BE622101A - - Google Patents

Description

       

   <Desc / Clms Page number 1>
 
 EMI1.1
 e D'ri. ", from 3¯" -dlhydronapbtelên., t
 EMI1.2
 The present invention does not relate to new 3 4 α3hydro-naphthalenes and more particularly relates to novel α-phenyl-lw (V8id.no4 <ralooacy) phenyl -3 4 alhydironapht6llne6 and their addition solos with the acids thereof. ammonium oxides, N-oxides, and N-oxides with an acid, as well as their purification processes.



  The new compounds according to i v.3ntion are oiaia

 <Desc / Clms Page number 2>

 
 EMI2.1
 in a clesme comprising Ca) the free bases, (b) the addition gel with the pharmaceutically acceptable acids (c) the N # oxidises, (d) the addition salts with the pharmaceutically acceptable acids of the N- oxidon and (e) the quaternary #! # #emmoniu of compounds having the formula 1 ei'-M '? e 8
 EMI2.2
 
 EMI2.3
 in which he and ÏL. iont radicals 0100710 lower * or --al00110 lower bound together to form a radical b4 "- = saturated cyclic with 5 to 7 nuclear atoaaa of which one of the It01111 '. of the nucleus independently of the nitrogen atom emluiquo4 is oarbone, since nitrogen or the other naeleat atoms are carbon, Bg and R are trtfluorom4tbyl, 8106n11 lower alkyl radicals. lower, b1dtOxr.

   lower aloozy, lower aloozy, 6-18 atom axyloxy of OR "1> OA.



  Includes lower halogen .10011.roapto and erylmeroapto of 18 carbon atoms 1nu., 'OnHI. represents an alkyl group of 2 to 6 carbon atoms * Included # m and y-mont of whole numbers * from 0 to 4 Included and R5 and ÏL has hydrogen or a group
 EMI2.4
 lower alkyl
 EMI2.5
 By lower alkyl is meant a croup 810011. oonenant 1 & 8 carbon atom included such as methylop 'thJ'10. propyl, butyl, amyl, hlx ... 71st, heptyl-, acetabulum and their .. isomeric forms * By lower oloenyl is meant an elkenylt group containing 2 to 8 carbon atoms, including such as vinyl,., 1; (, 18 ,

 <Desc / Clms Page number 3>

 
 EMI3.1
 tiutbn;

  3, a, paatdarJ., Hexenyl, heptenylop oct6nyle and their formed isomers By lower alooxy is meant a 6 - zi-4y group containing 1 to 6 carbon atoms inclusive such as methoxy ethoxy, butoxy, emyloxyp hexyloxy, heptyloxy, ootyloxy and their forming isomers. By lower alkenyloxy is meant an aloenyloxy group containing 8 to 3 carbon atoms inclusive such as vinyloxy, allyloxy, butenyloxyb pentonyloxy, hex6nyloxyt heptenyloxy, ootenyloxy and their isomeric forms. The term aryloxy of 6 to 18 carbon atoms Included includes the radicals pli4nom7p tolyloxy, xylyloxy, nophtylozyt btpbényloxp etc. The term halogen includes aaplaty.oxr, 'bpbda, Yloa, and texce alualoene oomprand' flow, chlorine, 1 t bromine / iodine.

   The term e.aoyl "lower ar. Oapto means an alooyimeroapto group containing 1 to 8 carbon atoms including such as methylmeroapto, ethylmercapto, propylmeroapto, butylmerceptop amylimercapto,, exy7, meraapto, hoptylmercepuoi ootylmeroapto and their isomeroapto forms. .9axylmaroapto of 6 to 18 carbon atoms included includes phenylmercapto, tolylmeroapto, xylwlmeroapto, naphthyl.maroaptCt t3p.bn.narorpto, eto.

   The term "inclusive alkylene group of 2 to 6 carbon atoms" includes ethylene # propylene, butylene, amylene, hexylene and their ieomeric forms.
 EMI3.2
 The term "lower alkyl groups bonded together."
 EMI3.3
 ble to form a saturated heterooyolic radical of 5 to 7 atoms
 EMI3.4
 nuclear, including one of the nuclear atoms, in addition to the nitrogen atom
 EMI3.5
 amiu3.c, u, is carbon, de4tozote or oxygen, the other nuclear atoms being carbon "* pyrrolidino 2-methylpyrrolldino 8, .Z-dim6thylpyrrolldinot and other similar alooylpyrrolidino groups, psp4rezjao, 4-methylpyrrolldino 204 .aim6thylpip6r & zino, and other alooyipiperazino, morpholino, piperidino ,, -mbthylpip, 6ridino, 3-methylpipéridiao and other similar alooyipiperidino groups, hexamethylene imino, homopiperazino,

   ? 4momorxakol.no, etc *

 <Desc / Clms Page number 4>

 
 EMI4.1
 Addition salts with ecidea according to. "Ixr, ettt include, however, compounds having the formula {1} ot the corresponding N-oxides with the acceptable effects such as hydrochloric, nitric, phosphoric, lactic acids. , benzoic methen, -aulfon1qu., p ... 1;

  Qld. ne-eulfonique, Ifl110111qu8, acetic, piapiotaiqua, 1U161quo, 34. l1que, tartaric, citric, oaiohayîlt3.'eriâ., ua, auoo1nlque,. nicotinic, ascorbic # oto Quaternary Dn \ mcn1u.'Co salts .010n'l e 1n'Y.t1OD
 EMI4.2
 are the salts obtained by reaction of the free formaldehyde bases
 EMI4.3
 z with quaternizing acenta, tele as interior alkyl halides, halides 4'a106% 1118. 1nt'r1'ue, atlfa. ! Lower dialooyl tone, dtsrelooy10 halides. Lower alkyl arylsulfate, etc. The term d, '810011e 1nt :: hu, ..the meaning previously indicated t The term ayalocyl means an aralooyl group containing 7 & 13 carbon atoms improper, such as benzyl, phenethylogphenylpropyland' bezùydryl,
 EMI4.4
 etc.

   Examples of quaternary salts of compounds of formula
 EMI4.5
 (1) are methobromide, meth3.odide9 ethobromide, pro. pylohloride, butylbroure, 11 ootylbrcitllUre. mast 1, -mtho sulfate, ethylethosultate, allylohloride, allylbromide. banzy9 bxomide, 'benzhyd171chloride, mdth11'! 'tOluèn ... au3. = vnate, etc.



  The new compounds according to the invention comprising the free bases of formula (their addition salts with acids, their quaternary ammonium salts and the N-oxides cor-
 EMI4.6
 responders and their addition salts with acids have
 EMI4.7
 a pharmaoolog1queo activity By way of illustration, the oom- posés according to the invention are useful as anti-inflammatory agents, contraceptives autîoestrosènen and agents for lowering the level of elulol este king blood in the matamites8, y including man and animals of economic value.

 <Desc / Clms Page number 5>

 
 EMI5.1
 



  For the edmird.l $ tl'l'Jt1QA eu :, lÍ1amxdt6rea, $ the new compounds
 EMI5.2
 according to the invention can be used directly, for example enclosed in a hard capsule for oral administration, or combined with solid or liquid pharmaceutical vehicles.
 EMI5.3
 and formulated in oomr1m's. powder seoheta, encapsulated, in
 EMI5.4
 using starch or similar excipient, or as
 EMI5.5
 of solution or of auspouston in a solvent or a vehicle fcppfêtrié pour 11 & d1n18t.t1on otel. or parental.



  Independently of their phermlQolog1qul activity. the. melon compound the invention also constitute useful internal "diaries, For example oomo8'8 of formula (1) can be reacted with fluosilic acid to form fluowilioateo which, in extended aqueous solution, are moth repellants effective # sum it is more fully described in US Patents S.076.359 of March 30, 1937 and 109150334 of June 27, 1933.
 EMI5.6
 



  The new compounds according to the invention having the for-
 EMI5.7
 mule (1) can be prepared by reacting a 1-oeto-1.2.a. tetrabydronsphtolene suitable substitute (either a # -t'tralone), of the formula (II) oi-after
 EMI5.8
 
 EMI5.9
 
 EMI5.10
 in which R, sa $ r Roi, nô $ x and ir have the xigni. ', c .axa w 3 oéâementi given (with the noted exception oi'apyavac a reactive da Orignard ayaat the formula (ZIZ) 01- scl *. '
 EMI5.11
 

 <Desc / Clms Page number 6>

 
 EMI6.1
 in which H, IL and 0 3- have the al <gnifio <tion previously given and Hal represents a halogen atom, The reaction is advantageously carried out in the presence of a drink, Inert under anhydrous conditions melon precedes it established for the * Grignard reactions.

     Inert * suitable * solvents are
 EMI6.2
 d11 & opropyl ether. 1 # 6tlier 411lobutyU, that the t'treh1drG- turent. summer. the lot1on can be tfftotttée k tompdrotures between approximately 000 and ln point of 6bu115.tion of 8Ql "." "18f and is pr <! f4yenee and: ttctudo'à de ttnp <lv 1lturfi !! ## Y6e. r example at the point dt'bul11lCn. of the mixture rdsoteo = tl or at neighboring ion.
 EMI6.3
 



  The duration of the rdootion dried up in wide limits. nelqu the temperature at which it is carried out ** From a ..- nU "g'ner18) when the reaction is carried out z high temperature or as the boiling point of the mixture fl: eotlotUlel. apply a reaction time of the order of several
 EMI6.4
 . time $ to be Ber to obtain a complete reoption *, te, d1hldron ",: 'Q. 8t talilne of formula (I) can be isolated from the reaction m61e1B by the usual methods * # for example by decomposition of, reaction mixture with water chloride a '81! n1oniuJ1 \, eto, oulvle de. & parat:

  removal of the organic layer and removal of the solvent therefrom. Many of these the product thus obtained is mainly the desired compound (I) contaminated with minor amounts of impurity and unaltered raw material which can be removed by simple methods such as isolation of the desired compound. (1) as an addition salt with an acid *
 EMI6.5
 However, in some ce *, the desired 3. <- dihydronapht <"lene (1)

   is contaminated with appreciable amounts of the correMondaht 1-hydroxy'-1 * &. 3 * 4-tetrahydronaphthalene having the formula (IV) oi-aprea t. # -? - * '

 <Desc / Clms Page number 7>

 
 EMI7.1
 
 EMI7.2
 and in this case the reaction product obtained is returned * 44 oampo. ot containing only a small amount of the composa (ï! detired * In formula (17) B, Rj Bg <R ,. laet 33, QnSj} n and X and Y have the meanings previously given).



  The compound (17}, when obtained as the main product of the reaction or when it is present in significant amounts in the described reaction product, can be converted into the desired compound (I) by dehydration. can be carried out in most cases by heating the compound (IV) in a solvent such as benzene, toluene, xylene, eto, which form an azeotrope with water, in the presence of traces of a strong acid such as ohlorhy- acids
 EMI7.3
 drric, sulfuric, p-tolubne-sultonics etc. The water formed in the dehydration is azeotropically removed from the reaction mixture.

   A solution of the desired compound (I) is thus obtained from which it can be isolated by evaporation or other usual processes,
 EMI7.4
 In some cases the dehydration of 1-hydroxy.



  1.2.3.4. Tetratiydroîiapiitalène (I?) Requires conditions over dinner. eg heating the compound to or slightly above its melting point, preferably in the presence of an inert gas. until the release of water is complete.



   When either of the groups R3 and R4 or the
 EMI7.5
 two of the starting Ita-tetralons (II) represent groups

 <Desc / Clms Page number 8>

 
 EMI8.1
 free hydroxyls, it is necessary, before removing the - Grignard reaction described in cl-doI8u "to protect this soy group from a radical which can then be removed by giving the desired compound (1) with ua or 11re hydroxyl groups ..



  One way pan1ouli '"m, nt 0011111041 as protdest etn # 4 the 0% hydroxyltw llbns priitnti groups in 3.' .t6trloa. Of d'pltt consists in their conversion into dtbet early: abr410P ':' AJ11. That corresponds to Oet ! t; w d.rni'r. conversion can be etteetude touch- limant by treatment of a "t <tp8loM (IX) containing one or more free hydroxyl groups with aoyaa of I 3 (dihjrdropyï? aû in the prediction trooea of p.tol.6nelUltonic acid or a mid-2161'81 acid such as hydrochloric acid.

   After conversion of Ituwtdtre * rented (II) whose $ hydroxyl groups are thus protected in
 EMI8.2
 corresponding compound (1) by the described reaction oi-4e88ul, t6trahydrop7ranyl ether can be hJ: dro116, for example, using an aqueous mineral acid to set free the free hydroxy group *
The Grignard reagents having the formula (III) which are used as raw materials in the process according to the invention can be prepared by reaction of magnesium
 EMI8.3
 the care of an inert organic solvent such as dilsopropylic acid, dibutyl ether, summer t6trahydrotaranes, with a suitable halobenzene of formula (V)

   here "after '0
 EMI8.4
 
 EMI8.5
 wherein 11 0 Ra 0 nHan and gel have the previously given 81gn1f1oat1ono, by application of well known methods of preparing the reagent. by Grignard.

 <Desc / Clms Page number 9>

 
 EMI9.1
 



  The formal talobeaçènet (V) can be prepared. by 6th61'1toation of the corresponding ahlophenol by means of ltb & 1os6nu1'8 4 * tertiary eminoalooyl
 EMI9.2
 appropriated
 EMI9.3
 
 EMI9.4
 in which R1p Bg and CnH2n and Hal.
 EMI9.5
 have the meanings given above.

