DK168422B1 - Use of a 3-aryloxyazetidine carboxamide or carbothioamide or a pharmaceutically acceptable acid addition salt thereof for the preparation of a pharmaceutical composition for the treatment of anxiety states - Google Patents
Use of a 3-aryloxyazetidine carboxamide or carbothioamide or a pharmaceutically acceptable acid addition salt thereof for the preparation of a pharmaceutical composition for the treatment of anxiety states Download PDFInfo
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- DK168422B1 DK168422B1 DK90186A DK90186A DK168422B1 DK 168422 B1 DK168422 B1 DK 168422B1 DK 90186 A DK90186 A DK 90186A DK 90186 A DK90186 A DK 90186A DK 168422 B1 DK168422 B1 DK 168422B1
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- azetidinecarboxamide
- azetidine
- methyl
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Description
i DK 168422 B1in DK 168422 B1
Den foreliggende opfindelse angår anvendelsen af visse 3-aryloxyazetidincarboxamider eller -carbothioamider eller farmaceutisk acceptable syreadditionssalte deraf til fremstilling af farmaceutiske præparater til behandling eller 5 profylakse af angsttilstande hos mennesker og dyr.The present invention relates to the use of certain 3-aryloxyazetidine carboxamides or carbothioamides or pharmaceutically acceptable acid addition salts thereof for the preparation of pharmaceutical compositions for the treatment or prophylaxis of anxiety in humans and animals.
Nogle af 3-aryloxyazetidincarboxamiderne, som anvendes ifølge opfindelsen, er beskrevet i US-patentskrift nr. 4.226.861 som midler med antikonvulsivisk aktivitet, der anvendes til behandling af epilepsi. Disse forbindelser har 10 formlen 15 hvor R er lavere alkyl, og R1 er hydrogen, aminocarbonyl eller trifluormethyl.Some of the 3-aryloxyazetidine carboxamides used in the invention are described in U.S. Patent No. 4,226,861 as agents of anticonvulsant activity used to treat epilepsy. These compounds have the formula 15 wherein R is lower alkyl and R 1 is hydrogen, aminocarbonyl or trifluoromethyl.
Andre 3-aryloxyazetidincarboxamider, som anvendes ifølge opfindelsen, har formlen O Λ i-V (R‘>n 20 HHt O-(Qr hvor R1 er H, F, lavere alkyl, lavere alkoxy, trifluormethyl, acetyl eller aminocarbonyl.Other 3-aryloxyazetidine carboxamides used according to the invention have the formula O Λ i-V (R '> n 20 HHt O- (Qr where R1 is H, F, lower alkyl, lower alkoxy, trifluoromethyl, acetyl or aminocarbonyl).
25 Sidstnævnte forbindelser er kendt fra EP 102 194 Al, hvori det anføres, at forbindelserne i US patentskrift nr. 4.226.861, der er nævnt ovenfor, har muskelafslappende egenskaber, og at de N-usubstituerede azetidincarboxamider ikke har muskelafslappende virkning ved en effektiv antikonvulsi- 30 visk dosis. Denne oplysning er imidlertid baseret på en mindre følsom test (tab af vridningsrefleks).The latter compounds are known from EP 102 194 A1, which states that the compounds of US Patent No. 4,226,861 mentioned above have muscle relaxant properties and that the N-unsubstituted azetidine carboxamides do not have muscle relaxant effect in an effective anticonvulsant 30 swab dose. However, this information is based on a less sensitive test (loss of torsional reflex).
EP 102 740 Al beskriver N-formyl- og N-hydroxymethyl--3-phenoxy-l-azetidincarboxamider med antikonvulsivisk virkning.EP 102 740 A1 discloses N-formyl and N-hydroxymethyl-3-phenoxy-1-azetidine carboxamides having anticonvulsant activity.
35 De 3-aryloxyazetidincarboxamider-carbothioamider, der ifølge opfindelsen anvendes til fremstilling af et far- 2 DK 168422 B1 maceutisk præparat til behandling af angsttilstande, har formlenThe 3-aryloxyazetidine carboxamides carbothioamides used in the invention for the preparation of a pharmaceutical composition for the treatment of anxiety disorders have the formula
\j__c— '°“Ar J\ j__c— "°" Ar J
5 ** b hvor Ar er pyridyl (i en vilkårlig stilling), halogensubstitueret pyridyl, phenyl eller phenyl substitueret med 1 eller 10 2 substituenter valgt blandt chlor, brom, iod, fluor, C(l-8)-alkyl, C(1-8)-alkoxy, nitro, aminocarbonyl..og tri-fluormethyl, Z er oxygen eller svovl, R1 og R2 hver for sig er hydrogen, C(1-8)-alkyl, aryl, allyl, C(1-8)-alkylsub-stitueret allyl, propargyl, cycloalkyl, C(1-8)-alkyl-cyclo-15 alkyl, cycloalkyl-C(1-8)-alkyl, aryl-C(1-8)-alkyl og di--c(1-8)-alkylamino-C(1-8)-alkyl, eller R1 og R2 sammen med nabonitrogenatomet betyder imidazolyl, og R3 er hydrogen, C(1-8)-alkyl eller aryl, hvor aryl betyder phenyl eller phenyl substitueret med halogen, C(1-8)-alkyl, C(1-8)-alkoxy, 20 nitro, cyano, trifluormethyl, carbomethoxy eller carboethoxy, og aryl-C( 1-8)-alkyl betyder en arylgruppe som defineret ovenfor bundet over en ligekædet eller forgrenet C(1-8)-alkylgruppe til amidnitrogenatomet, eller et farmaceutisk acceptabelt syreadditionssalt deraf, når R1 og/eller R2 har 25 en saltdannende basisk aminokomponent, eller når Ar er pyridyl. Formlen I omfatter de geometriske isomere, herunder cis-, trans-, (E)- og (Z)-isomere deraf.5 ** b wherein Ar is pyridyl (at any position), halogen-substituted pyridyl, phenyl or phenyl substituted with 1 or 10 substituents selected from chloro, bromo, iodo, fluoro, C (1-8) alkyl, C (1 -8) -alkoxy, nitro, aminocarbonyl and trifluoromethyl, Z is oxygen or sulfur, R 1 and R 2 are each hydrogen, C (1-8) -alkyl, aryl, allyl, C (1-8) -alkyl-substituted allyl, propargyl, cycloalkyl, C (1-8) -alkyl-cycloalkyl, cycloalkyl-C (1-8) -alkyl, aryl-C (1-8) -alkyl and di-c (1-8) -alkylamino-C (1-8) -alkyl, or R1 and R2 together with the neighboring nitrogen atom means imidazolyl and R3 is hydrogen, C (1-8) -alkyl or aryl, where aryl means phenyl or phenyl substituted with halogen, C (1-8) alkyl, C (1-8) alkoxy, nitro, cyano, trifluoromethyl, carbomethoxy or carboethoxy, and aryl-C (1-8) alkyl means an aryl group as defined above bonded over a straight or branched C (1-8) alkyl group to the amide nitrogen atom, or a pharmaceutically acceptable acid addition salt thereof, when R 1 and / el clay R2 has a salt-forming basic amino component or when Ar is pyridyl. Formula I comprises the geometric isomers including cis, trans, (E) and (Z) isomers thereof.
Forbindelserne med formlen I er hidtil ukendte bortset fra de tilfælde, hvor Ar er phenyl eller phenyl substitueret 30 med trif luormethyl eller aminocarbonyl samtidig med at Z er oxygen, R3 er hydrogen, og R1 og R2 er en kombination af hydrogen og C(1-8)-alkyl, og hvor Ar er phenyl eller phenyl substitueret med fluor, C(1-8)-alkyl, C(1-8)-alkoxy, tri-fluormethyl, acetyl eller aminocarbonyl samtidig med at Z 35 er oxygen, og R1, R2 og R3 er hydrogen.The compounds of formula I are novel except for the cases where Ar is phenyl or phenyl substituted with trifluoromethyl or aminocarbonyl while Z is oxygen, R 3 is hydrogen, and R 1 and R 2 are a combination of hydrogen and C (1- 8) -alkyl, and wherein Ar is phenyl or phenyl substituted by fluoro, C1-C8 alkyl, C1-C8 alkoxy, trifluoromethyl, acetyl or aminocarbonyl while Z is oxygen, and R 1, R 2 and R 3 are hydrogen.
Udtrykket "C(1-8)-alkyl" omfatter ligekædede og for- 3 DK 168422 B1 grenede grupper på op til otte carbonatomer og er f.eks. sådanne grupper som methyl, ethyl, propyl, isopropyl, butyl, sek.butyl, tert.butyl, amyl, isoamyl, hexyl, heptyl og octyl. Udtrykket ,lC(l-8)-alkoxy,, har formlen -0-0(1-8)-alkyl.The term "C (1-8) alkyl" encompasses straight-chain and branched groups of up to eight carbon atoms and is e.g. such groups as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, amyl, isoamyl, hexyl, heptyl and octyl. The term, 1C (1-8) -alkoxy, has the formula -0-0 (1-8) -alkyl.
5 Udtrykket "cycloalky1", som det anvendes her, omfatter i første række cycliske alkylgrupper indeholdende 3-9 carbonatomer og omfatter sådanne grupper som cyclopropyl, cyclo-butyl, cyclopentyl, cyclohexyl og cycloheptyl.The term "cycloalkyl" as used herein primarily includes cyclic alkyl groups containing 3 to 9 carbon atoms and includes such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Som defineret ovenfor under formlen I er også far-10 maceutisk acceptable salte omfattet, når R1 og/eller R2 har en saltdannende aminokomponent, eller når Ar er pyridyl. Saltdannende aminokomponenter forekommer f.eks., når R^ og/eller R2 er di-c(1-8)-alkylamino-C(1-8)-alkyl, eller når de tilsammen danner piperazinyl- eller imidazolylgrupper.As defined above under formula I, pharmaceutically acceptable salts are also included when R 1 and / or R 2 have a salt-forming amino component or when Ar is pyridyl. Salt-forming amino components occur, for example, when R 1 and / or R 2 are di-c (1-8) -alkylamino-C (1-8) -alkyl, or when they together form piperazinyl or imidazolyl groups.
15 Farmaceutisk acceptable syreadditionssalte er sådanne salte, der kan tåles fysiologisk af mennesker og varmblodede dyr. Syreadditionssaltene kan dannes af enten stærke eller svage syrer. Eksempler på stærke syrer er saltsyre, hydrogenbromid-syre, svovlsyre og phosphorsyre. Eksempler på anvendelige 20 svage syrer er fumarsyre, maleinsyre, ravsyre, oxalsyre, citronsyre, vinsyre, hexaminsyre og lignende.Pharmaceutically acceptable acid addition salts are such salts that can be physiologically tolerated by humans and warm blooded animals. The acid addition salts can be formed by either strong or weak acids. Examples of strong acids are hydrochloric, hydrobromic, sulfuric and phosphoric. Examples of useful weak acids are fumaric acid, maleic acid, succinic acid, oxalic acid, citric acid, tartaric acid, hexamic acid and the like.
Som anført ovenfor anvendes de farmaceutiske præparater indeholdende 3-aryloxyazetidincarboxamiderne med formlen I eller farmaceutisk acceptable syreadditionssalte·.- deraf 25 til at lindre angst hos mennesker og dyr. Til påvisning af et anti-angst-respons anvendes den såkaldte "Vogel-Conflikt-Test", der er baseret på hæmmet drikkeadfærd fremkaldt ved hjælp af chock. Denne test beskrives detaljeret nedenfor.As stated above, the pharmaceutical compositions containing the 3-aryloxyazetidine carboxamides of formula I or pharmaceutically acceptable acid addition salts thereof are used to relieve anxiety in humans and animals. For the detection of an anti-anxiety response, the so-called "Vogel-Conflikt-Test", which is based on inhibited drinking behavior induced by shock, is used. This test is described in detail below.
De fremgangsmåder, der anvendes til at fremstille 30 forbindelserne med formlen I, kan opdeles i fremgangsmådetyperne A, B og C.The methods used to prepare the compounds of formula I can be divided into process types A, B and C.
