BE682082A - - Google Patents

Description

  

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    Process for the production of new organic compost and compounds obtained.



   The present invention relates to a novel series of organic compounds. More particularly, the invention relates to novel derivatives of 3-morpholinone and of morpholinone-3-thione which may be represented by the general formula
 EMI1.1
 next: r 6 # 2 1 fi 4 (5 4 3 ¯X J Á 2 (1) The novel compounds of the invention can be used as, muscle relaxants and as tranquilizers.

   In the general formula given above, X is a member of group i

 <Desc / Clms Page number 2>

 
 EMI2.1
 comprising ox> geno and sulfur, R1 is selected from the group consisting of hydrogen, the hydroxy group and lower alkyl and aryl radicals, provided that when R1 is hy axy, X is oxygen, R is chosen in the group
 EMI2.2
 OMT- * '--.mt hydrogen, lower alkyls, amino-lower alkyls, (lower alkyl) -amino-lower alkyls, acyls and aryls, provided that when R2 is a
 EMI2.3
 acyl radical, X is an oxygen and R 1 a hydrogen, a, ', j., /. lower alkyl or aryl, "3 is a member of the> '80 class comprising hydrogen, lower alkyl radicals and aryl radicals, R4 is a member selected from the group consisting of:

   "r, hydrogen, lower alkyl radicals and radicals
 EMI2.4
 aryls, Ar is an aryl radical and the dashed line 'f¯ = / broken between carbon atoms 5 and 6 indicates the presence
 EMI2.5
 of an optional double bond with Ar as the only aUba% 1-. .. killing in position 6, provided that when this double
 EMI2.6
 bond is present, B is other than a hydro radical% Yf When X is oxygen, the corresponding saturated compounds can be called 2.R1- 4wRa - F-6.R46 ... A âmarphoYanane. y,, When X is Boufre, the corresponding% baturde compounds can be called R4 R - Ff.6-t6Amorph45..ss. thionea.



  More particularly, with respect to the designated killing UbB% 1 on the morpholine ring and as used herein, the term lower alkyl refers to saturated carbon, branched or straight chain carbon bonds containing 1 to 7 carbon atoms. , for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, heptyl, hexyl, etc.,
 EMI2.7
 haloalkyl groups, such as trifluoromethyl, chloromethyl * etc., aminoalkyl groups such as 2-aminoethyl, 3-methylaminopropyl, 3-dimethylamino-2-pentyl, etc., and substituted lower alkyl groups

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   lower alooxy, such as 2-ethoxyethyl,

     3-methoxypropyl, etc. ;
The aryl group is preferably a monocyclic aryl radical, such as the phenyl group which can be, if desired, substituted with one or more groups. These grou-! pemants include, for example, hydroxy, lower alkyl, lower haloalkyl groups such as, for example, trifluoromethyl, lower alkoxy groups such as, for example, methoxy, ethoxy, propoxy, butoxy, isobutoxy, etc., aryl groups to lower alkoxy substituent, such as phenylmethoxy, halo groups, such as chloro or fluoro, nitro, amino and lower alkylamino, and cyclic ethers, such as methylenedioxy.

   The Ar substituents, in addition to the phenyl and substituted phenyl groups indicated above, can be, if desired, polycyclic aryl groups, such as naphthyl and fluorenyl, or heterocyclic groups containing 4 to 5 inter carbon atoms. - broken by bonds of oxygen, nitrogen or sulfur, for example pyrrolidyl, piperidyl, morpholyl, thiamorpholyl, pyridyl, thienyl, furyl, piperazinyl, etc, The term acyl includes aliphatic, aromatic and heterocyclic acyls,
Typical examples of acyls which can be used in accordance with the invention include lower alkyl carbonyls, for example acetyl, propionyl,

       butyxyl, etc. benzoyl and substituted benzoyl radicals, such as trifluoromethylbenzoyl, halobenzoyl, etc., phenylaoetyl, diphenylacetyl, furoyl, etc.



   The compounds of the invention in which X is oxygen, R is a group other than hydroxy, R2 is a group other than acyl and in which a single bond exists between carbon atoms 5 and 6, are prepared from the following conventionally by converting the appropriate aminoalcohol (II) into its alkali metal salt (III) by reaction with a base of

 <Desc / Clms Page number 4>

 alkali or alkaline earth metal, for example a hydride, an amide or an alcohol. Sodium hydride is particularly useful for this purpose. Treatment of compound (III) with a suitable halogenated alkyl ester gives an ether bond (IV) by displacement of the halogen.

   Cyclization to lactam (V) occurs by breaking down the alkanol, the reaction being advantageously carried out in the presence of an inert organic solvent, such as a hydrocarbon, for example benzene, toluene, xylene, l. hexane, heptane, etc. The reaction scheme can be illustrated as follows: '
 EMI4.1
 
Another process for obtaining the compounds (V) defined above consists in reacting the amino alcohol (II) with an acylating agent, such as the halide or anhydride of an α-substituted acid. suitable halo (VI) to give the corresponding amide (VII) which, by treatment with a base, such.

 <Desc / Clms Page number 5>

 than an aloaline or alkaline earth metal hydroxide, gives the desired lactam (V).

   The reaction scheme can be illustrated as follows;
 EMI5.1
 
The introduction of a lower alkyl or a substituted lower alkyl into the 4-position of the morpholine ring, i.e. on the nitrogen ring, can alternatively be effected by treating the non-compounds. substituted in position 4 of formula (V) with the appropriate alkylating agent, for example an interior alkyl halide or a substituted interior alkyl halide, for example bromide or chloride, in the presence of 'a strong base, for example sodium amide or sodium hydride under reflux conditions in a suitable inert organic solvent, such as aromatic hydrocarbons, for example benzene, toluene, xylene , etc.



   The acylation of compounds of formula (V) in which

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 nitrogen in the ring is not substituted, ie where R2 is hydrogen, is effected by conventional acylation methods. Typical acylating agents include lower aliphatic acid anhydrides, for example acetic anhydride, propionic anhydride, n-butyric anhydride, isobutyric anhydride, valeric anhydride, and the like.

   The acid halides can also be used advantageously as an acylating agent, for example aoetyl chloride, butyryl chloride, benzoyl chloride, substituted benzoyl chlorides, phenylaoetyl chloride, furoyl chloride. , eto. The acylation reaction can be carried out in the presence of a base and several anhydrous non-hydroxylic solvents, such as benzene, toluene, chloroform, methylene chloride, tetrahydrofuran, diethyl ether, ando .



   The introduction of a hydroxy group in position 2 of the morpholine nucleus of the compounds (V.) is effected by acylation of the amino alcohol (II) with a halide of a dihalo-aoetyl, such as dichloroacetyl chloride (VIII ), in the presence of an alkali diluted to give the corresponding acetamides, such as (IX) which, upon subsequent treatment with an organic amino base, for example morpholine, preferably under reflux conditions in a solvent consisting with an anhydrous hydrocarbon, such as benzene, toluene, xylene, etc., gives the corresponding 2-morpholino-3-morpholinones (X).



   Conventional acid hydrolysis of the latter readily yields the desired 2-hydroxy-3-morpholinones (XI). Alternatively, dihaloacetamides, such as (IX) can be converted directly to (XI) by treatment with an alkaline metal base such as bicarbonate, sodium, potassium carbonate, sodium hydroxide. sodium, etc.



   The reaction patterns are as follows!

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 EMI7.1
 
Compounds in which X is oxygen, R1 is other than the hydroxy radical, R2 is other than an acyl radical and a double bond exists between carbon atoms 5 and 6 of the morpholine nucleus, can be obtained by aoylanting a A keto compound of formula (XII) with an acylating agent, such as a halide or anhydride of an appropriate α-halo substituted acid under conventional acylation conditions to give the corresponding amide (XIII).

   Subsequent treatment with a base such as an alkali metal hydroxide or alooolate, eg sodium hydroxide, potassium tert-butoxide, etc., and preferably a strongly basic ion exchange resin, eg resin. Quaternary ammonium polystyrene, etc., causes cycling of (XIII) to give the desired compounds (XIV). The reaction scheme

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 is illustrated below. '\ soue,
 EMI8.1
 
Another process for the preparation of compounds with; The lower alkyl substituents on the nitrogen of (XIV) involves alkylating the corresponding unsubstituted compounds of (XIV).



    Conventional acylation of the latter also gives the corresponding N-acyl derivatives of these compounds. Hydrogenation of the 5,6 double bond, for example by means of hydrogen catalytically activated by a platinum, palladium or niokel catalyst, affords the corresponding saturated morpholinones of the invention.



   The replacement of the oxo function in position 3 of the morpholine nucleus with sulfur is carried out advantageously. ment by treating the appropriate 3-morpholine with phosphorus pentasulfide at temperatures generally at or above room temperature and, preferably, in the presence of pyridine. This reaction is particularly advantageous for converting the 3-morpholinones of formula (XV) into the corresponding morpholine-3-thiones of formula (XVI) in

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 which R1, R2, R3 and R4 are each a member selected from the group consisting of hydrogen, lower alkyl and aryl radicals, and, when the double bond is present, between carbon atoms 5 and 6, Ar is the only substituent at position 6.
 EMI9.1
 



   Depending on the raw materials employed, the morpholine nucleus substituents can be either "cis" or "trans" configured with respect to each other in the stereochemical representation. Therefore, it is understood that the compost of the invention embraces both of these configurations and it is within the skill of those skilled in the art. matter of determining which final conjuration is desired by initiating the operation with the appropriate raw material.

     the examples given above should therefore be considered as discrete illustrations and not as limitations on the scope of the invention or as limiting examples of "cis" or "trans" configurations of a given compound.



   Example I
Has a suspension of 50 parts by weight of alcohol
 EMI9.2
  - (1-a.minoethyl) -benz, yliCJ.'1. ('(Dl-norephedrine) in 500 parts by volume of benzine, 24 parts by weight of 50% sodium dthYQride dispersion are added in portions. The mixture is stirred for 3 '. Then a C4 "" 4 solution containing 43 parts of 4 ethyl chloroacetate distilled in 50% of 3 volume of benzene is added. 'addition

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 requires 15 minutes. The clear solution obtained is stirred for 1 hour. After the first half hour, a solid
 EMI10.1
 precipitate. This suspension is treated with enough, ¯ .'.- water to dissolve the solid.