   The 6th & ritioat1Qn
 EMI9.6
 is advantageously carried out in an inert solvent such
 EMI9.7
 lower aloanol> eg nthanol, ethenolt, opropanol, eto :, in the presence of a base such as sodium hydroxide, sodium methoxide, etc. Phone\! tertiary aminoalocyl halide having the
 EMI9.8
 formula
 EMI9.9
 
 EMI9.10
 
 EMI9.11
 in which IL, Rzt 0 Ho and Hal
 EMI9.12
 have the meanings previously dominated, used in
 EMI9.13
 preparation of talobenzenes (V) can themselves be prepared by helo86notion of amino81oanol.

   corresponding tertiary}
 EMI9.14
 which can themselves be prepared by angina reaction
 EMI9.15
 .'oonds1r required
 EMI9.16
 
 EMI9.17
 in which B, and Bg have the sign
 EMI9.18
 po'd8mmen cation given, with the appropriate ata haloaloanol H81-nBanOB to Bal and CE. have the 11gn1t1oat1on8 previously 4ctn "., according to known methods * The condensation between the amine
 EMI9.19
 Mcondairt
 EMI9.20
 
 EMI9.21
 and halealeanol Baloc n a ft Or maybe 8be 'o-
 EMI9.22
 tmee for example by the method described by Moffettf ï.

   Now *; * # # 140 868, 19490 Les lt, i '"E'1" QE11! Cla' rH 'e, ll "i / t'6e.da 5.
 EMI9.23
 also, be prepared by heating the amine. ondary
 EMI9.24
 
 EMI9.25
 
 EMI9.26
 with l * At) MX $ star d t 801de h81oellano! qhu 1: 11? ropr1é j au1- 1
 EMI9.27
 Vte for reducing the ester thus produced with Th, yen of h1dru lithium and altminium according to the prcoé, described by 1'tct.



  (see ai-denatts)

 <Desc / Clms Page number 10>

 
 EMI10.1
 The conversion of the tertiary aainoalkanola thus obtained into the corresponding tertiary am1noaloo11e halides can be carried out by application of the halogenating agents * QOZMUOS such as thollle bromide, thionyl 01: 1101'111 "8, phosphorus tribromide, phosphorus trichloride . 181; 0, for example according to the method described by Mottett et al., Ame Chom. Soo. 77, 1565. 1955 The α-tetralones (XI) used as material.



  Tes in the process according to the invention can be prepared * by
 EMI10.2
 the proceeds follow.
 EMI10.3
 



  Α-tetralones (XI) except glue * in which Kg and represent a hydroxy or eloenyloxy radical and those in which 38 eulô an alkyl radical, can be prepared)! according to the reaction scheme 168 formulas (VI to XI) below
 EMI10.4
 

 <Desc / Clms Page number 11>

 
 EMI11.1
 In this series of reactions, 23 '<Rt IL x and y have the meanings previously given * $$ except the oi-desauo exceptions.



  In this series of reactions, the appropriate substituted alaoyl-JItJ phenyl- Ketone * (VI) is condensed with bezal-
 EMI11.2
 suitable substituted dehyde "V'II to produce the corresponding ohaloone (VIII) under the conditions usually applied to the preparation of Ohel001188, for example by condensing (VI) and (VII) in the presence of such a base. as sodium hydroxide potassium hydroxide etc. to the care of an inert solvent such as a mixture of water and a lower aloanol
 EMI11.3
 such as methanol, ethanol, etc. # The reaction is general-. ment conducted at room temperature or 8u-deJOU8 with retr01d1s / SelltflI't outside if nl! ceu81 .., ..

   Ohaloono VIII) is isolated from reaction 11! Ln.tt1 and purified by the usual * proc .. ",." 1el, for example by solvent extraction followed by dt. , tata, lation in these 'a liquid product, o. 't'ecristallie>: \ t1'. '\ in the case of a solid pro & vit.



   The ohaloone (VIII) thus obtained is then converted into the corresponding nitrile (IX) by reaction with hydrocyanic acid, for example, by treatment with an alkali metal cyanide such as potassium cyanide. , sodium cyanide, eto, in the presence of acetic acid and an inert solvent such as aqueous methanol, aqueous ethanol, eto,
 EMI11.4
 by the method described by Newman, J. Am. Chem.

   Solo. 600 z9470 1938 For the. # XX% conversion of benz81aoetophnone (ohaloone) to a-phenyl.Qbenzoylpropion1trile, The desired nitrile (IX) usually separates from the reaction mixture as a solid which can be isolated by filtration and purified by recris-
 EMI11.5
 tallisotion. cll:

  -
The nitrile (IX) thus obtained is hydrolyzed to the corresponding oeto acid (X) by the usual methods of hydrolysis of

 <Desc / Clms Page number 12>

 
 EMI12.1
 Tî rliet by execution by ohnuttaee its reflux in the presence of a mineral, aqueous as 1 * a.d * sulfuric acid Juoqqfk 09 that the hydrolysis is substantially complete. The desired acid (X) is generally separated from the reaction mixture in the form of an adbx of the solid which is isolated by descent and which is purified by Vt er-istslllsationi or other ueuelx methods, for example by conversion of a alkali metal sol followed by aloldifioation to regenerate the free acid * Lt keto-acid (X) thus obtained * and then subjected to reduction to form the corresponding 19-acid (XI).

     The reduction can be effected by any of the usual methods, both applied to the conversion of a ketone group into a group.
 EMI12.2
 eg methyldniquoo A particularly anpropr9.A reducing agent is amalgamated zinc and the treatment of aetaaoda (X) by means of amalgamated zinc in the presence of a mineral acid given the desired acid (XI) with excellent yields. (XI) can be isolated from the reaction mixture by the usual methods,
 EMI12.3
 for example by decantation of the liquid reaction mixture followed by eurasian by solvent of the decanted liquid and evaporates,

  .
 EMI12.4
 Mon of the solvent In general, the acid (11) thus kept is pure enough to be used in the following synthetic operation without other treatments. However, if desired, the acid thus obtained by the customary, for example by distillation in the case of a liquid or rewritten.
 EMI12.5
 tallization in these of a solid, or by conversion to an alkali metal salt followed by acidification of this one to regenerate the liter acid ...



   In the final stage of synthesis, the acid (XI) is
 EMI12.6
 Oyolized to the desired α-tetraloae (11) in the presence of a Lewis acid by the general method described by Iieser and Herehberg J. Att.ChenuSoo., 61, 1873, 1939. The term Lewis acid is

 <Desc / Clms Page number 13>

 technically well known;

   it is succinctly defined by fieser
 EMI13.1
 and Xionerf "Organio Chemistry", 3rd ed. ,, Po 138 (Rhointolds 1956) Examples of these compounds are hydrofluoric acid, bdler trlfluoride, arsenic trifluoride, pentatluoride, phosphorus stripe, tetrafluoride of titanium, concentrated cultural acid polyphosphoric acid etc * The preferred Lewis acid for application to the above process is hydrofluoric acid
 EMI13.2
 , a particularly convenient process for the oiolization of the acid (XI) according to the above process comprises adding the acid (XI) to liquid hydrofluoric acid with stirring.
 EMI13.3
 then allowing the hydrofluoric acid to evaporate to about 80 to 3080.

   The desired cheek (II) is then isolated from the residue by the usual methods such as dissolving the residue in a suitable solvent such as ether. washing the solution thus obtained with an aqueous solution of a base such as sodium carbonate, sodium hydroxide, etc., followed by evaporation
 EMI13.4
 of the solution washed with aPolt6o t'a-tdtralons (II) thus obtained can optionally be purified by the usual methods such as reor1atell1s8t10n.



  The acid (XI) can also be oyolized into alpha-t4tralon (II) by converting the acid (XI) into the corresponding chloride -l'aoi- 'and treating it with aluminum chloride or of melon stannic chloride the process described by
 EMI13.5
 7100 * r and others, 1. Âm. in * soc * z0, 170, 19389 The u-t'tralonee (II) in which Rg or represents the hydroxy radical can be conveniently obtained by dealkylation of the corresponding oonroods of fc-mul.

   (IX) in which Baou R represents the eloox radical; ' fa 1160elo0118- tion can be carried out by the usual methods, by extlplo by heating ave chloride or bromide ", ..1 t al.um.iui. :: J. the presence of an inert solvent such as benzene, xylene etc.

 <Desc / Clms Page number 14>

 
 EMI14.1
 the cetralonea of formula illt in which or 1-s present the alkenyloxy radical can be 00111 '! 11, 046 .. ment prepared by alct \ n, .les1on of the corresponding compounds $ in which% or R represents the radical h1drx7. 1. '& \ 106.

   The nylation can be carried out by the usual methods, by 8X. # - ple by reacting the appropriate hydroxyl compound .a "or lWhelogenur8 with the appropriate alkenyl in the presence of a base such as potassium carbonate, sodium aeboxide, etc. -tetralone of formula (II) in which D6 this an alkyl radical can be prepared by a Variant * of the synthesis described 01-dooau $ 4 Thus the o6ton1qu8 (X) acid is alkylated at IY6n of a suitable alkylating agent such as a halide deloo11me & 81u # apropr1 'B6UBHal in which B is a lower alkyl radical at Hal represents a halogen, preferably bromine or chlorine to produce garb4 = 1
 EMI14.2
 correspondent of formula (XII) below
 EMI14.3
 
 EMI14.4
 in which IL 0 a40 R5 ".Ox and) have the & **! de = have given # $ and 86 1'1pr & eenta a radical 1100.1 ..



  The reaction of o6to.ao1d. (X) ovo I'h * log4nurt is ffaa # .fcU'à under the aorno Semant conditions applied to the riaotloas of O: r1 $ na: d 1 a. p t6 "1101 * n using an 8xofll of arignord 1 ... '1enga reagent." lIot1on ,. nel is d6oompo. ' by methods, for example by treatment with water, ammonium chloride. of a 01d .. 't.ndu eta.

   The desired product (XII) is isolated by extraction by Col- 'Vent or other usual method * and purified by: recr1atellt..t1oA

 <Desc / Clms Page number 15>

   in the ces of a sellas or distillation in the ces of a liquid,
 EMI15.1
 Lt.1oo11 and! On odto-alde (X) in carbinol (XII) can also be carried out by ttalttment of ooepo, 86 (X) glue medium OoMpoed 4t.loo, l.1itbl in the presence of a lnettt solvent such that 1 # 4thero benzene, toluene, eto.



  The lithium compound is used in excess relative to the ato6ohiometric proportion and preferably an amount of at least 1.5 moles per mole of compound (X). The react. tion is advantageously carried out at high temperatures,
 EMI15.2
 Suitably # 4 the boiling point of the solvent used The oom "006 dairê (XII) can be isolated from the reaction mixture, for example by decomposing it with water followed by solvent extraction and removal. by solvent.

   The compound (XII) obtained can be purified as described above *
The oarbinol (XII) thus obtained is then dehydrated by treatment with a dehydrating agent such as zinc chloride or in many cases by heat alone.
 EMI15.3
 to form the corresponding olefinic acid of formula (XIII) below.

   
 EMI15.4
 followed by hydrogenation, oatalytic of the latter compound
 EMI15.5
 ldttkytm in the presence of a hydroednation catalyst such as platinum oxide, palladium or charcoal, etc., to obtain the desired saturated acid of formula (XIV) 01-after
 EMI15.6
 

 <Desc / Clms Page number 16>

 
 EMI16.1
 in which Rg 04 R6 tt have, the '1tt10.tlo. z '. yielded given and the, have a root loo71 ..



  The obturated acid (XXV) 1 '"blaes 07 11 .. in aotétrèloae #o or respond by the process p%" "' dI1'llMt orit po! 4r the oJo11J8t10n of the acid (X3 :).



  Lea (VI) used as starting materials for aid synthesis. Describes that 1-ttrelone (11) can be prepared. Starting from uuliaireo substituted boa "totquen acids by oonverl1on oeux-etz chloride deseideo # followed by r..t1on $ them-oi or medium of the appropriate d1looyl-cadm1um according to the d6orlt.don process. Ohtm1tll Reviews 40, 15, 1947 Many olooyl-phygyl are known.
 EMI16.2
 ketones (VI) in the literature
 EMI16.3
 Aldehydes (VII) used as material, $
 EMI16.4
 raw in the above synthesis described in α-titralonos (1 can be obtained by reduction of the corresponding substituted ben3oy. '! chlorides using tr3 ... tbutocyyi, p minitm-lithium hydride by the described process by Browa et al., Am. Chem. Soc. 00, 'Tt5b3 5377, 1956.

   Numerous benzaldehyde of formula (VII) are known in the literature.



  Another process for the preparation of a ére.onea, formulas (11) in which Ro represents hydrogen is that described bar Newman, J. soul cheme 3oc 0 on * # '. 8895, 1940 for the preparation of 2-o -tolyl-3-methyl-a 'tetralone. you process
 EMI16.5
 consists of reacting a suitably substituted benzyl cyanide
 EMI16.6
 r & * "î ,, - ¯ * \ * eo bxontuw appropriate phêjttët & yle [Hz) 0-. aveo .le bromide phê'thll, suitably eubetttu6. 9, 'CmaCIIBr
 EMI16.7
 , (where Bg, R, R5 t x and y. have the, $ e1gn1t1oa-

 <Desc / Clms Page number 17>

 
 EMI17.1
 tione given above) in the presence of sodium am1dide and in U74rolyse the nitrile thus obtained so as to obtain the corresponding acid (XI) which is then cyclied as it has been said for u-t6trelone (II).