3535
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4 DK 168422 B14 DK 168422 B1
Fremgangsmådetype A Ud fra phenoxyazetidin 5 H-N^O-^+X)r”n=c=z -, R3 Rs b) /\ „ 9 O /V Λ=Λίχ)η 10 Η'^γ/" "O + r1r2k-C-C1 —»R1RsN-C-/y-°-<Qr R3 -R3 H_lY^°~0^+ Η2Η-Ϊ-ΝΗΝ02 —> H2N-C-/^°H^' R3 R3 a) H/Yo_<nfx)” N /V» Λ-οJréx)*Process type A From phenoxyazetidine 5 HN 2 O - ^ + X) r "n = c = z -, R 3 Rs b) / \" 9 O / V Λ = Λίχ) η 10 Η '^ γ / "" O + r1r2k -C-C1 - »R1RsN-C- / y- ° - <Qr R3 -R3 H_lY ^ ° ~ 0 ^ + Η2Η-Ϊ-ΝΗΝ02 -> H2N-C - / ^ ° H ^ 'R3 R3 a) H / Yo_ <nfx) ”N / V» Λ-οJréx) *
20 Λ/ c=2 N,/ "O20 Λ / c = 2 N, / 0
R3 ^-1¾ C’2 R3 R3 30 35R3 ^ -1¾ C'2 R3 R3 35
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DK 168422 B1 5DK 168422 B1 5
Fremgangsmådetype BMethod type B
Via aryloxy-1-chlorcarbonylazetidin (Ar = phenyl, substitueret phenyl, pyridyl) a) 5 3 . Z λ, cl_C_jj\-0-Ar + R®NHg -> I^HN-C-N \^0-Ar R3 R3 10 d) Z λ. /vVia aryloxy-1-chlorocarbonylazetidine (Ar = phenyl, substituted phenyl, pyridyl) a) 3. Z λ, cl_C_jj \ -0-Ar + R®NHg -> I ^ HN-C-N \ ^ 0-Ar R3 R3 10 d) Z λ. / V
Cl-C-N \-0-Ar + HN—n /j-N—C—N \-0-Ar x O—Ό· xCl-C-N \ -0-Ar + HN — n / j-N — C — N \ -0-Ar x O — Ό · x
15 R15 R
Fremgangsmådetype CMethod type C
Via methan-(eller phenyl-)-sulfonylazetidin Z yvVia methane (or phenyl) sulphonylazetidine Z yv
20 H-N /\-OSOsW Ra -N=C=2 ^ RsNH-C-n\-0S02-WH-N / \ - OSOsW Ra -N = C = 2 ^ RsNH-C-n \ -0S02-W
^3 R3 w = CH3, phenyl, ,R3 w = CH3, phenyl,,
ii-CHg-phenyl Na%MFii-CHg-phenyl Na% MF
25 725 7
XX
R2 NH-C -N^>— 0R 2 NH-C -N 2> - 0
30 rS30 rS
35 DK 168422 B1 635 DK 168422 B1 6
Type A-reaktionerne omfatter en fremgangsmåde til fremstilling af phenoxyforbindelser med formlen I, hvorved en forbindelse med formlen s . ,-- -00 n R3 10 omsættes med en af følgende typer forbindelser: a) R2N = C = Z, b) R1R2N-C-C1/The Type A reactions comprise a process for preparing phenoxy compounds of formula I, wherein a compound of formula s. , -00 n R3 is reacted with one of the following types of compounds: a) R2N = C = Z, b) R1R2N-C-C1 /
IIII
0 15 00 15 0
IIII
c) h2n-c-nhno2, 20 d) -C=Z, eller e) produktet af formel -C=Z 25 og R2NH2c) h2n-c-nhno2, d) -C = Z, or e) the product of formula -C = Z 25 and R2NH2
Type B-reaktionerne omfatter en fremgangsmåde til fremstilling af visse aryloxyforbindelser med formlen If ved hvilken en forbindelse med formlen 30 Z /v ci-£-/V°-Rr B3 omsættes med en af følgende typer forbindelser: 35 a) R2NH2 eller b) imidazol.The type B reactions comprise a process for the preparation of certain aryloxy compounds of formula If in which a compound of formula 30 Z / v ci - / V ° -Rr B3 is reacted with one of the following types of compounds: a) R 2 NH 2 or b) imidazole.
Type C-reaktionerne omfatter en fremgangsmåde til fremstilling af m-fluorphenoxyforbindelser med formlen IThe Type C reactions include a process for preparing m-fluorophenoxy compounds of formula I
DK 168422 B1 7 ved omsætning af en forbindelse med formlenDK 168422 B1 7 by reacting a compound of the formula
Η—N 'S—OSO2 WΗ — N 'S — OSO2 W
iin
5 K5 K
hvor W er CH3, σ6/Η5 eller 4-CH3-C5H5, med et isocyanat med formlenwherein W is CH3, σ6 / Η5 or 4-CH3-C5H5, with an isocyanate of the formula
R2-N=C=ZR2-N = C = Z
10 <10 <
hvilket giver en forbindelse med formlen Rs NH-C-ί^^—DSO2 Wto give a compound of the formula Rs NH-C-ί ^^ - DSO2 W
15 hvorefter der omsættes med natriumhydrid og en metafluor-phenol med formlen hvilket giver en forbindelse med formlen R£Nh-c-/^>- o —(Q^15 and then reacting with sodium hydride and a metafluoro-phenol of the formula to give a compound of the formula R £Nh-c - / -> - o - (Q
Rs FRs F
Fremgangsmåder til fremstilling af udgangsphenoxyaze-tidinerne, der anvendes ved fremgangsmådetype A, er skitseret i reaktionsskema I. Fremgangsmåder til fremstilling af ud-30 gangsaryloxy-l-carbonylazetidinerne, der anvendes i fremgangsmådetype B, er skitseret i reaktionsskema II.Methods for preparing the starting phenoxyazidines used in process type A are outlined in Scheme I. Methods for preparing the starting aryloxy-1-carbonyllazetidines used in process type B are outlined in Scheme II.
De l-(diphenylmethyl)-3-hydroxyazetidiner, der anvendes som udgangsmaterialer ved fremgangsmådetype C (jfr. reaktionsskema III), kan fremstilles som anført af Anderson 35 & Lok. i J.Org.Chem. 73, 3953 (1972) ud fra benzhydrylamin og en passende epihalogenhydrin. Cis- og trans-isomere af 8 DK 168422 B1 l-(diphenylmethyl)-3-hydroxyazetidineme kan, når de forekommer, adskilles ved chromatografi. Udgangs-a-methylben-zyl-3-azetidinolen fremstilles som beskrevet af Tetsuya Okutani m.fl.'s metode, Chem. Pharm. Bull. bd. 22, 1490 5 (1974). Fremstillingerne 1-6 belyser fremgangsmåderne.The 1- (diphenylmethyl) -3-hydroxyazetidines used as starting materials of process type C (see Scheme III) can be prepared as stated by Anderson 35 & Lok. in J.Org.Chem. 73, 3953 (1972) from benzhydrylamine and a suitable epihalohydrin. The cis and trans isomers of the 1- (diphenylmethyl) -3-hydroxyazetidines may, when they occur, be separated by chromatography. The starting α-methylbenzyl-3-azetidinol is prepared as described by Tetsuya Okutani et al., Method Chem. Pharm. Bull. Vol. 22, 1490 (1974). Preparations 1-6 illustrate the methods.
Reaktionsskema IScheme I
Fremstilling af 1-usubstituerede udqanqsphenoxvazetidiner 10 R41 2 3 /\ ^CH-N y—OH (se fremstilling 2 & 5) C^Hs X l) CH3S02Cl/tøt3 R 2) NaOH, med eller uden + λ. fasekatalysator » r-WX)" V H°Åx)n1‘1 '—' (se fremstilling \ jfr. Cgså US pat.skriftPreparation of 1-unsubstituted substituted phenoxazazididines 10 R41 2 3/2 CH-N y-OH (see Preparation 2 & 5) C 2 H 2 X 1) CH 3 SO 2 Cl / th 3 R 2) NaOH, with or without + λ. phase catalyst (r-WX) "V H ° Ax" n1'1 '-' (see preparation \ cf. US Patent Specification
NaH 2 & 6) ‘ \ DMF 3 } 1 379 151NaH 2 & 6) \ DMF 3} 1 379 151
20 V-V"°"0^ 1> -P-a/g -> H^S-O-Q20 V-V "°" 0 ^ 1> -P-a / g -> H ^ S-O-Q
cii Ύ, el: % + Pd(0H)2/C Y yy (se fremstilling 4) R3 χ4 R4 = CH3, phenyl eller subst. phenyl. ·~ 2 X er begrænset til substituenter, der er elektron-25 fjernende, f.eks. fluor, chlor, brom, iod eller CF3.cii Ύ, el:% + Pd (OH) 2 / C Y yy (see Preparation 4) R3 χ4 R4 = CH3, phenyl or subst. phenyl. ~ 2 X is limited to substituents which are electron-removing, e.g. fluorine, chlorine, bromine, iodine or CF3.
3 Når X = 4-C1, 4-Br, 4-1, 4-F eller 4-CF3, er udbytterne meget lave.3 When X = 4-C1, 4-Br, 4-1, 4-F or 4-CF3, the yields are very low.
4 X kan ikke være chlor, brom eller iod i produktet, da hydrogenolyse fjerner disse grupper.4 X cannot be chlorine, bromine or iodine in the product as hydrogenolysis removes these groups.
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9 DK 168422 B19 DK 168422 B1
Reaktionsskema IIScheme II
Fremstilling af udgangs-l-carbonyl-3-aryloxy-azetidiner R4Preparation of starting 1-carbonyl-3-aryloxy-azetidines R4
5 'VCH-N//\—0H5 'VCH-N // \ - 0H
c£hs Yc £ hs Y
r3 (se fremstilling 1, nar \ R3 = CH3) \ \ halogen 10 \fel \ halogenr3 (see Preparation 1, when \ R3 = CH3) \ \ halogen 10 \ error \ halogen
\ NaH \ DMF\ NaH \ DMF
" ik-^r / R3"i- ^ r / R3
(se fremstilling i ] f Z(see Preparation in] f Z
20 reaktions skema' 1) C-Clg Z (Z=0 el. S)Reaction Scheme 1) C-Clg Z (Z = 0 or S)
Cl-C-N >~0ArCl-C-N> ~ 0Ar
XX
2525
Reaktionsskema IIIScheme III
Fremstilling af udgangs-methan-(el. phenyl)-sulfonylazetidinPreparation of starting methane (or phenyl) sulfonylazetidine
R4-CH-l/A_0H wSOeCl R4-CH-l/\-0S0aWR4-CH-l / A_0H wSOeCl R4-CH-l / \ - 0S0aW
30 ceBs HEt * C„Hj T,30 ceBs HEt * C „Hj T,
toluen · Rtoluene · R
R4 = CH3, CeHs- W = CH3, CeHg 1¾, -CeH4-4cH3 Pd/c 35 J, H-N Y-0S02W R3 DK 168422 B1 10 oR4 = CH3, CeHs- W = CH3, CeHg 1¾, -CeH4-4cH3 Pd / c 35 J, H-N Y-0S02W R3 DK 168422 B1 10 o
Fremstilling 1 trans-1-(Diphenylmethyl)-2-methyl-3-azetidinol-oxalat [1:1]Preparation 1 trans-1- (Diphenylmethyl) -2-methyl-3-azetidinol oxalate [1: 1]
En blanding af 126,4 g (0,72 mol) diphenylme-thylamin og 100 g (0,66 mol) 3~brom-l,2-epoxybutan i 300 5 ml methanol omrøres, medens det beskyttes mod lys, i 96 timer, opvarmes derpå ved tilbagesvaling i 30 timer, da farven skifter fra bleggul til dyb ravfarvet. En prøve analyseres ved 1H-NMR og viser 3 methyl-dubletter. Et fint beigefarvet bundfald fjernes ved filtrering (diphen-10 ylmethylamin-hydrobromid) , og filtratet inddampes på roterende fordamper, hvilket giver 174,6 g rå olie.' En prøve på .1,5 g neutraliseres og anbringes på en 4 mm tykA mixture of 126.4 g (0.72 mole) of diphenylmethylamine and 100 g (0.66 mole) of 3-bromo-1,2-epoxybutane in 300 ml of methanol is stirred while protected from light for 96 hours , is then heated at reflux for 30 hours as the color changes from pale yellow to deep amber. A sample is analyzed by 1 H NMR to show 3 methyl duplicates. A fine beige colored precipitate is removed by filtration (diphenyl-10-methylamine hydrobromide) and the filtrate is evaporated on a rotary evaporator to give 174.6 g of crude oil. A sample of .1.5 g is neutralized and placed on a 4 mm thick
RR
plade i en "Chromatotron" og elueres med 10% ethylace-tat/toluen. Der opsamles i alt 16 fraktioner, som består 15 af 6 klare pletter ved TLC. Den største komponent, der fraskilles, er på 700 mg og synes at være trans-isomeren. Denne prøve omdannes til oxalatsaltet. Hovedkoncentratet omdannes til den frie base med ammoniumhydroxid og eks-! traheres over i toluen, som tørres over magnesiumsulfat 20 og inddampes. Reaktionsremanensen opløses i methanol og behandles med 58 g oxalsyre, opvarmes, så at der fås en homogen opløsning, og får lov at køle af efter podning med en prøve af trans-oxalatsaltet. Filtrering giver 62 g hvidt granulat, smeltepunkt 147-148,5°C. Endnu, et ud-25 bytte fås på 26 g. ^H-NMR-Spektrummet viser kun en enkelt CHg-dublet med j (CH-j-H) på 6,1 Hz, hvilket svarer til trans-forbindelsen [Robert H. Higgins og Norman H. Cromwell, J. Hetero. Chem. 8 (6), 1059-62 (1971)]. Samlet udbytte af den i overskriften nævnte forbindelse er 30 88 g (38,8%).plate in a "Chromatotron" and eluted with 10% ethyl acetate / toluene. A total of 16 fractions are collected, comprising 15 of 6 clear spots by TLC. The largest component separated is 700 mg and appears to be the trans isomer. This sample is converted to the oxalate salt. The main concentrate is converted to the free base with ammonium hydroxide and excl. is extracted into toluene which is dried over magnesium sulfate 20 and evaporated. The reaction residue is dissolved in methanol and treated with 58 g of oxalic acid, heated to give a homogeneous solution and allowed to cool after inoculation with a sample of the trans-oxalate salt. Filtration gives 62 g of white granulate, mp 147-148.5 ° C. Still, an exchange of 25 g is obtained. The 1 H-NMR spectrum shows only a single CH 2 doublet with j (CH-j H) of 6.1 Hz, which corresponds to the trans compound [Robert H. Higgins and Norman H. Cromwell, J. Hetero. Chem. 8 (6), 1059-62 (1971)]. Total yield of the title compound is 30 88 g (38.8%).