   The mixture is extracted with a 5% aqueous hydrochloric acid solution. The solution
 EMI10.2
 acid is extracted back to ether. The ethe and benzene fractions are combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily solid obtained is washed with a small amount of ether and collected. 54.4 parts by weight (87%) of product are obtained.
 EMI10.3
 solid. Two reoristallizations in el.4yl acetate gave pure oia-5-methyl-6-phenyl-3-morpholinone, ranging from 136--140.5 C.
 EMI10.4
 



  ! 9N .... II A mixture of 21.3 parts by weight of norp9eUdO'Ph'- '' ,, drings 6.7 parts by weight of aodium hydrurf dispersion At 50 9 and 200 parts by volume of benzene this 4hAWf 'at reflux / for 4 heuroop then cooled. A solution containing 24, part% by POJ ', d of ethyl chloracetate tnichly distilled in 60 voluae puetion of benzene is added to this euepeneion * The resulting stirring is stirred for 1 hour with = 0 hydrochloric acid aqueous solution>, 5% and water. aqueous portiono are extracted in, dtOur with ether. The portion of beMene and to '> liAr are T'W4 * .t seoheea on anhydrous magaeium sulfate and at reduced pressure. the oily solid obtained: treated with a small quantity of ether and the product SolLd0 form4 is rewound by filtration.

   We obtain 16.8 r-4z ,, o in p9Lda> 1 eolide bland. Reoristalliaation in d d acetate; hy.e gives 15-0 parts by weight (57%) of trans-5-methyl -, - PhenYI-3-morpholinone, melting between 168 and 171 sec.

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 EMI11.1
 



  L: P 1. e III Phenethanolamine hydrochloride (20 parts by weight) is dissolved in 10% aqueous sodium hydroxide solution and is rapidly dissolved with two portions of sodium hydroxide. 'ether. The combined <= 6tblack portions are dried with magnifying glass sulfate and concentrated under a Vigreux column. The base 2.i'vr> J 5; .duella is taken in 200 parts by volume of buyàzbkq and 1), '\ adds, in portions, 8.3 parts by weight of disperai; an' sodium hydrorus. 50%. The mixture is stirred for Ù, 5 haux3. Then added a solution containing t4 parts by weight of ethyl chloroacetate distilled in 100 parts in vr., .. t. of benzene. The mixture is stirred for 2 hours, pu: .. s, 1], the extract with an aqueous solution of hydrochloric acid o. > -t water. The aqueous phase is extracted back at 11 f ') tL, n :.

   The ether and benzene fractions are combined over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual solid is treated nveo \ 1 ,, \! :; () ti to quantity of ether and collected.



  We obtain 11.1 pa1: tJ.QJ. ,}! lJ1dd (54 z) of white solid. By reoriste.ll1na: tIon diùaù. ' <., ethyl j-a, one obtains 6, 6 per-. parts by weight (32. ') of pure u ri'ziyl.3-norp? 401A11 melting between 108 and io9.5Te. a, .. C N., IV A un m {.l.: gu il- '.' partioa in weight of 1.ipluSdr1ne (& loalo1: de) dant,, 2FwL, p :::. , i., one volume of benzene, 9 parts by weight 4v diL? arion of .od1um hydride to 50.



  The mdltuk6 (i ;; Ct, (t ra d 1 hour) is stirred. A solution containing 15 pa1 "tj. +, ::, z <.,: 3, of ethyl ohloroaoetato tens in 100 is added thereto. ? a! ''; 'lN,. - 1dJlwnO of benzene. The angel is stirred for ih <,,; <. j ;; 4s extracted with a solution aq1 =>. + xa of ob7.orhydx ârtt acid . 5 1>. The aoid solution, 3t extracted in return with ten "h: 1.0); '1.il'O of methylene. The fractions of

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 Methylene chloride and benzene are combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual oil is passed over alumina to remove mineral oil.

   The oil is then distilled twice to give 11.2 parts by weight (45%), of 4,5-dimethyl-6-phenyl-3-morpholinone, boiling between 117 and 1202 (0.1 mm), n23D = 1.5428.



   Example V
To a solution of 15.7 parts by weight of [alpha] - (1-aminoethyl) -p-methoxybenzyl alcohol in 160 parts by volume of benzene is added 7.0 parts by weight of hydrogen chloride dispersion. 50% sodium. The mixture is stirred for 0.5 hour.



  Then a solution containing 11.8 parts by weight of ethyl ohloroacetate distilled in 120 parts by volume of benzene is added. The mixture obtained is stirred for 2 hours, then extracted with an aqueous solution of 5% hydrochloric acid.



  The aqueous portion is back extracted with ether. Benzene and ether are combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual solid is treated with a small amount of ether and collected. By recrystallization from ethyl acetate, one obtains.



  6.1 parts by weight (30%) of pure 6- (methoxyphenyl) -3-morpholinone, melting point 151.8-152.8C.



   Example VI
Dl-norephedrine (20 parts: 1 ... by weight) is added to a solution containing 5.8 parts by weight of sodium hydroxide in 150 parts by volume of water. The mixture is cooled and added, in portions, with vigorous stirring,
27.4 parts by weight of [alpha] -chlorophenylacetyl chloride.



   The solid obtained is collected by filtration and washed thoroughly with water, then dried. The solid is triturated with ether and collected. Reoristallization in ethanol

 <Desc / Clms Page number 13>

 
 EMI13.1
 gives 6.8 parts by weight (19%) of 2-chloro-N- (P-hydroxy-a-methylphenethyl) -2-phenylacetami.de, melting between 150 and 152 C.



   Example VII
To a solution containing 0.44 part by weight of potassium hydroxide in 20 parts by volume of absolute ethanol,
 EMI13.2
 2.37 parts by weight of 2-chloro-N- (P-hydroxy-o-methylplaenetyl) -2-.phenylaoëtamide are added. The mixture is stirred for 4 hours. The potassium chloride is removed by filtration and the filtrate is concentrated under reduced pressure. The residual material is crystallized from a mixture of ether and petroleum ether. Two recrystallizations from ethyl acetate
 EMI13.3
 yield 2,6-diphenyl-5-met2, yl-3.-morphalinone, melting between 177-182C.



     Example VIII
A solution of 11.2 g (0.28 mol) of sodium hydroxide in 150 ml of water is added to a solution of 20 g
 EMI13.4
 (0.0885 mol) of a-am; nomethylbenzhydrol in 200 ml of methylene chloride. The mixture was stirred and cooled, and 10.0 g (0.089 mole) of ch.aroaoty5.e chloride was added. A precipitate of the reaction mixture is collected by filtration. Recrystallization of the material from ethanol gives 2-ohloro-N-
 EMI13.5
 (P-hydroxy-a-methyl-p-phdnylphen6thyl) -aedtamide, melting point 180 ° C. Further purification is carried out by reoristallization in methanol and the product melts between 181 and 181.5 C.



     Example, IX
A solution of 4.9 g (0.086 mol) of po-
 EMI13.6
 potassium and 13.0 g (0.043 mol) of 2-ohloro-N- (p-hydroxy-a-methyl-j3-phenylphenethyl) -acetamide in methanol is stirred for 18 hours. The solvent is evaporated in vacuo and the residue is recrystallized from benzene to give 5-nothià-6,6-diphenyl-3-morpholinone in white crystals, being between 248 and 25iG. Subsequent reoristallization in benzene

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 produces a purer product which melts between 265 and 266 C.



   Example X
A solution of 9.4 g (0.236 mol) of sodium hydroxide in 50 ml of water is added to a solution of 25 g
 EMI14.1
 (0.118 mol) of dl-erythro-1,2-diphenyl-2-amiuoethanol in 500 ml of chloroform. Add dropwise to the mixture
 EMI14.2
 cooled and stirred 13.3 g (0.118 mol) of abloroaodtyl chloride.

   The voluminous precipitate which forms is collected
 EMI14.3
 by filtration after 30 minutes, it is recrystallized from methanol to give 2-chloro-N- (purified p-hydroxy <-a-phenylphenethyl-aoetamide, melting point between 187 and 189200,, r: Example XI
 EMI14.4
 To a solution of 2.73 g (0.0245 mole) of potassium tert-butoxide in 450 ml of tert-butanol was added 7.0 g (0.0245 mole) of 2-ohloro-N- (p-'hydroxy- < -phenylphenethyl3) -aoetamide. the mixture is stirred and heated for several hours and kept cold for 16 hours. The solvent is evaporated off under reduced pressure and the residue is dissolved in methylene chloride. The solution is washed twice with water, dried
 EMI14.5
 on magnesium sulphate and oonoentry & aeo.

   The residual solid (51 g) is reerietallized in benzene to give pure 5,6-diphenylmorpholinone, melting between 182 and 18390.



  EX6M) 1 XII Alcohol hydrochloride c. (1-amoâthr,) w. chlorobenzyl (28el go z 'mole) is dissolved in a mixture. of 300 ml of methylene chloride and 220 ml of 5% aqueous sodium hydroxide. The solution is stirred and cooled in an ice salt bath. Chloride is added dropwise
 EMI14.6
 of ohloroacetyl (21.5 g or 0.191 mol) in the reaction mixture. The reaction is stopped after 15 minutes. The alkaline phase is separated and discarded, then the methylene chloride phase is washed with 1N hydrochloric acid.

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  The organic phases are separated and dried over magnesium sulphate then concentrated to give a crude product melting between 87 and 91 C. Recrystallization from acetate
 EMI15.1
 ethyl gives 2-chloro-ti- (p-chlom-fi-hydroxy- + nethylphenethyl) -acetamide, melts between 92 and 9420,
 EMI15.2
 ± X r I'J 1 XIII We add U *. -ch1oro-N- (p-chloro- (3-hydroxy-a-methyl-phenethyl) -acetamid'3 (4 <,, \ g. 0.093 mol a moderate vitease, to a solution of ter;: oz,; iji Al of potassium (prepared by reacting 7.25 g or 0.16 gram atom of potassium with excess anhydrous tert-butanol in 750 ml of anhydrous tert-butanol.