   The addition solos with the * acid. compounds according to the invention having the formula (I) can be prepared by
 EMI17.2
 reaction of a free base of formula (1) with a phara8oo logically acceptable acid as defined above in the presence of a
 EMI17.3
 inert solvent such as methanol, ethanol # etc * The, * N-oxides according to the invention can be Pr6P $ - res by well known methods, for example by reaction of the free berry of formula (I) with an agent oxidant such as hydrogen peroxide, peraoetic acid, caro acid, etc.

   The reaction is preferably carried out at ordinary temperatures.
 EMI17.4
 nalron (for example of the order of 80 z 30 # 0) in the presence of an inert solvent such as benzene, chloroform, lower dtalcoyl 8108n08 -........ tes such as ethyl ilsoetate and * alo8AO 'l1 \ tefiluf' like 16 dthIA03., ethanol, alcohol 11O:

  OP) 'li. that, in summer, the oxidizing agent is used suitably in an etohiometric porportlon relative to the boa * liber (I) and preferably in slight excess. On completion of the reaction, the possible excess of agent can be removed. oxidizer by treating the reaction mixture with an agent such as /
 EMI17.5
 platinized, palladium, Raney nickel and organic hydrosulf !, 6 'such as sodium hydroaulfite, etc *,

   1 The. addition solo with * N-oxydea acids
 EMI17.6
 according to the invention can be prepared from the i-ox / djr <* roopondant and a pharmacologically safe acid by applying the processes described above for the preparation of
 EMI17.7
 ** the addition with the ecides of the compounds of gold = the (j) e Quaternary ammonium salts m.) Ion invdtr on can be prepared by reaction dtimeane free of formula *

 <Desc / Clms Page number 18>

 
 EMI18.1
 (1) with quatomatizing agent such as halogenide such as methyl iodide, ethyl chloride, isopropyl bromide, summer, alkyl sulfate such as chyl sulfate, ethyl sulfate, etc,

   an ara1coyl halide such as benzhyd171e chloride. phenethyl bromide, etc, or an atalkyl tryleultuate such as methyl p-toluene, etc. The reaction is preferably carried out by heating the reactants in the presence of an inert solvent such as.
 EMI18.2
 as aethanol, acetone, methanol, ethanol. etc.

   In general, the quaternary salt desired and separates the solution by cooling from the reaction mixture and can
 EMI18.3
 Otre 1s016 by filtration The purification of the quaternary salt can be carried out by the usual methods, for example recrystellinations
The following preparations and examples illustrate the process and the products according to the invention, but should not
 EMI18.4
 To be considered as limiting coïame * PARCN 1 - pMiethylMdaeethobbeMtM One agitates a! a <tl '"ï $ e of 474 gr flob7 = le) of the p." ONO-phenol, 1500 VI dtttuanol and MO gr (' qul ".ll11t, 1 , 87 SK1 $! Of sodium m & th11ate of a 25% solution of th11 $ t.

   of .0- a1um in methanol and heated to reflux and I the soluttorà at reflux is added dropwise in thirty minutes a 101'1'tion of 813 g of chloride 80.0 ..: L dvdthonols When the addition is complete - the mixture is stirred and heated to reflux for a further three hours * At the end of this
 EMI18.5
 time the reaction mixture is cooled and filtered and the filter is evaporated under reduced pressure.

   We dissolve the oil
 EMI18.6
 The ethereal solution is then washed with two 200 ml portions of an extended solution.
 EMI18.7
 aqueous sodium hydroxide followed by quetn.pon101 * t of water * The ethereal solution is dried over anhydrous magnesium sulfate and the t11trate is evaporated. OA the residue is distilled under

 <Desc / Clms Page number 19>

 
 EMI19.1
 p ,, ... 1on reduced and the fraction having a boiling point of 119 a is collected. 11500 exerts a pressure of 0.3 bus, of met- cure. 310 g of p- (2-diéthl1am1nothox1) bobe! .... zene Mud in oily form are thus obtained. The free base obtained in this manner is converted into the hydrochloride having a melting point of 2.39 and 140 Q analysis. Calculated for C12H19Br01NO t 0 m rQ, é9 R.?, 30! N, 5a Found 0 # 7.04 .; fi. &, 47; V 4.4V%.



  By the o1wdeuul process, but replacing the 8-diethylaNinoethyl chloride with 3 - <11methylenopropyl chloride, 8-diethyladnopropyl chloride, 8-ûlfcutjyltminoétïlt bromide, a-rútb. y3.'th.,: r.lm1J:!. O't1 \ J3. ', li 0h10ru8 of J-4i'thylaminobutylt, the br} mure of a-d1m'th, 1Imi. nopent; y1 .. the b: romu3; 'o of 8-diethylaiaiaopim'tylei the chloride of e "' r111U6tb.11em1ob8: X: 11 .. the chloride of a-.P1: t'3: '011d1no6thrle.

   3.8'diethylpyrrolidino) propyl bromide, 2-p1p4rldinoethyl bromide, 8-piperldlnopwpyl bromide, ..mvxphoiinobthyl chloride, a ... m.orpho11: nObutyl bromide, l. .methyl..4 (ch2o: ethy.) Piprazine, 2-hexem6-thy1ene-11! dnothyl chloride, 2..ho1! 101'tp6r4zinoethyl chloride and 2-homomo-rpho11noâthyle chloride are obtained respectively. p- (3-diaethylaminopropoxy) bromobenzene p '- (8-di'µthylamino'- propoxy) "brTaobenz & ne, p- (dîbutylemîno6thoxy) bzomobenzene, p .. (2..N-1'Iléthyll-N-éthylendnoéthoxy ) bromobenzene, p- (3 <'diethyl-aminobutoxy) bromobenzene, p (5d.mdthylam.nvpentoxy) bxomu.

   benzene, p- (2-d1ethylaminopentoxy) bromobenzene, p- (6Jd1- I1ethyleminohexyloxy) bromobenzene, p '' {8'-pyrrolAdinoethoxy) bro "mobenzene, p (diethy7.prr., dLno) pxopoxybrvmabeuzàus, p- (2pipêr1d1noêthoxy) brorn.obenzene, p - (<8-piperidinopropoxy)
 EMI19.2
 the
 EMI19.3
 'brom.obenzene' / P- (2-morp'ho11noethoX1), bromobenzene p '- (8 -') iorpho'- 11nobutx1) bomobenzene. p- (2 - (1 * -ttôthyl <-4 -piperazino) ehoxy) broaobeâienei p- (8-nexamethylene-iminoethoxy) broaobea2ènet p- (S..homop1péraz1noetllox; y) brom.obel1zene, and p- (a-1; omomo:

  t'pho-

 <Desc / Clms Page number 20>

 
 EMI20.1
 linoethoxybroaMbenzene * By the close oi above, norü replacing 'the p "bromophenol by the' o" broMophenol and the m-bromophenolt we get the o- and m 'arY3.arainoa.aoxrjbsamobazaas corresponding! - PREPARATION S bzz Sthoxyohaloone '## #. * #' "A solution of 45 gr of e-m4thoxysoëtopbd. None is added 75 ml of 95% 4'6tuanol & a cooled solution of 16 av dtty4roxlr4o of sodium in 1M ni d 'obi # On'Place the taelengo in an ice bath and add 31.8' x of benzalddhyde at a rate such that the temperature is maintained * at; ddca of 20600 The mixture is stirred for a further t- rent minutes cold then for ringt-seven lieuren at room temperature.



  The minet solution obtained is depleted by means of a lêtlier and one lays it ethey <tu ave a saturd gaumuïe * is equal to the 1st weight of the anhydrous naganesium sulphate and according to reduced pressure. The residue is reduced in size. One obtains aluni ZO # 9 gr of under volume of an oil having a boiling point of 180 to 16S * C us a pressure of 4 of mercury.



  The application of the oi-deeaua process, but ovoo replaces m-methozyaodtoph6rine by the following compounds 4'-aaylao6tophénonet 3 'broraôaoétophenone, 4' - 'onloroao6tophenone, 4 * oixloro 3l-étb.ylaoétoptéttoneo 5' '' - '&' <'! a.ethoïyaoetophenone, 4 -ethylaeêtop] aénon9, Zt-fluoroacétoph6nouoi 3' * allyl 4 enètno3cy aoétopMnone, 4 '"m6thylin.eroaptoaoétcphenone, k-phbny.meraonata- ao'ûbenone9" aoetopMnone, 4 " trifluorom6thylaceto ph6nonop propiopMnonCt butyrophenone, and volérophétionot allows to obtain respectively 4a! cylohaloone 3fwbrowoonaloone, 4 '' 'ohloroohaloone, 4' ûnloxo-3l * étliylohaloon and 'Sohiorone 4'o.oms3 laoxyohaloone t ', uoroaaal.ooua, la 3 * -allyl-4' '<ethoïyohaloono la 4.m, éthr, mexaaptoohA.aoaa, .e 4'- phenylmeroaptoohaloone, la 4 * iphéuoxyohaloone, la 3. ,,

  u.oco

 <Desc / Clms Page number 21>

 
 EMI21.1
 thy.aha.aot, l 'a-th; v1oheloone f 1.' Q: .cSthylohloOJ1Q and: .l 'a. ppopylobaloone * De & 6e, using the method described in which the
 EMI21.2
 
 EMI21.3
 preparation z, but replace the benzaldehyde with the following known compounds: 2-bromo-benzeld6hyde, bramo 2nétboxyban-zaldehyde, 3-oblorobenzeldéhYde, 'ah.ox'o-dw'.uoxobanza7.déhyda, Z.lS. .dibrom.o..2 ... 6thoxybenz81ahyd e, 2. 3-dichloro-benzaldehyde e, p-.

   tolualdehyae, .d.tixnethrlbenxeld6hrdax ntaaxyiazaidehyde, x4-d.ithocrbsnxaldehyde, 4-t -amyloxybenzaldehyde 4-hexyloxy-benzeld6hyde, 4-methylmeroaptobenzaldehyde, 4..phenylme-d.ithocrbsnxaldehyde, 4-t-amyloxybenzaldehyde -tri- 'huorométhr.benza3.déhyce, we obtain 3-bromoohaloone, 5 bromo - Z-methoxyohalcone, 3 * onlorooûaloone, ohl.crrod tluoroohaloonea 3t5 *' dibyomo-2-ethoxyoaloono, la .3, diahloxa oha100no, '-m6thylcheloone, 2.6-almethylohaoone. 4m, 6- thoxyohalconoi 3,4-diethoxyohalooQe, 4-t-emyloxychalcones, d: ryvoxaha9, aond, 4-mi5thylmBroeptoohaloon9, 4-pliônyl- meroaptoohalooae, 4prnoxrahallylcones, 4prnoxrahalaone . '1ua crm thy, aha, a we, a.



  PREPARATION 3 - a-phéaylHt- (3-méthoqcyphényl) -4-oétobutyronitrll A solution of 7.8 g of potassium cyanide dent 00 ta, of water a, a mixture of 60 g of 3cnbthoxahal oonef is added 13.0 g of acetic acid and 100 ml of ethanol, 95 in 8S-paoe. ten minutes. ON maintains the temperature at 45 * 0. We shake
 EMI21.4
 then 1 * cloudy mixture for six hours and allowed to stand
 EMI21.5
 The crystalline bolide which separates is isolated by filtration, washed with aqueous ethanol, cooled with ice and water and cooled with ethanol for about sixteen hours in the cold.

   49.32 gr of S-phenyl 4> (3-methoxyphd.- ttyl) w4 oetobutyronltrile are thus obtained in the form of a crystallized solid having a melting point of G8 & 101409 The infrared spectrum of
 EMI21.6
 compound, (slurry with mineral oil) manifests ma-
 EMI21.7
 xlma at 2800th 1880 and 1380 om-1

 <Desc / Clms Page number 22>

 
 EMI22.1
 By application of the procedure "r9. Deeao, may * en ei gent the 3 * -mêthoxyclialoon0 by the 4 H & myloaaloorte SbtMehal'- conat 4 olilor0OhBloone, 4Voaloro * 3f etayl oto.aloc> ne, 6 '-' ohloro'oonehoxyoha7.o , 4 etaylQaalaonal a *; flttoroo al0Otte, !! aHyl'- 4 * #:

  ! & ± taoxyeb.alooa, 'radthyleroaptoaha9.oQne, 9-pheny., Exaep- #ohalconef 4-'ph6noxyûhalcone, 3p tx3.uorctméthy.ohQ, Oaüd, a nr thyxohaloone, a-dthylahal, SylohalQone, a- -bromoohaloone, 5-b & rmo'-8 "metboxyohaloone 3.chloxQahs.oone, ah.aro d'.tcro chaloone, 3,5-dibromo-2-ethoxyahalooaa, 3.3-dioaloi'ooaalooae, 4-metîiyïohaIooaB, 'Z e 6 --d Ïm6thyl claal cons, 4-nidthoxyolialcoues - .4-diâthooha.oone, .t..em3rlvyoha'aon8, 4 -hexyloiyohal 4-m6thyl-aerceptoohelcone # 4.phény.meroaptaohe.oane, 4 phenoxychalaalaonot i and tx3.it.orambthy3.ohe3.oor .;

   we obtain recpeotivemeat lee 8''phënyl-'4 "(4 * aylph4ayl) - '4'- aitobutyroultriloo -phayx - (3bxamaphanyi, Iw4o6tabutrxon, i, txi les JI'-pbdnyIO4" (4-ohlorphén-3- <thylpho) ) 4'-otobutyronitpil <'<8 pliAoyl 4 (C> * 1., Chloro'-S-ethoxyphenyl) -4 "o <t6butyroaitrila ,. 8-pa4ayl * 4 - (4 ethyl * phnyl) .- aétAbutyxiartitr3, e , S paéayl 4- (8 * -fluoiiophenyl). 4 * star * butyronitrile, S-paéayl-4- (3 * allyl 4 <-me thoacyphéayl) * 4-oetobutyro * nitrile, S-pMnyl- (4-m4thyl! M'roaptoph <! Oyl) "4 'o.et & butyronityilWt 8-paéayl-4- (4-phéayl eroaptophéayl) -4-oét0butywaitPila, 8-ph4nyl- - (- ph6noxyphdnyl) - .. adtbutyroa.ttxi.e, S- ph <ayl '*'! 3 * 'tpifluoro "mdthylphenyl) -4-oêtàbutyrouitrilo $ a-4iphl-3-'m <thyl-4 <' 06tôbutyrouitrilet 3.4-dipMnyl'-3..ppopyl-4-wëtobutyronitril <, 3 -f S-bromophenyl)> 4 * phenyl-4-citobutyronitrile & 8- (5 bormo-8-! n * ihoxypaéayl) -4-phenyl * * -o6tùbutyronJ.trile,

   B- (3obloroph <nyl). '' Ph <ayl-'t-c <tabutyro trile, 8- (2aloro-6 fluorophéayl) 4 pheByl 4 <Jétiobutyifonl'bxlilal.