Analyse: Beregnet for ci7Hi9NO-C2H2®4: C 66,46, H 6,16, N 4,08 Fundet: C 66,38, H 6,16, N 4,07.Analysis: Calculated for C 17 H 19 NO-C 2 H 2 4: C 66.46, H 6.16, N 4.08 Found: C 66.38, H 6.16, N 4.07.
35 11 DK 168422 B1 o35 11 DK 168422 B1 o
Fremstilling 2 1- (Diphenylmethyl) -3-azetidinol-methansulfonat (ester) -hydrochloric! [ 1; 1 ]Preparation 2 1- (Diphenylmethyl) -3-azetidinol methanesulfonate (ester) hydrochloricl [1; 1]
En blanding af 60f02 g {0,22 mol) 1-diphenyl-s methyl-3-azetidinol-hydrochlorid og 48,94 g (0,484 mol) triethylamin i 800 ml toluen omrøres i 24 timer, afkøles derpå til 5°C i isbad og behandles med 27,7 g (0,24 mol) methansulfonylchlorid, der tilsættes med en hastighed, så at temperaturen holdes under 15°C. Reaktionsblandin-10 gen omrøres i 3 timer og filtreres for at fjerne trie-thylamin-hydrochloridet. Filtratet behandles med_40 g (0,242 mol) 4-trifluormethylphenol efterfulgt af 19,35 g (0,484 mol) natriumhydroxid og 1,6 g (0,005 mol) te.tra-butylammoniumbromid i 60 ml vand. Reaktionsblandingen 15 omrøres hurtigt ved tilbagesvaling i 18 timer og omrøres derpå i 72 timer, medens den afkøles til omgivelsernes temperatur. Reaktionsblandingen overføres til en skilletragt og vaskes med 4 x 200 ml vand (emulsion). Toluenfasen tørres over magnesiumsulfat og inddampes i 20 vakuum til 82 g olie. Denne remanens opløses i 200 ml isopropylalkohol og behandles med 20 ml koncentreret saltsyre. Efter afkøling fraskilles et faststof, som fjernes ved filtrering (5,1 g) · Filtratet behandles med isopropylether, hvilket giver en olie, der senere op-25 arbejdes. Faststoffet identificeres ved spektralanalyse som methylsulfonatet af udgangsazetidinolen. Omkrystallisation ud fra isopropylalkohol giver 3,3 g fint hvidt krystallinsk materiale, smeltepunkt 172-173°C (sammentrækning ved 167°C).A mixture of 60fo2 g (0.22 mol) of 1-diphenyl-s-methyl-3-azetidinol hydrochloride and 48.94 g (0.484 mol) of triethylamine in 800 ml of toluene is stirred for 24 hours, then cooled to 5 ° C in an ice bath. and treated with 27.7 g (0.24 mol) of methanesulfonyl chloride which is added at a rate to keep the temperature below 15 ° C. The reaction mixture is stirred for 3 hours and filtered to remove the triethylamine hydrochloride. The filtrate is treated with 40 g (0.242 mole) of 4-trifluoromethylphenol followed by 19.35 g (0.484 mole) of sodium hydroxide and 1.6 g (0.005 mole) of tert-butylammonium bromide in 60 ml of water. Reaction mixture 15 is rapidly stirred at reflux for 18 hours and then stirred for 72 hours while cooled to ambient temperature. The reaction mixture is transferred to a separatory funnel and washed with 4 x 200 ml water (emulsion). The toluene phase is dried over magnesium sulfate and evaporated in vacuo to 82 g of oil. This residue is dissolved in 200 ml of isopropyl alcohol and treated with 20 ml of concentrated hydrochloric acid. After cooling, a solid is removed which is removed by filtration (5.1 g). The filtrate is treated with isopropyl ether to give an oil which is subsequently worked up. The solid is identified by spectral analysis as the methyl sulfonate of the starting azetidinol. Recrystallization from isopropyl alcohol gives 3.3 g of fine white crystalline material, mp 172-173 ° C (contraction at 167 ° C).
30 Analyse: Beregnet for C17HlgN03S.HCl: C 57,70, H 5,70, N 3,96 Fundet: C 57,80, H 5,86, N 3,92.Analysis: Calculated for C 17 H 18 NO 3 S.HCl: C 57.70, H 5.70, N 3.96 Found: C 57.80, H 5.86, N 3.92.
3535
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12 DK 168422 B112 DK 168422 B1
Fremstilling 3 trans-1- (Diphenylmethyl) -2-methyl-3-13- (tr if luorme thyl) --phenoxy]azetidin-oxalat [1;1]Preparation 3 trans-1- (Diphenylmethyl) -2-methyl-3-13- (trifluoromethyl) phenoxy] azetidine oxalate [1; 1]
En omrørt opslæmning af 1,2 g (0,03 mol) natri-5 umhydrid (60% dispersion i mineralolie) i 50 ml tør DMF behandles med 3,45 g (0,001 mol trans-l-diphenylmethyl--2-methylazetidin-3-ol-oxalat tilsat i små portioner.A stirred slurry of 1.2 g (0.03 mole) of sodium hydride (60% dispersion in mineral oil) in 50 ml of dry DMF is treated with 3.45 g (0.001 mole of trans-1-diphenylmethyl-2-methyllazetidine). 3-ol oxalate added in small portions.
Når tilsætningen er afsluttet, og hydrogenudviklingen er ophørt, opvarmes reaktionsblandingen til 80°C i 2 timer, 10 hvorpå der tildryppes 1,64 g (0,01 mol) 3-fluor-trifluor-methylbenzen. Reaktionsblandingen omrøres ved 80°C i y-derligere 18 timer. Reaktionsblandingen fortyndes med isvand og ekstraheres med 3 x 25 ml toluen. Ekstrakterne kombineres, tørres over magnesiumsulfat, filtreres, 15 og filtratet behandles med 1 g oxalsyre. Det opnåede faststof opsamles ved filtrering. Omkrystallisation ud fra acetone/isopropylether giver 2,2 g (4,5%) fine hvide krystaller, smeltepunkt 146-147°C. Proton-NMR viser, at det er trans-forbindelsen.When the addition is complete and hydrogen evolution has ceased, the reaction mixture is heated to 80 ° C for 2 hours, then dropping 1.64 g (0.01 mole) of 3-fluoro-trifluoro-methylbenzene. The reaction mixture is stirred at 80 ° C for another 18 hours. The reaction mixture is diluted with ice water and extracted with 3 x 25 ml of toluene. The extracts are combined, dried over magnesium sulfate, filtered, and the filtrate is treated with 1 g of oxalic acid. The solid obtained is collected by filtration. Recrystallization from acetone / isopropyl ether gives 2.2 g (4.5%) of fine white crystals, mp 146-147 ° C. Proton NMR shows that it is the trans compound.
20 Analyse: Beregnet for C24H22F3NO*C2H2°4: C 64,06, H 4,96, N 2,87 Fundet: C 64,26, H 4,99, N 2,89.Analysis: Calculated for C24H22F3NO * C2H2 ° 4: C 64.06, H 4.96, N 2.87 Found: C 64.26, H 4.99, N 2.89.
Fremstilling 4 25 trans-2-Methyl-3- [3- (trifluormethyl) phenoxy] azetidin-oxa lat [1:1]Preparation 4 trans-2-Methyl-3- [3- (trifluoromethyl) phenoxy] azetidine oxide [1: 1]
En methanol/varmt vand-opløsning af 33 g (0,068 mol) trans-l-diphenylmethyl-2-methyl-3- [3- (trifluormethyl) -phenoxy]azetidin-oxalat behandles med ammoniumhydroxid,A methanol / hot water solution of 33 g (0.068 mol) of trans-1-diphenylmethyl-2-methyl-3- [3- (trifluoromethyl) phenoxy] azetidine oxalate is treated with ammonium hydroxide,
30 indtil den er basisk, og ekstraheres så med 4 x 150 ml me-thylenchlorid. De kombinerede methylenchloridekstrakter vaskes med vand, tørres over magnesiumsulfat og inddampes i vakuum, til en bleggul olie. Denne olie opløses i 200 ml 190 ethanol plus 5 ml triethylamin og hydrogeneres på 35 et Parr-apparat med 3,3 g 5%:s palladium-på-trækul-kata-lysator ved et hydrogen tryk på 2,8 kg/cin atm. ved 70°C30 to basic, and then extracted with 4 x 150 ml of methylene chloride. The combined methylene chloride extracts are washed with water, dried over magnesium sulfate and evaporated in vacuo to a pale yellow oil. This oil is dissolved in 200 ml of 190 ethanol plus 5 ml of triethylamine and hydrogenated on a Parr apparatus with 3.3 g of 5% palladium-on-charcoal catalyst at a hydrogen pressure of 2.8 kg / cin atm . at 70 ° C
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13 DK 168422 B1 i 12 timer. Efter at den beregnede hydrogenmængde er blevet absorberet, fjernes katalysatoren ved filtrering, og filtratet inddampes i vakuum, hvilket giver 26,73 g råprodukt. En portion på 8 g omdannes til oxalatsaltet 5 i isopropylalkohol, hvilket giver 6,1 g fint hvidt pulver, smeltepunkt 155-156°C. Samlet udbytte ekstrapoleret ud fra den aliguote mængde omdannet til oxalatsaltet er 84% af det teoretiske.13 DK 168422 B1 for 12 hours. After the calculated amount of hydrogen has been absorbed, the catalyst is removed by filtration and the filtrate is evaporated in vacuo to give 26.73 g of crude product. A portion of 8 g is converted to the oxalate salt 5 in isopropyl alcohol to give 6.1 g of fine white powder, mp 155-156 ° C. Total yield extrapolated from the aliguous amount converted to the oxalate salt is 84% of theory.
Analyse: Beregnet for cnHx2F3NO*C2H2^4: 10 C 48,61, H 4,39, N 4,36.Analysis: Calculated for cnHx2F3NO * C2H2 ^ 4: 10 C 48.61, H 4.39, N 4.36.
Fundet; C 48,67, H 4,38, N 4,34.found; C, 48.67; H, 4.38; N, 4.34.