   The mixture r # ,. acrcl is stirred overnight at room temperature. \ "): 1 concentrate it under reduced pressure to remove the tvâ t .. w bsmal,. The residue is dissolved in methylene chloride c -iana water .. The organic phases are separated, dried on magnesium sulphate and concentrated to give a hvlh which crystallizes.Recrystallization from i, 1; ylo acetate gives 6- (p-ohlorophenyl) -5-methyl - morpha..uo : 1 <. ;; being between 146 and 1 48, ska.



  Txc rrt XIY A solution C0n, cnnnt 13.2 g of ephedrine in 100 ml of chloride of ath ;; l.f3 eue mixed with 100 ml of sodium hydroxide in solution qut; u: c: a 1 i. The mixture is cooled in an ice bath and quenched quickly with 17.1 g of N-chlorophyll U.tyl chloride. After 15 hours of stirring at temperature <. U.ta, the phases are separated and the aqueous phase is e ;: v, e with methylene chloride, the solution organ1 <rr 0 ... '1 ic is washed with dilute hydrochloric acid and ari .V' ';' '1! Clied on anhydrous magnesium sulfate and oOl1. (:(, nt :: ',:,:.' sec. The residual oil is da..1 'to a large extent on <...> 0:' 0- : \ - (pb.ydroxy-a-methyl .enethyl) -lt- &éihyl-2-phenylz,;;%, am # <ie, cc-un.o shows its infrared spectrum.

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  Example XV
 EMI16.1
 A solution of 16.6 g of 2-chloro-N- (-hydxQxy-c- /, ¯ methylphenethyl-N-methyl-2-phenylaaetamide in 100 ml of 95% ethylenol is added with stirring to a solution. 4.0 g of potassium hydroxide in 100 ml of ethanol After stirring at room temperature for 5 hours the mixture is filtered and the filtrate is concentrated to dryness Distillation of ¯ / ¯
 EMI16.2
 the residual oil gives in the pure state 4, 5-dimethyl-2, 6-diphenyl-3-morpholinone, boiling between 172 and 176 ° C (0.05 mm) r.



  Example XVI / .Il A - To 10.0 g of 5-methyl6-phenyl-3-morpholinone dissolved in 100 ml of benzene, 2.6 g of 50% sodium hydride in oil are added. After stirring the mixture at room temperature for 3 hours and heating under reflux for 1 hour, the theoretical amount of hydrogen evolved. A solution containing 0.11 mole of diethylaminoethyl chloride in 250 ml of anhydrous benzene is then added and the heating is continued at reflux for 15 hours. After cooling, the solution
 EMI16.3
 Benzene cation is extracted twice with dilute hydrochloric acid. The aqueous phase is basified and extracted three times with ether.

   After drying over anhydrous magnesium sulfate and filtration, the ether solution is concentrated to dryness to give the base product as an oil. Conversion to the hydrochloride with anhydrous hydrochloric gas in ether, followed by two recrystallizations from a mixture of ethanol and ether gives the hydrochloride of
 EMI16.4
 Pure 4-diethyl-aminoethyl-5-methyl-6-phenyl-3-morpholinone, melting between 224 and 225.5 C.



   B - By following the process of Example XVI-A, but
 EMI16.5
 replacing with an equivalent amount of ethylenimine and 3-methylaminopropyl chloride, respectively, the diethylaminoethyl chloride, which is used there, one obtains the derivatives

 <Desc / Clms Page number 17>

 
 EMI17.1
 4-aminoalkyl * l., <: # - \: 3 5-methyl-6-phenyl-3-morpholinone.



  ] "¯ '' '¯, .Lill De .'hyftft 1'r (4.5 5 gr 0.09 mole, dispersed at. 50% dance ::. J! 1; j. N-i) is washed three times with anhydrous benzene in mineral oil. 50 ml are then added to 1. <:% i -: this is the reaction mixture. The reaction mixture is dissolved. :) of a-aminomethyl-p-chlorobenzyl alcohol = .I. =: 3, anhydrous benzene and slowly added to a. the b <.: ''>,, ... The reaction mixture is then stirred Wnd > -r-1- 1 '' 1 adds 7.5 g (0.06 mol) of.; β.. .r, y7.e dropwise. The reaction mixture is stirred for <1s = c <5 1 water is added to decompose the hydride and 1; <1 ". . "¯: ¯: 31 is stirred overnight, the beu2t. Phase <i.J '. \ R.: E the alkaline phase and washed with 11 aC:!. De;,: l ... (. '11 diluted.

   The organic phases are dried mu '.i .. i \ ugnnesium and concentrated to give an oil da; ..u .., trituration aveo a mixture of benzene and é'1> uv ;. ', .1 crude sodium hydroxide melting between 142.5 and 14. T: O =. 1: .. .L.lisation of a sample of this 8 ', Iide in the bG:. : ... 6- (p-chlorophenyl) -3-morpholinone f 6YIt i3 1.;: '; ,>. i '. #. T'I.:. 'j7,: 1. ,.;, 1 d..1C () ol a-aminoethyl-3,4,5- trimëthoxyben <; yl 1 L,.>: 'C <.. J in 70 ml of methylene chloride and 40 1 d The solution is 10% aqueous sodium. . 3.5 g (0.031 mole) i l of chloroacetyl are added dropwise.

   The reaction mixture is stirred: L <.:. <J xnutas, The chloride phase of IIlG ', i' J 'is separated. !, 1 saw with 0 of dilute hydrochloric acid we have the UO'Jh: 4 magnesium e'1 "we concentrate to obtain it., ', .Roxy-3, 4, 5.tx., wethoxyphnthyl

 <Desc / Clms Page number 18>

 
 EMI18.1
 acetamide melting between 11 and i i 20,
 EMI18.2
 gxemole XIX 13.9 g (0.046 mole) of 2..ah.aro N- (-hYdroxy-3, 4, 5- / trimethoxyphenet% 1) -acetamide are added at a rate of mo-
 EMI18.3
 derived from a solution of potassium tert-butoxide (obtained by reacting 3.14 g or 0.096 gram-atom of potassium with an excess of tert-butanol anhydride in 35 ° C. ml of tert-butanol = anhydrous. The reaction mixture is stirred throughout the entire process. end
 EMI18.4
 week.

   Then, the reaction mixture is concentrated to 1.] remove tert-butanol. The residue is dissolved in water and methylene chloride. The organic phase is separated, dried over sulfate, magnesium and concentrated to give a
 EMI18.5
 crude product melting between 159.5 and 1 6 1 k 0. Recrystallization from ethyl acetate gives 6 t3 r 4, 5-tr.mthoxy ph ± nyl) -3-norpholinone, melting between 161.5 and 161 # 820.



  Exemule X7 A dispersion of sodium hydride in oil ¯¯¯ / (5, g of 50% dispersion) is washed three times with portions of 200 ml of anhydrous benzene and left in suspension in 200 ml of anhydrous benzene. We add to this mixture under
 EMI18.6
 stirring 10.0 g of -methyl .-- 6..phenyl - anarpho3.inone. Once the reaction is complete (1 hour), a solution is slowly added
 EMI18.7
 of 8.4 g of acetyl chloride in 3 mil of anhydrous benzene. the mixture obtained is stirred for 15 hours, extracted with water and with a dilute solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness.
 EMI18.8
 



  Distillation of the residual oil gives pure 4-aoetyl-5-methyl-6-phenyl 5-mUrpholmone boiling between 108 and 12990 (0.06 to 0.08 mm).



     Example, XXI
 EMI18.9
 A dispersion of sodium hydroxide in oil (7.5 and 0.16 mol) is washed three times with 200 ml portions of

 <Desc / Clms Page number 19>

 anhydrous benzene and is suspended in 200 ml of anhydrous benzene. To this mixture is added while stirring 15.0 g (0.079 mole) of 5-methyl-6-phenyl-3-morpholinone. Once the reaction is complete (1 hour), a solution of 16.7 g (0.16 mol) of isobutyryl chloride in 150 ml of benzene is slowly added. The mixture obtained is stirred for 15 hours, extracted with water and with a dilute aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness.

   Distillation of the residual oil gives pure 4-isobutyryl-5-methyl-6-phenyl-3-morpholinone boiling between 126 and 12820 (0.06 mm).



   Example XXII
A dispersion of sodium hydride in oil (4.32 g of 50% dispersion) is washed three times with 150 ml portions of anhydrous benzene and is suspended in 200 ml of anhydrous benzene. 15.0 g of 5-methyl-6-phenyl-3-morpholinone are added to this mixture with stirring. When the reaction is complete (1 hour), a solution of 12.0 g of benzoyl chloride in 100 ml of anhydrous benzene is added. The mixture obtained is stirred for 4 hours, extracted with water and with a dilute solution of sodium bioarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Trituration of the residual oily product with ether gives a crystalline solid.

   Two recrystallizations from the mixture of ethyl acetate and hexane and one recrystallization from the mixture of benzene and hexane gives pure 4-benzoyl-5-methyl-6-phenyl-3-morpholinone melting between 119.5 and 124.5 C.



   Example XXIII
Sodium hydride (2.78 g, 0.058 mol, 50% dispersion in mineral oil) is washed three times with anhydrous glycine. 100 ml of monoglyme are added. and the mud is agitated. 10 g (0.052 mol) of 5-methyl-6-phenyl-3-

 <Desc / Clms Page number 20>

 morpholinone. The mixture is stirred and heated for 30 minutes, after which the evolution of hydrogen ceases. Slowly added @ 7.95 g (0.058 mol) of butyl bromide. the reaction mixture is heated at reflux for 1 hour, then stirred at room temperature overnight. It is then heated at reflux for an additional 1.5 hours. Water and ether are added and the phases are separated. The aqueous phase is extracted again with ether.