  8- (3 5 dlhronio-2 *> etaoxypû * nyl) -4-pnenyl-4 oé tobutyroalt rile f t <* {8 3-dloaloiophêayl} -4-pûôayl-4-çétobutyï? Oaltrilfl | ..8-p * tolyl¯4 phenyl..l-adtobutyxantri3.e, 8 - (;. aditbylphenyl 4phdny.-Odtu butyranitrilac, 3 '' (<- m <thoxyph <Spyl) -4'ph <nyl <- * '' c <tobutyroait) 'tl,; 5

 <Desc / Clms Page number 23>

 
 EMI23.1
 (44 * Qthoxpp'hdnyi) r phdnyx * odtbutyroaitrile, * - (4-t- emyloacyph6ngl) rph8ny.-odtbutynitrile, 8- (4-hexyloxyphenyl) 4phdnyl-4oetrbut'ronitrile, 3- (4-methylmercaptophenyl) 'phenyl-4 "oetobutyronitrile, S- (4-phenylmoroapto) -4-phéayl-4 - o'tobutyronlji: 11. S" (4'-phenoxyphenyl) -4'-phenyl-4- oetobutyronitrile, 2- ('-el111hênl) -4-PhénY-4fo & tobutyronitrl1e, and 2- (tritiuoramétbyiphn ly.) - 4phdnyi * ioetobutyronitrila.



  PREPARATION 4 - Acid -phdayl.4 (3-méthoxyph.dayi) -d; odtobutyx uni that We heat a81n.mar1e boiling with vigorous stirring during ..t8 four hours a suspension of 49.38 gr of wphényâ.-4 * (3-, ethoxyph8ny,) odtobutyronitri.s in a mixture of 140 ml of concentrated sulfuric acid and 135 ml of e & u.



  The mixture thus obtained is cooled and quenched with ice water. The solid which separates out is isolated by filtration and is reopiatallized with aqueous ethanol, then benzeno.



  In this way, 39.5 g of 3-phenyl-4- (S-m4thoxyphenyl) - 4 '* oetbuty!' It) M are obtained in the form of a crystalline solid having a melting point of 143 145 ° 0. An analytical sample having a melting point of 143-145 * 0 was obtained by recrietal11aa-
 EMI23.2
 yours within benzene *
 EMI23.3
 Analyet Calculated for 27! 6 i 0 71.82 d H # 5. & 7 Found 0 - 72.10;

   H - 5.74 ±, By the oi-deasus method, but replacing the 2-pneayl-4 (3-metiioiyphenyll-4-o * tobutyronitril with the appropriately substituted 2.4wd1-phenyl-4-oetobutyronitrile (pre-
 EMI23.4
 trimmed as described in preparation 3) we obtain res-
 EMI23.5
 pectively the balance -phdnyi -.- (4..amyl, phdzy.) - 9 odttbutyriua, the aoid 8 pb.ênyl-4- (3 -bromoplxenyl-4 oetobutyrlque, 2-phenyl'-4 'acid * (4'-ohlorophenyl) -4-ketobutyric acid, 8-phbny acid ..,

 <Desc / Clms Page number 24>

 
 EMI24.1
 (9.ahl.axobthy3.phbny.) - ^ - abtAbtttyrip, the 8014. 1.pb.'Dl1-f ,.



  (3-ah'lora - mbthoaypbSnr.j-aftbctrriqnr, e-phenyl-4- (4-bthrlphbny .'- abtbul.Que1 aegid Z-phenyl-4 <. (4- <thyl <. ph6nl1) -4.c6tôbutf1'1que, phbar acid, 4 (2 t ', raxaphbb, r, j .. ,,, otjbutlr1que, o1de a * phenyI-4- (alXyX 4r-inétlxoxypaénylî-4. ( s4to butyric, l'801de 8-.pïi6nyX - * - (4-n * t> 'ûyXm roeptoph4nyX) i4 .oétclJu ty: 1que, 2-Ph'nYl., - (' - ph6n11m.ro8PtoPh6n11): '.c6tutl.



  - ic, 2ghényl acid. 4 .. (. Phdnaxyphbnyi j.4aétabutyriue, rphburi acid .- (3wbri'laarôbthyiph6ny, - abtbutr, qus, 1 '.. oide 2 .'- diph6nl1-3-m6thyl -'- c6tobutrrlque, acid 8 .'- 41ph'D) 1- 3-'thyl-'o'tObut11'ique, 2..lphnyl-3-proP11 ".o'to. Butyric acid, 1 (-bromophdnyl! -Phéuyl ..abtobubyx.qua, Xfaoide (5wbrom, o - mbthoxyphbnyi) .. 4-a6tabutyr.que, 1'eaide 2 (8-ohloro 6-fXuorophényi) 4-pb nyi-4-oetobutyriq, uel acid,. . (. drd9.becrno.bthoxyphbnri.) phënrl.4-abtabutrxic acid .. (. wd.oh.orophény.) - 4..pb, ény, 4-abt4butgriqur, 0 acid 8-p. toly9,4-phdnyl.9-odtabutyri, ue, acid 2 - (. 6-dizaethr, p3bn ,,, 4 phenyX-4-oétobtttyrf.q, ue, acid - (mbthocpphbnyl) -phbny7 ,.



  4-oeto) utiyrlq.ue, 3- (3.4-dithoxyphenyl) -4.-ph6nyl-4-oeto- butyric acid, E-, rt-az.l.cxyphbnyl) - ph6nyi-oetrbutyx, c, ue ,, '3 (4-hexyloxyphenyl) -4-phenyl-4-o4tibutyric acid, 2- (4-methl1-eroeptophenyl} -4-Pb6n11-4-0 & totutlr1que acid, acid: 1 3- (4-ph6nylmaroapto) -4phenyl'-oetobutyric, the balance 2 (,. Phb, noxypb6nyl) -4-phenyl04-o6t butyrlque. Lt 801de 2- (ellylph6nYl) -...



  # phônyX-4-oétoibutyrlq.ue and 2- (4-trifluorometûylphéayi) acid
 EMI24.2
 
 EMI24.3
  4-piiényX-4 -oé "tobu" tyriq? I 3- PREPARATION 5 -, ide / phenyl, .- (. Bthoxyph6ny3,) but:, rtqp4 We wash a to'si of 300 gr of zinc foam quickly by means of 2.5 N hydrochloric acid then & water. The metal is annealed with a solution of 6.7 g of mercuric chloride in 500 TnX-et-et-n and the mixture is left to stand for thirty minutes while occasionally.

   We decant the phaee

 <Desc / Clms Page number 25>

 liquid and the amalgamated metal is washed thoroughly with water. to the zinc amalgam thus produced, a mixture of 29 3 gr is added
 EMI25.1
 3-phanyl-4 '' (3-methoxyphenyl) '- 3-'catobutyriQKe acid and 400 ml
Hydrochloric, The mixture is carefully heated to reflux temperature and then at reflux for a total of twenty hours, adding after five hours and ten hours of heating additional portions of hydrochloric acid. The mixture thus obtained is cooled and the solid is separated from the liquid by decantation.

   The solid residue is washed thoroughly with ether and the decanted liquid is exhausted with ether. The ethereal extract and the liquors of the mixture are combined.
 EMI25.2
 Vage and the mixture is washed with water, then with the aid of a matur6o brine before porking over anhydrous magnesium sulfate. The peroolate is evaporated to dryness, thus obtaining S <5.8 gr of hëny9 .-. (3-mdthaxhdn, y,) butyxic acid in the form of a viscous oil * which is used without further purification in the procedure of Preparation 6.

   The infrared spectrum of the compound (as an oily slurry) xxx showed a maximum of & 1705 cm-1.
 EMI25.3
 using the above procedure, but replacing the acid with the appropriately substituted 8 # 4-diphenyl-4-oetobutyric acid (prepared as described in Preparation 4), the acids are respectively obtained -phëny.

   (4-N, y1h4zy.) '"1"' ghany'1, ¯ 4 * (3-bromophenyl) -, 8-phenyl (4-chlohenyl) - ', 3-phenyl "' 4'-, {4- ohloro "3 '<ethyl' <phonyl) -, 3'-phenyl-4- (o-ohloro-8-'metboxypMnyl)" S''phenyl '' - (4'-ethylpenyl) -, gtéry.9. ( 2-.uaragbdy,)., S "phenyl-4- (3-llyl-4 methoxyphenyl) -f -gb.ényl-4 - :( 4-uthy..zcxaptp ph6nyl) - $ ..p.énrl, r -4-pheny.reroepagh6nyl) -., S-ph6nyl-4f *. (4'- pinoxyphEnYl)., Ghenyl-4- (3-tx.fluoxomtb.ylFdny.) -, 2.4-dl- p2atY. -bthyl,.-diphdnyl.-3-ethyl, S.4-- phenyl-S-propyl-, S "(3-bromophenyl) -4-phenyl'-t 8 - '(S-bromo'-3-' :

  i. <hoxyphAnyl). "phenyl-t 2- (Z-ehloroph6nyl) -4-ph6nyi-0 S- (3-ohloro-s-'fluorophe- 'nyl} 4-pehnyl-, 2- (3.5-dibromo- 3-Ethoxyphenyl) -4-phenyl-,

 <Desc / Clms Page number 26>

 
 EMI26.1
 8 -. (8.S-diohloropheyl) <<, - pet $ nyl, # p-tolyl-pBéayl '-' i S (8.G dimethylpti <5nyl) -4 s> hényl * M4 methoxy-pnenylM-pnéayl- , #! 3.4-dlethoxyphenyl) -4-phenyl, 8- (4 tert # -emyloxyphenyl} - * # paenyl- M4¯hexyloxyphenylM ph $ nyl-, 8mbhâanaxadptz phenyl) '' 4-phenyl''t S- (4- phenylmeroapto) <4phenyl-t 8- (4 * 'phenoxy- paeaayl) -4 <-pb.éayl-i S- {4-aXlyIpîienyl) -4-piienyl- and 8 <- (4-'trifluo * romethylphenyl)' -4-phenylbutyriques * PEJkpATXQN 6 # s phenyl-5 <-mebhoxy-1.â, 3 4 t) etrahydro-1-n0p) biti - leuone A total of 150 MI of liquid hydrofluoric acid is added to 86.8 gr 8-> phéayl-4- (am (Staoxyphéayl) toutyriqu0-M acid with cooling and stirring.

   The P610080 thus obtained is left to stand in the sandblast for three days. The residue is dissolved in methylene chloride and the solution is poured into an exoea of concentrated potassium carbonate solution. The organic layer is separated and left with water and by means of brine, saturated * then evaporated. h eicoitet The residue is dissolved in ',? * liter * of a mixture of hexanedr (Skellyaolve B) containing 9% by volume of acetone and made
 EMI26.2
 sand the solution in a column of magnesium silicate
 EMI26.3
 (.oroax7. ") t washed beforehand using the m3me solvent mixture *.