Fremstilling 5 trans-1- (Diphenylmethyl) -2-methyl-3-azetidinol-methansul-15 fonat-(ester)-hydrochlorid [1:1]Preparation 5 trans-1- (Diphenylmethyl) -2-methyl-3-azetidinol-methanesulfonate (ester) hydrochloride [1: 1]
En opløsning af 6 g (0,025 mol) trans-l-diphe-nylmethyl-2-methylazetidin-3-ol (opnået ud fra hydrochlo-ridsaltet ved opdeling i organisk opløsningsmiddel og vandig base, fraskillelse og inddampning af den organi-20 ske fase) i 40 ml tør benzen behandles med 10 ml trie-thylamin og afkøles til 5°C. Under omrøring behandles reaktionsblandingen med 3,54 g (0,03 mol) methansulfo-nylchlorid med en hastighed, så temperaturen holdes under 10°C. Efter omrøring i 3 timer viser TLC (2Q,% ethyl-25 acetat/methylenchlorid på silicagel), at reaktionen er u-fuldstændig. Der tilsættes yderligere 1,14 g (0,01 mol) methansulfonylchlorid, og omrøringen fortsætter i en time. Reaktionsblandingen fortyndes med 100 ml vand, og benzenlaget fraskilles, vaskes med 300 ml vand, tørres 30 over magnesiumsulfat og inddampes til en olie. Olien opløses i isopropylether og behandles med etherisk hy-drogenchlorid. Det faste salt fjernes og omkrystalliseres ud fra 190 ethanol, hvilket giver 3,4 g (37%) fnuggede hvide krystaller, smeltepunkt 152-153°C.A solution of 6 g (0.025 mol) of trans-1-diphenylmethyl-2-methyllazetidin-3-ol (obtained from the hydrochloride salt by partitioning in organic solvent and aqueous base, separating and evaporating the organic phase ) in 40 ml of dry benzene is treated with 10 ml of triethylamine and cooled to 5 ° C. With stirring, the reaction mixture is treated with 3.54 g (0.03 mole) of methanesulfonyl chloride at a rate to keep the temperature below 10 ° C. After stirring for 3 hours, TLC (2Q,% ethyl acetate / methylene chloride on silica gel) shows that the reaction is incomplete. An additional 1.14 g (0.01 mole) of methanesulfonyl chloride is added and stirring is continued for one hour. The reaction mixture is diluted with 100 ml of water and the benzene layer is separated, washed with 300 ml of water, dried over magnesium sulfate and evaporated to an oil. The oil is dissolved in isopropyl ether and treated with ethereal hydrogen chloride. The solid salt is removed and recrystallized from 190 ethanol to give 3.4 g (37%) of fluffy white crystals, mp 152-153 ° C.
35 Analyse: Beregnet for C-Lgl^-iNO^S.HCl: C 58,77, H 6,03, N 3,81.Analysis: Calculated for C-Lgl 2 -NO 3 SHCl: C 58.77, H 6.03, N 3.81.
Fundet: C 58,68, H 6,08, N 3,80.Found: C, 58.68; H, 6.08; N, 3.80.
1414
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DK 168422 B1DK 168422 B1
Fremstilling 6 1- (Diphenylmethyl) -3- [3- (trifluormethyl) phenoxy] azetidin N-Diphenylmethyl-3-hydroxyazetidin-hydrochlorid (I) fremstilles ud fra benzhydrylamin og epichlorhydrin 5 ifølge Anderson og Lok, J. Org. Chem. 37, 3953 (1972).Preparation 6 1- (Diphenylmethyl) -3- [3- (trifluoromethyl) phenoxy] azetidine N-Diphenylmethyl-3-hydroxyazetidine hydrochloride (I) is prepared from benzhydrylamine and epichlorohydrin 5 according to Anderson and Lok, J. Org. Chem. 37, 3953 (1972).
41,33 g (0,15 mol) I og 42 ml (0,30 mol) triethylamin omrøres i 250 ml toluen, idet der tildryppes 12 ml (0,15 mol) me-thansulfonylchlorid i løbet af 10 minutter under omrøring, og temperaturen holdes mellem 4 og 12°C. TLC (silicagel, 10 1Q% ethylaoetat i methylenchlorid) efter 1 time viser, at alle udgangsmaterialer er omsat. Blandingen filtreres for at fjerne triethylamin-hydrochloridet, som skylles to gange med toluen. Filtratet og vaskevæskerne kombineres til ca. 450 ml opløsning. Til denne opløsning 15 tilsættes 27,5 g (0,17 mol) m-trifluormethylphenol, 2,4 g tetrabutylammoniumbromid, 24 g (0,3 mol) 50%*s natriumhydroxid og 24 ml vand, og blandingen omrøres kraftigt og opvarmes under tilbagesvaling og under nitrogen i 2,5 timer. Toluenlaget i blandingen fraskilles og va-20 skes én gang med vand, tørres over natriumsulfat og inddampes til en olie. Denne olie podes og pumpes på en oliepumpe natten over. Der fås en fast kage, der vejer 49,7 g. Noget af dette faststof opløses i isopropanol under kortvarig opvarmning. Derpå tilsættes vand-, så 25 at der opstår en let uklarhed. Blandingen podes og afkøles for at fremkalde krystallisation. Det hvide faststof opsamles ved filtrering, vaskes med 50%'s vandig isopropanol og tørres under vakuum natten over. Proton--NMR viser let forurening med siliconeolie, smeltepunkt 30 82,5-84°C.41.33 g (0.15 mole) of I and 42 ml (0.30 mole) of triethylamine are stirred in 250 ml of toluene, dropping 12 ml (0.15 mole) of methanesulfonyl chloride over 10 minutes with stirring, and the temperature is kept between 4 and 12 ° C. TLC (silica gel, 10 1% ethyl acetate in methylene chloride) after 1 hour shows that all starting materials are reacted. The mixture is filtered to remove the triethylamine hydrochloride, which is rinsed twice with toluene. The filtrate and washings are combined to approx. 450 ml of solution. To this solution is added 27.5 g (0.17 mol) of m-trifluoromethylphenol, 2.4 g of tetrabutylammonium bromide, 24 g (0.3 mol) of 50% sodium hydroxide and 24 ml of water, and the mixture is stirred vigorously and heated under reflux and under nitrogen for 2.5 hours. The toluene layer in the mixture is separated and washed once with water, dried over sodium sulfate and evaporated to an oil. This oil is seeded and pumped on an oil pump overnight. A solid cake weighing 49.7 g is obtained. Some of this solid is dissolved in isopropanol under short heating. Water is then added so that a slight haze appears. The mixture is seeded and cooled to induce crystallization. The white solid is collected by filtration, washed with 50% aqueous isopropanol and dried under vacuum overnight. Proton NMR shows slight contamination with silicone oil, mp 82.5-84 ° C.
Analyse: Beregnet for C23H20F3NOi C 72,05, H 5,26, N 3,65.Analysis: Calculated for C 23 H 20 F 3 NO 1 C 72.05, H 5.26, N 3.65.
Fundet: C 71,62, H 5,29, N 3,61.Found: C 71.62, H 5.29, N 3.61.
35 15 DK 168422 B135 15 DK 168422 B1
De følgende eksempler belyser fremstillingen af 3--aryloxyazetidincarboxamider eller -carbothioamider med formlen I.The following examples illustrate the preparation of 3 - aryloxyazetidine carboxamides or carbothioamides of formula I.
5 Eksempel 1 N-Methyl-3-[3-(trifluormethyl)phenoxy]-1-azetidin-carbo-thioamid Rå 3-[3-(trifluormethyl)phenoxy]azetidin fra katalytisk debenzylering af 26,0 g (0,078 mol) 1-benzhy-10 dry1-3-[3-(trifluormethyl)phenoxy]azetidin opløses i 100 ml methylenchlorid, og der tildryppes under nitrogenatmosfære en opløsning af 5,0 g (0,0678 mol) methylisothio-cyanat i 15 ml methylenchlorid. Reaktionsblandingen omrøres i 16 timer ved omgivelsernes temperatur og henstår 15 en weekend over. Opløsningen filtreres gennem en "Ce-lite'^-filterpude for at fjerne et fint krystallinsk bundfald, og filtratet inddampes under formindsket tryk. Residualolien krystalliseres ud fra isopropylether, hvilket giver 12,6 g produkt, smeltepunkt 79-86°C. En prø-20 ve på 5,0 g omkrystalliseres fra isopropylether (trækul) , hvilket giver 3,2 g, smeltepunkt 89-93°C, som ved TLC på silicagel (10% methanol/toluen) viser sig at være forurenet af et materiale med lavere Rf. Filtratet inddampes under formindsket tryk, kombineres med de -3,2 g 25 faststof og opløses i 100 ml methylenchlorid. Opløsningen omrøres med 25 g silicagel i 0,5 time og filtreres gennem et sintret glasfilter. Silicagelen vaskes med et lille volumen methylenchlorid, og filtratet inddampes under formindsket tryk. Residualfaststoffet omkrystal-30 liseres ud fra isopropylether, hvilket giver 1,3 g rent produkt, smeltepunkt 96-98°C.Example 1 N-Methyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine carbothioamide Crude 3- [3- (trifluoromethyl) phenoxy] azetidine from catalytic debenzylation of 26.0 g (0.078 mol) 1 -benzhy-10-dry-3- [3- (trifluoromethyl) phenoxy] azetidine is dissolved in 100 ml of methylene chloride and a solution of 5.0 g (0.0678 mol) of methyl isothiocyanate in 15 ml of methylene chloride is added dropwise. The reaction mixture is stirred for 16 hours at ambient temperature and left for 15 a weekend. The solution is filtered through a Ce-lite filter pad to remove a fine crystalline precipitate and the filtrate is evaporated under reduced pressure. The residual oil is crystallized from isopropyl ether to give 12.6 g of product, mp 79-86 ° C. -20 ve of 5.0 g is recrystallized from isopropyl ether (charcoal) to give 3.2 g, mp 89-93 ° C which, by TLC on silica gel (10% methanol / toluene), is found to be contaminated by a material with Lower the Rf. The filtrate is evaporated under reduced pressure, combined with the -3.2 g of solid and dissolved in 100 ml of methylene chloride. The solution is stirred with 25 g of silica gel for 0.5 hour and filtered through a sintered glass filter. The residual solid is recrystallized from isopropyl ether to give 1.3 g of pure product, mp 96-98 ° C.
Analyse: Beregnet for C 49,65, H 4,51, N 9,65 Fundet: C 49,58, H 4,48, N 9,58 35Analysis: Calculated for C 49.65, H 4.51, N 9.65 Found: C 49.58, H 4.48, N 9.58
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16 DK 168422 B116 DK 168422 B1
Eksempel 2 N- (2,6-Dimethylphenyl)-3- [3- (trif luorme thyl) phenoxy] -1--azetidincarbothioamid Rå 3-[3-(trifluormethyl)phenoxy]azetidin fra 5 katalytisk debenzylering af 30,0 g (0,078 mol) 1-benzhy-dryl-3-[3-(trifluormethyl)phenoxy]azetidin opløses i 100 ml methylenchlorid, og der tildryppes under nitrogenatmosfære en opløsning af 12,7 g (0,078 mol) 2,6-di-methylphenylisothiocyanat i 25 ml methylenchlorid. Pro-10 duktet begynder at udfældes under tilsætningen, og- der tilsættes yderligere 50 ml methylenchlorid for atrlette omrøringen. Efter omrøring natten over ved omgivelsernes temperatur opsamles produktet ved filtrering (13,5 g, smeltepunkt 196-199°). En prøve på 6,0 g omkrystalli-15 seres fra isopropanol, hvilket giver 5,3 g produkt, smeltepunkt 197-199°C.Example 2 N- (2,6-Dimethylphenyl) -3- [3- (trifluoromethyl) phenoxy] -1 - azetidinecarbothioamide Crude 3- [3- (trifluoromethyl) phenoxy] azetidine from catalytic debenzylation of 30.0 g (0.078 mol) of 1-benzhydryl-3- [3- (trifluoromethyl) phenoxy] azetidine is dissolved in 100 ml of methylene chloride and a solution of 12.7 g (0.078 mol) of 2,6-dimethylphenyl isothiocyanate is added dropwise. in 25 ml of methylene chloride. The product begins to precipitate during the addition, and an additional 50 ml of methylene chloride is added to agitate the stirring. After stirring overnight at ambient temperature, the product is collected by filtration (13.5 g, mp 196-199 °). A sample of 6.0 g was recrystallized from isopropanol to give 5.3 g of product, mp 197-199 ° C.
Analyse: Beregnet for C^gH^F^NjOS: C 59,99, N 5,03, N 7,36.Analysis: Calculated for C ^ gH ^F₂N₂OS: C 59.99, N 5.03, N 7.36.
Fundet: C 60,04, H 5,04, N 7,35.Found: C, 60.04; H, 5.04; N, 7.35.
2020
Eksempel 3 N-(Phenylmethyl)-3-[3-(trifluorme thyl)phenoxy]-1-azeti-dincarboxamidExample 3 N- (Phenylmethyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
Til en omrørt og afkølet (10-20°C) oplosning 25 af 0,04 mol 3-[3-(trifluormethyl)phenoxy]azetidin i 100 ml methylenchlorid tildryppes 6,12 g (0,046 mol) benzyl-isocyanat. Reaktionsblandingen omrøres ved stuetemperatur i 2 timer og filtreres. Filterkagen vaskes med 2 x 50 ml petroleumether, 2 x 50 ral fortyndet vandigt natri-30 umbicarbonat og 2 x 50 ml vand, hvilket giver 12 g (86%). Omkrystallisation to gange . fra ethylacetat giver 9,0 g klare hvide flager, smeltepunkt 173,5-175°CTo a stirred and cooled (10-20 ° C) solution of 0.04 mole of 3- [3- (trifluoromethyl) phenoxy] azetidine in 100 ml of methylene chloride is added dropwise 6.12 g (0.046 mole) of benzyl isocyanate. The reaction mixture is stirred at room temperature for 2 hours and filtered. The filter cake is washed with 2 x 50 ml petroleum ether, 2 x 50 ml dilute aqueous sodium bicarbonate and 2 x 50 ml water to give 12 g (86%). Recrystallization twice. from ethyl acetate gives 9.0 g clear white flakes, mp 173.5-175 ° C
Analyse: Beregnet for ci8Hi7F3N2°2: C 61,71, H 4,89, N 8,00 35 Fundet: C 61,57, H 4,87, N 7,99.Analysis: Calculated for C18H17F3N2 ° 2: C 61.71, H 4.89, N 8.00 Found: C 61.57, H 4.87, N 7.99.