   The combined organic phases are dried over magnesium sulfate and concentrated to give an oil. Distillation gives 4-butyl-5-methyl-6-phenyl-3-morpholinone boiling at 115 ° C (0.03 mm).



   Example XXIV
2.88 g (0.06 mole, 50% dispersion in oil; mineral) of sodium hydride are washed three times with anhydrous distilled motor glyme (distilled over lithium aluminum hydride) . Then 100 ml of monoglyme are added. We stir, @ the mud. 9.6 g (0.054 mol) of 6-phenyl-3-morpholinone are added and the reaction mixture is stirred until the evolution of hydrogen has ceased (30 to 45 minutes). Solvent is added because a bulky precipitate forms. Butyl bromide (8.2 g, 0.06 mol) is then added and the reaction mixture is heated at reflux for 4.75 hours. The reaction mixture is then stirred overnight at room temperature, then water is added. The mixture is extracted twice with ether.

   The combined organic phases are dried over magnesium sulfate and concentrated to give a crude oil. Distillation gives 4-butyl-6-phenyl-3-morpholinone boiling between 123 and 125 ° C (0.075 mm).



   Example XXV
5 g (0.024 mol) of [alpha] -aminomethyl-p-trifluoromethyl-benzyl alcohol are dissolved in 50 ml of methyl chloride.

 <Desc / Clms Page number 21>

 ne and 30 ml of 15% aqueous sodium hydroxide. The solution is cooled and stirred. 4.2 g (0.037 mol) of chloroacetyl chloride in 42 ml of methylene chloride are added dropwise in the reaction mixture. After stirring for 0.5 hour, the organic phase is separated and washed with 1N hydrochloric acid. The organic phases are dried over magnesium sulfate and concentrated to
 EMI21.1
 give 2-cYiloro-N- (fi-hydroxy-p-tnfluorom4thylphenethyl) - acetamide melting between 92.5 and 9520.



   Example XXVI
12.4 g (0.11 mol) of technical potassium tert-butoxide are dissolved in 500 ml of anhydrous tert-butanol.
 EMI21.2
 2-Ohl..oxo-h - (- hydroxyp-trà.luoromethyphéndthy3,) - acetamide (11 g, 0.039 mol) is added at a moderate rate to the butanol solution. The reaction mixture is stirred overnight, then concentrated to remove tert-butanol. The residue is dissolved in methylene chloride and water. the organic phases are separated, Beaked over sulphate of
 EMI21.3
 magnesium and concentrate.

   By reoristallization in ethyl aaétato, 'one obtains the 6- (a, a, a..tr, luoro.p-to.yl) -a8rphoâ..w none melting between 115.5 and 116.520,
 EMI21.4
 m-ole MY..t "A solution of ethylmagn'S1um bromide is prepared by carefully adding 134 ml (1.81 moles) of ethyl bromide to a suspension with stirring of 45 g (1.86 mole). mole) of magnesium in 600 ml of anhydrous ether.
 EMI21.5
 Completed, 101.4 (0.60 mol) of m-trif.uoromethylbenzonitrile is added and the dark solution stirred for 18 hours.



  The reaction mixture is poured into 1 liter of crushed ice containing 200 ml of concentrated hydrochloric acid. The mixture is then heated on a steam bath for hours and cooled to room temperature. The oily phase is extracted

 <Desc / Clms Page number 22>

 in the ether. The ether phase is separated and dried over magnesium sulfate. The ether is evaporated under vacuum to
 EMI22.1
 give 31-trifluo-i5methylpropiophenone as a purified yellow oil by distillation through a short Véreux column, boiling between 58 and 60 C (0.05 mm).



   Example XXVIII
 EMI22.2
 A stream of hydrogen chloride gas is passed at a moderate rate through a solution of 43.3 g (0.213 mol) of 3'-trifluoron ± thy19ropiophenone in 300 ml of ether. N-Butyl nitrite (24.1 g, 0.234 mol) was added to the stirred solution over a 15 minute period. The addition of hydrochloric gas is maintained and continued for 20 minutes after the end of the addition of butyl nitrite. The solution is stirred at room temperature for 3 hours. The solvent is evaporated off in vacuo and the crystals obtained are triturated with hexane.
 EMI22.3
 and collected by <.1% ra% ion to give 2-hydroxyimino-3'-trifluoromethyropiophenone which melts between 115 and 116 sec after purification by raoristallization in methyloyolohexane.



  'nlP! ..' T w 3 g of .0al ". 10% mdïum attached to carbon are \ ..... added to a d (, '. 1.1.t: l.on of 15.1 g (0.065 mol) of 2hydxoxyimia9; 3'otr, l, o.;, P; hy, pxap3o. ,, none and 7 g of hydrochloric gas,. '<Hydr: in 500 ml of ethanol abô>, iu, Le The mixture is hydrogenated at a pressure of 3.5 g / cm2 for 17 hours in a Paar shaker * 3 equivalents of hydrogen are absorbed. The catalyst is removed by filtration and the solvent is evaporated under reduced pressure. .

   The residue is tri-
 EMI22.4
 tured with 3. ' Etae- e 'the white cyiatals Zie a- (1-amlethyl) -m-tru: .uoromethylbexzyl alcohol hydrochloride are collected by filtration (melting point 202-20420) and are purified by recrystallization in lans the mixture of ethanol and ethor - melting point (4.3 2042

 <Desc / Clms Page number 23>

 Example XXX
 EMI23.1
 To 1.0 g of alcohol hydrochloride - (1-amino ± thyl-m-trifluoromethylbenzylic acid in 10 ml of dichloromethane and 10 ml of 15% sodium hydroxide, 0.86 g of chloride is added at room temperature. The mixture is stirred for 1 hour, the phases are separated and the aqueous solution is extracted once with dichloromethane.

   The combined organic solutions are washed twice with 0.5N hydrochloric acid, dried over magnesium sulfate, filtered and concentrated. Recrystallization from a mixture of ether and petroleum ether gives 2-chloro-N - (- hydroxy-
 EMI23.2
  -m6thyl-m-tri: Eluoromethylphen6thyl) -acetamid melting between 65.5 and 68.5 C.



   Example XXXI
To a solution of 0.76 g of potassium tert-butoxide in 10 ml of tert-butanol is slowly added in portions 1.0 g of 2-ohloro-N- (P-hydroxy-a-methyl-m-trifluoro-
 EMI23.3
 methylphenethyl) -acetamide The solution is stirred at room temperature for 15 hours and then concentrated. The residue is dissolved in water and dichloromethane and the phases are separated. The aqueous solution is washed once with diohloromethane. The combined organic solutions are washed once with water, dried over magnesium sulfate and concentrated to give an oily product which crystallizes on standing.

   Recrystallization from a mixture of ether and petroleum ether
 EMI23.4
 gives 5-methyl-6- (a, a, a-trifluoro-m-tolyl) -3-morpholinone melting between 100 and 101.5 C.



   Example XXXII
To 3.2 g of sodium hydride (54% in oil) washed with 1,2-dimethoxyethane to remove mineral oil) in 100 ml of 1,2-dimethoxyethane is added slowly by por-
 EMI23.5
 8.4 g of 5-ethyl-6-phenyl-3-morpholinone, The mixture is

 <Desc / Clms Page number 24>

 stirred for 10 min at room temperature and for 20 min at reflux, then cooled to room temperature.
 EMI24.1
 10 g of p-trifluoromethylbenzQyl chloride in 50 ml of 1,2-dimethoxyethane are added to the mixture and the resulting mixture is left to stand at room temperature overnight. After heating under reflux for 0.5 hour, the reaction mixture is cooled and diluted with a solution of 98 ml of water and 1.2 ml of crystallizable acetic acid.

   The solution is extracted twice with ether. The organic solution is washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residual oil is triturated twice with petroleum ether. Trituration with the mixture of etharet of petroleum ether gives a semi-solid. Recrystallization in the
 EMI24.2
 mixture of benzene and hexane gives 5-methyl, -6phenyl.A.- (a, a, a-.trifluoro-p.-toluoyl) w3-morpholi.none mowing between 119.5 and 120.5 C.



    Example = 111
A - 7.7 g (0.16 mol, 50% dispersion in mineral oil) of sodium hydride are washed three times with anhydrous monoglyme to remove the mineral oil. Then 100 ml of monoglyme are added, followed by 20 g (0.105 mol) of 5-methyl-
 EMI24.3
 6-ph4nyl-3-morpholinono, The reaction mixture is stirred for 0.5 hour, then heated to reflux and stirred for a further 0.5 hour. It is then cooled in a bath of
 EMI24.4
 ice cream. 28 g (0.16 mol) of p-chlorobanzoyl chloride are dissolved in 200 ml of monoglyme and the solution is added slowly to the reaction mixture. This one is agitated during. overnight then concentrated to eliminate the monoglyme.

   The residue is dissolved in benzene and water containing a few drops of acetic acid. The organic phase is separated and the aqueous phase is washed again with benzene. The combined organic phases are dried over magnesium sulfate.

 <Desc / Clms Page number 25>

 and concentrated to give an oil, which is triturated with ether and hexane to give p-chlorobenzoic anhydride. The mother liquors crystallize on standing.



  Filtration gives a crude solid melting between 104 and 11120.



  Recrystallization from ethyl acetate gives 4- (p-chlorobenzoyl) -5-methyl-6-phenyl-3-morpholinone, melting between 113 and 114 C.



   B - The process of Example XXXIII-A is followed, except that an equivalent amount of 6- (p-chlorophenyl) -5-methyl-4H- 1,4-oxazin-3 (2H) -one (Example XLI -A) and 5-methyl-6-phenyl-4H-1,4-oxazin-3 (2H) one (Example XLVII), respectively, is used instead of 5-methyl-6-phenyl-3- morpholinone to give their corresponding 4- (p-chlorobenzoyl) derivatives.



   Example XXXIV
A Grignard reagent is prepared by adding 134 ml of ethyl bromide in 300 ml of ether to 45 g of magnesium in 100 ml of ether and heating the mixture to vigorous reflux.