   Evaporated 1161uet to alcoît4 and the residue (17 * 0 sr) is crystallized twice in cyolohexenrw This gives 1 <3.36 g of t-phenyl - & - methoxy-lt8.S <4 * tetre * hydro '' '1-naphthalenone gives us a crystalline compound having a melting point of 113wi16C "Analysis * Calculated for 1714C 8 Qu .8, t3, f 9 .., 3DG Found t 10 a 81,, C8. , 9S%. Sa applying the above method but by replacing the acid with the appropriate substitution product of this acid (pképoriN..odmmd it is described in Preparation 0) # the napMtM & o "

 <Desc / Clms Page number 27>

 
 EMI27.1
 M following 8 8-pbéByX-7 amyX 8-phnyl'-6-bro! M-, 3-phenyl "j 7-cM.or <-pMnyl-7''ohloM-6-ethyl-, S-ptényk-8 -ohloro-N''ïaétho "7cf, 8 pîienyl 7" 'ét3ayX' 'S-pMnyl-6-'fluoro-, 3pxidny'9.4al.j:

  'lr' thoxy-, -pha, 'âthylmeroapo, 8 "pMnyl''7-ph <Snyl-meroap'- -10-4. Sphyl-7-pMnoxy-', phdy, ... tx9., uaraadthy, 8 -phenyl'- 3-îrwbttyX-, 8-phéayl-3- # tliyl S-plienyX-31-propyl- "8 (S-13wimo ph6uyl), S" (B''brQmo-'8-! aethoxyph <ayl) ", 8" (3-oM.oropMnyl) t 8 "> (a-oM.oaro-6 n.iiorophenyl) '" i a- (3tO' - <Hb'ï'o'mo-3 "<thoxyphenyl) -ta <(8fl3 iiolilorpiiényX) i 8-T'-tolyl "t 8 '' (8t6'.iBthylpMnyl} -,
 EMI27.2
 (3 "laldh '3.4ithoxyphenyl)' '' t s-tttrt.-amylexyw phenyl} <-, i S '' (4''a <xyloxyph4nyl) '-, a' - (4'ëthylmeroaptophenyl) -, g- (4-piienylmorûaptcplienyl) -, 2- (4-phenoiyphenyl) -, 2- (4-alXylphenyl! * $ Tt i ('kok, irÂfi! I: S 4h ", i, A, ßYlsEin'sü' - ein i 1 1'I'wtDlhydtoé "'ol. nap, htoldron yBBFAtUffXON 7 - ^ i? dnyeth, -6mdthx' ', .. ïtdtrahrdc0.



  1-aep-t awl We cool 0 * 0 a solution of 5 g of acid. 8- ph <nyl-4- (3-'m-thoxyphnyl) -3-ketobutyric in 100 ml of stealer and treat dropwise z, drop while stirring with 29 ml of 2M solution of methylmagneelum bromide in ether. The D-
 EMI27.3
 After finishing, the mixture is stirred for several hours at room temperature and then heated under reflux for one hour. The reaction mixture is decomposed by the addition of water.
 EMI27.4
 ice cream and extended hydrochloric acid. We separate the layer
 EMI27.5
 ethereal, washed with an aqueous solution of ammonium chloride and with water and then dried over anhydrous sodium sulfate.

   The dry solution is filtered and the mixture is evaporated.
 EMI27.6
 filtrate at sioolt6e then the residue is recrystallized from aqueous ethanol * This gives 2-phenyl'-4- (3-methoxy "phenyl) * 4-hydrox" eleric acid. A mixture of 1 is heated to reflux. gr of acid a- phda5.-4 - (- nethpxrphdnl) - hdrctcxvalër.g, ue, 100 mZ of p- acid.

 <Desc / Clms Page number 28>

 
 EMI28.1
 toluene-sulfonic acid and 100 ml of benzeno remove the digestive content until the reaction mixture no longer gives off 4%.



  The residual solution is depleted with an exoea of an aqueous tolution of sodium hydroxide and boiled with a solution of hydrochloric acid. The solid which does not seize by filtering is isolated, washed. z water and we wick it, we d1: 8out the acid solution in etho- Roi and it is subjected to hydrogenation in the presence of a palladium catalyst on charcoal Until absorption of hydrogen is complete. The solution obtained in situ is filtered and the filtrate is evaporated to zero. This gives 8-phenyl 4i- (3- 'ethoxyphenyl) -ir li'riq acid, which is the last acid. then oyolod by the procedure described in Preparation of which gives Z-h9nyl'-met <hyl''6 - !! thoxy-'1.8.3.-t <trahyd !! fo''l "naphthalenone * Examples 1 to 56 below illustrate the preparation of 2 plienyl-1 "[(p -t-ainiaoaloo2y)

  phenyl3 # 3.4-Sihydroxy-naphthelenes, free bases and addition salts with an acid quaternary ion salt !, -N * -oxides and that of addition with the acids of the N-oxides The 2 'phenyl'-1' -! o '') 3i * '{t-umânoalooxyi ph6nyl J -a.4-dihydronaphtaHnea, bases librast addition salts with acids, quaternary ammonium salts, N-oxidon and addition salts with N- corresponding oxides are prepared as follows. O- and m- (t.am1noalooxy) bromobenzene lees are substituted. aux p-t-a! Binoalooxy) bromobenz & n9s dtas exempted 1 be to obtain leo 3-phenyl-l- (o- 'and m ît-aminoalooxy'iplienylj 3 4 [' di
 EMI28.2
 hydronaphthelenes, free bases and mole addition ,, 'The addition salts with acids thus obtained are substituted for
 EMI28.3
 addition salts with 2..phenyl acids ... l ...

   ((p-t-am1UQ2tlOoXY) ph6nyl) -3.4-dihydronephthalene corresponding in ori Examples 53 and 54 so as to obtain the quaternary sala Il '8''l'11on1um,
 EMI28.4
 N-oxides and addition salts with acids of the corresponding N-oxides'

 <Desc / Clms Page number 29>

 
 EMI29.1
 Bxm & LB .¯ p (ad, 6tkayl ari.ro8thoxy pb.éuY, 'a..hdn, -amthaxp, 4dihy xanaphthal8, a and its oh.lhydrate4 A 0.73 gr of dry magnesium fragments maintained all nitrogen atmosphere on add 5 ml of tetrahydrofuran and 4 drops of methyl iodide and the mixture is stirred until the reaction begins.

     To the mixture thus obtained is added
 EMI29.2
 a solution of 8.13 g of p- (diethylamlnoethoxy) -bromobenzene in 85 ml of tetrahydrofuran. The resulting binary mixture is heated to reflux until substantially all of the magnesium has been consumed and to the residual solution is added.
 EMI29.3
 while stirring a solution of 7% of 2-phenyl-6- <iethoxy-1.a.3t <'tetrehydro-1-naphthalenone in 90 ml of tiktrahydroturenoe The mixture thus obtained was heated under reflux for sixteen hours a-
Both cooling The cooled solution is treated with ether and a small amount of water.

   The gel formed is removed by filtration and washed well with ether. The ethereal filtrate and the washings are mixed and washed with water before drying over anhydrous sodium sulfate and the dryness evaporated.



   The residual oil is dissolved in a mixture of ether and benzene, and the solution thus obtained is exhausted with an excess of 0.5N hydrochloric acid. The acid extract is exhausted by means of
 EMI29.4
 methylene chloride and the ethylene chloride extract is evaporated off. The residue (6.48 g) is reWristalléy in the healthy form of one half due to the hydrochloride and ethyl chloride. obtains 2.42 ai 'of hydrochloride, â, pīdthaâ.aa ethoxy) phenyl]' '8''phenyl'-6' & ethoxy <-3 * dihydron phT.alene eoua .form of a crystalline solid having a melting point 171-17300 after partial melting and resolldification & * 186 * 0 Analytical 4 & 69tilon is obtained by drying peai: t quatxn3., t. .gels $ 11000 hours under vacuum.



  Analysis * Calculated for N3401N0 = 0 -7S.OS; Il? *, Zei N 3003% Found: 0-74g74; R 7.40; N # 3jO3% 0 OM

 <Desc / Clms Page number 30>

 
 EMI30.1
 We make a solution of 18r M hydrochloride 4) i ... in the water that we aloglinitt'per the addition of a solution * tail * of sodium hydroxide * The basic solution is exhausted by means of ether. it is washed with water and dried over anhydrous sodium sulfate. The wick solution is filtered xx and the wire is evaporated off
 EMI30.2
 claolté trat. The residue is recrystallized from 4 "aqueous thanol, to give 1-p '- (2''di6thyla: ninoethoxy) phe" to form a crystalline solid.



  EXAMPLEa
 EMI30.3
 1- p- (8 * diethylamino <thoxy) ph4nyl] -phenyl-5 * Wihydro-naphth ien4 and its hydrochloride
 EMI30.4
 We. adds a solution of 1100 gr (OOD5 mol) of 8-phenyl l * 8.3.4 * tetrahyâro-l-ttaphthalene (Newmant Âm.Chem. Soc, 60, 29470 1938) in 100 ml of t4trohydroturans with Grignard's reagent prepared from of 13.6 gr (0003 mole) of p- (α-di6 thyleminoêthozy) bromobouzene and 1 # 84 gr (CJOO aole) of magnesium in 130 ml of tetrahydrofuran. The mixture thus obtained is heated for sixteen hours under reflux then allowed to cool and treated with 5 ml of water.

   The gel thus formed was removed by filtration and the filtrate was spread with the aid of ether.
 EMI30.5
 we wash it in water and we wash it ..100it6, we take again the .1. du with ether and the solution thus obtained is washed with hydrochloric 4'eoldo 0 $ 0 N. The acid extract is diluted by means of 8M ml of chloroform and the eftnit cb1oroto1'1d.q, u.1 is evaporated. to wicoita. We diioûut the riaidu including 950 ml of blaa6n..t'o heats the benzene solution with 980 * 9 4 # eoÎdt ptelu & no '' "omltonic for two hours under a 0011eot.u1 'de Dean-" 8te) The solution is allowed to cool and washed with 4% aqueous bicarbonate solution.

   The washed benzene solution is evaporated off with water and the residue is dissolved in ether. The ethereal solution is exhausted with 4.Eold. 0h1Ó: h1dtS.qU. ,. ,, '

 <Desc / Clms Page number 31>

 
 EMI31.1
 0, & 5 and the oh3.oroox.i.que extract is exhausted and the residue is re-solilized twice in a mixture of methylene olide and benzene. 6030 g of hydrochloride dt I * "[3> (3 diethylaminoethoxy) phenyl] -1-hydro3cy 8¯ are thus obtained in the form of a crystallized solid having a melt paint of 180 to 182 C (with decomposition ).
 EMI31.2
 



  Analysis * Calculated for aaH3.01NOal 0 "74.39; E 0 7, M; N 0 3010% Found! 0" 74.0lr; E a 7.55; N "to 3%.



   The above component, besides its value as an intermediate, manifests anti-inflammatory, anticonceptual activity.
 EMI31.3
 tional, anti-oetrogenic, and lowering of obDiLesterol blood levels in tII.m1terol15, including humans and animals of economic value
0.5 gr of the above compound is heated under a ballast
 EMI31.4
 stream of nitrogen using a bath & oil at 200-210 * 0 until no more effervescence occurs * The residual vitreous mass is crystallized by triturating it with means of ac-
 EMI31.5
 ethyl tata. The product is then reoristallioer in a mixture of methylene chloride and ethyl acetate.

   0.45 g of 1- [P- (2-di6thylaminoethoxy} phenylJ-2-phenyl-3.4-dihydronaphthalene hydrochloride is thus obtained in the form of a crystalline solid having a melting point of 174-17780. an analytical sample with a melting point of 174-17e0 .. by two new re-crystallizations in the same solvent mixture The ultraviolet spectrum of this compound (ethanolic solution) shows maxima at 230, 238 (shoulder ) 253 (shoulder), 280 (shoulder) and 299 millimicrons.
 EMI31.6
 



  Analysis. Calculated for C2gHCiNO 0 76,084; H 7.29: H # 3 * 16% Found t 0 - 76.13; He has 7881; s 3.3 '.



  The corresponding free base is obtained using the

 <Desc / Clms Page number 32>

 
 EMI32.1
 du nous closes a wolide criatellieé by the method described in Example If, [p- ddthylam.nnéthoanr? p.dnl. tolyl-3bthr 3.à.l dronaphthalene and its hydrochloride By applying the process described in Example 1, but yeatplaqant the 8''phenyl - & - 'thoxyl.8.3. * <' t4trahydro-'l'- naphthalenone by -o-tls.at, al ....- ttrahd, .. naphthalnd INewma ,, y.

   At. chenu sooo 0 is 88958 1940) one obi holds the lp - (- diethylotnnodthox)) ph6o .. vto.rl 6tlgyl 3.4dihydcan aphta.éne and its oaloraydrattt iaBMPH, 4 p..3 - ,, ét, .aminaabt3oxgÎphénrphy & ny, 7 em .. 'Dihydronaphthelene and aoa hydrochloride Sa using the procedure described in Example 10, by replacing 3-phenyl-6-! n6thoxy''1.8.S, 4-tetrahydro-'l-naphthelenone by 3''ph < Snyl-7-ai! Tyl-'ït2.34-tetrahydro-'l <-naphtha "
 EMI32.2
 lenone, we obtain the ip diéth.arniaothoxph8r.phéz 7-amyl-3.4-dihydronaphtaleno and its hydrochloride * SX'E # 'LE 5 1- [poo ta "' d1éthylam1noéthoxy) phenyl -hbnl-vb2ortop d3.hd, a
 EMI32.3
 naphthalene and its hydrochloride
 EMI32.4
 Using the procedure described in example 1:

   t me1. by replacing 2-phenyl <-c-aiethoxy-'lt8 <3t4-'tetrahydro''l * 'n <phta'-lenone. by -phny3, .. d-bron.o-1.a3.-tëtrah; dro-1, -nxphte3.none one obtains l- [p <(S-diethylaïainoetltoxy) phenyl-S-pûenyl-6 bromo- 3.4-d1hYdronaphthalene and its hydrochloride *! "TPLE 1- p- (S-iethylamino..hoxy) phn .-. Phenyl.7-oi.oro.4'-dihydro-
 EMI32.5
 naphthalene and its hydrochloride
 EMI32.6
 By the process described in Example 1, replacing # phcnyl-6-8thogy - .. 2..G-tetrahydro-.ahtaldnone with ..pheny3, - .. uhlorv -., 2.3. ttrahydro-, tephtelnone, on

 <Desc / Clms Page number 33>

 
 EMI33.1
 obtains la, t (.t, i'G1'lj, 'noTtxlObrl, oJC, y'aPhdtJnp..phali'x .-' i'ahLs'rp and o4d1h1dronaphelàD and its hydrochloride * i1, 'h i - (. dthylaa .x dtho? ni? k.yl .. 'hlora 6-ethy .ihrdxonahta7. ne and his oh: rhrr8t.