DK 168422 B1 17 O -DK 168422 B1 17 O -
Eksempel 4 N-(2 ,6-Dichlorphenyl)-3-[3-(trifluormethyl)phenoxy]-1--azetidincarbothioamidExample 4 N- (2,6-Dichlorophenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarbothioamide
En opløsning af 0,04 mol 3·1-[3-(trif luormethyl)-5 phenoxy]azetidin i 100 ml absolut ethanol omrøres i et bad af ledningsvand, medens der på én gang tilsættes 8,16 g (0,04 mol) 2,6-dichlorphenylisothiocyanat. Reaktionen er let eksotermisk, og efterhånden som isothiocyanatet begynder at opløses, begynder der udfældning af produkt.A solution of 0.04 mole of 3 · 1- [3- (trifluoromethyl) -5 phenoxy] azetidine in 100 ml of absolute ethanol is stirred in a bath of tap water, while adding at once 8.16 g (0.04 mol 2,6-dichlorophenyl isothiocyanate. The reaction is slightly exothermic and as the isothiocyanate begins to dissolve, product precipitation begins.
10 Efter omrøring i 45 minutter opvarmes reaktionsblandingen pa et dampbad for at sikre, at al isothiocyanatet_opløses, og efter afkøling giver filtrering 15,2 g hvidt krystallinsk produkt. En del (7,9 g) af dette materiale omkrystalliseres fra absolut ethanol, hvilket giver 4,3 g 15 rent krystallinsk pulver, smeltepunkt 196-197°C.After stirring for 45 minutes, the reaction mixture is heated on a steam bath to ensure that all the isothiocyanate is dissolved and after cooling, filtration gives 15.2 g of white crystalline product. A portion (7.9 g) of this material is recrystallized from absolute ethanol to give 4.3 g of pure crystalline powder, mp 196-197 ° C.
Analyse: Beregnet for C^H^FgC^i^OS: C 48,47, H 3,11, N 6,65.Analysis: Calculated for C ^H ^FgCl₂ OS: C, 48.47; H, 3.11; N, 6.65.
Fundet: C 48,40, H 3,07, N 6,54.Found: C, 48.40; H, 3.07; N, 6.54.
20 Eksempel 5 N- [ 3-(Diethylamino(propyl]-3-[3-(trifluormethyl)phenoxy]--1-azetidincarbothioamid-oxalat [1:1]Example 5 N- [3- (Diethylamino (propyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carbothioamide oxalate [1: 1]
En 0,0548 molær opløsning af 3-[3-(trifluor-methyl) phenoxy] azetidin omrøres ved 10°C, medens ..der til-25 sættes 10,66 g (0,0584 mol) 3-(diethylamino)propylisothio-cyanat på én gang. Efter omrøring natten over ved omgivelsernes temperatur inddampes reaktionsblandingen ved 50°C på en roterende fordamper til en tyk sirupsagtig remanens. Remanensen opløses i isopropanol og behandles 30 med 5,3 g oxalsyre, opvarmes på dampbad for at opløse syren, og ved afkøling udfældes et fast salt. Der tilsættes et lige så stort volumen isopropylether for at sikre fuldstænding fældning. Filtrering giver 26 g råprodukt. En del (13 g) omkrystalliseres fra isopro-35 panol/methanol/isopropylether = 100:50:50 (afkølet i køleskab), hvilket efter filtrering giver 7,5 g hvidt pro-A 0.0548 molar solution of 3- [3- (trifluoromethyl) phenoxy] azetidine is stirred at 10 ° C, while 10.66 g (0.0584 mol) of 3- (diethylamino) propyl isothio is added. -cyanate all at once. After stirring overnight at ambient temperature, the reaction mixture is evaporated at 50 ° C on a rotary evaporator to a thick syrupy residue. The residue is dissolved in isopropanol and treated with 5.3 g of oxalic acid, heated on a steam bath to dissolve the acid, and upon cooling a solid salt precipitates. An equal volume of isopropyl ether is added to ensure complete precipitation. Filtration gives 26 g of crude product. A portion (13 g) is recrystallized from isopropanol / methanol / isopropyl ether = 100: 50: 50 (cooled in a refrigerator) to give 7.5 g of white propylene after filtration.
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18 DK 168422 B1 dukt, smeltepunkt 155-157°C. Proton-NMR bekræfter, at dette er det forventede produkt.18 DK 168422 B1 cloth, mp 155-157 ° C. Proton NMR confirms that this is the expected product.
Analyse: Beregnet for C]_8H26F3N3®’^2H2°45 C 50,10, H 5,89, N 8,76.Analysis: Calculated for C 18 H 26 F 3 N 3 • 2H 2 ° C 45.10, H 5.89, N 8.76.
5 Fundet: C 50,02, H 5,97, N 8,89.Found: C, 50.02; H, 5.97; N, 8.89.
Eksempel 6 N- [3- (Dimethylamino) propyl] -3- [3- (tr if luorme thyl) phenoxy] --1-azetidincarbothioamid 10 En omrørt opløsning af 0,0584 mol 3-[3-C'triflu orme thyl) phenoxy Jazetidin ved 10°C behandles med.8,42 g (0,0584 mol) 3-(dimethylamino)propylisothiocyanat på én gang og omrøres ved omgivelsernes temperatur natten over. Reaktionsblandingen behandles med 5,3 g (0,0584 mol) oxal-15 syre og fortyndes med 200 ml isopropylether, hvilket kun giver 3,8 g produkt. Voluminet reduceres til 100 ml ved 50°C i vakuum og fortyndes med 500 ml isopropylether, hvilket giver yderligere 15,3 g produkt. Det kombinerede faste materiale opløses i isopropylalkohol, og efter af-20 køling dannes et fint bundfald (N ,N-dimethyl-l, 3-propan-diamin-oxalat), som fjernes ved filtrering. Produktet krystalliserer ikke; tilsætning af isopropylether giver kun en amorf gel. Efter i 3 uger at have forsøgt' at opnå et mere tilfredsstillende produkt omdannes reaktionsmate-25 rialet til den frie base og tages op i isopropylether. Etheropløsningen omrøres med 300 ml vand natten over for at fjerne diaminen. Produktet krystalliserer som den frie base ud fra den heterogene blanding og filtreres, hvilket giver 11,3 g fine beigefarvede krystaller. Gen-30 oparbejdning af filtratet giver yderligere 2,3 g produkt.Example 6 N- [3- (Dimethylamino) propyl] -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarbothioamide A stirred solution of 0.0584 mol of 3- [3-C'-trifluoromethyl ) phenoxy Jazetidine at 10 ° C is treated with 8.42 g (0.0584 mole) of 3- (dimethylamino) propyl isothiocyanate at one time and stirred at ambient temperature overnight. The reaction mixture is treated with 5.3 g (0.0584 mole) of oxalic acid and diluted with 200 ml of isopropyl ether to give only 3.8 g of product. The volume is reduced to 100 ml at 50 ° C in vacuo and diluted with 500 ml of isopropyl ether to give an additional 15.3 g of product. The combined solid is dissolved in isopropyl alcohol and after cooling, a fine precipitate (N, N-dimethyl-1,3-propane diamine oxalate) is formed which is removed by filtration. The product does not crystallize; addition of isopropyl ether gives only an amorphous gel. After trying for 3 weeks to obtain a more satisfactory product, the reaction material is converted to the free base and taken up in isopropyl ether. The ether solution is stirred with 300 ml of water overnight to remove the diamine. The product crystallizes as the free base from the heterogeneous mixture and filtered to give 11.3 g of fine beige crystals. Reconstitution of the filtrate gives an additional 2.3 g of product.
En portion på 8 g omkrystalliseres fra benzen/ligroin, hvilket giver 5,8 g meget fine beigefarvede krystaller, der tørres ved 82°C under vakuum, smeltepunkt 107-108°C.A portion of 8 g is recrystallized from benzene / ligroin to give 5.8 g of very fine beige crystals which are dried at 82 ° C under vacuum, mp 107-108 ° C.
Analyse: Beregnet for c;l6H22F3N3OS: 35 C 53,17, H 6,14, N 11,63.Analysis: Calculated for C 16 H 22 F 3 N 3 OS: 35 C 53.17, H 6.14, N 11.63.
Fundet: C 53,29, H 6,15, N 11,60.Found: C, 53.29; H, 6.15; N, 11.60.
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19 DK 168422 B119 DK 168422 B1
Eksempel 7 N- (2-Propenyl) -3- [ 3- (trif luormethyl) phenoxy] -1-azetidin-carboxamidExample 7 N- (2-Propenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En opløsning af 18,9 g (0,05 mol) rå 3-[3-(tri-5 fluormethyl)phenoxy]azetidin (indeholder en lige så stor molær mængde diphenylmethan) i 100 ml isopropylether omrøres under nitrogen, meden der langsomt tilsættes 4,16 g (0,05 mol) 2-propenylisocyanat. Reaktionsblandingen, der er noget uklar, klares, og efter en times forløb be-10 gynder der at dannes et fint krystallinsk bundfald. Efter omrøring i 18 timer fjernes produktet ved filtrering, vaskes med frisk isopropylether og lufttørres, hvilket giver 9,5 g hvide krystaller, smeltepunkt 75-76°C.A solution of 18.9 g (0.05 mole) of crude 3- [3- (trifluoromethyl) phenoxy] azetidine (containing an equal molar amount of diphenylmethane) in 100 ml of isopropyl ether is stirred under nitrogen while slowly adding 4.16 g (0.05 mole) of 2-propenyl isocyanate. The reaction mixture, which is somewhat cloudy, is clarified, and after an hour, a fine crystalline precipitate begins to form. After stirring for 18 hours, the product is removed by filtration, washed with fresh isopropyl ether and air dried to give 9.5 g of white crystals, mp 75-76 ° C.
Analyse: Beregnet for ci4Hi5F3N2°2: 15 C 56,00, H 5,04, N 9,33.Analysis: Calculated for C 14 H 15 F 3 N 2 O 2: C 56.00, H 5.04, N 9.33.
Fundet: C 55,98, H 5,05, N 9,31.Found: C, 55.98; H, 5.05; N, 9.31.
Eksempel 8 N-Cyclopropy1-3-[3-(trifluormethyl) phenoxy]-1-azetidin-20 carboxamidExample 8 N-Cyclopropyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine-carboxamide
En blanding af 1,9 g (0,033 mol) cyclopropyl-amin og 4,9 g 1,1'-carbonyldiimidazol i 60 ml tetrahy-drofuran omrøres ved omgivelsernes temperatur i en time.A mixture of 1.9 g (0.033 mol) of cyclopropylamine and 4.9 g of 1,1'-carbonyldiimidazole in 60 ml of tetrahydrofuran is stirred at ambient temperature for one hour.
Den klare opløsning, der dannes, behandles med en opløs-25 ning af (0,03 mol) 3-[3-(trifluormethyl)phenoxy]azetidin i 20 ml tetrahydrofuran. Efter omrøring natten over fjernes det faste bundfald ved filtrering, hvilket giver 4,4 g gråhvidt pulver. CI-Massespektret viser en p+1 ved 381 m/e, hvilket svarer til det forventede pro-30 dukt. Omkrystallisation fra benzen/ligroin giver 2,3 g lysegråt pulver, smeltepunkt 152-153°C.The clear solution formed is treated with a solution of (0.03 mole) of 3- [3- (trifluoromethyl) phenoxy] azetidine in 20 ml of tetrahydrofuran. After stirring overnight, the solid precipitate is removed by filtration to give 4.4 g of greyish white powder. The CI mass spectrum shows a p + 1 at 381 m / e, which corresponds to the expected product. Recrystallization from benzene / ligroin gives 2.3 g of light gray powder, mp 152-153 ° C.
Analyse: Beregnet for ci4Hi5F3N20: C 56,00, H 5,04, N 9,33.Analysis: Calculated for C 14 H 15 F 3 N 2 O: C 56.00, H 5.04, N 9.33.
