DE2056589A1 - Morpholindenvate - Google Patents

Description

PATENT LAWYERS

DR.-ING. H. FINCKE SMONCHEN ₅ ,

Müllerstrasse 31

DIPL.-ING. H. BOHP
ÜIPL.-ING. S. STAEGER

F e r η r υ fi * 26 60 60

Folder 22433 ~ Or, Z.
Case PH 2 <

Imperial Chemical Industries Ltd. London, UK

Priority 1 ?. 11. 19S9 - Great Britain

Addition to P 16 95 295.7

The invention relates to new morpholinders, which show valuable tkerapevitic properties. Or else they have an inhibiting effect. the central! flermnaysteia of warm-blooded animals, x ^ ao by dirshabenexu. <g which is spontaneously demonotated in muas, a ütandax'dtfcst Tüx cii & hfüinmende effect ouf the üontral em. You bxüxI dijshalb in treating '/ οί> Augst · mid-yio'uj otiiichen states hojni mensché: al · ^»r * uchbar

109822/2220 bad original.

The compounds also have thynioleptic activity in warm-blooded animals, which is demonstrated by reversing reserpine-induced hypothermia in Hausen becomes, a standard test for tbyoioleptic activity. These compounds are therefore also useful in the treatment or prophylaxis of depressive illnesses in humans.

According to the invention, new morpholine derivatives of the formula

X-O-

where R stands for a hydrogen atom or for sin alkyl, Al-

2 2) Ll

kenyl- or cycloalkyl radical is wherein u, Jr una S, 3An which are the same or different, are hydrogen atoms or alkyl radicals {standing, with the proviso that H ~ R ^J and R are not all atom for a hydrogen, or wherein R and R ^ together with the two adjacent carbon atoms to form a cycloalkyl ring

4th
are connected and R is a hydrogen atom or an alkyl radical, and where Σ is an optionally substituted aryl radical _T and the acid addition salts thereof are proposed.

It should be noted that the above definition of Horpholine derivatives all possible ßbereoisomers of the same and mixtures of the same and specific also individual ones

109822/2 2 29

BATH

includes optically active enantiomorphic and racemic mixtures.

A suitable value for E when it is an alkyl radical is, for example, an alkyl radical with up to 6 carbon atoms, such as methyl- »ethyl-, isopropyl-, n-propyl-, s-butyl or t-butyl radical.

A suitable vert for H ₁ when it stands for an alkenyl radical is, for example, an alkenyl radical with up to 6 carbon atoms, such as, for example, allyl radical.

A suitable vert for R when it is for a cycloalkyl radical is, for example, a cycloalkyl! radical with up to to 5 carbon atoms, such as B.B. the cyclopropyl, cyclobutyl or cyclopentyl radical "

A suitable vert for ir, H or H if they are for a Al Icy! Radical is, for example, an alkyl radical with up to 3 carbon atoms, such as 8.B. the methyl, Ethyl or n-eropyl radical.

A suitable value for that of H, Br and the two neighboring ones Is cycloalkyl ring formed carbon atoms for example a cycloalkyl ring with up to 8 carbon atoms, such as the cycloaxyl ring.

A suitable vert for X is, for example, a phenyl or haphthyl radical which is unsubstituted or which by one or more substituents and in particular by one or two substituents from the following Selection is substituted: halogen atoms, such as fluorine, chlorine, bromine and iodine atoms; Alkyl, alkoxy and alkylthio

10383 2/222 »bad obisinal

raü. ti ■■ ii'ii- · _v for example ü lfcr.! - _} Alkoxy- and Alkylthior-adi · - lcaJe with up to? U "H) EcKUiiietofiätomen, like sB« Ke ^ hyl-. Ethyl-, a-Propy. "! ..-, Iscpropjl · -. n-Butyl "-, t-Butyl-, t-iinrfi · ^ He'i.koi ^ y- '" Athoxy - = *, a -Propoxy- _} Isopropoxy "-, n-Butor ^ y-, Isobutosy -, a-iieptyl o:? ": y- and methyl thiorediks Ie; HaJ.ogenaXfcfl ™ and Ealogenalkox; vraäika3e, for example haloalkyl- ud. '' 1 Ealogenalkoicj -radikal ^ each with 1) 1.8 au 5 IOIi-I east off Atoms, such as sB TrifluoromGthjJ.- and 2,2-Dich 1 ox-o-1 _{ 1 -difXiioroätliOiLTraciJ; iale; Alkenyl ™, kl » kenylojsj-, AlkynylOx7- and Cyci oalkox; - radicals ₅ bc: i ~ sp. Generally alkenyl, alkenyl or j., Alkinyloay- "and cycloalkoxy radicals each with up to 6 Jiohlenstof fat omen, such as ζ.B. ΑΙΙ, τΙ, illylo.Ty, propar ^ / loacy and cyclopentyloxy radicals; Aryl-, aryloxy · "-, alkylarylO3 ^ y« '· »aralkyl- and aralkoxj - ra.dikp.le _s oeißpielsvreise aryl-, arylox; r ~, alkylarylo ^ -, üralkyl- υηα AraXkoxyradi'is.ele with jev / eils up to % n 10 carbon atoms; like κ. 13. Phoryl-r Fhr.-noxy-, '+ -''ToIvIcXy-., Benzyl- and Be ^ .iiyloxyradlkale; Hydroxyalkyl- and AlJfcoxyalkylradikal, ti ei spie law :;! Se Alky! Radicals with up to 5 carbon atoms, which are substituted by Eyaroxyrs.dical cd sr- by Alko ^ radSJnüe with up to 5 carbon atoms, e.g. Metlioxjiaeth; yI ~ - Ithoxymothyl "·, i-Methoxyäthr / 1- wed xi-Proposyme'b3."> Ylrao 3 kale j acyl radicals, for example alkanoyl radicals3.e with up to ¹ j Kol? - lenatoffatcraen »w: 5e eg acetyl radical; AcylamixKrea-difcale, teispislsveise AlkaiAoyXMiianor ^ cals with up to 6 carbon atoms, such as Acet .'- anidoradikßli ^1; Alkoxycai'bonylrad.jike.le, bcispir ενιαχ ^ -: iikoiiC.ycarboaylradikale with bio to 6 Eohleii3tofi '? ston ^ n _; like ζ / Β. Nethoxycarbonyl " t: nd At-lioxycarboo. ^ - Lrai 'ika le; iiyd:. ·: ^: · ^ · -. Amino ™ »Carloxy- ^ HethylendioaQr.- imd i ^ .ltrorsdjkal. ;; \ nd alkylene radicals] 0, beiapiolowoi ρλ> / ■ l'k ~ \> j.vnradn kale »ir.I- 3

109822/2229 BAD original

Ο & Θ2? M- carbon atoms, id. «Ζ ^ B * {üriaetfeyle?. \ - i'e3.tx» «iB« tii / lenre.dIlcalo (these are those Badilcale, which together with the arylra & iical X an In & a & yl- or tetrakydron & phthy! radical to the, like a «3. the 4-indanyl-, 5-indaayl- ₃ 5 * 6,7, S-Sstraü.jdro-1 -naphtbyl- or 5,6,7,8-

Special connections according to the invention are, for example, those detailed in Examples 1-16 below. Tone these are preferred: 2- (1-Hethyl-I-phenoxyethyl) moppholine, 2- (1-phenolethyl) morpholine, 2-iietliyl-2 "pli8noxymethylmorpholine" 2- (I-O " ltho3 ^ ypheno3Ey - 1 - methylätayl) mörpholin and 2- (1-o ~ l.th-O3cypheno3 £ y-1 -methylätiijl) - ^ - isopropyliDorpliolin as well the Säiareadditionssalsse of the same.

Suitable acid addition salts of the invention & n morpholine derivatives are, for example acid addition salase _$ which are derived from inorganic or organic acids, such as hydrochlorides, hydrobromides, Biosphate, sulfates, oxalates, lactates, tartrates, acetates, gluconates, salicylates, citrates, ascorbates, Beazoate, ß-lYaphthoate , Adipate or 1,1-Methyleß-bis- (2-hydroxy ~ 3 ~ naphthoate!) »Or the acid additioixa salts, which are derived from acidic synthetic resins, such as sulfonated polystyrene resins, such as z * B. "Zeo-Karb" 225 ("Zeo-Karb" is a registered trademark) *

According to the invention, a method for the production of the morpholine derivatives according to the invention is also proposed, which is carried out in that a compound finv formula,

^109822/2229

H Q

ίΠ 1

. ¹ X

1 ο '-ζ ί | -
wherein H, R "', H". R '' ma Ί the meanings given above, with a complete Metallfcydrla reauai «rt.

The complex "IiatalLhyilrid can be, for example,; The Eedusttion can be l; a ε-ineiß inercsea or liösuiigSDii.ttel erwafü'hx'i; werdön _} i / ie z; B «· 5 a Ätb.ex% Tetx ^> ahjdj? ofm? an or 1 ₅ 2-Diinstb.o:; qratsh & a _i and. außeräem it can carry, the application of heat bä _s: i ^ £ Piel IWE "if e diixch heating to the boiling point of the diluent or beachletmigt IiösiangsiQ.itte3.s or finished {f; efiihrt i-zc-rcUm ■.

The starting materials for the above processes can be cooled by the fact that their "compound of the formula

B ³ OH

XOCC-CH ₂ NHR ¹

H ²

wherein R, H ^, H, R and X have the above ar possess, with a compound of the formula ZGiLy-OOii, in which

109822/2229 '

BATH ORIGINAL

2 and Z , which: - same or different se Ιο. can. here? ό.ϊν preserved connection of the rorinel

R ⁵ OH

X-O-O-G

R ²

cyclized. The VerbiDdiing of the formula

CH

XOC- G ! ι

H ⁴ R ²

can even be obtained by using a carbonyl compound of formula,

2 - 0 - C - 00 - E ²
!