  By) rooêd6 of examp Ile maie replacing? '# 2 .... ph "n; yl ... 6-m6tho :: r ... 3.tbtxa4 d xota htldnone speaks 5 *! J; 1 #p) ü phenyl 7 oii:.> ro ... 6-6thyl-l: J., 3.4 ... t61'8h1drc ... 3:! i..phte16nonot:,: we get the 1 'p- (3-Diethylnlnoetho. "7) plienyl3 '* 2-Pûényl * y * ohloro-G-éthy .... 4r ... \ 1hydroJ1R / Jhtalene e ;, its hydrochloride. mWLE 9 1- [P "" (2 .., a.16thy- em1.1loetho7) phtSnyl] -2 ... phtSnylt; 8..ohloro-t5-: methox1 '"" - 3. 4.-r. .hrdronarhtelba 6 non hydrochloride EelOt 1 1 rrobédé described in example 1, maie en raxcp.a.nt i pién, .- r¯méth6acy -... 2.3.4.-tetxahdro- l-naahta ,.

    non6 by 5-pûéntl-à ckloro- ± '' raêtnoxy-l 8 3e4-tetr8hydro-l-na: phta16 non J one obtains the 1 "fp (S * diethyl9! ainoetho: Ey) phenyl! '' 2uphn71-a hlo ... 5-mthox1-304-d1hY4ronerht81ene and its OhlQln7- dretoo .N # CPLB '-' "" LL! <L! "r -fp - '(. 8J: h11m1no'thoX1) PhnrlJ I IGi" "dnA 'rD 5liyL' "'l.di, l, i4Aa, âp4'C. and the hydrochloride By rt1111Sant the process described in the example but here% ru', ':' el1t 1 2-phenyl- '-' métJio3cy-l 8 3 ** tetr hydïiofl-l | apftt - Afcttime by the 2 "J.en1: 1 ..." th; Yl-l.2: w3.4 ... t6tnh: rdro-l ... .naPhta Hi; W '1t> t l- {p <. (8' '.btllarT, nodtb, Ctxyjhdzty .. phen. 7dthy..



  \ .4 \ 33ycronaphtha, dnr "t its hydrochloride r-, 'lJr.2 # [p ..' .., di6htylemÚ1.o6the q) Ph'nyl) -2 ... ph6nyl-O" '1 d, xo 3.4-slihy ..



  .trôna-: "awl and its hydrochloride According to the method described in 1 '' they DI.I: tl an xtmplatliat the S-pûenyl-3 aethoxy-l.? 3 4¯t5trahydro-l-rwîr salà © all , paf la s..phbayi x ".ucxo-3 ... * -t6 * r # / dro-1 -'-" "" talent "1,

 <Desc / Clms Page number 34>

 
 EMI34.1
 lfpSiethylanoethoieyphenylj #a -phenyl- & fXuûrō3 4-dihydronapataXèae and ohlorh1dret 'EU are obtained:! PU 3.1 1- [p (-diethylamà, noét3acxif phdnyljtény, .â.al, lithay- 3 ..- atihdx. na * t its hydrochloride.



  According to the procedure as the exe '! 1plt! l Kings in xamp3.gaa the 2-phdny'1 "B.XQthai .e.3r-'dt ': Bi.t'xas'iaphtadrlGna by the 8phdnl-d-ai..71? mdthoxy-x b. .tdtxohtdxa -x-aphtsâ6nax, we obtain 1- [P "(2-dlethylam.ino-âthoxy) pb.én; rl)", S ... phtn, 1.G "" allyl-7 "methoxy" 3.- dihydronaphthal & ne and its oh1odrhldrete, 1UE.tPL !: 12 .1- p- (S <-d1ethylaminothpxy) pPény] phdr.'meraep, a3t4 li h1dron8phtelne and its hydrochloride According to the method of Example X, harmful by replacing the phdnl-6 - :. dtha - ..?. 3.4-tdtrshdxo-1-naphtaxnaxa by ¯ -pény3 .- ?. 'rthylmercapto-.p.,. # ttrahydra 3.napata3.dnna, we obtain the J.-p .. $ .. disthy2arn, nobthax? phny? hdnI.? ' . nethylmeaptc9.-dihd. ^ aphthalna and 8ohlorhldGt ..



  .



  , -p- (a .dethyla! inothaaPhdnpl.-Ph6n. ..ph6ymxaapts.



  .3 "4-dihdrcnep3ata3, bne and its ohlorhydxrte According to p1'OoÓd6 described in Example 2 omit a replacing 2-phenyl-6-a <Sthoxy-l * a.3. * - 't' <trahydt ' 'AspiitaXéao- ne by -phângâ.9.pün, mexaapta-1 .. .tbtxahydao, nephta Xenone, we obtain, -. pdthrlem.réthaxjp3ndr3'thr, meroapto-3 <4'-dihydronaphthalene and its hydrochloride 3 . p Bdi6thylam.inoéthoar) phen;, - phn.?-.phenoxyy - d1h1dronaphtene and its hydrochloride According to the procedure of Example 1, friend en = la9aAt 2-phn "'. : '11l'1a3,' ': Z.3.', - tYtrah, ', t, 1 "L1'.tlI: rll" tJnaéivl: by 1 phân3 .-' phbnaxT, .2.3.9ttrabydro-i.aahta, nona, we get the 1-pr-ddt? a3.en.nodthoxph:

   y- thbzty. '-p3tenoxy3.r d1hydronaphtelene and its o! :: i.'1rhyè /t.te#

 <Desc / Clms Page number 35>

 
 EMI35.1
 ntI .1 -¯J, p (,. 6thr, azanobtSaxyIPhény..p6tzi'luorombthy.- 3 4 dibyaroQaphthalen and its hydrochloride By means of the procedure described in Example 1, but using 16 2..ph6nl1 .. &. methoX1.1.a..4.t6trBh1drcwl..naphthal ', j none by 2-phenyl 6-trifluororaethyl-1.2 3,4-tetraliydro-l-, naphthalenone, we obtain 1- (P- (2-d16thylBm1n06thoxY ) Ph6nylJ pCbuyl, -4-trxl, uamethyl-.4..dihydxanrphte, èns and its chlorhy-
 EMI35.2
 drate.
 EMI35.3
 E. <: E:.! PLE 16, .. p - (.. d, 6tylexaiaobthoxyi phbny, .. hbnylabthy.-f * t-dihydxo
 EMI35.4
 naphthalene and its hydrochloride
 EMI35.5
 According to the process de.oi t in Example 1, but in rsmplea, phdnyl-6-za6hoxy-1 ...- tbtrahydxo-1-nephtha-, none by -phbnyl-tb..yl-l. $ .â.4-rbtrahydro-1;

  , .naphta.bnona,,! - l <'fp' '(8'-diethylaminoethoxy) phanylj "3-'phenyl''3' methyl-3.4.d.hydxousphthalene and its hydrochloride * 15XF.ÎPLB 17 1 are obtained - (p. (2-d1'thYlam1no6thOXY) Ph'nYl) -2-phênYl-.6th11-3., - d1hydro.: naphthelene and its hydrochloride According to the procedure described in Example 1 but replacing 2-phbny3 , 6.mbGhoxy -. *. 3.btxahydro:, - 3rnephtalbna \ ne by -phbnyl3-bthy.-... 3.4.tbtrahydro.-naphthalbnans, .on obtains 1- [P- (S-d1êthYlem1noéthOXY) Ph6nyl ) -2-Ph6nYl-3- | ethyl <-3 * 4 to hydronsphthalen and its hydrochloride.



  1E: XJJ1! PI, E 18 '.pwd.éthy.ami.a, oethwxyiplenyl-2iphbnyl-3-propyl- * 4 d.hydt.
 EMI35.6
 



  , naphthalene and its hydrochloride According to the process described in Example 1, but in
 EMI35.7
 replacing 2-phenyx-6..rnbthoxy-1 ... 4..tdtrahydca-naphthalbnone by -, phenyl-, propyl1.2..9rtbtxahydrQ-. ta, phta.bnoae, we get l-fp - '(3'diethylaminoethoxy) phAnyl' \ "a-phenyl-3 * '

 <Desc / Clms Page number 36>

 
 EMI36.1
 propyX-3 4-dlhydroa piit | alètte et tOn, 0b1o: rb14nt ... '' ::

   "" "## :! K #.! PIJ! C '1-p - ($ wdibthylaainoéthoxlhbtyl-2 - (- bromophénr) <. Rdhrâxo
 EMI36.2
 naphthalene and its hydrochloride
 EMI36.3
 According to the process described in Example 1, badly by replacing S-phéayl ô-methoxy-lf 2.3 t4 tetrahydro-l -naphthaline- ne by 8 (d.brcn.ophbnyl, 1 ...- tbxshyQxo1araphtaldnona, we obtains 1g (, -. ethylanoâthoxy-phbrl $ .3banophb uyi) 3.di.hydrpuephta, âno and its hydrochloride.
 EMI36.4
 
 EMI36.5
 txaasx 20 1 (p- (2-d16thY1Bl111no6thoxy) phenyl) -a- (O-b: omo-S "" ",, thoxnh'ayS;

  ) - 3.d.hrdranaphtelbe and .on hydrochloride According to the process in Example 1, but replacing the phenyl.-6..raethpz..l.2..bxBtxa? Ydro1riaphta7tenone by the 2 5b xoma2 ne thozyphényJ. ) -1. .3. r-tbt rehyàro.lnapht albaao, one obtains the h p (2d1 $ thyltiminaéthsejpheny, -2. (4rtbxcz8 mbthozyhânyl) 3.4-à.hydronaphtha, èrre and its hydrochloride.
 EMI36.6
 EXAMPLE
 EMI36.7
 1, p (2-dibthyleminoethaxr 1 rhdzyl 2 (-ah, .orclphbny,) -.:bwâihdtxa
 EMI36.8
 naphthalene and its hydrochloride
 EMI36.9
 According to the process described in Example 1., May 1. by replacing the -phënyr, -6nbichazy .... 3t-tbtrehy.dr.- .;

  ephthalbnaar by l, a- (3-chlorophenyl) -1.2.3.4-tetrahydro-l-naphthalenone, one obtains 1- [P- (2-i6thYlaminoéthoXY) Ph'n11) - (Z.ohlorOPh'n1) -. ' d1hYdronephtslene and its hydrochloride * Bm.! 1'LE a8 l fp (-diethylaminoethoycyphenyl., ohloro-6 *, orophenyl) 3.9âihydronaphthalene and its hydrochloride
 EMI36.10
 According to the process described in Example 1, but in
 EMI36.11
 replacing a-phenYl-6;

  methoxy-1.2.3.4..t6trahYdro1 "n.pht816DO.
 EMI36.12
 ne by 2 (2-chloazo6luoro-pheny9, .- l, a..étrehydr-'lphta 16none. we obtain 1. (p- (a16th11smino6thoXy) Ph6n11) -2 (a-

 <Desc / Clms Page number 37>

 
 EMI37.1
 oMoro'-6-fluorophenyl! "St4. '' dihydroMpht leQe its hydrochloride, BOSMHJI 33 ''", (x6tylam, nabtù)) py, '(. d.bxamo - ,. âthoxhyl .2w.riydxo, phta.bna at its hydrochloride according to the method described in the example Ip male by rea placing the & <'pnyl "6 * .m'fthoxy-1.8 * 4tet!' ahydyo-l <'naphthalenoM! by the B * (3 <5' * dibroMO-8thoxypMnyl) '- lt8.3,4''tetrahydro-laphta lénouer we obtain the 3.-p. (2wd.tkr'ennothorjphëny.-2 (. dbro! M8-thox $ phenyl)' '3.4'-dlhydronaphthal $ ne and its obloxiiy- - 'Ci7, a'6r-.



  MMMLZ 24 l '') P- "diethylandnothoxyphnyl) 2 (ta.a, ahx.ooph6nyx..3 ..- dtbydronaphtholene and its hydrochloride According to the process described in Example 1 but replacing 8-p1yl * 6 *! Thoxy-lt3t9-t9trahydro '' 'l'-naphthalenone by 8diohlorophenyl) -l * 3.3 * 4-tetrahydro * l-naphthalenone, one obtains lp (2 di6thylaninaéthoyPhényl.2 (.- dioh9.axa pli6ny, r .di, lydxcrnaphtaZèa, a and its hydrochloride 3BEffi, ÎPLB 45 lt ..