Fundet: C 55,97, H 5,07, N 9,28.Found: C, 55.97; H, 5.07; N, 9.28.
35 DK 168422 B1 20 o35 DK 168422 B1 20 o
Eksempel 9 N-[3-(Diethylamino)propyl]-3-[3-(trifluormethyl)phenoxy]--1-azetidincarboxamid-oxalat [2:3]Example 9 N- [3- (Diethylamino) propyl] -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide oxalate [2: 3]
En blanding af 4,3 g (0,033 mol) 3-diethylami-S nopropylamin og 4,9 g (0,033 mol) 1,1'-carbonyldiimidazol i 60 ml methylenchlorid omrøres ved omgivelsernes temperatur i en time. Den opnåede opløsning behandles med 3--[3-(trifluormethyl)phenoxy]azetidin (opnået ud fra 9,21 g (0,03 mol) af oxalatsaltet) i 30 ml methylenchlorid.A mixture of 4.3 g (0.033 mol) of 3-diethylamino-S nopropylamine and 4.9 g (0.033 mol) of 1,1'-carbonyldiimidazole in 60 ml of methylene chloride is stirred at ambient temperature for one hour. The obtained solution is treated with 3- [3- (trifluoromethyl) phenoxy] azetidine (obtained from 9.21 g (0.03 mol) of the oxalate salt) in 30 ml of methylene chloride.
10 Efter omrøring i 18 timer overføres reaktionsblandingen til en skilletragt og vaskes med 3 x 20 ml vand, jtørres over magnesiumsulfat og inddampes i vakuum til en mørk olie. Remanensen (8 g) chromatograferes på en 150 g neutral aluminiumoxidkolonne, idet der elueres med chloroform.After stirring for 18 hours, transfer the reaction mixture to a separatory funnel and wash with 3 x 20 ml of water, dry over magnesium sulfate and evaporate in vacuo to a dark oil. The residue (8 g) is chromatographed on a 150 g neutral alumina column eluting with chloroform.
15 Koncentration af begyndelsesfraktionen giver produktet som en ravfarvet olie, som opløses i methylisobutylketon og behandles med 2 g oxalsyre. Fortynding med isopropyl-ether giver en olie, der størkner og omkrystalliseres ud fra acetone/isopropylether, hvilket giver 6,25 g (41%) 20 beigefarvede krystaller, smeltepunkt 91-93°C.Concentration of the starting fraction gives the product as an amber oil which is dissolved in methyl isobutyl ketone and treated with 2 g of oxalic acid. Dilution with isopropyl ether gives an oil which solidifies and recrystallizes from acetone / isopropyl ether to give 6.25 g (41%) of 20 beige crystals, mp 91-93 ° C.
Analyse: Beregnet for C^gH^F^NgC^.l/SAnalysis: Calculated for C ^ gH ^F ^NgC ^.1 / S
C 49,61, H 5,75, N 8,26.C 49.61, H 5.75, N 8.26.
Fundet: C 49,56, H 5,73, N 8,24.Found: C 49.56, H 5.73, N 8.24.
25 Eksempel 10 N-2-(Propenyl)-3-[4-(trifluormethyl)phenoxy]-1-azetidin-carboxamidExample 10 N-2- (Propenyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En opløsning af 8,7 g (0,04 mol) rå 3-[4-(tri-fluormethyl)phenoxy]azetidin i 75 ml isopropylether om-30 røres under et nitrogentæppe, medens der tildryppes 4,2 g (0,05 mol) 2-propenylisocyanat. Efter omrøring i 3 dage udfældes der intet krystallinsk produkt. Reaktionsblandingen inddampes til en mørkerødlig olie. TLC (20% ethylacetat/methylenchlorid på silicagel) viser mindst 35 6 pletter, alle godt adskilt. Remanensen opløses i chlo roform, chromatograferes på en 350 g silicagelkolonne ogA solution of 8.7 g (0.04 mol) of crude 3- [4- (trifluoromethyl) phenoxy] azetidine in 75 ml of isopropyl ether is stirred under a nitrogen blanket while dropping 4.2 g (0.05 mole) 2-propenyl isocyanate. After stirring for 3 days, no crystalline product precipitates. The reaction mixture is evaporated to a dark red oil. TLC (20% ethyl acetate / methylene chloride on silica gel) shows at least 35 6 spots, all well separated. The residue is dissolved in chloroform, chromatographed on a 350 g silica gel column and
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21 DK 168422 B1 elueres med chloroform, indtil den rødlige forløb er fjernet. Kolonnen elueres derpå med en ethylacetat/chlo-roform-gradient til 4% ethylacetat. Alle fraktionerne kombineres og inddampes, hvilket giver 4,8 g orangefar-5 vet olie, der krystalliserer ved henstand. Omkrystallisation fra acetone/cyclohexan giver 3,3 g (27,5%) beigefarvede krystaller, smeltepunkt 91-92,5°C.B1 is eluted with chloroform until the reddish course is removed. The column is then eluted with an ethyl acetate / chloroform gradient to 4% ethyl acetate. All the fractions are combined and evaporated to give 4.8 g of orange-colored oil which crystallizes on standing. Recrystallization from acetone / cyclohexane gives 3.3 g (27.5%) of beige crystals, mp 91-92.5 ° C.
Analyse: Beregnet for : C 56,00, H 5,04, N 9,33.Analysis: Calculated for: C 56.00, H 5.04, N 9.33.
10 Fundet: C 55,98, H 5,17, N 9,36.Found: C, 55.98; H, 5.17; N, 9.36.
Eksempel 11 N- (Cyclopropylmethyl)-3-[3- (trifluormethyl)phenoxy]-1- : -azetidlncarboxamid 15 En opløsning af 2,6 g (0,024 mol) (aminomethyl)- cyclpropan-hydrochlorid i 50 ml pyridin omrøres under nitrogentæppe, medens der tilsættes 3,9 g (0,024 mol) 1,1'-carbonyldiimidazol. Efter omrøring i 45 minutter viser TLC (5% methanol/methylenchlorid på silicagel) in-20 gen reaktion; derfor tilsættes 2 ml triethylamin. Reaktionsblandingen bliver efter 10 minutters forløb uklar, og TLC viser et nyt produkt. Reaktionen behandles med 6,2 g (0,02 mol) 3-[3- (trifluormethyl)phenoxy]azetidin--oxalat. Efter omrøring i en time udtages en prøve, og 25 efter fortynding med vand udfældes et faststof. CI-Mas-sespektret viser, at det var produktet. Efter 2 dage fortyndes reaktionen med 5 volumendele vand, og det opnåede bundfald opsamles ved filtrering, hvilket giver 6,5 g bleggult krystallinsk produkt. Omkrystallisation 30 fra * ethanol/vand giver hvide pladelignende krystaller, som tørres ved 82°C i 3 timer i en tørrepistol under vakuum; produktets vægt er 5,8 g (92%) , smeltepunkt 132-133°C.Example 11 N- (Cyclopropylmethyl) -3- [3- (trifluoromethyl) phenoxy] -1-: -acetidine carboxamide A solution of 2.6 g (0.024 mol) (aminomethyl) cyclpropane hydrochloride in 50 ml of pyridine is stirred under nitrogen blanket , while adding 3.9 g (0.024 mol) of 1,1'-carbonyl diimidazole. After stirring for 45 minutes, TLC (5% methanol / methylene chloride on silica gel) shows in-reaction; therefore, 2 ml of triethylamine is added. The reaction mixture becomes cloudy after 10 minutes and TLC shows a new product. The reaction is treated with 6.2 g (0.02 mol) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate. After stirring for one hour, a sample is taken and 25, after dilution with water, a solid precipitates. The CI-Mas spectrum shows that it was the product. After 2 days, the reaction is diluted with 5 parts by volume of water and the precipitate obtained is collected by filtration to give 6.5 g of pale yellow crystalline product. Recrystallization from ethanol / water gives white plate-like crystals which are dried at 82 ° C for 3 hours in a drying gun under vacuum; the product weight is 5.8 g (92%), mp 132-133 ° C.
Analyse: Beregnet for Ci5Hi7F3N2^2: 35 C 57,32, H 5,45, N 8,91.Analysis: Calculated for C 15 H 17 F 3 N 2 2: 35 C 57.32, H 5.45, N 8.91.
Fundet: C 57,22, H 5,44, N 8,86.Found: C 57.22, H 5.44, N 8.86.
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22 DK 168422 B122 DK 168422 B1
Eksempel 12 N,N-Diethyl-3- [ 3- (trif luorme thyl) phenoxy] -1-azetidin--carboxamidExample 12 N, N-Diethyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine - carboxamide
En omrørt opslæmning af 5 g (0,0163 mol) 3-[3-5 -(trifluormethyl)phenoxyazetidinoxalat i 50 ml tetrahy- drofuran behandles med 5 ml triethylamin, og efter en times forløb tilsættes 2,5 g (0,018 mol) diethylcarbamo-ylchlorid. Efter omrøring i yderligere 15 timer behandles reaktionen med 10 ml vand og mættes med calciumchlo- 10 rid. Tetrahydrofuranen dekanteres fra den faste remanens og inddampes i vakuum til en olie. Den rå olie chromato-graferes på "Water's Prep-LC", idet der anvendes 50% ethylacetat/toluen som elueringsmiddel. Efter inddamp-ning af hovedfraktionerne fås 3,1 g (60,1%) bleggul olie.A stirred slurry of 5 g (0.0163 mol) of 3- [3-5 - (trifluoromethyl) phenoxyazetidine oxalate in 50 ml of tetrahydrofuran is treated with 5 ml of triethylamine and after one hour 2.5 g (0.018 mol) of diethylcarbamo is added. -ylchlorid. After stirring for an additional 15 hours, the reaction is treated with 10 ml of water and saturated with calcium chloride. The tetrahydrofuran is decanted from the solid residue and evaporated in vacuo to an oil. The crude oil is chromatographed on "Water's Prep-LC" using 50% ethyl acetate / toluene as the eluent. After evaporation of the main fractions, 3.1 g (60.1%) of pale yellow oil is obtained.
15 Analyse: Beregnet for ci5H19F3N2°2: C 56,96, H 6,05, N 8,86.Analysis: Calculated for C 15 H 19 F 3 N 2 O 2: C 56.96, H 6.05, N 8.86.
Fundet: C 65,69, H 6,01, N 8,77.Found: C 65.69, H 6.01, N 8.77.
Eksempel 13 20 N,N-Dimethyl-3-[3-(trifluormethyl)phenoxy]-1-azetidin- carboxamidExample 13 N, N-Dimethyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En omrørt opslæmning af 5 g (0,0163 mol) 3-[3--(trifluormethyl)phenoxy]azetidin-oxalat i 50 ml'tetra-hydrofuran behandles med 5 ml triethylamin, og efter en 25 times forløb tilsættes 1,95 g (0,018 jol) dimethylcarba-moylchlorid. Efter omrøring i yderligere 15 timer behandles reaktionsblandingen med 20 ml vand og 10 g cal-ciumchlorid. Tetrahydrofuranlaget dekanteres, og remanensen udrives med 20 ml ethylacetat og dekanteres så.A stirred slurry of 5 g (0.0163 mole) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate in 50 ml of tetrahydrofuran is treated with 5 ml of triethylamine and after 25 hours, 1.95 g is added. (0.018 µl) dimethylcarbamoyl chloride. After stirring for an additional 15 hours, the reaction mixture is treated with 20 ml of water and 10 g of calcium chloride. The tetrahydrofuran layer is decanted and the residue is triturated with 20 ml of ethyl acetate and then decanted.
30 Den kombinerede tetrahydrofuran- og ethylacetatopløsning inddampes i vakuum. Den rå remanens chromatograferes på "Water's Prep-LC", idet der som elueringsmiddel anvendes 50% ethylacetat/toluen. Efter inddampning af hovedfraktionerne fås 3,6 g (76,6%) bleggul olie.The combined tetrahydrofuran and ethyl acetate solution is evaporated in vacuo. The crude residue is chromatographed on "Water's Prep-LC" using 50% ethyl acetate / toluene as the eluent. After evaporation of the main fractions 3.6 g (76.6%) of pale yellow oil is obtained.
35 Analyse: Beregnet for C-^gH^j-Fg^Og: C 54,17, H 5,25, N 9,72.Analysis: Calculated for C- gHH ^-Fg ^ And: C 54.17, H 5.25, N 9.72.
Fundet: C 53,73, H 5,20, N 9,60.Found: C, 53.73; H, 5.20; N, 9.60.