  The Grignard solution is cooled to room temperature and treated with a solution of 101.4 g of p-trifluoromethyl-benzonitrile in 200 ml of ether. The reaction mixture is stirred for 4 hours and left to stand at room temperature for 15 hours. The Grignard mixture is hydrolyzed by pouring it carefully into 2 liters of crushed ice and
200 ml of concentrated hydrochloric acid. After filtration to remove excess magnesium, the solution is heated for
2 hours on a steam cone. It is then cooled and extracted three times with ether. Ether extracts are
 EMI25.1
 washed with l.'c. .

   G ,,. (, R ;. dried over magnesium sulfate, filtered and concentrated to give low melting 4t-trifluoromethyl-propiophenone, soJ: s.



  Exemie XXXV A l 1 2 to 4 '-trifluorom ± thylpropioph ± none in 750

 <Desc / Clms Page number 26>

 parts of ether, pass rapidly for 20 minutes while cooling anhydrous hydrochloric gas. Gas addition is continued while adding 59.5 g of butyl nitrite over a period of 15 minutes. The addition of hydrochloric gas is continued for 20 minutes and the solution is allowed to stand at room temperature for 15 hours. The solution is concentrated to a small volume and diluted with petroleum ether. The crystals are filtered off, washed with petroleum ether and air dried to give 2-hydro-xyamino-4'-trifluoromethylpropiophenone, mp 134-137 C. An additional amount of the product can also be obtained. the mother liquor.



   Example XXXVI
A mixture of 30 g of 2-hydroxyimino-4'-trifluoromethyl-propiophenone, 6 g of 10% palladium fixed on charcoal and 500 ml of 2N hydrochloric acid in ethanol is hydrogenated on a shaker shaker. laar. The theoretical quantity of hydrogen is used over 18 minutes and the reduction is stopped. The mixture is heated and filtered and the catalyst is washed 6 times with hot 95% ethanol. The filtrate is concentrated to a small volume in vacuo and the crystalline hydrochloride is collected by filtration to give 2-amino-4'-trifluoromethylpropiophenone hydrochloride, mp 255-256 ° C.



   Example XXXVII
A mixture of 27.3 g of 2-amino-4'- 'trifluoromethylpropiophenone hydrochloride, 6 g of 10% panade fixed on charcoal and 50% alcoholic hydrochloric acid is hydrogenated on a Paar secarses apparatus. . The reaction is complete in 35 minutes and the mixture is filtered. The catalyst is washed thoroughly with ethanol, and the filtrate is concentrated to a small volume in vacuo. The crystalline product is.

 <Desc / Clms Page number 27>

 
 EMI27.1
 collected by filtration, washed with ether and dried over calcium chloride, to give, after purification, α- (1-αoethyl) -p-trifluoromethylbenzyl alcohol hydrochloride, mp 240-5G.



  .r '"' Jl.e XXXVIII A. 10 g dl.: .A = :; alcohol drate oe- (1-amino ± thyl) - p-trifluoromethylbcr.xrLique in 100 ml of 15% sodium hydroxide % and 100 ml of iicoroehane, cooled in an ice bath, 6.8 g of chloroacetyl chloride are added The mixture is stirred at room temperature for 15 hours.

   The phases are separated and the aqueous GLN is washed once with dichloromethane, the combined organic solutions are washed twice a7., C \ i (; 0.5N hydrochloric acid, dried over sulphate in s ,,. I. ., vum, filtered and concentrated in vacuo to give after purification 2-chloro-N- (-hydroxy-a-methyl- p-.trifluoromthyl, aâun: 2j.csCVtatu.de melting between 93 and 95 ° C. re.; ne XXXIX At a sc.utw ;: of 8.05 g of potassium tert-butoxide in 100 ml of tex ß.t7hu ßt, ol, slowly added in portions while stirring at -; ClJ, P01'l, Ure ambient 10, 7 g of 2-chloro-N- (- hydroxy-a-méthy.-pt: ix..uororaethylpheneth, yl) -. Acetamide. The mixture is stirred at room temperature for 15 minutes. hours, then concentrated in vacuo The residue is dissolved in water and the dichloromethane is separated off.

   The aqueous solution is extracted with diohloromethane and ethyl acetate. The combined organic solutions are washed after having been taken out of vacuo with water. The product crystallizes and is ',' ",.;: Rrj, 1..l1ized in a mixture of ether and petroleum ether.c-;. -W to give 5-zaethyl-.6- (a, a,: -trit3.uoro- p-tolyl) -3-morph- ;. melting between 127.5 and 29 ° C.



  ; .f., X1 A - 2.5 g (isolated) 2-amino-4'- hydrochloride

 <Desc / Clms Page number 28>

 chloropropiophenone are dissolved in 20 ml of water and 25 g of ice. Chloroacetyl chloride (2.5 g, 0.022 mole) is combined with a concentrated solution of sodium acetate (4.5 g, 0.055 mole) in water. The mixture is added all at once to the amine hydrochloride. The reaction mixture is stirred for 2 hours (crystals begin to form immediately) and has then reached room temperature. The reaction mixture is filtered to give wet crystals. Drying gives a crude solid.

   Recrystallization of part of this solid from ethyl acetate gives 2-chloro = acetamido-4'-chloropropiophenone, melting between 104.5 and 105.5 C,
B - According to the method of Example XL-A, but using an equivalent amount of 2-amino-4'-trifluoromethylpropiophenone hydrochloride, # -amino-ketophenone hydrochloride and 2-amino-3 'hydrochloride , 4 ', 5'-trimethoxy-propiophenone, respectively, instead of the hydrochloride of 2-amino-4'-chloropropiophenone of this example, the corresponding product is obtained 2-chloracetamido-4'-trifluoromethyl-propiophenone, l' # -chloroacetamidoacetophenone and 2-chloracetamido-3 ', 4', 5'-trimethoxypropiophenone.



   XLI Example
A - A basic ion exchange resin (IRA-400, chloride form, 60 g) is brought into the hydroxyl form by stirring. for 45 minutes with excess sodium hydroxide 10% aqueous solution. The resin is then washed with water until the washings are neutral to paper, pH. Then the resin is washed thoroughly with methanol to remove as much water as possible. The resin is suspended in 400 ml of methanol and stirred. 2-Chlorcacetamido-4'-chloropropiophenone (1.2 g,
0.005 mole). The reaction mixture is stirred overnight and then filtered. The resin is washed several times with methanol.

 <Desc / Clms Page number 29>

 



  The filtrate is concentrated to give an oil. Trituration with ether gives a crude solid. By recrystallization from chloroform, 6- (p-chlorophenyl) -5-methyl-4H-1,4-oxazin-3 (2H) one is obtained, melting between 205 and 207 C.



     B - In accordance with the process of Example XLI-A, but using an equivalent amount of the respective products obtained in Example XL-B for 2-chloracetamido-4'-chloropropiophenone of Example XLI- A, the following products are obtained: 6- (p-trifluoromethylphenyl) -5-methyl-4H-1,4-oxazin-3 (2H) one, 6-phenyl-4H-1,4-oxazin-3 ( 2H) one and 6- (3 ', 4', 5'-trimethoxyphenyl) -5-methyl-4H-1,4-oxazin-3 (2H) one.



   Example XLII
5 g, (0.022 mole) of 6 - ([alpha], [alpha], [alpha] -trifluoro-p-tolyl) -3-morpholinone and 4.6 g (0.022 mole) of benzoic anhydride are combined in 100 ml of xylene. A catalytic amount of p-toluene sulfonic acid is then added. The reaction mixture is heated at reflux overnight. Then, the reaction mixture is cooled and washed with dilute aqueous sodium hydroxide. The organic phases are dried over magnesium sulfate and concentrated to give an oil.

   Tritura- tion with petroleum ether gives a crude solid melting between
148.5 and 15220. By recrystallization from ethyl acetate, 4-benzoyl-6 ([alpha], [alpha], [alpha] -trifluoro-p-tolyl) -3-morpholinone, flux is obtained. between 156 and 157QC.



   Example XLIII
A - 5.0 g (0.033 mole) of norephedrine are dissolved in
50 ml of methylene chloride and 30 ml of 10% aqueous sodium hydroxide. The solution is cooled in an ice bath and stirred. 5.35 g of dichloroacetyl chloride (0.036mole) are dissolved in 20 ml of ethylene chloride and added slowly dropwise to the reaction flask. The mixture is then stirred for 20 minutes. The chloride phase of

 <Desc / Clms Page number 30>

 
 EMI30.1
 .........: ...... .. '? 5.1.>. "Methylene is separated and washed with 1N hydrochloric acid. The organic phase is dried over magnesium sulfate and concentrated. to give white crystals melting between 90.5 and 92.520.

   Recrystallization of one part gives 2,2-dichloro-N- (P-hYdrOXY- -m6thYlPh6r'6thyl) -ae6tamide, tondan1 ', - between 96 and 9720.
 EMI30.2
 



  B - according to the procedure of Example XTTIA but using an equivalent amount of a- (1-methyli. Aminoethyl) -benzyl alcohol, a- (1-aminoethyl) -benzhydrol, dl-drythro-1 , 2-diphenyl-2-aminoethanoll of alpha-aminodthyl-3,4,5-trimethoxybenzyl alcohol and -arUnom6thyl-p.,. Trifliloro. methylbenzyl, respectively, instead of norephedrihe, the following corresponding product is obtained 2,2-d3ahloro- N-metn.Y.-N (-hydroxy-amethylphenethyl) aoetam. of 2, Z-diehloro-Nx- phenY'Z-hydroxy..a..mêth, ylphnthy.) acetmide 2, 2-.dichloro = -: - (hydroxy-a-plxy ,, a., methylphenthyl) actde, le, 2-dichlorrN- (whydroxy -, 4, -tt.m, .oxyphenethy.) Aodtald
 EMI30.3
 and,
 EMI30.4
 the 2,2-. ohloro-N- (hydroxy-ptrifluoromethylphenëi) MMii.