B ⁴

■ ζ y, h

where H " . 3" _t R and I have the meanings given above, with 3) imethylsulfor.c; ntuL3Methylicl, or by the fact that a phenol AeT for X-OE, v. ^r orin X has the above sng-iigeb ^ nö Eedeut \ mg, nit ein.sai Epihalohjdrin äer formula,

ι / '

1 ti 9 9 Γ 2/2 2 2 3 "," ..

BATH ORIGINAL

2056583

2 <~ 3 4
wherein R, R, B and S beeitlen the Bedoucixagen given above, converts and then the epoxy. the formula,

XOGC CH ₂

i!
R * S ²

2-5 4

wherein R * R, R and X have the meanings given above and obtained by both of the above reactions

1 1

can, with an amine of the formula E HR ^, wherein R is the above Possesses meaning, implements, as it does in the British 994.918, 1025 214 and 1069 34-5 is"

According to the invention there is also a method of manufacture of those morpholine derivatives according to the invention

1
proposed, in which R stands for a hydrogen atom, which is carried out by adding a removable fl ^ arylalkyl or alkyl radical of a compound of the formula

X -

2 7. h

wherein R, R, R and X are the. Have the meanings given above and in which PS is a removable «3> -A ryl alkyl or alkyl! radical,

H) 9 8 2 2/2 2 2 ^f J

BATH ORIGINAL

Sin appropriate value for 'H ^ if it is for a removable & -Arylalky! Radical is, for example, an alkyl radical idt to au * - carbon atoms, which on the a-X carbon is radically substituted by a Phany! »like e.g. the benzyl radical. A suitable value for S- if it stands for a removable Älky! radical is, for example an alkyl radical with up to 6 carbon atoms, such as, for example, the methyl or isopropyl radical.

The Or-Arylalkylradikal can by catalytic hydrogenolysis be removed, for example with the aid of hydrogen in the presence of a palladium-on-charcoal catalyst and in the presence of a diluent or solvent. The catalytic Hydrogeno3.yae is used in expediently carried out at room temperature and at atmospheric pressure and it is expediently «lurch the presence of an acidic catalyst, such as hydrochloric acid, accelerated.

Alternatively, the ou-arylalkyl or alkyl radical can also be used be removed by a compound of the above formula with an alkyl or aryl chloroformate, such as z * B. Methyl, ethyl or bienyl chloroformate, reacts with during this reaction the Ou-arylalkyl or alkyl radical by an alkoxy or aryloxy carbon! radical, such as e.g. the methoxycarbonyl, ethoxycarbonyl or eaenoxycarbonyl radical, is replaced. The alkoxycarbonyl radical mentioned can then be obtained as an intermediate product by hydrolysis obtained alkoxy or aryloxycarbonyl derivative removed will.

The implementation of the Cv arylalkyl or alkyl derivative with the alkyl chloroformate can in a diluent or IJösTinif ^ iaittel. vie e.g. benzene- are carried out o? i,

109822/2229 bad original

xmö it can through the application of heat, for example by heating the VerxiünmangBiEittela or solvent to the boiling point, beaciüettnigt or brought to an end who-1 "? ■ · *.

The hydrolysis of the Alkoxyearbony! Derivate can mil; help of an alkaliYes, like ».3. Sodium or Xaljum hydroxide, carried out and it can also be in an aqueous diluent or solvents such as water, aqueous Methanol or aqueous ethanol. The hydrolysis can be achieved through the application of heat, for example by heating to the boiling point of the diluent or solvent accelerated or brought to an end.

It is pointed out that if the Arv-J.radical X has a reactive substituent, such as z / 3, ζ inen, unsaturated substituents, for example an alkenyl, alkenyloxy or amnyloxy radical, or one accessible for hydrogenolysis. Sübetituenten, such as the benzyloxy radical, or a halogen substituent, such as the ChloratoQi, contains, the reactive substituent itself can be modified if the -arylalkyl radical is removed by catalytic HydroRenolysis. For example, an alkenyl radical can be reduced to an alkyl radical; an alkenyloxy or alkynyloxy radical can be converted to a 43rd koxy radical; the benzyloxy radical can be converted to the hydroxy radical by hydrogenolysis; vmd the chlorine atom can be replaced by a hydrogen atom - If accordingly a reactive substituent is never above, defined in the A3? yl radical reading X, and this substituent is not changed. or if an AXJfcylthJosubstituent,

109822/2229 _8AD ordinal

dar de »catalyst? Ts ^ gxires. cäniw ;. im Arejlradi kai X an weEsiid ± & v, C. & im becomes <ls. $ alt ^ -ne. ^ vcj Terfalirsn .. in which an alkyl "or arylcliIoroiOrniia.t is veivwcndst, door the Eatfersmag of the" S.-Ä.ry3 allrjlradilials preferred.

The starting saiatsrial in the last euaianten procedure according to the invention »ksrii dadtirch eriialteu. ⁷ .4ei ^ den _t that roan cias «nt-

Horpxu3lin- * i5'-ohn.-deri'7a .- & with eirc.em complexsii id _r "as 2.Bc LithiumaIuiid.niir.B.liyl; i? Id _s by a © Imlxcbe-F .. VerfaJiren rßcliiaie ^ t, as it is just described for the production of eggs srfijidümgsiaäßaa Hor-pholiaderivate "

The erf JiidrncHgemäSen KctpholindcriTTS.ts Irimnen through implementation der- llerphoiinder5 ν ate in il ^ -fer free base form with an acid diircli are called conventional HsJ? nahiaen in the acid addition saline be uagewauaelt.

According to the invention, pharmaceutical additives continue to be used proposed «which as an active ingredient at least one inventive Hcrphölinderi vat or eJJi acid addition salt of the same together with a pharia-arseutic external diluent or questionnaire for included.

The pharmaceutical composition can have a form which is suitable for crale or parenteral preparations, for which purpose it is known in the art for example in the form of tablets, capsules, aqueous or oily solutions odex * _t suspensions injisierbs.ren ISmulsioner ^ aqueous or oily solutions or suspensions, odor Dishan J ^ lver be converted, "can.

109822/2229

The pharmaceutical according to the invention. Compositions may also contain, in addition to the morpholine derivative or salt thereof, one or more known drugs such as the following: neuroleptic agents such as chlorproatazin, prochlorperazine, trifluoperazine and sharkoperidol; other sedatives and tranquilizers such as sB »chlordiazepozide, phenobarbitone, and amylobarbitone; anti-jronvulsants such as primidone and phenytoin; ß-adrenergic blocking agent such as propranolol _t} agent "for the treatment of disease Parkin son'sehen be used, for example benzhexol; and other antidepressant agents such as imipraain, desipramine, anitriptyline, liortriptyline, amphetamine-type agents and monoamine oxidase inhibitors such as EB phenelzine and sebanazine.

The preferred pharmaceutical ingredients of the invention are those suitable for oral administration in unit dose forma, wit 8.B. Tablets and capsules that are between 1 and 100sg from the active part included.

The pharmaceutical compositions according to the invention are normally used both for the treatment of angata and neurotic conditions as well as for the treatment or prophylaxis of depressive illnesses in humans, with doses being used such that the patient wipes out one dose at a time 5 and. 400 mg of aa active ingredient; If a highly active compound is used, a total amount between 5 and 40 mg per day is preferred. The compositions are administered 3 or 4 times a day.

> 10982 ^ / 2229

BATH ORIGINAL

The invention is illustrated by the following examples explained «

A JiOsvsis of '1.1 g ^
MorpiLoliB-ii.fdrßclilorid-jaotliaiiolat in 30 ml absolute ethanol is shaken with 0.3 g of a 30 sweet balladium-on-charcoal-SJetalysatore in a hydrogen atmosphere "at room temperature and with a Sruci of 1 atm *" until the hydrogen take up stops. The mixture is filtered »and the solvent is reduced by evaporation under! Pressure removed. 50 ml of aqueous 2b. Batriumhydroxidlösung added ,, and the ba ~ sischs mixture tiird ahiert three times with 50 ml of ethyl acetate ex "tx. ⁴ The combined Xthylacetatexferakte are washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure 'or Iroekne evaporated. The residual free base is durcfe Conventional JPI measures are converted into the oxalate , especially the Qzs. · »lat is crystallized from a mixture of acetone and methaiol. In this way, 2-methyl-2-phenoxyme1; hjlmorpho ^ lin-oxalate with a melting point of 168 to 1? 2 ° C

The ^ - bensyl-2-methyl-2 used as starting material pheno ^ qymethylmorpholine hydrochloride 'methanolate can be like follows received

^ ₁ ^ 32 g of a 50 # strength dispersion of jiatrium hydride in HineraXSl are added to a solution * oa 19 * 8 g of irimethylsulfoxonäumjodid in 160 ml of dry dimethyl sulfoxide, which is kept under a nitrogen atmosphere. The mixture is stirred for 30 min at 50 to 60 * 0, and in this way a mixture is obtained which contains Dimethylsulfoxoniummethylid »Ζυ this mixture becomes a

ORIGINAL.

i »clsting τοπ 12.0 g of Pfeenosjacetone in 40 ml dry of dimethyl sulfoxide added, mid. the mixture is 3 st gp-37ülxrt and ezbitzt and to 50 to 6O ^e C then cooled. 1 water is added to the eye, and the aqueous mixture is extracted three times with 250 ml of ethyl acetate each time, and the combined ithylacetate extracts are washed with Vaase? washed, dried over anhydrous magnesium sulphate and evaporated to Sroekne under reduced pressure. In this way, the residue obtained is * 1j2 "^> 02j-2: -methyl" -3 "Pfe3sio3g ⁱ pzOpa] s. A mixture of this product and 12 _; 5 ml of bensylamine is stirred for 18 hours and heated to 140 ° ö heated, cooled and extracted with 500 ml of petroleum ether (Ip 60 to 80 ⁰ C). The Petaralätherlöaung is extracted four times with ^ e 200 ml of aqueous 2N Salasäure to give a thick brown oil in each acidic extract ausfällt- The Aiit dom oil combined aqueous saireen extracts are basified with aqueous 2N sodium hydroxide ;, uad the mixture is washed three times with $ 3 200 ml Ithjlacetat extracted "Dis combined lthy lace did exti ^ tkte are washed with water, dried over anhydrous Kagnesiunisulfat dried and evaporated under reduced pressure to dryness The remaining free base is converted into the oxalate by conventional measures, including the oxalate being crystallized from methanol.