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23 DK 168422 B123 DK 168422 B1
Eksempel 14 N-(2-Propynyl)-3-[3-(trifluormethyl)phenoxy]-1-azetidin-carboxamidExample 14 N- (2-Propynyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En blanding af 3,9 g (0,024 mol) 1,1'-carbonyl-5 diimidazol og 1,32 g (0,024 mol) 2-propynylamin i 50 ml tetrahydrofuran omrøres ved omgivelsernes temperatur i en time og behandles derpå med 6,2 g 3-[3-(trifluormethyl)-phenoxy]azetidin. Reaktionsblandingen behandles med 3 ml triethylamin og omrøres i 18 timer. Reaktionsblandin-10 gen fortyndes med et lige så stort volumen vand og filtreres, hvilket giver 8 g vådt produkt. Omkrystallisation ud fra isopropylether giver 3,8 g gråt faststof, en blanding af produkt og det symmetriske urinstof af ud-gangs-2-propynylaminen. Endnu en omkrystallisation 15 fra ethanol/vand giver 2,6 g (43,6%) råprodukt, smeltepunkt 105-106°C.A mixture of 3.9 g (0.024 mol) of 1,1'-carbonyl-5-diimidazole and 1.32 g (0.024 mol) of 2-propynylamine in 50 ml of tetrahydrofuran is stirred at ambient temperature for one hour and then treated with 6.2 g 3- [3- (trifluoromethyl) phenoxy] azetidine. The reaction mixture is treated with 3 ml of triethylamine and stirred for 18 hours. The reaction mixture is diluted with an equal volume of water and filtered to give 8 g of wet product. Recrystallization from isopropyl ether gives 3.8 g of gray solid, a mixture of product and the symmetrical urea of the starting 2-propynylamine. Another recrystallization from ethanol / water gives 2.6 g (43.6%) of crude product, mp 105-106 ° C.
Analyse: Beregnet for C,.H,~F~N,,09: C 56,38, H 4,39, N 9,39.Analysis: Calculated for C ,HH, ~F ~N₂O: C 56.38, H 4.39, N 9.39.
Fundet: C 56,32, H 4,34, N 9,44.Found: C 56.32, H 4.34, N 9.44.
2020
Eksempel 15 N-Cyclohexyl-3~ [ 3- (trif luorme thyl) phenoxy] -1-azetidin-carboxamidExample 15 N-Cyclohexyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En omrørt blanding af 5 g (0,0163 mol)- 3-[3-25 -(trifluormethyl)phenoxy]azetidin-oxalat og 2,04 g (0,018 mol) cyclohexylisocyanat i 50 ml tetrahydrofuran behandles med 2 ml triethylamin og omrøres derpå i 18 timer. Fortynding af blandingen med vand giver et fast bundfald, som opsamles ved filtrering, hvilket giver 12 30 g råprodukt. Omkrystallisation fra acetone/vand giver 5 g fine hvide krystaller, smeltepunkt 148-150°C.A stirred mixture of 5 g (0.0163 mole) of 3- [3-25 - (trifluoromethyl) phenoxy] azetidine oxalate and 2.04 g (0.018 mole) of cyclohexyl isocyanate in 50 ml of tetrahydrofuran is treated with 2 ml of triethylamine and then stirred. for 18 hours. Dilution of the mixture with water gives a solid precipitate which is collected by filtration to give 12 30 g of crude product. Recrystallization from acetone / water gives 5 g of fine white crystals, mp 148-150 ° C.
TLC (ethylacetat på silicagel) viser spor af symmetrisk cyclohexylurinstof samt produktet. Endnu en omkrystallisation fra isopropanol giver 1,65 g (29,6%) hvidt 35 pulver, der tørres under 0,5 mm Hg-vakuum, smeltepunkt 153-154°C.TLC (ethyl acetate on silica gel) shows traces of symmetrical cyclohexylurea as well as the product. Another recrystallization from isopropanol gives 1.65 g (29.6%) of white powder, dried under 0.5 mm Hg vacuum, mp 153-154 ° C.
24 DK 168422 B124 DK 168422 B1
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Analyse: Beregnet for C^7H21F3N2^2: C 59,64, H 6,18, N 8,18.Analysis: Calculated for C 17 H 21 F 3 N 2 2: C 59.64, H 6.18, N 8.18.
Fundet: C 59,52, H 6,20, N 8,17.Found: C 59.52, H 6.20, N 8.17.
5 Eksempel 16 N-Cyclopropyl-3-[4-(trifluormethyl)phenoxy]-1-azetidin-carboxamidExample 16 N-Cyclopropyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En omrørt opslæmning af 4,4 g (0,027 mol) 1,1’--carbonyldiimidazol i 50 ml methylenchlorid under nitro-10 gen behandles med 1,54 g (0,027 mol) cyclopropylamin.A stirred slurry of 4.4 g (0.027 mol) of 1,1 '- carbonyl diimidazole in 50 ml of methylene chloride under nitrogen is treated with 1.54 g (0.027 mol) of cyclopropylamine.
Efter en kort (2 min.) induktionsperiode bliver den klare opløsning pludselig eksotermisk, idet reaktionen bringes til mild tilbagesvaling. Efter 1 time, når reaktionsblandingen er afkølet til omgivelsernes temperatur, 15 tilsættes på én gang 9,6 g (0,025 mol) 3-[4-(trifluormethyl) phenoxy Jazetidin, 56,66% renhed (indeholder diphe-nylmethan), og omrøringen fortsættes i 18 timer. Reaktionsblandingen inddampes på en roterende fordamper, hvilket giver en delvis krystallinsk remanens. Remanensen 20 deles mellem 30/60 pertoleumether og vand, og det opnåede voksagtige faststof fjernes ved filtrering. Omkrystallisation ud fra isopropylether giver 5,7 g (75,9%) pladelignende sølvagtige krystaller, smeltepunkt 145-147°C.After a short (2 min) induction period, the clear solution suddenly becomes exothermic, bringing the reaction to gentle reflux. After 1 hour, when the reaction mixture is cooled to ambient temperature, 9.6 g (0.025 mol) of 3- [4- (trifluoromethyl) phenoxy] Jazetidine, 56.66% purity (containing diphenylmethane), is added at once. continued for 18 hours. The reaction mixture is evaporated on a rotary evaporator to give a partially crystalline residue. The residue 20 is partitioned between 30/60 pertoleum ether and water and the obtained waxy solid is removed by filtration. Recrystallization from isopropyl ether gives 5.7 g (75.9%) of plate-like silvery crystals, mp 145-147 ° C.
Efter tørring ved 80°C under 0,5 mm Hg-vakuum formind-25 skes vægten ikke, smeltepunkt 152-153°C.After drying at 80 ° C under 0.5 mm Hg vacuum, the weight does not decrease, mp 152-153 ° C.
Analyse: Beregnet for cx4Hi5F3N2°25 C 56,00, H 5,04, N 9,33.Analysis: Calculated for cx4H15F3N2 ° C 56.00, H 5.04, N 9.33.
Fundet: C 55,77, H 4,98, N 9,44.Found: C, 55.77; H, 4.98; N, 9.44.
30 Eksempel 17 N-(Cyclopropylmethyl)-3-[4-(trifluormethyl)phenoxy] -1--azetidincarboxamidExample 17 N- (Cyclopropylmethyl) -3- [4- (trifluoromethyl) phenoxy] -1 - azetidinecarboxamide
Til en omrørt blanding af 4,4 g (0,027 mol) 1,1'--carbonyldiimidazol og 2,9 g (0,027 mol) (aminoethyl)cy-35 clopropan-hydrochlorid i 50 ml methylenchlorid tildryp- pes 2,73 g (0,027 mol) triethylamin. Reaktionen er ekso-To a stirred mixture of 4.4 g (0.027 mol) of 1,1 '- carbonyl diimidazole and 2.9 g (0.027 mol) of (aminoethyl) cyclopropane hydrochloride in 50 ml of methylene chloride is added dropwise 2.73 g ( 0.027 mol) of triethylamine. The reaction is exo-
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25 DK 168422 B1 termisk. Blandingen afkøles under omrøring i en time, derpå tilsættes på én gang 9,6 g (0,025 mol) 3-[4-(tri-fluormethyl)phenoxy]azetidin 56,66% (indeholder diphen-ylmethan), og omrøringen fortsættes i 18 timer. Reak-5 tionsblandingen inddampes på en roterende fordamper, hvilket giver en ravfarvet remanens. Udrivning af denne remanens med 30/60 petroleumether giver kun en uopløselig olie. Udrivningstrinnet gentages med 2 x 20 ml 30/60 petroleumether, og remanensen behandles med vand, hvilket 10 giver et hvidt faststof. Faststoffet omkrystalliseres fra isopropylether, hvilket giver 4,8 g (61,8%j hvi de pladelignende krystaller; efter tørring ved 80°C uner 0,5 mm Hg-vakuum, smeltepunkt 132-133°C.25 DK 168422 B1 thermal. The mixture is cooled with stirring for one hour then 9.6 g (0.025 mol) of 3- [4- (trifluoromethyl) phenoxy] azetidine is added at 56.66% (containing diphenylmethane) and stirring is continued for 18 minutes. hours. The reaction mixture is evaporated on a rotary evaporator to give an amber residue. Extraction of this residue with 30/60 petroleum ether gives only an insoluble oil. The rubbing step is repeated with 2 x 20 ml of 30/60 petroleum ether and the residue is treated with water to give a white solid. The solid is recrystallized from isopropyl ether to give 4.8 g (61.8%) of the plate-like crystals; after drying at 80 ° C under 0.5 mm Hg vacuum, mp 132-133 ° C.
Analyse: Beregnet for ci5Hi7F3N2°2: 15 C 57,32, H 5,45, N 8,91.Analysis: Calculated for c15 H17 F3 N2 ° 2: C 57.32, H 5.45, N 8.91.
. Fundet: C 57,26, H 5,46, N 8,93.. Found: C 57.26, H 5.46, N 8.93.
Eksempel 18 N-[3-(Diethylamino)propyl]-3-[4-(trifluormethyl)phenoxy]-20 -1-azetidincarbothioamidExample 18 N- [3- (Diethylamino) propyl] -3- [4- (trifluoromethyl) phenoxy] -20 -1-azetidinecarbothioamide
En omrørt opløsning af 1,92 g (0,005 mol) 3-[4--(trifluormethyl)phenoxy]azetidin, 56,66% (indeholder di-phenylkethan) i 20 ml isopropylether behandles med 0,88 g (0,005 mol) 3-(diethylamino)propylisothiocyanat og omrø-25 res i 3,5 timer. Reaktionsblandingen behandles med 0,5 g oxalsyre opløst i 2 ml methanol. Efter omrøring i 18 timer opsamles faststoffet ved filtrering, hvilket giver 1,9 g fint gyldenbrunt pulver, smeltepunkt 147-150°C. Faststoffet opløses i vand og behandles med fortyndet na-30 triumhydroxid. Der fraskilles en olie, der størkner og opsamles ved filtrering. Omkrystallisation fra cyclo-hexan giver 1,1 g (56,5%) fine gyldentbrune krystaller, smeltepunkt 109-110°C.A stirred solution of 1.92 g (0.005 mole) of 3- [4- (trifluoromethyl) phenoxy] azetidine, 56.66% (containing diphenyl kethane) in 20 ml of isopropyl ether is treated with 0.88 g (0.005 mole) of 3 - (diethylamino) propyl isothiocyanate and stirred for 3.5 hours. The reaction mixture is treated with 0.5 g of oxalic acid dissolved in 2 ml of methanol. After stirring for 18 hours, the solid is collected by filtration to give 1.9 g of fine golden brown powder, mp 147-150 ° C. The solid is dissolved in water and treated with dilute sodium hydroxide. An oil is separated which solidifies and is collected by filtration. Recrystallization from cyclohexane gives 1.1 g (56.5%) of fine golden-brown crystals, mp 109-110 ° C.
Analyse: Beregnet for C^g^gF^N^OS: 35 c 55,51, H 6,73, N 10,79.Analysis: Calculated for C ^ g ^FFN NO: 35 c 55.51, H 6.73, N 10.79.
Fundet: C 55,68, H 6,67, N 10,73.Found: C 55.68, H 6.67, N 10.73.