   (-diâthylami, nobthoxy) phnyl w 'rtolyl-3 rtdhydraphteld me and its hydrochloride $ floc the prooefi * has written <tan <t the exampln It malt by replacing it by the gui' pttoly., lrbtatrahydrown phtla2a one obtains the l ' * fpt d darao lhoxyyhy '- lyl-3dihydGoapha, eta and oa, 1'ib'yl "1 M-211 lit .pw ditby.atai, hd hoxy phbny (. dâmâthylp'hnyl a -" dihydronaphthalene and hydrochloride Depending on the process described in 10 but in ffftiplaqanf. 8''phenyl''6''methoxy'-l * S.34-'téyahydro''l "aaphtalea.o 'ne by .la - (S, 6HHmethylphenyl) -li, 2 3.4trtetra ydro-l naplitaléRo-

 <Desc / Clms Page number 38>

 
 EMI38.1
 ne * one obtains the l.f (i thy.dl'4..thoxr'phdâ, r ', "(â * ^ tf' aiaethylpnênylM.4 dihydr <ïttaputaXètte and ohlorhydMte ..

   vl'.4iai rJ '*, # i l -] ($ - (, ilyt8r1.n0.htty) phën # l rirlth0ptëny "" 4thy' dronaphthalene and not 0410 *, Ydrate According to P4-006dé described in lioxemplo 10 but wa x8'ip.aQal.t plnylb-lethoxy'w, .kst6trilyxQ .üaphttl- none by S - (- mthoxyT) h <nyl) - 'lt8.3.4' <'t <trahydM "l <' a.apht <tl <'' ne, one obtains the l- [p¯ (2-diétiiylainlno4tho 3r) -plaényi; 3-2 (4-meticj syphdzylj-3.4- .hydxttnaphtelèûo and not hydrochloride * gcs;

  ,! PL5 88 X jp- (2 dIethylamlnoethoxy) piiiiyl] -â (3 * 4-diethoxyphéayX) 3 4- dthydronaphthalene and its hydrochloride According to the procedure described in Example 10 = the Or replacing 3-'phéyl - & - mathQxy * 'lt8e3.4-t <trahydro'-l''naphtaleno "not by S <(3.4-diethoxyphenyl)' '1.8.3.4-tetrahydr9'-l-nephthae". none, one obtains l-tp- (diethylan! inoathoxy) ph <nyl) "S '' {3t4- 'diethocyphnri,? -. 3.i-à, .hyxtanephtelne and its hydrochloride aurptz 89 -p- (r3iethyenoethrr) phny (Attnrlh. dihydtouaphtalàna and its hydrochloride Silo the process deorit dMt 1 Example 10 Mit by yeaplasant the hnrtrâ "ht;

  ipitiïrhâr tl.r none by the i ('' t'1! 'lohllia', l) -.,. '' tit.h'rl "tr'w ait'A none, we get the, p (-di, ôthraanitt, o? phnyl, rt araylûxyphinyl) -3.4 dihydroniphtelene and its hydrochloride JPCSIP3LB 3C ltafp- {S-diethyl ndno4thoxy) phenyl3-S- {4wmethylmereiptoph * nyX) 3 * 4odihydronaphthaléno
 EMI38.2
 According to the method 60, d-ons Ilex ple 1, milt or rempleqant la -phâ.tho. * Xhlr none by rahxHrGâ.r ,, lit .: 1 'naphthalenone, we obtain l) 4t l- [p- (2 -dîethylft! Blno4thoxy) phenyl) fl ± - (4-aéiiiylmorcapto? iiényl} -3,4 diliydroûaph, tal * (heads Q & l <K? ii: fl

 <Desc / Clms Page number 39>

 
 EMI39.1
 iî.Lldaff7i. f. #; E 3 '1 ... p .... dbthr.am.aadth4xy) phd, yl. (9phay..exvaptaph8ny.D .. i 3.4-dihydronephthalene and its hydrochloride Salon le p:

  rooéd6 of 1 example 1, but by replacing the phenl bmâhox i..3,4 tbtxaaydxox-adphta, saoae by ($ ph8y, zru.axptvpdnyl) -h * .3.-ttxahydraaphta.énone, one obtains the 3l- p.-à6thyl, am.zoéthaxyDphén, - (9-phdnylmeroap. topaenyl} 8 4-'dikydron? patalèn and its hydrochloride * Ë2 # HPLS 32 1 i '. r- {N "6AG 3IId, yaüliasSlti4a.lyipJCnüiCL" Ip 4 heoxyphbnyli - .4-d- bydronaphte16ne and its hydrochloride /
 EMI39.2
 
 EMI39.3
 According to the process described in Example 1;

   but replacing t-a 2-ph6ny-6-methoxy-l.2.3.4-tetrahydfO-l-nephte1 '. none by (-phaaxyphéxayl). * .. 4.ttxehyd3ro.aaphta, enuo ne we get the l "> fp (S 'dlétnylaminoôtlioxy) phânyl3'" S (4wpWao - xy, ph6x, y9D..d3hyxanaphta, aa and eou hydrochloride * .EXE'S lri r1t h'it'Ixnx, ii.althCS'a ') hl4ily. w (rpa,; yl. "; htiyr) .iif hydronaphthalene and its hydrochloride According to the process dêo: 1t in Example 1, maie en co.eaa.t the S-paêayl-6-methoxy ltat3 * 4-tetrahydï? ol naphtha- * none by the "'(9:' w4.lt.iLJüO, vn4'w.7, paV.1" 11w "Mtüy4lx" "ro4Xâaphtv, lenone, we get the," i '"' S" p (and ddirhra.atl, tothoxy) phnyl, -. d9, bhydro-nephthalene and .on hydrochloride.



  SmiPLE 34, .. p. i8athylminothoxy) hnya w -. ((4.tx, luoromt.yz: a .. 3.4-dihydronaphthalene and its oorh1d 'According to the process described in Example 1 <Maie by replacing phenyl-d-methoxy ..... 9-ttxah.ydro- .. naphtha, éza no par la -t..trotloethylphnyl) -1.3..4..atyxdro-l. Naphthalenone, we obtain l'-fp '- (S-dlethylamino6thoxy) ph $ nyl 'i-3-' (-t, '. uoxambthy3, phayrlj, 3..diîxdacaaaphta.l8ne and its ohlorhy "". dratet

 <Desc / Clms Page number 40>

 
 EMI40.1
 EXAMPLE 35. '' 1, '. $? j '-, 1.t' 1- (p .. (2 "" \ 11dthyll! Üno6thoxr) p6n11 J..a1h6JÍf..etSW! '. h1dronaphthalne and 80n hydrochloride? <': ',. "' #]. . "4 r 'According to the process' 6ont dane it-uèmile '1. u1.'.,: Replacing the p- (a-d1IJ'h11EUÚ06thOXli'bt'Onaob.nZ'A '.pa 1e' pf:" jf .



  (a-d1m6thrlm1no & tho% 1) romobtnz'ne, we obtain, the l [p * (8 * ài * '! m6thylaminoeethocy) phenyl 8hâarx bhacy 3.4lxrdl "r 1I," ne and /! Ion chloraydretef: KttItPLE 36 1 p ( "di ëthy. an, nap ropoxy j yhéay, thay1 da, b thQay â dihy âxonaphthalena and ion hydrochloride According to the method described in Example 1, May. by replacing the p- (a..d1'thrlem1no'thoxr) bromobenzno by p "(<tw d1thl1ero1noppox1) bromobenz ne. we obtain l '* p' '(8' <l <thyl <- aminopropoxy) piienyl} -3-phéayl-fi-méthoïy'-3c4-dIiiydron8phthale and its hydrochloride . F <#,! PLJ 37. P E âibutylaminothoxy $ phayl -S-phny, .t rndtaI â 4 41h14: onephthalinl and the hydrochloride According to 1 proceeds deorit in Example 1, but replacing the p- (S-d16thrlam1no 'thoxl) bromobo1 \ zèn. by the 5 (..



  41butylem1no'thox1) bromobenzina. we obtain lM (-tl-d1butrl- an, naëtb.aacyj phenyx hénrl6.mthoxy 3., "lihydanaphtx8u
 EMI40.2
 and, its hydrochloride.
 EMI40.3
 



  ,! PLE 35 l- "p .. -Nm.thrxpÏ '.- éthylatn.rttsbthcxy r.'lhbllji .-? Xldiyx-btha', 44d.hydxca, aahtexne and its hydrochloride According to the p'roe'µde described inana l Example 1, better by reapaqant the p- (2-d16thyleminothox1) bromobenzene j * r the pu (2-N-methyl-N éthylacilaoéthoxy5tiroraobeiizèii9, one obtains the 1 ... p (2..i méthy. N-thylazrno â thoxy pha.y ..-- hénrx 6.zmthoxy.r d1hYdtOncphteènt and its hydrochloride

 <Desc / Clms Page number 41>

 
 EMI41.1
 ] B # '# MS 1- (3-diethylat! Dnobutoxy) phenyl *' S''phenyl'-6 '-' methoxy '<' St4- 'd1hydronephthalene and its hydrochloride According to the procedure described in Example 1, hand in replacing p '<' (8-'diethyla'minoethoxy) broaobenzene by Po. (3. d1thhylam1nobutoxy) brom.obenzèb.e, one obtains lt 1- (p- (3-d16'thyl '"emia.obutoxy) phnyl 1 -8-phenyl'-6'-me <: hoxy-3.-dihydronaphtha <
 EMI41.2
 lene and eon hydrochloride.
 EMI41.3
 



  ! .PL1i: M 1-fp- (Sithylaminopentoxy) phenyl-SpMayl-6-itthoxy-S. dihydronaphtelene and its hydrochloride According to the process described in Example Li but by replacing p- (2-diethYlam4noêthox1) bromobenzene by p- {5 "dImethyl'Ùnopen'toxy) bro1'll.Obenzne, we obtain 1-cp - (Odlmêth'ylm aminopentoxy) phenylj -% - phnyl-6 <-mathoxy-'S, 4-dihydronaphthalene
 EMI41.4
 and its hydrochloride.
 EMI41.5
 



  BXEÎPLX 41 l-fp-fs-diétaylamtaopeatoxyîphéaylj "Shenyl-C'ethoxy'-S # 4- dihydronaphthalene and its hydrochloride
 EMI41.6
 described
 EMI41.7
 According to the process / in Example 1, but replacing the p- (2-dUth718rúnothoxy) bromobenzene with p- (8'-diethyl'- em1nopentoxy) b1'Omobeudne, one obtains 1 <-fp "> (8 <diethylanino pentoxy) phenylj-2-phenyl-6-iethoxy-5.4-dihydronaphthBiene and its Ohlorh1drate.



  XBPLE.¯4 $ l * {6-dinthylaminohexyloxy) phonylj-a-phenyl '' << aethoxy4- 'dihydronaplitolene and its hydrochloride According to the procedure described in Example lv killed by replacing the p' ''. (8'- diethyla'ninoethoxy) bromoben '' by p- (6-d1mth118m1noheX11oxy) bromobenzene, one obt1A '<.e l-fp- (8 d1m6thrllrdnohex; rloxr) P11! n11) "S'phenyl-'o-'met' - y-5 * 4-diîiydro> - ntpatolene and its ohlorhr8te.

 <Desc / Clms Page number 42>

 



  EXAMPLE 43
 EMI42.1
 l- p (ayrrolidinc ethoxy) ph6nib, daddthoxJ, r. . -d ha o 'naphthalene and its hydrochloride
Salon proceeds as described in Example 1, but
 EMI42.2
 Mating p- (a-d16thl1am1no6thox1) bro. # Ob.nznl by pst pyrrol1d1no & .thoJ: yJ bromo1> enzene. we obtain 1. / CIJ (p- (8.pyrrol1 ';' dinoethxrj; hbnY. Phny.-B..mthaxr-3.d, bydronephtelbna at its hydrochloride, oelui-oi having a point of tu.l0A of 196 to 172 C.



  EXAMPLE 44
 EMI42.3
 1 ... p. - (s .d imé thy7 p, a. id ina fp aGac, abv6tyl -8-pitéayl-'0 methoxy-3.4-d1hydronaphthelene and its hydrochloride According to the process used in Example 1 but replacing the p- (S- 4iet> iylaminoéthoiyîbroraobenzèn by p-'j [3 '"(2.8-dlm6th11pyrrolldlno) p.opoxr) broaobenztne. We obtain l, l'w g3 .. (g" 8, üuuthlpyrrol, dinaa raparyth6nrla- "phtylb-d x, r..4dihyàranephtalbna and .on Qhorh1dnt ..



  EXAMPLE 45
 EMI42.4
 lp (a-pip: "il, ix9.0t15, a7, y) phiriyl) -, 8w phen, '1-fz1'li ^ t $ a: gy4ie4.di1" wr dronaphthalene and its hydrochloride' According to the procedure described in example 1, but in
 EMI42.5
 replacing the p '' (8''diethylMino <thoxy) bro! OobeMtne by the p {l 1p4r1dln06thoxl) bro.ob'nzên .. we get l, the 'fp -' (<* 'pip <ridia9 <* < thoxy) phenyl]) - 'a-'ph <nyl-'6-'mathoxy <-St4 "dihydronephthal <tne and soa hydrochloride, which has a melting point of 218-219 C.



  EXAMPLE 46
 EMI42.6
 1, -Cp .. (, .. Orpha.inAéthaxyiphét'3. 8hdal6-dthacrd, 4dhyw
 EMI42.7
 dronaphthalene and its cgo: tyanto According to the procedure described in example 1, mats filled a hundred
 EMI42.8
 the by the p -'- atoholiae "èthozy) bromobouzinet we obtain the l <-fp * '(a <-BM'ypholinthoïy)' had its oblerbl4m dratet whose tu4ton point is from 200 to 1Wl'4,

 <Desc / Clms Page number 43>

 
 EMI43.1
 B # MFLB l.p-a- -thyl. .p, pax3no) étar ,, phzy, -i-é .. thaxy.4.rd, kpl:

  o, aphta.no and Bon hydrochloride According to the method described in, ea, 1, but an. replacing the p- (2¯âlethylairiLnoétû0xy) brifto1> tjisene by the j7 $ (X'-methyl-4 -piperazino) étîioxy] bromob8nzôa, one obtains the ip (ithyl .. p.pé razino)., thoxy] pb.n "Tinlrb methoxy-3t4" dihydTonaphthalene and its hydrochloride,.! PLX 48 lp- (..hexahyx ene..i, minothoxy) p, ay, .pbmy, 6n4thoxy3. dihydronaphthalene and its hydrochloride According to the prooéd6 described in Example 1, malt by replacing the p- (3-diétaylamlno * thoxy) l> romol> en! Bee by p-CI. haacamethylene-iminoethoxyjbirooobenzèiae, 1 l'-fp '- (a-hexaro; thylzne-imlnoethoxy) phenyx -.phenyr, ethoxy- .4dihy- oonephthalene is obtained and hydrochloride is obtained.