2-methyl ~ 3-pheno35--2-propaneQl ~ O3alat with von 1? «} - to VV ⁰ O obtained.

2-phenoxy-3-propßnoI a guided slskaX 's solution of 8.13 g of 1-amino-2- ~ Benayl> methjl "(isolated from the oxalate by conventional Kaßnahmen) in 200 ml trockaueu Methylencblorid dropwise \ ma at the same time Solutions of 3.39 S chloroacetyl chloride in 30 ml of dry

109822/2229

BATH

HefchjXerteh: i ^ r5.au ~ 2d mm 5 * 03 g iTriätJ ^ iaisiK in *> Q ail dry ?. HstIiyXe: nc; ucrid with an x * such Seschiiindigbeit added that DXi * iateriia.lb iO ° C, remains ieraperatur of Semischs After 2i .gab ^7-i is znende is, "the mixture stirred at room temperature for 18 fct, with aqueous 2u hydrochloric acid and then iait Viass & r- gawasch, getx'ock & et rand under "? e3? mi" ide ^ - tsm Brack e "xc Ivroofene clamped. AuX this ©"% 'sise wi.i? d as .residue ^< 1- > (IJ-B © ^ izylciiloroacetaiaido) ~ 2-iieti2yl- ~ 3-plienosy-2-propanol "säialtsn" A solution of the fructose in 50 ml of dry? Iebhaxj, ol is in a solution toh 0.69 g hatri ??. m in IGO ml of dry methanol sugegebea, and the mixture becomes. G st touched imd on Hüokfluss srb.itz «ad that: '?. T5B.1; ©;.? ^T -e3? 3idertem pressure ziir srockne t * T) c5r Rü.cB: sts.m ti? Ird asvrisclxen 100 ml of water and 100 al Ithjl aestat TeIi-OiIb, -and the wäöa ^ igs layer "is vesimal with _t 1e 50 ail Itr ^ lacetat exbrairlert. The combined AtLyI-acetatlösOnssja werdea with wäesx ^ ISSR 2N hydrochloric acid ¹ UDD Dami adt water, dried wad. ujiter venßinderteia pressure to! dryness. Ber residue from a MschuEig from Petro3, ether (bp 60 to 80 ' ⁴ O) nxsä. Ithjlacetat k-? istal3..isiert, tied in this way «ird 4-ΒΘηκ7ΐ ~ 2- · κδϋ1 ^ 1-2-ρ ^ βηοχ7ίΠθΐ] ιΐ7ΐΐηο2? ϊϊ1ιο1ίιι- · 5- · θ3ΐ with an Ip of 82 to 84 ° 0.

A solution toi ». 3 »^ S ^ -BeB.isjl - 2 ~ Eiethyl ~ 2-pheno25TaetIi.ylmorpholine-Ii-oa iu 100 ml trooken ether becomes drop by drop to sine ::? stirred S »23pensio: a" son 1.1 g LitCaiairaluminiiimhydrid ia 100 ml dry li; her with such a speed suggests »£ yes that ice moderate reflux takes place» ¥ eon the addition at the end of ₁ the mixture is 4 n% s « sriiiivt iinl heated to reflux, and df "<in 18 st ⁷ OeL BaumteffiperatOrgsrukrc * let mixture r Blsküiilü;>:. g itnd under Rül ^. ^ n 2; d« iu.iuideruisse

109822/2229 _0R . _GmAU

1.1 ml of water, 1.1 ml of aqueous 2N KatriurihydroxidlÖ3uiig and 3.3 ml of water were added. The mixture is filtered and the ethereal solution is dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The remaining free base is converted into the hydrochloric by conventional means, and the hydrochloride is crystallized from a mixture of methanol and ether. In this way ^ benzyl ^ -methyl ^ -phenoxymethylmoiTphalin hydrochloride containing methanol of crystallization and having a melting point of 112 to 114- ⁰ C (with decomposition) is obtained.

Example 2

A solution of 2.1 g of 4-benzyl-2- (1-methyl-1-phenoxyethyl) morpholine hydrochloride in a mixture of 4Ό ml of absolute ethanol and 40 ml of water is mixed with 0.5 g of 5% palladium - Charcoal catalyst shaken in a hydrogen atmosphere at room temperature and at a pressure of 1 atm until the hydrogen uptake ceases. The mixture is filtered, the filtrate is evaporated to dryness under reduced pressure, and the residue is crystallized from a mixture of ethanol and ether. In this manner is obtained with a Pp 129.5 to 130.5 ⁰ C 2- (1-methyl-1-phenoxyethyl) morpholine hydrochloride.

The 4-benzyl-2- (1-methyl-1-phenoxyethyl) morpholine-h3 "drochloride used as starting material can be obtained by a similar process _; as it is described in the second part of Example 1, v; obei, however, 13, C g 2 "Mothy! ~ 2" pheno £ j'prcvplonaJ.dehy & a η. = Te lie df.-r 12.0 £ Piienoxyecetone and equivalent Me · "igen de: ·" kidney Reagan-

109822/2229

BATH ORIGINAL

tisji VMd solvent vexn / snda, * weudaa. Aiii the way t: liiincler. Generally obtained: 1 »2 ~ Epo3r, y ~ 3-iiethyl--

t & nol (characterized as Hydrogencacalat, mp 199-201 ⁰ C after crystallization aua Siller Misuhimg & uu Ithanol and Ither);

phene: iqr - 2 - butaneQl 5 4 '

morpliolin-5 ~ oa; imd 4-BenayJ -2- (1 -methyl-i - »egg arpboline, the hydrochloride of which has a melting point of 216 except for w.

The 1 "bar" .zylaminO "3 - raetfo5 <l ~ 3" -pheiioaq? "2 - 'biL"!; Oil is isolated by dissolving the cold reaction mixture in 50 ml of ether and an excess of a saturated ethereal hydrogen chloride solution is added, the mixture is filtered and the precipitated ßenzylamin- »li ^ rörachlorid is""rervrorfen," ind the essential;? ILTI at iünfmaX is aqueous l with 50 ^ * 2n BFatrium-. ". hjäroxidlöstmg_und then once with water Gewaaciaen, dried and evaporated to dryness. The beet consists of 1-nol.

Example 3

itliie solution of G:; 4 - Beiiiiyl-2 ~ (1-phenoxyethyl) morijiii) -1 in li / drug- o; cal-it in Ί00 ml absoX-Atam ethanol L-iird mi. · !; Ί g oi / i «f 5 ^ρ Μ% * η i ^> &'».1ad3.U'Ä-au:?-'Kol3kohle-'K^; -. Ay ·· aat, c / ia in eint; ' . Wa-ä.s * 95Titi; oi ^? 'Jatn> oi} pjifi.i - & at Haumüa -: - tpe:? A-

vx ' i-nd bfci eiuein ■' -. ικι ^: from '! ai; ^ e.?;. hut te It, bifi d: L: i v / a, i .'- ju "{>tf> ii? ■; 'ff'». ''; m: - .iuj.U «· {-". Oaa OromiiJcb becomes, fi tR-ίθΛ-ί; » im '"' Μ * '3 ^r jö'-j» t:> [.., y''ilf, i, ui wi. * ^! ' L Oureh Verd

109822/2229 bad ORIGINAL

under vermiiidsT.'fcfvij) pressure «ntfaori ;. The rear wall is crystallized from a mixture of ethylated spirit ur-d Ät :: .. üp , and on this '-feise 2 -' 1 "Pi <.5no: x; ethyl) morpholine ~ hydrogen ~ o: a: alat obtained with a melting point of 94-96 ° C »

iv '..; ^ -BeiizyX-i. ''■ - (ϊ -plisnoxyäthyl) morpholin-hydrogen - oxalate can be obtained durcii _s EIU ah.:a~ pending procedure as ea beschrieben.ist in zwlten portion of Example 1 except that 18 g of the known "Yerbin-la'. - »* i, 2-EpOXy-5-pheiioxjbutane (Journal of Organic Chemistry, 1960, 2 ^, 863) instead of 1,2 ~ epoxy-2-meth, yl = 3" phenoirjpropans and equivalent amounts of the other reagents and solvents be used. In this way the following are obtained in succession: 1 -Benylaniiio-3-pheno3 ^ -2-butanol (isolated by the process described in Example 2 for dia iBolation of 1-benzylamino-3-methyl-phenoxy-2-butanol); 1- (H ~ benzylchloroaeetamido) »3-pbeno *: 7 ~ ^ - butanol; 4-benzyl-2 "(1" pheno33rathyl) mox ^> pb.olin - 5 one; and 4-benzyl-2- (1- »pheno2eyäthyl) morpholin-hydrogen oxalate ~ (F $ 157-160 ⁰ C after crystallization AVU ^ a mixture of Xth and & nol Ither).

Dag in the last i.bsacz ron example 1 described ft.r.!. "• you: m vcLrd * αβο recovered, nt.it luai Un! 2- (o-Ä tixo χvphauov ^ iaööhyJ.) ■ -'i -: ϊ.jjopi 2-methylmorpiioläjti «!? ' oi \ P.nstellü dv-is'! - Tienzyl-2-iü «th * '2 ~ phenoa: ymeth _t yliiioi-pholit» .-' 5 --without v.lä itiiiigangwvua 1; ^:,. · 1 al

109822/2229

BATH

is used. In this way 2- (o ~ ethoxyphenoxy- methyl) -4 ~ isoprcpyi-2-metb: flH) orpholine.