  ExemBl.ē.XLIV A - 8, g (0.033 mol) of 2, 2-d3, chï.oro-N .- (S-hydroxy.aw methylphenethyl) -aoébam9.da are combined with 5.8 g of mulrphôliae (0.066 mol) in 100 ml of toluene. The reaction mixture is stirred and heated / refluxed overnight. Crystals of morpholine hydrochloride are deposited continuously throughout the reaction, The reaction mixture is then allowed to cool to room temperature, filtration gives 5 g of hydrochloride. of "'rpholine. The filtrate is cooled in a bath.
 EMI30.5
 of ice and we, joust of ether.

   The solid obtained is eliminated
 EMI30.6
 by fi1trat4'T. to give an impure product melted between 195 and 1972C ua recrystallization from ethanol dom.a 2-mor-,, .j-methyl-6-phônyl - $ - worpholinone, pure, melting between

 <Desc / Clms Page number 31>

 
B - In accordance with the procedure of Example XLIV-A, but using an equivalent amount of the respective products obtained in Example XLIII-B instead of 2,2-dichloro-
 EMI31.1
 N - (- hydroxy-a-methylphenethyl) -acetamide of Example CZIY-ï, the following products are obtained: 2-morpholino-4, 5-dimethyl-6-phenyl-3-morpholinone; 2-marpholino-5-methyl-6,6-diphenyl-3-moxpholinone; 2-morpholino-5,6-diphenyl-3-morpholinone; 2-morpholino-6- (3 ', 4', 5'-trimethoxyphenyl) -3-morphal.inone, and 2-morpholino-6 - (- trifluoromethylphenyl) -3-morpholinone.



   XLV example
A - 1 g (0.0036 mole) of 2-morpholino-5-methyl-6-phenyl-3-morpholinone is suspended in 36 ml (0.0036 mole) of 0.1N hydrochloric acid. The suspension is placed in a shaker overnight. The suspension obtained is filtered
 EMI31.2
 to give 2-hydroxy-5-methyl-6-pheny.3-morphol.none, melting between 197 and 198.5 sec.



   B - In accordance with the procedure of Example XLV-A, but using an equivalent amount of the remaining products
 EMI31.3
 pectife obtained in Example XIV-3 instead of 2-morphonr.a- 5-methyl-6-phenyl-3-morpholinone of Example XLV-A, the following 2-hydroxy compounds are obtained:
 EMI31.4
 2-hydroxy-4,5-dimethyl-6-phenyl-3-marpho7.inane 2-hydroxy-5-methyl-6,6-diphenyl-3-morpholinone; 2-i, ydroxy = 5, 6-d.phenyl-3-morpholinone; 2-hydroxy-6- (31,41,51-trimdthoxyph6nyl) -3-morpholïnono, and 2-hydroxy-6- (Z-trifluoromethylphenyl) -3-morpholinone.



  XLVI Example
 EMI31.5
 35.9 g (0.19 mole) of 2-aminop: p10ph6-none hydrochloride are dissolved in 45 ml of water and 50 g of ice are added.



  The flask is completely cooled in an ice bath. 44 g (0.39 mol) of chlorinated chloroacetyl are mixed with

 <Desc / Clms Page number 32>

 a concentrated solution of sodium acetate (79.7 g, 0.97 mol), in water. The mixture is added all at once to the amine hydrochloride. White crystals form immediately.



  The reaction mixture is stirred for one hour, then filtered.



  The wet product is air dried to give a white solid melting between 84 and 8520. Recrystallization of part
 EMI32.1
 in ethyl acetate gives pure 2-chloroacetamidopropiophenone, melting between 87 and 88 sec.



   Example XLVII
A - A basic ion exchange resin (IRA-400, chloride form, 750 g) is brought into the hydroxyl form by stirring for 45 minutes with excess 10% aqueous sodium hydroxide. The resin is then washed with water until the washing waters are neutral to the pH paper. Then, the resin is washed thoroughly with methanol to remove as much water as possible. The resin is suspended in 1500 ml of methanol and stirred. 25 g (0.11 mol) of 2-obloro- aoétaaido propiophenono are added. Stir the reaction mixture overnight, then filter it. The resin is washed several times with methanol.

   The filtrate is partially concentrated, then filtered, to give white crystals melting between 228 and 229.590. Subsequent evaporation of the filtrate gives a solid
 EMI32.2
 gross. Reoristallization in methanol gives 5-metl, yl.



    Pure 6-phenyl-4H-1,4-oxazin-3 (2H) one, melting point 227-229 C.



   B - The alkylation of the preceding product with butyl bromide, in accordance with the procedure of Example XXIII, gives the corresponding 4-butyl derivative of 5-methyl-6-phenyl-4H-1,4-oxazin-3 (2H) one,
Example XLVIII
178 g (0.74 mol) of 4'-benzyloxypropiophenone are suspended in 1 liter of anhydrous ether and stirred. While bubbling hydrochloric gas through the solution, add

 <Desc / Clms Page number 33>

 slowly (over 1 hour) 84 g (0.81 drilled) butyl nitrite.



  The gas is bubbled for 10 more minutes. The cedons go into solution during the course of the addition, a precipitate begins to form at the end; about 0.5 hour. The reaction mixture is stirred overnight, then filtered and an impure product is obtained. 'Recrystallization from ethanol
 EMI33.1
 gives α-hi, α-hydroxYîmino-41-bfnzyloxypropiophenone, melting between 137 and 138 C. The concentration of the other solution of the mixture
 EMI33.2
 reaction gives additional bx-ut product. Reoristallisatiol in methanol gives α-hydroxyimino-4'-benzyloxypropioan melting between 138 and 13990.



   XLIX example
 EMI33.3
 t 0 g (0.037 mol) of cc-hydx; oxy.miz.o-. -beo.zy.pypp, i4- phenone are hydrogenated in 150 ml of crystal acetic diacid- '
 EMI33.4
 irisable under pressure of 3e5 5 kg / c. They UE ± '4% ± P40 do washed nickel catalyst. The oxygenation is left to stand overnight. 3 equivalents of ky4ro, r. aat absorbed.



  The remaining mixture is filtered. Catalyst Y-1, washed over hay with ethanol. The filtrate is concentrated ;;; iW¯ ,,, 1 '¯i to give an oil which crystallizes on friction j ,,. P6urtonne.t a crude product (acetate). The crude solid is dissolved in dilute sodium hydroxide and the solution is extracted twice with methylene chloride. The organic phases are dried over magnesium sulfate and concentrated to give
 EMI33.5
 crude α- (t-aminwthyl) -p-benzyloxybenzyl alcohol melting between 114 and 12lp520. An eohan - '. Illon is converted to hydrochloride melting between 195 and 200 C.



   Example
 EMI33.6
 28 g (0.088 mol) of alcohol - (1-aoinoétbYl) -P-benlYlOXY- benzyl are dissolved in 200 ml of methylene chloride and
 EMI33.7
 100 ml of 15% aqueous sodium hydroxide. The solution is cooled and stirred. It g (0.097 mole) of ohloro chloride

 <Desc / Clms Page number 34>

 acetyl are dissolved in 110 ml of methylene chloride and added dropwise to the solution. The reaction mixture is stirred for 1.5 hours. the aqueous phase is acidified (this operation is carried out because a thick emulsion is 1 with the base and the methylene chloride). The organic phase is separated. The acid phase is washed with methylene chloride.

   The combined organic phases are washed with dilute sodium hydroxide. They are dried over magnesium sulfate and concentrated to give a crude solid.



  By recrystallization from carbon tetrachloride, one obtains
 EMI34.1
 holds 2-ohloro-N- (p-benzyloxy-p-hydroxy-a-methylphenethyl-) "acetamide, melting between 123 and 124.5 C.



    LI example
 EMI34.2
 12 g (0.036 mole) of 2-ahloro-N- (p-benzylozy-9-hyd = xy- o-methylphenethyl) -aoetamide are added to a solution of potassium tert-butoxide (technical, 9.1 g, 0.081 mole) in 500 ml of anhydrous tert-butanol. The reaction mixture is stirred overnight and then concentrated to dryness. The residue is; dissolved in water and methylene chloride. The methylene chloride phase is separated, dried and concentrated to give a crude solid. Reoristallization in soft chloroform. taken together gives 6-p-benzyloxyphenyl) -5-methyl-3-
 EMI34.3
 pure morpholine melting between 181.5 and 182.5SO.



  Example LU 8 # 2 è, OrO28 mol) of 5- (p-benzyloxyphenyl) -5-methyl-3-morpholinone sol \ 't' hydrogenated in 150 ml of ethanol under a pressure of 3.5 kg / cmG r 0 , 82 g of 10% palladium fixed on charcoal. After hydrogen uptake has been obtained, the reaction mixture is removed and filtered. The catalyst is washed several times with 4 th = ol. The mixture is concentrated. and gives a crude product., between 26, and 230, C. By in water, 04 obtains, the 6. (p-hydroxyphenYl) -

 <Desc / Clms Page number 35>

   Pure 5-methyl-3-morpholinone melting between 240.5 and 242.0 C.



   Example LIII to - An intimate mixture of 10.0 g (0.0523 mole) of cis-5-methyl-6-phenyl-3-morpholinone and 4.7 g (0.0212 mole) of phosphorus pentasulfide is treated with 10 ml of pyridine and the dark viscous mass obtained is stirred for 20 minutes in a steam bath. The mixture is poured into water and the solid is collected by filtration. The solid is washed with a medium
 EMI35.1
 cold ethersethano (5Qt5Q) mixture. It is xear3, stallized three times in benzene to give a white powder of a.e-5 .. methyl-6-phenyl-morphcline -, - thione, melting between 160 and 1610.



