydroxy is thus obtained thiochroman.

"

Claims

The embodiments of the invention about which an exclusive right of property or privilege is claimed, are defined as follows:

1. A new process for obtaining thio- derivatives chromans corresponding to general formula I:

I
in which A is hydrogen or an atom halogen, R1 is hydrogen or a lower alkyl radical having from 1 to 5 carbon atoms in a straight or branched chain, and R2 is a lower alkyl radical having 1 to 7 carbon atoms or a cycloalkyl radical having 3 to 6 carbon atoms, as well as the salts of these compounds with a mineral acid or therapeutically compatible organic, characterized in that a hydroxy thio- is reacted chromanne of general formula II:

II
with a halo hydrine of glycerol in a strongly basic medium to form the hydroxy propylated derivative of general formula V:

V

in which the substituents A and R1 have the meanings previously provided, which is reacted with an amine of general formula IV:

in which R2 represents an alkyl radical lower or a lower cycloalkyl radical, in the presence of an amino phosphonium halide of formula general VI:

VI

in which R'1 and R'2 are identical or different rents and represent a lower alkyl radical or the phenyl radical, and X is an anion derived from a halogen.

2. A method according to claim 1, wherein the reaction between hydroxy thiochroman of general formula II and l-halo 2,3-dihydroxy propane, is carried out in presence of a strongly basic agent.

3. A method according to claim 2, wherein the strongly basic agent is an alkaline motel hydroxide.

4. A method according to claim 1, wherein the reaction between hydroxy thiochroman and 1-halo 2,3-dihydroxy propane is carried out in an inert solvent or in a polar solvent.

5. A method according to claim 1, wherein the reaction between hydroxy thiochroman and 1-halo 2,3-dihydroxy propane is carried out by heating to a temperature ture between 50 and 150 ° C.

6. A method according to claim 1, wherein the phosphonium salt of general formula VI is a halide of N-methyl N-phenylamino triphenyl phosphonium.

7. A method according to claim 1, wherein the amination reaction is carried out in an inert solvent and polar.