The 2- (o ~ ÄtlioxyphenoxymethylV ^ - isoprcpyl. '"2 - meth; 7lmorpholiii" 5 "-one used as starting material can be obtained as follows:

Sine solution of 25 S chloroacetone and 1.5 g of potassium iodide in 25 ml of dry Ac ston becomes one for 30 min vigorously stirred mixture of 27.6 g of o-ethoxyphenol, 28.5 anhydrous potassium carbonate and 75 ml dry acetone, which is held at reflux is added. Stirring and heating is continued for a further 8 hours, the mixture is allowed to cool to room temperature and stirring is continued for an additional 20 hours. The mixture is filtered and the piltrate is evaporated to dryness under reduced pressure. The residue is in Dissolve 100 ml of chloroform, and the chloroform solution is twice with 30 ml of 2N sodium hydroxide solution and Washed once with 50 ml of water and then over anhydrous dried magnesium sulfate. The chloroform is removed by evaporation under reduced pressure, and the residue is crystallized from cyclohexane. In this way, o-lthoxyphenoxyacetone is used with a Mp of 42 ° C obtained.

The procedure described in the second part of Example 1 is repeated with the difference that an equivalent amount of o-ethoxyphenoxyecetone is used instead of the phenoxyacftone. In this way 1, H-Spoxy - ^ - o-athoxypheno ^ y - ^ - metLiy-Lpropene is obtained. A solution of 20 ζ this Verbindlang in 200 ml of ethanol and 35 nl IrO] Irop;? '/ Fuain * ird 18 st heated to reflux.

103 ft 22/2229

BATH ORIGINAL

The ethanol and the excess isopropylamine. been through Evaporation under reduced pressure is removed, the residue is dissolved in 100 ml of Ither, and the ethereal solution is extracted four times with 50 ml of aqueous hydrochloric acid each time. The combined acidic extracts are made basic with 11N aqueous sodium hydroxide solution and three times with Ether extracted. The combined ethereal extracts are washed with water over anhydrous magnesium sulfate dried and evaporated to dryness under reduced pressure. In this way 1 ~ o ~ Etho3: yphenoxy-3-isopropyl becomes amino-2-methyl "2 ~ propanol (which is obtained as hydrogen oxalate is characterized? that after recrystallization a mixture of methanol and ether has a melting point of 104 bis having.)

The procedure described in the third part of Example 1 is repeated, using an equivalent amount of this compound instead of the 1-benzylamino-2-methyl-3 ~ pheB.oxy ~ 2 ~ propanol is used. In this way the following are obtained in succession: 1 ~ o ~ Xthoxyphenoxy-3- (N "isopropylchloroacetamido) -2 ~ methyl-2-propanol and 2- (o - lthoxjphen-03q5rmethyl) -4-isopropyl-2.methylmorpho3in-5-one, both of which can be used without further purification.

Example 5

The procedure described in the last paragraph of Example 1 is repeated, with the difference that an equivalent amount of 2- (c-ethoxyphenoxyraethyl) -2--4-isopropylmorpholine-5 ™ one instead of the 4-Ban2yJ-2-methv ? -P-- pheaoxymethylmorpl: .OL ^"i .n-5 ~ oiis as Ausgangsmateiial \ ER.

109822/2229

BATH ORIGINAL

t wl: eä, In this way 2 ~ (n-lthO3cypheno3tymetbyl) 2-äcIryJ .- '4-: isoprcpjlHorpiioHn is obtained, which is characterized as Pierat. After crystallization from ^wäsf3x% methanol The picrate has a mp 79-82 ° ö.

The air * starting material used 2- (o ! • ieth ^ vl) -2-ät} iyl »4-isoprop3rlmorpholia" 5-one can be as follows will be received *

A üsiniscti from £ 7 * 6 go ~ Ithoxjpheno3., 15 j1 g of chloro & cetonitrile »27.6 g of anhydrous potassium carbonate and. = 200 ml of dry acetone is consumed vigorously for 18 hours and heated to reflux. The mixture is cooled and filtered, and the filtrate is poured under reduced pressure to the Tp-ackae singedarapfbb. The Eückstaud is dissolved in 100 ml of ether and c3.e ethereal solution is then washed twice with 25 ml of aqueous 2N Hatriumhydroxidlösung with 50 ml Wassei ^1, abim, üb ^ v 'waasarfxeiem magnesium sulfate and dates'! localized pressure to the srockne. The residue is a ^ AS Petrolätber krintallisiert (b.p. 30 to 40 ⁰ O) at 0 ⁰ C, Mia is in this Wei.fJö 0 Äthox.Tphenoxyaceto- "nitrii. obtained with a m.p. from 38 to - '+ 5 ^° C. A solution of 8.05 g of diesel ¹ compound in 50 ral dry ether is added drop by drop to a well-stirred solution of ethyl magnesium iodide, which can be mixed in the usual way. _; 7 g of kklxjl $ uä \ d imd 1, & g of magnesium prepared in 80 ml of dry ither were added _{va.r t.} After the addition has ended, the mixture is stirred for 1 hour and heated to a low temperature and then cooled to ^{13 ° C.} Thereupon 50 ml e watery n-uslza'anreloaxuiQ t:> ⁱ opferiweiae ϊΐυςβ-Die ätiierischv; Bohicht wii. * D afc separated, "ii: 50 ml of water K & w.v-.har *., Ge-eocknet and uuto.x * vermlndarteiu .Di-uck ■ .Ά.-. '^{> μ} ro ·, ''.nt; eini, i3i.;. aiap.! fc. Oe: e residue is de st ^ "''<iei.'fc,

109822/2229

and on this Voise 1-o-Athoxypneno: xybutan ~ 2-an with a bp of 138 to 142 ⁰ C / 2mm is obtained.

The procedure described in the third and fourth part of Example 4 is repeated, but it was decided that an equivalent amount ^{/ I} "O-thoic, ypheno: cybutria-2on is used in place of the o-lthoxypheno: ryacetone in this way the following are obtained in succession: 1,2-epoxy-3-o-ethoxyphenoxy-2-ethylpropane, 1 -o-a-fchozyphen-O3cy-2-ethyl-3-isopropylamino-2-propanol (v / which is characterized as hydrogen oxalate is that having a melting point of 128 to 13O ⁰ C after crystallization from ethyl acetate containing 1% by volume methanol); 1-o-Äthoxyphenoxy-2-ethyl ~ 3- (N-i3opropylchloroacetain.ido) -2- propanol and 2- (o-ithoxyphenoxymetbyl) ~ 2-ethyl-4 ™} .sopropylaorpholin ~ 5-one.

Example 6

The procedure described in the second paragraph of Example 1 is repeated, with the difference that an equivalent amount of 2- (o-ltho.-E7phenojtymi3thyl) -4-isopropyl-2-n-propylmorpholine-5-one instead of 3 4 -Benayl-2-iieth; ⁱ / l-2-phenoxymethylmorpholin-5-one is used as the starting material, in this way 2- (o ~ ethoxyphenoxym3thyl) <4 ~ isopropyl-2 ~ n-propylmorpholine is obtained as an oil.

Use ue 2 ~ (o-ethoxyphonox:; - oethyl) -4-i3opropyl ~ 2-n-propylmorpholine-5 "on as the starting material can aun o-lthoxyphenol through a similar sequence of stages as they are in the second and third part of

109822/2229

6AD ORIGINAL

Example 5 is described, with the difference that n- propyl magnesium iodide is used instead of ethyl magnesium iodide. The intermediates that have been characterized * are ^ -o-Xthox ^ pheno: rypentan-2-one (KP 1? 2 to 156 ^e C / 2 ram) and 1-o ~ Äthoxyphenoxy-3-isopropylamina-2 - n ~ propyl-2-prop & nol (hydrogen oxalate, which besitct mp 128-130 ⁰ C after crystallization from Athylacetet.

Example 7

The procedure described in the last paragraph of Example 1 is repeated, with the difference that an equivalent amount of either 2- (o-chlorephenoacymetiyl) ~ 4-isopropyl- or of ^ -allyl ^ -methylmorpholin-S-one as starting material instead of the 4-Benzyl-2-methyl-2-phen ~ oix ^ ethylniorpholin ^ -onß is used. In this way, 2- (o-chlorophenoxyiaethyl) -4-isopropyl-2-aethylfflorpholine or. 4-Allyl-2- (o-chlorophenoxymethyl) -2-Biethyliaorpholine (oxalate hemihydrate, Pp 107 to 109 ⁰ C after crystallization from ethyl acetate) obtained.

The 2- (o-chlorop * ianoxymethyl) -4-iaopropyl- used as starting materials and 4-allyl ~ 2-methylinorpholin-5-ones can be obtained by methods similar to they are described in the second, third and fourth part of Example 4, with the difference that o-chlorophenol is used instead of o-thoayphenol »

The intermediates that have been characterized are o-chlorophenoxyacetone (bp 15-114 ° C / 2.5 to 3 am);

109822 // 229 _irMN . _L.