     B - The procedure of Example LIII-A is followed with the difference that an equivalent amount of 5-methyl-6,6-
 EMI35.2
 diplidnyl-3-morpholinolium, 5,6..diphnyl-3-maxpholinons, 4,5-dimethyl-6-phenyi-3-morpholinonot 4-butyl-5-methyl-6-phenyl-3 <-morpholinone, A.butyl , -phenyl-3 marpho..nna, 6- (trifluoro- m ±% hyiph6nyl) - $ - morpholinono and 6. (p, ah.axophny, j.5aethyl..h. l, 4-oxazin-3 (2X ) -ono, reapootively, is used instead of 5..methyl-6., phenyl-pmoxpho, inona to give as product the corresponding morghoiino-3-thionos * Example LIV
 EMI35.3
 2.0 g (0.832 gram-atom) of magnesium turn = 'are stirred in 100 ml of anhydrous ether The mixture is cooled.

   82.4 g (0.756 mol) of ethyl bromide are dissolved in t
250 ml of anhydrous other added at a moderate rate. The reaction mixture is stirred for 30 minutes. Then we ;
 EMI35.4
 dissolve 43.1 a (0.252 mole) of o-trifluoï'omethylbenEonitrile in 50 mil of anhydrous ether and this solution is added. We altele! rdaotiannel mix: .gnd ant one night. The reaction mixture is then poured into a mixture of concentrated hydrochloric acid (300 ml) and ice (1.5 liters). Ether int oha 4 by boiling. The acr's mixture is heated in steam for 2 hours during which a black oil is deposited.



  The mixture is extracted twice with ether. The solution

 <Desc / Clms Page number 36>

 ether is dried over magnesium sulfate and concentrated -. to give a black oil. Distillation gives the 21-trio. fluoromethylpropiophenone, boiling between 55 and 58 C (0.5 mm).



   LV example
 EMI36.1
 71.0 g (0.35 mole) of Zt-trifluoromdthyl propiophenone are dissolved in 800 ml of anhydrous ether. Anhydrous hydrochloric gas is bubbled through the stirred solution. At the same time, butyl nitrite (40.2 g, 0.39 mol) is added dropwise. Hydrogen chloride gas is bubbled through the solution for 20 minutes after the addition of butyl nitrite is complete. The reaction mixture is stirred for a further one. hour. It is concentrated and the crystals obtained are washed with
 EMI36.2
 hexane.

   Filtration gives 2-hydroxy.m.no-2 tr.'uorô .. methylpropiophenone, melting between 96 and 9720, eg LVI, (0 # 043 mole) of 2-hyàToxyinino-2 '-% rifluoTomé% hyl - propiophenone are hydrogenated in 150 ml of hydrochloric acid
 EMI36.3
 z 'in solution ±% hAnoliqUa under a pressure of t5 kg / oa2 on. 1.0 g of 10% palladium fixed on charcoal. the <c'4uo% ion was complete in 2.5 hours.

   The catalyst is separated by filtration% ion, The filtrate is concentrated and the white crystals obtained
 EMI36.4
 Triturated with ether to give 2-aminc- 'F,' - 2'-trioxomethylpropiaphenone hydrochloride; melting between 223.5 and 22420,
Example LVII 7.5 g (0.03 mol) of 2-amino-2'- hydrochloride
 EMI36.5
 trifluoromdthylpropiophénoue are hydrogenated under a pressure of 3.5 kg / om 2 in 150 ml of water to the addition of 5 ml of hydrochloric acid concentrated on 0.8 g of 10% palladium fixed on charcoal. Once the reduction is complete, the catalyst is removed by filtration.

   The filtrate is concentrated to give a.
 EMI36.6
 crude product melting between 237.5 and 242 # 520, Reoristalliaa- tion in isopropanol gives the hydrochloride of alcohol a-

 <Desc / Clms Page number 37>

 
 EMI37.1
 1-anû, noethyl) -0-tr: 1.fluoromethyl'benzyl: l.que, melting between 247 and 25020,
Example LVIII
18.0 g (0.07 mole) of alcohol [alpha] - (1- hydrochloride)
 EMI37.2
 anin0é% hyl) -o-% rifluoromé% hylbenzylique are dissolved in 250 ml of methylene chlorine and 150 ml of 10% aqueous sodium hydroxide. The solution is cooled in an ice bath and stirred.

   8.35 g (0.078 mol) of chloroacetyl chloride were dissolved in 85 ml of methylene chloride and slowly poured into the solution dropwise. The reaction mixture was stirred for 15 minutes. The methylene chloride phase is separated and washed with dilute hydrochloric acid.

   The organic phases are dried over magnesium sulfate and concentrated to give, in the form of an oil
 EMI37.3
 colorless, slightly impure 2-ohloro-N -'-hydroxy-cx-metb.yl-o..trifluoromethyl-phenethyl) acetamide. xem "9.e, 20.0 gas (about 0.07 mole) of 2-ohloro-N- (µ-hydrcXy- mthyl-o-tr1fluoromethylphenethyl) -ao.tamid. slightly impure is added to a solution of pota.um textiobutoxide (prepared by reacting 5.5 g or 0.14 gram atom of potassium with an excess of anhydrous tert-butanol) in 500 ml of anhydrous tert-butanol. The reaction mixture is stirred overnight. , then concentrated to remove tert-butanol The residue is dissolved in methylene chloride and water.

   The methylene chloride phase is separated, dried over magnesium sulfate and concentrated to give a crude product melting between 137 and 14020. By reoristallization in ethyl acetate.
 EMI37.4
 pure 5-mdthyl-6.- (a, a, a-tri.uaro-o.toz.y: â, -3morpbo.h-none, melting between 142.5 and 144.520, is obtained.



    LX example
 EMI37.5
 A solution of 5-born% hy1-6-phenyl-4E-1,4-oxazm-3-

 <Desc / Clms Page number 38>

   (2H) -one (0.20 g, 0.01 mole) in 50 ml of oristallisable acetic acid is hydrogenated over a palladium catalyst (10% palladium fixed on carbon, 0.04 g) under a pressure 3.5 kg / cm2. The reaction mixture is shaken overnight. Hydrogen absorption is 0.635 kg (theoretical absorption 0.227 kg). The catalyst is removed by filtration. The filtrate is concentrated to dryness to give an oil. which crystallizes. The crystals are washed with ether and the ether is removed by filtration.

   The yield is 0.07 g (35%) of 5-methyl-6-phenyl-3-morpholinone identical by its infrared spectrum and by thin layer chromatography to a sample prepared beforehand.
 EMI38.1
 



  Comparison of xelaxatidn activity of mus ee otor of a counterpart of 'inven.on, (6- "p -." (. A ,, a.tr3.P.uooylz ,,% ho.3none and drugs olag2îquee,
This experimental method consists of administering the compound at varying dose levels either orally,
 EMI38.2
 or intraperitoneally. The relaxation activity of the motor muscles is estimated by the righting reflex gate. of the test animal subjected to the action of the drug. Loss of the righting reflex is defined as the animal's inability to return to a normal position after placing it on its back. The comparative activity of the compound of the invention and four compounds clinically used as muscle relaxants is shown in the following table.



  The columns marked "PD50" relate to the dose of compound expressed in mg of this compound per kg of body weight of the animal required to induce the decrease in the righting reflex to 50% in the animals. ,

 <Desc / Clms Page number 39>

 'Muscle relaxation activity in rats and mice
 EMI39.1
 
<tb> PD50 <SEP> of <SEP> sub- <SEP> PD50 <SEP> of <SEP> rats
<tb>
<tb>
<tb>
<tb>
<tb> ris, <SEP> mg / kg, <SEP> mg / kg, <SEP> limits
<tb>
<tb>
<tb>
<tb> trust <SEP> limits <SEP> <SEP> to
<tb>
<tb>
<tb>
<tb> ¯¯¯¯Compound <SEP> Channel <SEP> cies <SEP> to <SEP> 95 <SEP>% <SEP> 95
<tb>
 
 EMI39.2
 6¯'p ..

   (a, a, a-txifluoro. tolyll7-3-morPholinOne oral 283 (257 to 311) 420 (336 to 525)
 EMI39.3
 
<tb> intraperitoneal <SEP> 122 <SEP> (113 <SEP> to <SEP> 132) <SEP> 66 <SEP> (<SEP> 52 <SEP> to <SEP> 85)
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 1-carbamate <SEP> from <SEP> 3- (o-
<tb>
<tb>
<tb> methoxy-phenoxy) -2-
<tb>
<tb>
<tb> hydroxypropyl <SEP> oral <SEP> 1050 (880 <SEP> to <SEP> 1250) <SEP>> <SEP> 2000 <SEP>
<tb>
<tb>
<tb>
<tb>
<tb> intraperitoneal <SEP> 450 <SEP> (402 <SEP> to <SEP> 504) <SEP> 347 <SEP> (313 <SEP> to <SEP> 385)
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 5-ohlorobenzoxazolidone <SEP> oral <SEP> 540 <SEP> (400 <SEP> to <SEP> 729) <SEP> 1950 (1560 <SEP> to <SEP> 2438)
<tb>
<tb>
<tb>
<tb>
<tb> intraperitoneal <SEP> 159 <SEP> (130 <SEP> to <SEP> 196) <SEP> 125 <SEP> (<SEP> 98 <SEP> to <SEP> 159)
<tb>
 
 EMI39.4
 5- (3,

  3.5-dimethylphenoxy-metxryl) -2-oxazolidinone oral 1400 (1250 to 1568)> 2000
 EMI39.5
 
<tb> intraperitoneal <SEP> 455 <SEP> (361 <SEP> to <SEP> 573 <SEP>) <SEP> 150 <SEP> (<SEP> 96 <SEP> to <SEP> 236)
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> 1., - dioxide.de <SEP> 2- (4-
<tb>
<tb>
<tb> ohlorophenyl) -3-methyl-
<tb>
<tb>
<tb> 4-metathiazanone <SEP> oral <SEP> 410 <SEP> (293 <SEP> to <SEP> 574) <SEP> 785 <SEP>. (664 <SEP> to <SEP> 942)
<tb>
<tb>
<tb>
<tb>
<tb> intraperitoneal <SEP> 395 <SEP> (314 <SEP> to <SEP> 498) <SEP> 313 <SEP> (285 <SEP> to <SEP> 344)
<tb>


 

Claims (1)