  EXll '.! PL1t 49.-P- (-ho: nopiprazinoethoxy) pheny,' 'pld,' -., Bt ,, xr3.4 d1bydron.phtcnG and hydrochloride According to the method described in the example, maie by replacing p- (3-diethylaniinoethoxy) bromobenzene by p - '(8 "homop1pfraz1noethox.y) bromobenzèno, we obtain l-fp- (8-ho'mopi" paxexirrr, othoxyj p, hény, -8-phanyl -b -methoxy .9-dd.bydronaphthalene
 EMI43.2
 and its hydrochloride *
 EMI43.3
 EXKJPM 50 â, 'p - (- homomoxpholinoathoxy) phenylJ pkdnr, dmthoxyw3.cdi hydronaphthalene and its hydrochloride According to the procedure described in Example 1 Mit by replacing the p- (2 diethylaminoethoxy) bromobeazèae by the p (8 homomorphotlllnoethoXe) brobenzene, 1 [pi- {8 horamorpha is obtained. inoethoxy) phenyl -2-.phenyl-6-methoxy-'3.

    d .hydrxanap; at8 Xene and its hydrochloride.

 <Desc / Clms Page number 44>

 
 EMI44.1
 r ± caw 51 l-fp- (3-dlethylaMdmoethoxy) ph9nyl-S-phenyl-6-hydroxy <-3.-dihy'- -dronaphthalene and its hydrochloride JS-'yhenyl-e''hydrojEy-l 8.3 4- t <trahydye-'l-'naphtholenone 0 & :. heats a = 6101kae of S <'ph <ayl "&' 'm <thoïy-l <t8.3t4 ëtrehpdro-x-n8pha.bnane atao of the aluminum bronmer in benzene according to the procedure described by Sam,',, Am. Qhom. Soc, 88
 EMI44.2
 5n5, I960, to give 1-n8phtelnone phenyl $ hydxoscy..l.8 ..- tetxshycixa 1-n8phtelnone as a crystalline compound.



  B. 2h6nyl¯ô¯ (2 tetrahyôropyraayloxy) 1.3.3.4-tetr nydro-l- 'nephte16none A solution of B $ hényid .hydxoz3rwi., 2 .. tetrahydro-1-naphthalenone in ether is treated with a quantity 6q1o18ir 4th .3.dihydxapyxaze and one drop of concentrated hydrochloric acid. The m6, an; d thus obtained is allowed to stand for a few hours, washed with a very extensive aqueous sodium hydroxide solution, then with water and evaporated to alooit6. This gives 8-ph6n11 - &. (2t'tr8h7droP1r.nJlo. Xy 1 .. â.4tbtrahydxa.naphte.dnaaa.



  0 * l- "p - (- d, tlyiszam, noethoxy) phânyl phdnyl-6-hydroxr. Dihydronephtelène and its hydrochloride According to the process of Example 1, but replacing ..phënyl-b.mthaxy, .2. .4-ttrahyàxbx.raphteesone by, ... 2-ph6nyl - & - (2-t & tr8hldropyranyloxy) -1.aa.-t6trah7dro-l1sphte16none and leaving the 0.6 H hydrochloric extract obtained to stand for some. Hour In order to allow the hydrolysis of the tetrahydropyraniliquo ether to be completed before final extraction with methylene chloride, the hydrochloride of 1- [p '<' (3-diethylandnoethoxy) phenylj-a "phda.y is obtained. , .. & hydacaxy-3.4 dhydranephta.ne1 The latter compound said to be converted into free base by the process described in the last paragraph of 3 'Example 1.

 <Desc / Clms Page number 45>

 



  EXAMPLE 52
 EMI45.1
 'p -' {S '* diethyla (iinoethoxy) phenyl] -8-pMnyl-6 "allyloxy-'3. <t- hydronephthalene and its hydrochloride., 10 a-phenyl -8 -allyl oxy l S # 3 4-t and rabyd ro-1 random naphth * noâe Treating slowly while stirring a solution of 2-
 EMI45.2
 phi $ ixyl-ô-byaroïy-1,2,3,4-tetrahydro-l-naphthelé] ion * (oxefeple SI part A) in mâthanol containing a slight excess of sodium p "bl1ate by means of an excess of chloride of allyl * When the addition is complete, the mixture is heated under reflux for several hours before cooling and pouring into water.

   The mixture thus obtained is operated with ether and the ethereal extract is washed with an aqueous solution of bdium hydroxide.
 EMI45.3
 and water before evaporating to alocity to obtain 8-phenyl-6-allyloxy * 1.2. 3 # 4 tet rahydro-1-naphth lenone l '. [P- (8-'dlét.hylaminoethoxy) phenyl]' '8'hényl''6 *' ellyloxy '* 3t4 41hydronephthalene and its hydrochloride According to the process described Cana l 'example 1, but in
 EMI45.4
 replacing 3'-pQényl * S''méthoxy-1..8tS.4''tétrahydyo "l'-naphthaléno * 'ne by 3-phenyl-6-Bllyloxy-1.2.3.4 -tetrahydro-1-naphthalenotte is obtained 1-fp (S''diéthy3.aTiinoéthoxy) phenyl-24-ellyloxy 3,, 4-dihydronaphthalbue and its hydrochloride.



  EKN: PL3:, S3) .tp * '(2-dlethyla!'Iinoethoxy) * phenylS * phenyl-6- ethoxy-'3t4-dlhydronaphthalene A solution of 1 g of water is cooled with ice. -! p- (3iethyl! & iaethoxy) phenyl'-8-phenyl '- & - mé'tn6xy <S.4-di-' hydronaphthalene in ml dtaitonitriloo At 8outio. retro1 ... die 1.5 ml of methyl iodide are added and the mixture is left to stand for about sixteen hours before pouring into 100 ml of ether. The solid which separates is isolated by filtration and is recrystallized from a mixture of ethyl acetate.
 EMI45.5
 and ether.

   The methiodide of 1'-fp "(3 <.dthyl-

 <Desc / Clms Page number 46>

 
 EMI46.1
 an.vthoxi) hnyl] w phnz - dthuaxy 4.d, hydronphthalen. sludge as a crystallized solid
From led, using the above procedure
 EMI46.2
 Methyl methyl bromide is employed by ethyl bromide. B =, propyl bromide, allyl bromide and benzyl bromide; etaylbromide, propylbromide, propylbromide, and benzyl bromide are obtained, respectively. el1: ylb: r: omur & and the bonzyl-bromide of l "" (P- (S-dUthyllm.1no- âthoxy 'i hur ,, dphnyl-amthtrpk''dhydonepht a.na.



  From 8.na using the method described in example 53, but not including 1 (d, thra.nadthoxhâry, S-phenyl - & - mthoxy-3 .'- d1hydronephthalen, by any of the free bases prepared cocas it is described in Example 2 A be 1nolus, the corresponding biathiodides and analogous quaternary emmonium salts are prepared *
 EMI46.3
 N "oxide of. P (dithylatothoxrjphnylphnr1 latethoxr.



  S 4 * diliyâroaapatalèae and its hydrochloride A a solution of l- [p * (2¯t * y * 41'trlam1AO & thoxl) - phenyl-'8 * 'phenyl''6- "tethoïy'-3 * 4" dihydronaphthalene in 50 , nor 4'6-absolute thanol, an aquimolar amount of peroxide is added
 EMI46.4
 t of hydrogen at 30. The mixture is left to stand for four days at room temperature and at the end of this time the mixture is shaken with 0.5 g of platinum oxide until the peroxide test is negative @,

     The mixture is then filtered and the filtrate is evaporated at siocity under reduced pressure.
 EMI46.5
 t5xs or18tal118er the residue in a mixture of ohloro-melting and ethyl acetate. There is thus obtained N "oxide of ((dithpaanodthoxrphnyl, hdnrli ^ .bethoxy-3.4-dihTdtronaphthalene.
The N-oxide thus obtained is converted into the hydrochloride.
 EMI46.6
 by dl $ 801Tent in ether and treating the ethereal solution with an excess of one salidm g, ai aa sare ar iltrat.on * in ether. The solid which separates is isolated by filtration.

 <Desc / Clms Page number 47>

 
 EMI47.1
 



  In this way the hydrochloride 4e N..OX1d is obtained. flt 1 "'(1) .. {116thl1-aznothoxy) phenyl) - phryâ, .d.mdtixrer-d; artoxhaâe.



  According to the process c1 "" deeaulil. lU ""; 011 reaspleqant the 1- fp -., x.inothoxy) x -8-ph !! nyl '' * ahoyy3. <* dihydro-naphthalene by some of the \) 88011 1M 1u.t5pa0. As it is d6o1t in Examples 8 to 2 inol $ t one obtains the M "oxides and their hydrochloride has corrupo4dJ \ h \ t.



  Ja.lt.tPLE 55 Prepare 10,000 oompr6. containing 4aoun 135 word of l .. (3-d, thlem, ohr) hydrochloride, renr, -3-phen.l. z5haty5.4 Qhrdxoza, alne and clean. Acquired cyalt with the following materials .., l -. [P "{8-dMthylX !! dno <thcxy) dh, -a-ay.b..methoxy.âe94-dih3aea'a hydrochloride. ra 1, BGO sir phosphate d1ol101que 8.600 gr SC'th11QI11u1o .. de Codex (10 99) / Se gr Talc bluté 41S0 II 'Stearate oalo1um. fine powder 3G gr The hydrochloride of l [p8lhylnethexy)' 'phnyl) .hyl- â-: rdhoxy-3.r-dihydarnaphtha, .e and! # alumium phosphate powdered acm1? 6len mixed and granulated by means of a?, 5j5 aqueous solution of 4thrloel10o.

   We pass the granules through a sieve with a mesh of, 99 cm and we know ourselves "very soon at 49 * 0. The aees are passed through a sieve with a mesh of ,, 68 mm, they are mixed entirely with the tala and oaloiumt stearate and then omp1me in ooplm8.



  To produce tablets containing 280 M8 of active ingredient, the amount of oelulo1 used is given in formula c. dess.rus to 2OO gram.


    

Claims (1)

EMI48.1 i! i I i y A.1Y EMI48.2 Process for the preparation of a 4ih1úonaphtha16ne EMI48.3 formula EMI48.4 EMI48.5 4 to which He, t "1a pepyttMtwat of groups * & 3.00,11 or, EMI48.6 EMI48.7 &. '0 the attached nitrogen, an annuity hét'roo7011quI, n2n reprdsoute in radical alo011De, R5 and 26 r <tpr4eent <nt ï.'Jaydfogèn or an aloo111 radical, 17 and R8 a trifluoromethyl radical, * 1007169 & 10'11111 , t6trebydropyrajqloxy # alkoxyt & lo4nylexyt U71oX7. halo, & loo11..roapto or ar, J1aeraapto, and x and 7 are whole numbers * do 0 to 4, characterized in that one reacts an l-'ct (t "1.2.3.4 <-t4t! r <Lj3ydjPon <tphta3.tn <of formula 1 EMI48.8 EMI48.9 .. in which R51 $ t6 117 'B8 # x and y have the..1nj.t: Loat1on¯, pre * etemta doxnë, x, renas itwut o, rnt og; i., tr t 0440 e.nt given, in the presence of an inert organic solvent with a Grignard reagent of formula; at EMI48.10 EMI48.11 * to which 1l, s R2 and ous2a have the attributes 0ataa8 precedes * - <Desc / Clms Page number 49> EMI49.1 have indicated * and Bal represents a halogen. 2.The process of the resale 1, o.rat'r18 ': what, when one of $ cut Ry and Ra or both taken again has <. the final product X hydropyranyloxy radical is; subject to hy- EMI49.2 drolysis by means of a mineral acid so as to convert the EMI49.3 tetrahydropymoyloxy group has free hydroxy group 3. The method of claim 1 # characterized in that, when it is formed as dt or * -product, 1-bj4roo, EMI49.4 corresponding to all others EMI49.5 4g (tydx) to the desired product, the crude reaction product is or dehydration to convert said I¯bydro3ty-1.2.3.4-ttrah1dronaphthalen. into desired product 4. The process of claim 1, characterized in that 1-ketolo2, '. 4-t'trah1dronaphthalene is produced from 1'-eeto-2-phenyl-.6-methoxy "1.2.3.4-tetrahydronaphthalene and Grignard's reagent is p - '(2-pyrrolidiao- étûoay) phenyl-magnesium bromide, which gives ÎL-fp- (2'-pyrrolidino-ethoXT) phe1] -phé1-6-.ethOX1-.4 -didronaphthalene. 5 The process of claim 1 characterized in that the starting material is 1 * - <} star-2''phenyl-6-rmethoxy '' 1 * 2 * 3 * 4-t6trabydronaphthalene and the reagent of Qrignatd is bromide of p (2-diethTl "ino-ethoX1) phégn68iua. which gives 1- [p- (2-d1etlatl.1noetho% Y) Ph6% Q" 1] -2 ... phé1-6- Betuoxy-3 * 4-dlbydronaphthalen9 60 Le <t products obtained by the following process EMI49.6 any of the preceding claims *