BATH ORIGINAL

Pp 145 to 147 ° C after. Crystallization from a Με c hung; from methanol and ether); and 1-amino AlIyI "3" O ~ EHL οnop] ienoxy "H ~ methyl-2 ~ propanol '(flydrogenoxalat, m.p. 146 to 148 ⁰ C after crystallization from a mixture of ether and ftethanol) ·

Example 6

The procedure described in the last paragraph of Example 1 is, viiäder -holt, with the difference, that a-! equivalent hengu of either 2- (1 ~ o-ethoxypheno3cy - "" imethylethyl) - or of 2 "(1" 0 "tolyloxy-1 ™ methylethTl) -" 4-isopropyl-2-meth: flmorpholine-> 5- * one is used as the starting material instead of the A-benzyl-2-methyl-2-pheno3qsnaethylmo: rpholin 5-one. In this way, 2- (1 ~ c * -lth-

O3cypheno3cy1-methylethyl) -4-isopropyl-2-methylnio rpholine (hydrogen oxalate, melting point 145 ° to 147 ° C. after crystallization from a mixture of kethanol and ether). ? - ('i o-Tolyloxy-i-methylethyl) ^ - ieopropyl-2-methylBiorpiioliii (hydrogen oxalate, m.p. 112 to 114 ^e C after crystallization from a mixture of ethyl acetate and ether) obtained,

The 2 ~ (1-oorcy-i -mothylethyl) -4 ~ isopropyl ~ 2-methylmorpholine ~ 5- «J« can be obtained as follows:.

A solution of 29 * 25 g of 3-bromo-5-niöthyl ~ 2-butaneM?.: 25 ml of dry acetone is added dropwise for 15 minutes to a vigorously stirred mixture of 25 g of o-ethoxy phenol for 28 g of vasi- ierXreiem Kaliumcsrlionat luid 7.5 ml iie · * Ac - _ton: -'ielcherj; ~ uf Bückilwß heated xm \} _v

109822/2229

SAD ORiGiNAL

., α xä das Gea & sch. is heated for a further 8 atm. i) The gain is cooled to skin temperature, and the Eükreri viiva continued for a further 20 days. The mixture is filtered and the residue is washed with dry acetone. The combined filtrate and aschflüssigkeitön * are evaporated under reduced Drr.ck 2or dryness, \ md the residue is aii'gelöst in 100 ml of chloroform. The chloroform solution is vjässrJ ^ ej? 2n sodium hydroxide solution and then, washed with 50 ml Waoser, over anhydrous maize-siiimauLfat getrocJr.net and x under reduced pressure to dryness. on with a Kp from 90 to 102 ⁰ CZO ,? up to 1 mm.

The procedure described in the third and fourth part of example 4 is repeated, with the difference that an equivalent amount of $ "O-etho-typhenoxy-3-methjlbutan-2-one is used instead of the o-ithoxyphenoxyacetone. In this way the following are obtained in succession: 1,2-epoxy ~ 2,; 5-dimethyl ~ 3- C i> -ethoxyphenoxy) butane; 3- (o-ithoxypbenoxy) -1-isopropylamino-2,3-dimethyl-2-butanol (characterized as oxalate, Sp 174 to 175 ° 0 after crystallization from a mixture of methanol and ither); 3 ~ (o-lthoayphenoxy) -1- (F-isopropylchloroacetamido) -2,3-diiüethyl-2-butanol j and 2 ~ (1- o - ethoxyphenoacy-1-methyl-

Used as a starting material 2 "(1-o-3iolyloxy - 1 ~ methjrläthyl)", 4-iaopropyl-2-methylmorpholine-5-one '' drive uranium a ahnlicia.es Ya ι as daa described above are obtained honeycomb! , jedoah o-Cr-f-aol instead of

109822/2229 _ßA D original

o-Ethoxyphenol is used * Diο Z-wischeiipxoduxte, which have been characterized, aind 3-Mefrh; jrl ~ 3'-o-tolylGxybutane ~ 2-cn (KP 75 to 80 ° C / 0.7 to 1.0 mm) and 1-Isopropylamino-2 _t 3-dimetb.yl ~ 3-o-tolyloxy-2-butanol (Bydrogenox & Iat, mp 130 to 132 ^o 0 after crystallization from a mixture of methanol and ether).

Example 9

The procedure described in the last paragraph of Example 1 is repeated, with the difference that an equivalent amount of 2- (1-o-ethoxyphenoxyethyl) -4-isopropyl 2-diethylmorpholin-5-one is used as the starting material for the ^^ - benzyl -2-methyl-2-phenoxymethylmorpholine = ■ 5-oneε ^l · is used. In this way, 2- (1-o-lthoxyphenoxyethyl) -4-isopropyl-2-methylmorpholine is obtained as an oil.

read 2- (1-o-Ethojypheno3cyäthyl) -4-isopropyl-2-methylmorpholin-5-one used as starting material can be obtained by a method similar to that of the vast majority P and third part of Example 8 is described, wherein but 3-bromo-2-butanone instead of 3-bromo-3 · ynethyl-2-butanone is used. The intermediates that have been characterized are: 3 - o-lthoxypheno3cybut £; i-2-one (Bp 95 to 106 ° 0 / 0.9 to 1.3 mm) and 3-o ~ ÄthoxyphenoTcy-1 ■ i3opropylamiao-2-methy3.-2-butanol (Hydrogenoxal & t, m.p. 93 to 95 ° C after crystallization from an itchuDg Ethyl acetate and ether).

109822/2229 "bath C.

The procedure described in the last paragraph of Example 1 ren is repeated, with the difference that an equivalent Meiiga 2- (1 "a ~ etho: Ethfphenoxy-1-methylethyl) - or 2 ~ (1-m-Msthoxypbenoxy-i -methylSthyl) ~ 4-isopropylmorpholin ~ 5-one as i ^ uegangamaterial instead of the 4-bensyl-2-methyl-S-pheaoaqrmethylfflorpholiJi ^ -one is used. In this way, 2 ~ (1-o ~ ithoxyphenoxy-1-methylethyl) ~ 4 ~ isopropyJmorptolin b? .W # ^ Iaopropyl ^ -CI-m-metlioxr- ' phenoxy-1-methylfithyl) raorpholine obtained * Both products are oils.

Pas used 2- (1 ~ o ~ xtho2qrphenoxy-1-methylethyl) -> 4 "isopropylmorpholin-5-one as starting material can be obtained as follows:

A vigorously stirred mixture of 21.4 g of o-ethoxyphenol, 27 ml of acetone and 36 g of sodium hydroxide pellets is heated to reflux and 16 ml of chloroform is added dropwise at such a rate that the mixture will boil without further application of heat . After the addition is complete, the mixture is stirred and refluxed for a further 5 hours. The acetone is removed by distillation under reduced pressure and the residue is dissolved in 500 ml of anhydrous hydrochloric acid. The acidic solution is extracted three times with 200 ml of chloroform each time, and the combined extracts are stirred, during which time 300 ml of a saturated aqueous sodium carbonate solution are added each with 200 m3 of sodium bicarbonate solution orAn-r: 1 «-" o ~ 't

109822/2229

are carefully acidified with aqueous 2N hydrochloric acid, and the mixture is filtered. The residue is dried and crystallized from Oyclohex & n, and on this way, 2- (o ~ ethoxyphenoxy) -2-methylpropionic acid becomes obtained with an mp of 64 ° C

A solution of 18 g of this product in 100 ml of dry ether is added dropwise to a stirred suspension of 5 6 lithium aluminum imhydride in 200 ml of dry ether at a rate such that the mixture boils moderately and the mixture is then. Stirred for 18 st ηηά heated to reflux. The ^f ? <; Mix ^ 3rd cooled {and the excess lithium aluminum hydride is removed by successive addition of 5 ml of water,

more watery
5 ml / 2N sodium hydroxide solution and 15 ml water decomposed.

The mixture is filtered, the ether is removed from the filtrate removed by distillation under reduced pressure, and the residue is distilled. In this way, 2-o-Äthox3 ^ heno: ^ - 2-methyl-1 "-propanol with a Kp of 117 ° σ / 3ηπΗ obtained.

A mixture of 14 g of this compound, 57 g of dicyclohexylcarbodiimide and 270 ml of dry dimethyl sulfoxide is stirred for 1 second and heated to 90 to 95 ° C., complete dissolution taking place. 2.7 ^ l of an 85% aqueous phosphoric acid are added, and the mixture is stirred for 1 hour and then 90 to 9%. ^p ^ c> rhitat. The mixture is cooled to room temperature and stirring is continued for 16 hours. The mixture is then up to 90. Heated to 95 ° C and stirring is continued for an additional hour. 13 ml u'asMcr »earth added,

SAD GBiGiNA.

109822/2229

tmd ds .. · ■} t> eiüi3c! i wi ^ d cooled to RauffiteiLp ^ ratur b. The mixture is filtered, and the mince stand is then washed with 500 ml of ether. The combined liquid and liquid are shaken together and the layers are burned. The aqueous layer is extracted twice with 200 ml of ether each time, and the combined ethereal solutions are extracted ^. eiffl.a2 washed with .js 200 nil water, over anhydrous Kagneeium-Biilfat götrocJine t and evaporated to dryness under varmiadertem bridge. The residue is distilled, and in this way 2-o ~ ithoxyphenoxy ~ 2: ~ iaeth * _c flprop.ionalde ~ h; / a with a Kp τοπ 108 Ms 110 ° 0/5 »5 ^ m is obtained »

The fourth in over ui-.d part dea Example 4 no V'exrtahxfin v / ill be repeated ö.om _Uhtorschied} that an equivalent amount of 2 ~ o-lthü3cyphenoxy "2-methylpropion" aldehyde instead of o- ~ Äthoxyphenoxyacetons used L 'u £ these lines are obtained in sequence:

o-ethoxyphenox: j) ~ 3 ~ ethylbutane; 3- (o ~ lth- Ά -isopropyla? Nino-3 ~ xae fchyl »2 ~ butaiiol fchaä'.b ^ targeted as Hyclrogencwcalat» mp 134- at 136 ° C after crystallization from a mixture of methanol and ether); 3- (o-IthO3qrpheno, a ^ r) -1 - (H-iaopropylchloroacet-.rJHido) -3-raethyl-2-l> Tifcanol j and 2- (1 ~ o ~ Itho: irjphenoyj "1- - isop: t'Opjlmorpholin-5-one. "

That as 2- (1 -m
The initial material used can be used in a similar way as described above: -S: - " ¹ - hold white / i, ndt the difference that w instead of <> ~ £ .tho : q? ph ©} iol is used.. The products that have been characterized are P

109822/2229 _βΑ 0

pheno2;, f »2 - metjti; / i - 1 -yropanol (Kp '" ΓΙΟ his Ίΐ2 ° 0 / · ί, 2, .π. ·) j 2 ~ m--iIethoxypxiei3.oM:; / - - ^_i: i "-met3iylprop4.0ii.a: i dehyd (Sp 108 Ms 112 ° C / 3.5 mm); trad 1-isopropylamino ■ -S ^ m-Möthoxjfo.enoxy · - 3-methyl - 2 --butanol (Hydrogen c ^ alate, p.p. 100 to ' ^! 02 ° C after crystallization from a mixture of methanol and ethylene oxide).