CLAIMS 1 - Production process of a compound of general formula EMI40.1 wherein X is a member of the group consisting of oxygen and sulfur, R1 is selected from the group consisting of hydrogen, the hydroxy group and lower alkyl and aryl radicals, provided that when R1 is hydroxy, X is a oxygen, R2 is selected from the group comprising hydrogen, lower alkyl and amino-lower alkyl radicals. (lower alkyl) -amino-lower alkyls, acyls and aryls ,. provided that, when R2 is an acyl radical, X is oxygen and R1 is hydrogen, lower alkyl or aryl, -. R is a member of the class comprising hydrogen, lower alkyl and aryl radicals, R4 is a selected member. in the group comprising hydrogen, lower alkyl radicals and aryl radicals, Ar is an aryl radical and. the dashed line between carbon atoms 5 and 6 indicates the presence of an optional double bond with Ar as the only substituent in position 6, provided bzz¯ that, when this double bond is present, R1 is other than hydroxy radical, characterized in that a compound of general formula III is reacted EMI40.2 <Desc / Clms Page number 41> with a haloalkyl ester of general formula EMI41.1 to produce a compound of general formula IV EMI41.2 which compound IV is then cyclized by removing the alkanol to produce a compound of general formula V EMI41.3 or by cyclizing a compound of general formula VII EMI41.4 in order to produce a description of general formula V and, when R1 of compound (I) is hydroxy, to. reacting a compound of formula (IX) EMI41.5 with an organic amino base and hydrolyzing the product to give a compound of formula XI. <Desc / Clms Page number 42> EMI42.1 or converting compound IX directly into compound XI by treatment with an alkali metal base and, -when X is hydrogen, R2 is other than an acyl group and a double bond exists between carbon atoms 5 and 6 of the morpholine nucleus of compound I, to cyclize a compound of formula XIII EMI42.2 with a base to give a compound of formula XIV EMI42.3 in which Ar, R3 and R4 have the definitions given above, halo is a halide and R1 is hydrogen, lower alkyl or aryl, and if necessary introducing a lower alkyl or a substituted lower alkyl into the 4-position of the morpholine ring by treating the corresponding unsubstituted compound in the 4-position of formula V or XIV with an appropriate alkylation or, if necessary, acylating a compound of formula V or XIV at position 4 by treating the unsubstituted compound at position 4 with an appropriate acylating agent and, when X is sulfur, treating the appropriate 3-morpholinone with phosphorus pentasulfide for the <Desc / Clms Page number 43> transform into the corresponding morpholine-3-thione. 2 - Process according to claim 1, in the case where the product obtained contains a double bond at 5, 6, characterized by the hydrogenation of the double bond by means of catalytically activated hydrogen. EMI43.1 3 - Process for the preparation of 6- {a, a, a-tr.'uoro-p-tolyl) -3-morpholinone, characterized in that the 2-ohloro-N- (p-hydroxy-p -trifluoromethylphenethyl) -acetamide in the presence of a base. 4 - Compound of general formula: EMI43.2 wherein X is a member of the group consisting of oxygen and sulfur, R1 is selected from the group consisting of hydrogen, the hydroxy group, and lower alkyl and aryl radicals, provided that when R1 is hydroxy, X or oxygen, R2 is selected from the group consisting of hydrogen, lower alkyl, amino-lower alkyl, (lower alkyl) -amino-lower alkyl, acyl and aryl radicals, provided that when R is an acyl radical , X is oxygen and R1 is hydrogen, lower aloyl or aryl, R is a member of the class comprising hydrogen, lower alkyl and aryl radicals, R4 is a member selected from the group consisting of hydrogen, lower aloyl radicals and aryl radicals, Ar is an aryl radical and the dashed line between the carbon rings 5 and 6 indicates the presence of an optional double bond with Ar as the sole substituent in the positive 6, provided that, when this double bond is present, R1 is other than a hydroxyl radical, prepared according to the process of <Desc / Clms Page number 44> EMI44.1 Claim 1 .. ¯ ... z '5 - â .. (a, ac, a-tr, .uoro-p-tolyl) -3-morphol3none px ^ separated according to the method of claim 3. 6 - 5- (lower alkyl) -6-aryl-3-morpholinone prepared by the process according to claim 1. EMI44.2 7 - 6-halo- (lower alkyl) -phenyl-3-morpholinone prepared in accordance with the process of claim 1. 8 - 5- (lower alkyl) -6-halo- (lower alkyl) - phenyl-3-morpholinone prepared according to the process of claim 1. 9 - 6-aryl-3-morpholinone prepared according to the process of claim 1. EMI44.3 10 - 5-'methyl-6,6-diphenyl-3-morpholinone prepared according to the process of claim 1. 1 "'5t6-diphenyl-3-morpholinone prepared according to the process of claim 1. 12 - 6- (p-ohàoàph ± nyl) -5-methyl-3-norphoÀinone prepared by the process according to claim 1. 'bill i 3 - 4e5-dimethyl-2e6-diphdnYI-3-morpholïlione pre-, trimmed according to to the process of claim 1. l 4 - 4-diethylamino% hql-5-met% 1-6-phenyl-3-norpho <linone prepared by the process according to claim. 1, 15 - 6- (3,4,5-trimethoxyphenyl) -µ-morpholinone prepared according to the process of claim 1, 16 - 4-aoetyl-5-methyl-6-phenyl-3-morpholmone prepared according to the process of claim 1, '17 - 4-.sobutyryl.-5-methyl-6-phenyl.-3-morpholinone prepared according to the process of claim 1. EMI44.4 18 - 4-Benzoyl-5-methyl-6-phenyl-3-morpholinone pr4-.,] Trimmed according to the process of claim 1. 19 - 4-Butyl-6-phenyl-3-morpholmona firmly prepared in accordance with the process of claim 1. <Desc / Clms Page number 45> EMI45.1 20 - 5-methyl-6-phenyl-4- (, at,% nflsoro -> -% ol1Dyl) - 3-morpholinone prepared according to the process of claim 1. EMI45.2 21 - 4- (p-chlorobenzoyl) -5-methyl-6-phenyl-3-nor2hO-linone prepared by the process according to claim 1. 22 - 6- (p-chlorophdnyl) -5-methyl-4li-lt4-OxaziU-3- (2H) -one prepared by the process according to claim 1. 23 - 2-hydroxy-5-methyl-6-phenyl-3-morpholinone prepared according to the process of claim 1. 24 - 5-methyl-6.-phenyl-4H-1, 4-aazin-.3 (2H) -one, prepared according to the process according to claim 1 25 - 6- (p-ber.zyloxyphenyl) -5 -methyl-3-morpholinone prepared by the process according to claim 1. 26 - 6- (p-hydroxyphenyl) -5-methyl-3-morpholinone prepared by the process according to claim 1. EMI45.3 27 - 5-methyl-6-phenylmorpholina-3-thiane prepared by the process according to claim 1. 28 @ Compound of general formula: EMI45.4 wherein X is a member of the group consisting of oxygen and sulfur, R1 is selected from the group consisting of hydrogen, the hydroxy group and the lower alkyl and aryl radicals, provided that when R1 is hydroxy , X is an oxygen, R2 is chosen from the group comprising hydrogen, radioal lower alkyls, amino o-alkyls EMI45.5 interiors, (lower alkyl) -amino-alooyl8 -.inter1eu .; "acyls and aryls, provided that when R2 is rad @@ al aoyl, X is oxygen and R is hydrogen, lower alkyl or <Desc / Clms Page number 46> aryl, R3 is a member of the class comprising hydrogen, lower alkyl and aryl radicals, R4 is a member selected from the group consisting of hydrogen, lower alkyl radicals and aryl radicals, Ar is an aryl radical and line extracts interrupted between carbon atoms 5 and 6 indicates the presence of an optional double bond with Ar as the only substituent in position 6, provided that, when this double bond is present, R1 is other than a hydroxy radical . 29 - 6-aryl-3-morpholinone. EMI46.1 30 - 5- (lower alkyl F6-aryl-5-morpholmone. 31 - 6-halo- (lower alkyl) -phenyl-3-morpholinone. 32 - 5- (lower alkyl) -6-halo- (lower alkyl) - phenyl-3-morpholinone. 33 - 5-methyl-6-phenyl-3-morpholinone. EMI46.2 34 - 5-methyl-6,6-diphenyl.-3-morphol.inoxe. 35 - 5,6-diphenyl-3-morpholinone. 36 - 6- (p-chlorophenyl) -5-methyl-3-morpholihono. 37 - 4,5-dimethyl-2,6-diphenyl-3-morpholinone. 38 - 4-Diethylaminoethyl-5-methyl-6-phenyl-3-morpholinone. EMI46.3 39 - - (3,4,5-trimethoxyphenyl) -3-morpholinone, 40'- 4-aoetyl-5-methyl-6-phen; 1-3-norpholinone. 41 - 4-bMnaoyl-5-methyl-6-phenyl-3-morpholinon9t 42 - 4-butyl-6-phenyl-3-norpholinone. 43 - & - (alala, -trihucrc-rtoZy) -3-morpha.inone. 44 - 5-methyl-6-phenyl-4- (a, a, c.tr3.luoro -to.toy.) 3-morpholinone. EMI46.4 45 - 4 - '(p-ohlorobenzoyl) -5-methyl-6-phenyl-'3 "morpholinone. 46 - 6- (p-oh, orophenyl) -5-methyl-4hwi, 4ota3 (2H) -one, <Desc / Clms Page number 47> EMI47.1 47 - 2 ... hydl "cxy-5 '., Yl-6-phenyl-3-morpholinone. 48 - 5-methyl-6-phenyl-4E-1,4-oxazin-3 (2E) & x9. 49 - 6- (a-henzyloxy ii ± nyl) -5-methyl-3-moroenolii: one, 50 - 6- (E-hydroxyphéAY1) -5-methyl - morpholinone. 51 - 5-methyl ... 6 ... hÓnylmorpholine "" ... thione. 52 Process for the preparation of a compound of formula 14n4ra 'It satisfying the description given and the examples described. 53 - A compound of General Form I, prepared according to the method of any one of claims 1 or 3 or 52.