1.6 β FhenylchloroforiQiat become a lorning of 2.9 g

(Beiapiel 4) in 5 ml ^ örockenem Bern; oil added ₅ and the mixture ^ ill 18 st a \ if reflux erbatst * The Lö "ungsnit ^ t"! is removed by evaporation under veriniadertem Dxnick, and the residue is dissolved in a Loaviiui of 6 g potassium hydroxide in 60 ml n-propanol. The mixture is heated to 48 atm under partial reflux, the solvent is removed by evaporation under reduced pressure, and the residue is dissolved in 100 ml of aqueous 2N hydrochloric acid. The acidic solution is washed twice with 30 ml of ether each time and then made basic with 11N sodium hydroxide solution and extracted three times with 50 ml of ether each time. The combined ethereal extracts are washed with water, dried over anhydrous magnesium sulfate and filtered. The ether is removed by evaporation under reduced pressure, and the residual free base is converted into the oxalate salt by conventional means. The oxalate is crystallized from an urine of ethanol and ether, and on this white 2- (o-Äbhoxyphenojc; 7ni3fchyl) -2 ~ meth; (under Zersetauyg) received.

109822/2229 construction orjcünai

The procedure described above is repeated, with the difference that the corresponding 4-isopropylmorpholine derivative, the preparation of which is described in Examples 5 to 10 above, instead of 2-o-ethoxyphenoxymethyl-4-isopropyl-2-methylmorpholn is used »In this way, the compounds specified in the following table obtain:

_eA0 109822/2229

Substituents in ring X

o-lthoxy

o-Ohloro o - lthoxy

o-methyl o-ethoxy

o-lthoxy m-methoxy

2 ethyl

n-propyl

Methyl methyl

Methyl methyl

<* ^ imtt,

r5 H H H Π H H methyl Hethyl Hethyl Ifethyl H methyl methyl methyl methyl Hethyl

M.p. ( ⁰ C) d.

Sal ζ it

Hydrogeno ^ relat-moiiohydrate 5759 (d)

Hydrogen oxalate-h mihydrate 5 * 56 (d)

Oxalate hemihydrate 130-132

Hydrogen oxalate 120-122

Oxalate 170-172

Hydrogen oxalate 132-134

Hydrogenoxa.l at

Oxalate 192-193

Crystallization solvent

ethyl acetate

ithylacatau / Ä fche.c.

Methano 1 / Etho.r Methano1 / ether

Methanol / ether methanol / ether

Methanol / ether H-aethol / ether

109822/2229

BATH

A solution of 2.5 g of 4-Ben £; yl-2- (m ~ iiicthü.x _t ypheao ^ metiiyl) ~ "i-iHe- ^ lmorplxolIn-h / driOgon-ojEalat in a mixture of 100 ml of ethanol and 100 ml water with 1 g of a 5% PaIladiTim-on-EOL2; charcoal - Eatalysators in a Wasserstoffs.-t; ijioapliä £ ö at Batjaitemperatur lind shaken at a pressure of 1 until the hydrogen absorption ceases, the overall. m ±?:>: ili mrd filtered _} and the filtrate is evaporated to dryness under reduced pressure. crystallized from Höthanoi and Itlier, νηΊ in this manner is to Wi obtained with a mp of 140 ⁹ g of 2- (ffl ~ MsthoxjrLthenojQrwethyl) -2-meciivinorpiioliiji-hydrogen oxalate.

The alfö starting material used 4'-BenKjl-2 - (m-inetho2cy ~ pheno3j ^ methyl) -2-ffethyliuox? Pliolin. can be obtained by a method similar to that described in the second, third and fourth chapter of Example 1, with the difference that an equivalent henge m-methoshenoxy- ticetone is used in place of phenoayacetone , be obtained sequentially · _1., 2-Ερ-

; I-Benaylamino · «

(characterized as hydrogen oxalate, pp 179 to 180 ° 0 i after crystallization sv.s a mixture: of methanol and ether); 1- (N-Benayl-

no 1; 4-benzyl-2- (m-methoxyphenoxy meth '1) -2-methylisiorpbolin-5-one; and 4-ßenajl-2 ~ (is-inetho ^, 7-phenoxymethyl) -S ~ rcef: hylatorpholine (egg / drug oxalate, melting point 16? to ^l' 168 ° C x: acb. EriHtallisatioii aiis methanol).

Bas / fl-Ii & biioxyphencitynce-bon (Kp 118 ° ü / 'i, 5 mm) can be so. Lbst

109822/2229 BAD ORiGSNAL-

by a similar procedure orhaltcm v ^ rdci! .. vie 03 in the Z ^ n & Ith part of Example 4 for the. ^ ci ^ ötwllur; * ;; , -on o-Il "ho3g? phenoxj? acetone is described, trobei ό ^ άοοα an equivalent amount m ~ Hethoxyphenol ay.stölle of o» ithoxyphenol is used.

example

A solution of 1.6 g of 4-Banayl 2 - (ra-methoxypho; aü.xymethyl) - = - 2-ffl3thyl-morpholiü and 0.76 "phenylchloroformate in 30 ml of dry benzene - / irrl 24 hours Heated to reflux and then evaporated to dryness under reduced pressure. The residue is dissolved in a solution of 3 g of potassium hydroxide in 20 ml of ethanol, and the mixture is heated to reflux for 24 hours and then partially reduced! Pressure evaporated to dryness. The residue is dissolved in 50 ml of aqueous 2a hydrochloric acid, and the acidic solution is washed twice with 20 ml of ethyl acetate each time and then made basic with an aqueous 11jaN-Mtriumhydroxldlösung. The mixture, i / ird four times with 30 ml! & Lbhylacet t extrahiert- and dia combined Ithylace bataxtrakte are washed with 50 ral Waaser, dried and evaporated to sr vsrmindertem pressure Isur l ^l i'ockne. The remaining free Baae is transferred by conventional methods into the Gxalat, χάνι on this Ws is ε- 2 "(ni - i'-ietho3cyphenoxyui * tbyl,) '- 2 - methylmorpholine hydrogen oxalate is obtained, which i \ ach Crystallization from a mixture of methanol and ether with a melting point of 140 to 141 ⁰ g

109822/2229 "- orjü; nal

Lc sun? "

S'-on in 50 ml dry

n is added drop by drop to a serühx'fcezi Suepi? i <m of 1 f ·· Lithiutaaluminrlujrahydrid in 150 ml dry jti "] ier sugegebei>., and the mixture is stirred for 8 st and heated to reflux. "-Cooled, and the excess idthiuraalumiaiuiaiiycirid vtivä. By the successive addition of 1 ml of water, 1 ml -dissolved water in Hatiduml ^ droxi-dissolved and 3 al of water with stirring-""tKtc. The mixture is stirred for 30 minutes filtered »u && the filtrate is charged under reduced pressure

In this way the residue obtained is cis-H-oisopropylclohexane-spiro-S'-morpholine, which is converted into the drug-gxalate as a substance by conventional means and is then characterized. It had a melting point of 146 hX, i 1 * 7 ° 0 after crystallization from a 1% strength (V / T) solution of ethanol in ethyl acetate *

The el & output material used

«Ißopropylcyelohexan-spiro-S · -morpholine - ^ - oii can can be obtained as follows:

`` 3 '' 25 K 2 ~ Gh3.oro jyclüliexe ^ ioa are added to a stirred mixture of Ί5 _Τ 8 g of o-thoxj'jjljeiiol, f5-8 g washer-free potassium carbonate and 100 ml of dry acetone, and the mixture will. Stirred for 18 hours and heated to reflux. The mixture is cooled and filtered, and the filtrate is evaporated to dryness under reduced pressure. Dar Huckat and vdrd in ICO icl ethyl acetate

109822/2229

dissolved, and the ithylacetate solution is successively with aqueous 2N sodium hydroxide solution and water washed and then dried. The solvent will removed by evaporation under reduced pressure and the mince stand is distilled. That way will 2-O "Ätlioxypl) .ej3O5cycyclo] iexanone with a bp of 84 to 86 ° C / Maintain 13 to 14 atm.

^ 2 * 3 g of a 50% dispersion of liatrium hydride in a mineral oil is added to a stirred suspension. 10.56 g of trimethylsulfoxcmiumjpdid in 60 ml of dry dimethylsulfoxide are added, and the mixture is ^{heated at 50 to 60 °} C. in a nitrogen atmosphere until the evolution of hydrogen ceases and a clear solution has formed. A solution of 9 »36 g of 2-o ~ lthüxyphenQxycyclohexei <.on in 10 ml of dry dimethyl sulfoxide is eye enter, and the mixture is stirred st in a nitrogen atmosphere for a further 4 and heated to 50 to 60 ⁰ C. Daa Gemi & ch is cooled, diluted with 200 ml of water and extracted with three times 60 ml of ethyl acetate. The combined ethyl acetate extracts are washed with water, over

P dried anhydrous ifefynesium sulfate and evaporated to dryness under reduced pressure. The residue is dissolved in a 1: 1 mixture (V / V) of benzene and petroleum ether (bp 60 bits 80 ⁰ O), and the solution is dissolved on a 200 g chromatography column of silica gel ("PIorisil";"Plorisil" is a registered trade oak) is applied. The column is filled with 300 ml of the 1: 1 G © -mjash (V / V) from benzene and petroleum ether (Έρ 60 to 80 ° C) eluted to remove the mineral oil and the elution is continued with benzene alone, collecting fractions of 150 ml. The first fractions are pooled and dried under reduced pressure

109822/2229

BAD C ^ iQiNAl

evaporated, and in this way the residue obtained is cis-2-o-lthoxyplienoxycyoloheranspirooxiran. The following 6 fractions are discarded and the elution is then continued with a 9: 1 mixture (v / v) of benzene and ethyl acetate. The next ten fractions are combined and evaporated under reduced pressure _{ and in this way trans-So-AthoxyphenoxycycloLoxan ^ irooxiran is obtained »

A solution of 2.7 S cis ^ -o-ÄthoxyphenoxycyclGhexanspirooxiran in a mixture of 60 ml of ethanol and 15 ml of isopropylamine is heated to reflux for 5 hours. The mixture is evaporated to dryness under reduced pressure, the residue is dissolved in aqueous 2N hydrochloric acid, and the solution is extracted twice with 50 ml of ether each time * The extracts are discarded. The acidic solution is made alkaline with 11N aqueous ammonium hydroxide solution and extracted three times with 50 ml of ether each time. The combined ethereal extracts are washed with water and dried "and the Ither is removed by evaporation under reduced pressure * In this way, cis-2-olthoxyphenoxy obtained ~ 1-isQpropylajnlnomethylcyclohexan-1-ol _t which alssormales oxalate is characterized, while a Has melting point of 162 to 164 ° C. after crystallization from isopropanol.

will ml Cailoroecetylqhlorid "eye give" a geröhrten Lösiaag of 7 u »0 g cis-i-Isopropylaminometfcyl-2-o-äthoxyphenoxycyclohexan-1-ol and 3.22 ml Eriäthylamin in 50 ml of dry Mathylenchlorid which is maintained at 0 ⁰ C was added dropwise , and the mixture is stirred 10 st at room temperature. The mixture is

109822 / 222t

58 -

subsequently washed with aqueous 2N hydrochloric acid and then with water and dried, and the solvent is passed through. Removed evaporation in vacuo. In this way, cis-ao-ethoxyphenoxy-iH-isopropylchloroacetamidocyclohexari-1-ol is obtained. This compound is added to a solution of 0.54 g of Katriuni in 120 ml of dry methanol and the mixture is refluxed for 18 hours. The methanol is removed by evaporation under reduced pressure, the residue is dissolved in 100 ml of ether, and the ethereal solution is washed successively with aqueous 2N hydrochloric acid and water and then dried. The ether is removed by evaporation under reduced pressure, and in this way cis-2-o-ethoxyphenoxy-4- ^t -i3öpropylcyclohexanspiro-2'-morpholin-5'-one is obtained.

Ee it should be noted that in this description the term "cis-" as applied to cyclohexane derivatives "states that the two oxygen atoms attached to the cyclohexane ring are such as an oxygen atom an aryloxy radical, such as the o-Jlthoxyphenoxy radical, and a second oxygen atom of an oxirane ring or a hydroxy radical or a corpholine ring, exist in such a way that in relation to the. Cyclohexane ring an oxygen atom in an equatorial one Arrangement and the other is in an axial arrangement. It should also be noted that the The term "trans-" as applied to a cyclohexane derivative says that the two oxygen atoms, such as they were described above, for example, with regard to the cyclohexane ring, either both in Squatorialer Arrangement or both are in an axial arrangement.

109822/2229

SAD

Example 15

The procedure of Example 14 is repeated, with the difference that 5i & g trans-2-o-ethoxyphenoxy-4 ^l -isoprcpylcyclohexanspiro-2'-moi ^> pholin-5 ^l -one are used in place of the corresponding cis-isoicer. In this way, trans-2-oA "thoxyphenoxy-4 '-isopropylcyclohexane-spiro ^' morpholine is obtained, which is characterized in that it is converted by conventional measures into the hydrogen oxalate monohydrate, which has a melting point of 131 to 133.degree having.

The trans-2-o-Äthoxy ~ phenoxy-4 · '-isopropylcyclohexanspiro-2' -morpholln-5 'one used as starting material can be obtained by a method similar to that described in the penultimate paragraph of Example 14, with the difference that trane-2-o-Athoxypti.enoxycyclohexanspirooxiran is used as a starting material instead of the cis isomer. In this way the following are obtained in succession: trans ^ -ol-tdüiOxyphenoxy-iisopropylaminOTOthylcycloheran-i-oil (characterized as hydrogen oxalate, Pp 150 to 152 ⁰ C after crystallization from isopropanol); trans-2-o-ithoxyphenoxy-1-K ~ isopropylchloroecetamidomethylcyclDhexan-i-ol; and trans-2-o-ithoxyphenoxy-4 '-isopropylcyclohexansplro ^' -morpholine-

The trans-2-o-lthoxyphenoxyc3rclohexanspirooxiran can even as in Example 14 can be obtained. Alternatively it can be obtained by the following procedure which confirms its identity as a trens isomer

109822/222 *

0.5 g of a 50% dispersion of sodium hydride in one Mineral oil is added to 8 ml of dry dimethyl sulfoxide and the mixture is mixed in a nitrogen atmosphere heated to 70 "to 75 ° C until the evolution of hydrogen ceases. The mixture is brought to room temperature ture cooled, and 10 ml of dry tetrahydrofuran are added. The mixture is stirred and adjusted to between -10 and -5 ° C cooled, and a solution of 2.14 g of triicethylsulfonium iodide in 20 ml of dry dimethyl sulfoxide is added for 3 min. The mixture is a further 2 min stirred »and a solution of 2.54 g of 2-o-lthoxyphenoxycyclohexanone in 10 ml of dry tetrahydrofuran is added. The mixture becomes 15 fflin between -10 and -5 ° 0 and then stirred for 1 et at room temperature. The mixture is diluted with 100 ml of water and three times with 50 ml each Ethyl acetate extracted »The combined extracts are washed with water, dried and reduced under reduced pressure Pressure evaporated to dryness. In this way, as Residue trans ~ 2 ~ o-ethoxyphenoxycyclohe3: anspirooxirane obtained, which practically not with the isomeric cis compound; is contaminated.

Example 16

Paa method τοπ Example 11 is repeated with the Difference that an equivalent henge -eis- or

morpholine as starting material instead of the 2-o-Ätbosyphenoiiyiiet] ^ rl-4 - ieopropyl-2 - aethylmorpholine is used. In this way, cis-2-o-A "th.oxypHenorycyclohexanspiro-2'-morpholine" which all bydrogen oxalate hot bihydrate with an mp of 126 bia 128 ° C is characterized (crystallized from a

109822/222)

BATH ORIGINAL

Solution of methanol in ethyl acetate) or trans ^ -p-Äthoxyphenoxycyelohexanspiro-S '-morpholine, which is characterized as hydrogen oxalate sesquihydrate with an mp of 158 to 160 ⁰ C (crystallized from a mixture of ethyl acetate and methanol) obtained.

■ "ι .-

BATH

109822/2221

Claims (1)

Morpboline derivatives of the formula where R stands for a hydrogen atom or for an alkyl, Al- PI Ix. kenyl or cycloalkyl radical cteht, in which R ", Ir and R, which can be the same or different, represent hydrogen atoms or alkyl radicals, with the one 2 3 4
Limitation that R, R ^ and R are not all for hydrogen » 2 5 atoms , or in which R and R ^ are connected and together with the two adjacent carbon atoms form a cycloalkyl ring and R stands for a hydrogen atom or for an alkyl radical, and in which X stands for an optionally substituted aryl radical, as well as the acid addition salts thereof. 2. Morpholine derivatives according to claim 1, wherein R stands for a hydrogen atom or for an alkyl or alkenyl radical with in each case up to 6 carbon atoms or for a cycloalkyl radical with up to 5 carbon atoms, wherein R _1, R ^ and R, which can be the same or different , stand for hydrogen atoms or for alkyl radicals with up to 3 carbon atoms, with the restriction that R, R- ^ and R do not all represent hydrogen atoms, or in which R and R * are connected to one another and together with the two adjacent 109822/2229 ' BAD OHiGiNAL barten Koli3.eu.ntcfj? atorn.sn siren Cycloall-ylring sdt bi.3 on S Kohl feiistuf fat oji 3n and H 'f "Lr> a hydrogen atom or for an alkyl radical with M.3 zn 5 carbon atoms stands, imd where3.in 1 stands for a phenyl «- or 1iap.b.thylradilcal, animate ε» is unaubstituted or can be substituted by one or more of the following substituents: alkene atoms, alkyl, alkoxy and alkylthio radicals with in each case up to to 10 carbon atoms, Halogenalkyl- and Halogenalkoücyradikalische each with up to 5 carbon atoms, alkenyl-, alkenyloxy-jAlkinyloxy - and cycloalkyloxy radicals each with 6 carbon atoms, Aryl-- aryloxy-, alkyl, aryloxy-, aralkyl- and Aralkoxy radicals with up to 10 carbon atoms each, alkyl radicals with up to 3 carbon atoms, through Hydroxy radicals or dux ^ ch alkoxy radicals with up to 5 carbon atoms are substituted, alkanoyl radicals with up to 5 carbon atoms, alkanoylamino radicals with up to 6 carbon atoms, alkoxycarbonyl radicals with up to 6 carbon atoms, hydroxy, amino, carboxy, methylenedioxy and nitro radicals and alkylene radicals having 3 to 4 carbon atoms, and the acid addition salts thereof. 3. Morpholine derivatives according to claim Λ , wherein E stands for a hydrogen atom or for the methyl, ethyl, isopropyl, n-propyl, s-butyl, t-butyl, allyl, cyclopropyl, cyclobutyl or glyclopenty! radical, in which H, Στ and H, which can be the same or different, represent hydrogen atoms or represent methyl, ethyl, or n- 2 propyl radicals, with the restriction that R, and E ^r do not all represent hydrogen atoms, or in which R ⁴ ″ and Ir are linked to one another and together with the two adjacent carbon atoms one 109822/2229 _eA o ORIGINAL 4th
Form cyclohexyl ring, and R stands for a hydrogen atom or for the methyl, ethyl or n-propyl radical and where X stands for a phenyl or naphthy! Radical which is unsubstituted or which can be substituted by one or two of the following substituents: Fluorine, chlorine, bromine and iodine and methyl, ethyl, n-propyl, isopropyl, n-butyl, t "butyl, t-alayl, methoxy", ethoxy, n Propoxy, Isopropaty ™, n-Butoxy, Isofoutoxy, · n-Fteptyloxy-, Methylthio-, Trifluoromethyl-, 2,2-DlcUoro-1, 1H3ifluox * oethoxy-, Allyl =, Allyloxy «, Propargyloxy-, Cyclopenfcyloxy -, "Phenyl, phenoxy, 4 -Tolyloxy - ₃ Benzyl, Benzylory-, Hydroxymethyl-, 1-Hydro.xyäthyl-, Methoxyiaethyly, Äthoxyntethyl-, 1-Methoxyäthyl", n-Propoxymethyl-, Methoxycarbonyl-, Äthoxycarbonyl- , Hydroxy, amino, carboxy, methylenedioxy, nitro, trimethylene and tetramethylene radicals, as well as the acid addition salts thereof. 4. morpholine derivatives according to claim 1, wherein R is a hydrogen atom or for an alkyl or alkenyl radical each with up to 6 carbon atoms or for a cycloalkyl radical with up to 5 carbon atoms 2 3 4
stands in which R, Br and R, which can be the same or different, stand for hydrogen or alky! radicals with up to 5 carbon atoms, with the one 2 "5 4 restriction that R, R ^y and R do not all represent hydrogen atoms, and in which X has the meaning given in claim 2, as well as the acid addition salts thereof .. 5. morpholine derivatives according to claim 4, wherein R represents a hydrogen atom or for the methyl, ethyl, n-propyl, isopropyl, allyl or cyclopentyl radical stands in which R is a hydrogen atom or for 109822/22 29 bad original Hebhy-X-, kuki ^ l- νανϊ n ~ i ^ opylradi] .r.al represents, where Ir and If ", soft gJeicfe. Or vei'SchieeL-.ii S3in can" for ^ ofV'atOiiiii or stand for iisthyl radicals ,: nit der dan ii ", .a ^ and B. not all for water Fabric ω · -; einm ,, wherein X and having defined in claim 3, as well as the Säiireadditiojiss & lse DER 6 «Morpholine diet according to claim. 5? in which R stands for a hydrogen atom or the isopropyl radical and in which X stands for the ¥ n <mjl- .. o-lthoxyphenyl or m-Metliozypheny! radical, as well as the Simreadditi-onssalae / '* Norpholindii.ri-occurred after An & prucii 1, v / orin H and Z have the meanings given in spoke 6, before R stands for the Nethyl-, Äthyl- or n-Propylradi.fcal and where R ″ waä. R both for hydrogen s; as well as the acid addition ss thereof. 1 8 4 horpholine derivative according to claim 1, in which B. and X have the meanings given in claim S, and in which: 2 · ί
a) R and Ir both for the Mfcth; flradikal standon ιΐϊί. represents a hydrogen atom; or ;,? and W both stand for x * sin hydrogen; and R ^ for the Yt chylra <11cal ateht; or R represents a hydrogen atom and ^E-7 and H both door are the methyl radical; as well as the acid P's it. b "i St ν S t-uad P. ' all stand for the methyl radical; or P. aAditi on-j sals e same « 1 y, - fiorpholiiiderivate also!. Ruspr ^ cli 1, v; o; oin R imß. I. dia in claim 6 arsgcgend'äiBcde-atime'fn besitsen, ν. * Or in BT and Ir connected to each other Bind mici rrit "'" for- adn Weoser-stoxffiitom sfceht, soxflie the Säiireadditioraesalse dsraslben. 10. The Terbindmigea 2- (1-K? -Tfcjl-1 raorpkolin, 2- (1-Pjiieno :: 5: yrithyl) iaorp '! 3LOliia and S-fetb ^ l-S-phenoxymetliylmorpholine as well as the Säiireaddit.iOiiBsaXse the same" 11 * The connections 2 "(1-ö» iitho:; £ 2rpß.eno / ry- "i ■■ i.-itlyrl-» ätl ^ f 1) morpho 1 in and 2- (Ί - © «Atb.oxyp.b.ej.ios ^ - 'I - / a ■ :: th, rlätbyl) · 4-isopropyl morphine and the acid addition sails of the same. 12 »The acid addition salse after, dsr claims 1 to 11, characterized in that it de.ß sjcti the hydrochlorides, hydrobromides, Fn.ospb.ate _s Siilfate, oxalates, lactates, tartrates, acetates, gluconates, Qaixoj late, Citrate, Aacorbate, Bsnaoate, ß-Hapiitkoat; ::, Adipate or 1 _} 1-MethyleE ~ bis ™ (2->j; ydroxy "3" BapM -]: Aoa - .; e) or around the acid addition salary ^ e, di ·; Esicb. tol. iv-. ^? lfo ·· nated polystyrene harsens:.: ·, Ii.; oid'3lt. 13-. Acid additioassalse aach dai claims 4 to 8 vmä 10, because there are kBimaeicbiiet that it is, inter alia, the% drochlori € e, hydrobrtimide, Pb.oephat ©, Suli.ate, oxalate, Lactat®, 0-artrate, acetate, Glueonate, 'Salicy BATH ORIGINAL late, citrate, / iscorbate, benzoate, ß-haphthoate, adipate ode r 1,1 -K ϊ thylea-bis- (2-33ydroxj-3- = Häplit; hoate) or mn the acid addition salts, the τοη sulfonated Pol; fstyx ^s olliax'3en derive _s acts. i4, Terfahrsn for the production of the Borpfeoliaderivate and the acid additioiissalKe. eiaem according to any of claims 1 to 13, characterized in _t that a compound of the formula, wherein B _s R _'5 R', R * and Σ have the meanings given in a DER claims 1 to 9 "with a complex ^υ Metallliydrid _reduced? or in that for the production of those Mox-pholinderivate in which E represents hydrogen , the removable flk-Arjlalfcyl- or Alky! radical iron a Yerbincl.ung the formula, ^ T h ri η R ⁴ VR ^p , K \ wä Z the in a dex aiisprüclie. . 109822/2229 BAD 1 to 9 have meanings in which R ^{J stands} for a removable dkarylalkyl or alkyl radical, removes and that if an acid addition salt is desired, the corpholine derivative in the free base Morro. reacts with an acid. 15- method according to address 14, thereby gekenasi «leh net that as konplex.es MetalIhydrid Lithinmaluminituoliydrid used idi 16 "The method according to claim 14 or 15 _} characterized in that it is carried out in ether, oil, or uranium or 1,2-metaoxyethane as a diluent or solvent" 17 * 'method according to claim 14 characterized in that Ή? for the Benssylradik & l stands. 18. Veriahreai according to one of the claims 14 or 17 * characterized in that the «sr-Arylalkylradikal by catalytic hydrogenolysis in a diluent «! or solvent in the presence of a palladium-on-charcoal catalyst Will get removed. 19 · Method according to claim 14, characterized in that gekeimzeich ™ net that R ^ stands for the methyl ™ or isopropyl radical. 20. The method according to any one of claims 14, 17 or 19 »characterized in that the Or-Arylallqflraäikal- or the Alky! Radical by Umsyfczung the starting material with an alkyl or aryl * Arylchloroformiat mid UUi ¹ ClI subsequent hydrolysis of the alkoxy- · or arylo '^ carbcvj ^' lde ~: ' ^: .νε.ij.e removed v. "ij ei .. 109822/2229 BATH ORIGINAL ΡΙι * Τψΐ | Β! Π! Ί | Π !! π | ιιι;: || Η --- in 21 »'The method see claim 20, characterized thereby» ά & · 8 as chloroformate methyl, ethyl or pianyl chlorofoxmate is used. 22 «Bäarmaiäsruitische composition, marked by this * that they are at least an active part of the Beatand a morpholine derivative or an acid addition salt of the «* same according to one of claims 1 to 13 together with a pharmaceutically acceptable diluent © the 2). Carrier means for this contains « 2 $, Bi ^ rmaseutische ensemble system according to claim 22 _7, characterized in that they have the correct tablet capsules, aqueous or oily solutions or suspensions, emulsions, iD ^ izable aqueous or oily solutions or suspensions, or dispersible powders. 24, Pharmaseutische gu & ammensetzung Naeh claim 22 or 231 gekenns5eichnet characterized _t that they additionally to Morpholinderi-irat or saia thereof one or more known means including, the sindi selected from the following neuroleptic drugs, other sedative agents and Beruhigtmgsmiifcel, antikomrulsive means 5 beta-adrenergic Blocking Agents, Gowns "Used for Treating Parkinson's Disease, and Other Antidepressants" 25 «A pharmaceutical composition according to claim 22, 25 or 24, characterized gekennsseichnet that it is suitable for oral elae Terabreichung in Einheitsdoaieryngaformen and τοη tablet form or capsules Open 109822ml · ' indicates that between 1 and 100 mg of deia a & tivss ingredient contain" BATH 109822/2229 *