26 DK 168422 B126 DK 168422 B1
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Eksempel 19 N-[3-(Diethylamino)propyl]-3-[4-(trifluormethyl)phenoxy]--1-azetidincarboxamid-oxalat [1:2]Example 19 N- [3- (Diethylamino) propyl] -3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide oxalate [1: 2]
Til en omrørt opløsning af 4,4 g (0,027 mol) 1,1'-5 -carbonyldiimidazol i 50 ml methylenchlorid under nitrogen tildryppes 3,52 g (0,027 mol) 3-(diethylamino)propylamin. Reaktionsblandingen omrøres i en time, hvorefter den noget eksotermiske reaktion afkøles til omgivelsernes temperatur og derpå på én gang behandles med 9,6 g (0,025 10 mol) 3-[4-(trifluormethyl)phenoxy]azetidin, 56,66% (indeholder diphenylmethan). Efter omrøring i 18 timer inddampes reaktionsblandingen på en roterende fordamper, og remanensen opløses i toluen. Toluenopløsningen vaskes med 3 x 20 ml vand, behandles derpå med 2,5 g oxalsyre i 10 ml 15 isopropanol. Det opnåede faststof opsamles ved filtrering og udrives med kogende acetone. Efter filtrering dannes 1,8 g uidentificeret fint hvidt bundfald, som fraskilles ved filtrering. Acetoneopløsningen inddampes til et faststof, som omkrystalliseres fra isopropylalkohol/iso-20 propylether, hvilket giver 9,2 g råprodukt (4 pletter på TLC, 10% methanol/methylenchlorid på silicagel). Omkrystallisation ira methylethylketon giver 6,8 g (49,1%) fiiit hvidt pulver, smeltepunkt 129-130°C.To a stirred solution of 4.4 g (0.027 mol) of 1,1'-5-carbonyldiimidazole in 50 ml of methylene chloride under nitrogen is added 3.52 g (0.027 mol) of 3- (diethylamino) propylamine. The reaction mixture is stirred for one hour, after which the somewhat exothermic reaction is cooled to ambient temperature and then treated at one time with 9.6 g (0.025 mole) of 3- [4- (trifluoromethyl) phenoxy] azetidine, 56.66% (contains diphenylmethane ). After stirring for 18 hours, the reaction mixture is evaporated on a rotary evaporator and the residue is dissolved in toluene. The toluene solution is washed with 3 x 20 ml of water, then treated with 2.5 g of oxalic acid in 10 ml of isopropanol. The solid obtained is collected by filtration and triturated with boiling acetone. After filtration, 1.8 g of unidentified fine white precipitate is formed, which is separated by filtration. The acetone solution is evaporated to a solid which is recrystallized from isopropyl alcohol / isopropyl ether to give 9.2 g of crude product (4 spots on TLC, 10% methanol / methylene chloride on silica gel). Recrystallization from methyl ethyl ketone gives 6.8 g (49.1%) of white powder, mp 129-130 ° C.
Analyse; Beregnet for cigH26F3N3°2.202^0^: 25 C 47,74, H 5,46, N 7,59.Analysis; Calcd for cigH26F3N3 ° 2.202 ° C: 25 C 47.74, H 5.46, N 7.59.
Fundet; C 47,82, H 5,68, N 7,76.found; C 47.82, H 5.68, N 7.76.
Eksempel 20 N-(2-Propynyl)-3-[4-(trifluormethyl)phenoxy]-1-azetidin-30 carboxamidExample 20 N- (2-Propynyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En opløsning af 4,4 g (0,027 mol) 1,1'-carbonyldiimidazol i 50 ml tetrahydrofuran omrøres under nitrogen, medens der tilsættes 1,49 g (0,027 mol) 2-propynyl-amin med en sprøjte og nål gennem en væg monteret i den 35 ene hals på reaktionskolben. Efter omrøring i 2 timer tilsættes på én gang 9,6 g (0,025 mol) 3-[4-(trifluorme-A solution of 4.4 g (0.027 mol) of 1,1'-carbonyl diimidazole in 50 ml of tetrahydrofuran is stirred under nitrogen while adding 1.49 g (0.027 mol) of 2-propynylamine with a syringe and needle mounted through a wall. in the one neck of the reaction flask. After stirring for 2 hours, 9.6 g (0.025 mol) of 3- [4- (trifluoromethyl)
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27 DK 168422 B1 thyl)phenoxy]azetidin (56,66% renhed, indeholder diphenyl-methan), og omrøringen fortsættes i yderligere 18 timer. Reaktionsblandingen fortyndes med isvand og ekstraheres med 30/60 petroleumether for at fjerne diphenylmethanen.B (thyl) phenoxy] azetidine (56.66% purity, containing diphenylmethane) and stirring is continued for an additional 18 hours. The reaction mixture is diluted with ice water and extracted with 30/60 petroleum ether to remove the diphenylmethane.
5 Den olieagtige vandige del ekstraheres med 4 x 50 ml me-thylenchlorid. Disse ekstrakter kombineres, tørres over natriumsulfat og inddampes til en ravfarvet olie på en roterende fordamper. Olien størkner, når den udrives med en lille mængde (50 ml) isopropylether. Filtrering giver 10 6,1 g rosafarvet fast produkt. TLC (10% methanol/methyl- enchlorid på silicagel) viser en blanding af 3 produkter og noget udgangsmateriale. Omkrystallisation fra e- 4 thanol/vand giver produktet i flere små fraktioner. Disse kombineres og omkrystalliseres fra isopropylether, 15 hvilket giver 4,1 g blegt beigefarvet pulver, smeltepunkt 135-137°C. TLC viser stadig noget symmetrisk 2-propynyl-urinstof. Faststoffet omkrystalliseres igen fra ethan-ol/vand, hvilket giver 3,5 g (46,9%) bleggult krystallinsk produkt, smeltepunkt 140-141°C.The oily aqueous portion is extracted with 4 x 50 ml of methylene chloride. These extracts are combined, dried over sodium sulfate and evaporated to an amber oil on a rotary evaporator. The oil solidifies when applied with a small amount (50 ml) of isopropyl ether. Filtration gives 10 6.1 g of rose-colored solid product. TLC (10% methanol / methylene chloride on silica gel) shows a mixture of 3 products and some starting material. Recrystallization from e-4 thanol / water gives the product in several small fractions. These are combined and recrystallized from isopropyl ether to give 4.1 g of pale beige powder, mp 135-137 ° C. TLC still shows some symmetrical 2-propynyl urea. The solid is recrystallized from ethanol / water to give 3.5 g (46.9%) of pale yellow crystalline product, mp 140-141 ° C.
20 Analyse: Beregnet for ci4Hi5F3N2°2: C 56,38, H 4,39, N 9,39.Calcd. For C 14 H 15 F 3 N 2 O 2: C 56.38, H 4.39, N 9.39.
Fundet: C 56,34, H 4,36, N 9,32.Found: C 56.34, H 4.36, N 9.32.
Eksempel 21 25 N- (2-Methyl-2-propenyl) -3- [4- (trif luormethyl) phenoxy] -1- -azetidincarboxamidExample 21 N- (2-Methyl-2-propenyl) -3- [4- (trifluoromethyl) phenoxy] -1- -azetidine carboxamide
En omrørt opløsning af 3,6 g (0,022 mol) 1,1'--carbonyldiimidazol i 75 ml methylenchlorid under nitrogen behandles med 1,6 g (0,022 mol) 2-methyl-2-propenyl-30 amin (tilsættes via sprøjte og nål gennem en væg anbragt i reaktionskolbens ene hals) . Efter omrøring i en time tilsættes på én gang 6,2 g (0,02 mol) 3-[4-(trifluormethyl) phenoxy] azetidin-oxalat efterfulgt i løbet af 30 minutter af 5 ml triethylamin, og omrøringen fortsættes i 35 3 timer. Reaktionsblandingen vaskes med 2 x 25 ml vand, tørres over magnesiumsulfat og inddampes i vakuum. Den DK 168422 BlA stirred solution of 3.6 g (0.022 mol) of 1,1 '- carbonyl diimidazole in 75 ml of methylene chloride under nitrogen is treated with 1.6 g (0.022 mol) of 2-methyl-2-propenyl-amine (added via syringe and needle through a wall disposed in one neck of the reaction flask). After stirring for one hour, 6.2 g (0.02 mole) of 3- [4- (trifluoromethyl) phenoxy] azetidine oxalate is added at once, followed by 30 minutes of 5 ml of triethylamine and stirring is continued for 3 hours. . The reaction mixture is washed with 2 x 25 ml of water, dried over magnesium sulfate and evaporated in vacuo. DK 168422 Bl
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28 olieagtige remanens størkner ved henstand og omkrystalli-seres fra isopropylether, hvilket giver 3,7 g (58,9%) fine hvide krystaller, smeltepunkt 101~102°C.28 oily residue solidifies on standing and recrystallizes from isopropyl ether to give 3.7 g (58.9%) of fine white crystals, mp 101 ~ 102 ° C.
Analyse: Beregnet for ci5Hi7F3N2°2: 5 C 57,32, H 5,45, N 8,91.Analysis: Calculated for c15 H17 F3 N2 ° 2: 5 C 57.32, H 5.45, N 8.91.
Fundet: C 57,45, H 5,51, N 9,23.Found: C 57.45, H 5.51, N 9.23.
Eksempel 22 N- (2-Methyl-2-propenyl) -3- [3- (tr if luorme thyl) phenoxy] -1-10 -azetidincarboxamidExample 22 N- (2-Methyl-2-propenyl) -3- [3- (trifluoromethyl) phenoxy] -1-10 -acetidine carboxamide
En opløsning af 3,6 g (0,022 mol) 1,1'^carbonyl-diimidazol i 75 ml methylenchlorid omrøres under nitrogen, medens 1,6 g (0,022 mol methallylamin tilsættes med sprøjte og nål gennem en væg monteret i reaktionskolbens ene 15 hals. Reaktionen er let eksotermisk. Reaktionsblandingen omrøres i én time, behandles så med 6,2 g (0,02 mol) 3- [3- (trifluormethyl) phenoxy] azetidin-oxalat efterfulgt i løbet af 0,5 time af 5 ml triethylamin, og omrøringen fortsættes i 16 timer. Reaktionsblandingen vaskes med 20 2 x 30 ml vand, tørres over magnesiumsulfat og inddampes på en roterende fordamper, hvilket giver 6,7 g olieagtig remanens, som størkner. Remanensen omkrystalliseres · fra isopropylether, hvilket giver 5,4 g (85,9%) fine hvide krystaller, smeltepunkt 90-91°C.A solution of 3.6 g (0.022 mol) of 1.13 carbonyl-diimidazole in 75 ml of methylene chloride is stirred under nitrogen, while 1.6 g (0.022 mol of methallylamine is added with syringe and needle through a wall mounted in one neck of the reaction flask The reaction is slightly exothermic The reaction mixture is stirred for one hour, then treated with 6.2 g (0.02 mol) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate followed by 0.5 hour of 5 ml of triethylamine. The reaction mixture is washed with 20 x 30 ml of water, dried over magnesium sulfate and evaporated on a rotary evaporator to give 6.7 g of oily residue which solidifies. The residue is recrystallized from isopropyl ether to give 5 4 g (85.9%) of fine white crystals, mp 90-91 ° C.
25 Analyse: Beregnet for C;l5H17F3N2^2: C 57,32, H 5,45, N 8,91.Analysis: Calculated for C 15 H 17 F 3 N 2 2: C 57.32, H 5.45, N 8.91.
Fundet: C 57,20, H 5,50, N 8,95.Found: C 57.20, H 5.50, N 8.95.
Eksempel 23 30 N- (3-Methyl-2-butenyl) -3- [4- (trif luormethyl) phenoxy] -1- -azetidincarboxamidExample 23 N- (3-Methyl-2-butenyl) -3- [4- (trifluoromethyl) phenoxy] -1- -azetidine carboxamide
En opløsning af 3,6 g (0,022 mol) 1,1'-carbonyl-diimidazol i 100 ml methylenchlorid afkøles i ledningsvandbad, og under omrøring under nitrogen tildryppes 1,87 35 g (0,022 mol) 3-methyl-2-butenylamin. Efter omrøring i en time tilsættes på én gang 6,2 g (0,02 mol) 3-[4-(tri-fluormethyl)phenoxy]azetidin-oxalat efterfulgt i løbetA solution of 3.6 g (0.022 mol) of 1,1'-carbonyl-diimidazole in 100 ml of methylene chloride is cooled in tap water bath and, while stirring under nitrogen, 1.87 35 g (0.022 mol) of 3-methyl-2-butenylamine are added dropwise. After stirring for one hour, 6.2 g (0.02 mol) of 3- [4- (trifluoromethyl) phenoxy] azetidine oxalate are added at one time followed by
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29 DK 168422 B1 af 0,5 time af 5 ml triethylamin, og omrøringen forsættes i yderligere 16 timer. Reaktionsblandingen vaskes med . 2 x 50 ml vand, tørres over magnesiumsulfat og inddampes på en roterende fordamper, hvilket giver en halvfast re-5 manens. Udrivning med isopropylether og filtrering giver 7 g råprodukt, som omkrystalliseres fra ethanol/ vand, hvilket giver 5,5 g (83,8%) hvide krystaller, smeltepunkt 156,5-158°C.Of 0.5 hour of 5 ml of triethylamine and stirring is continued for an additional 16 hours. The reaction mixture is washed with. 2 x 50 ml of water, dried over magnesium sulfate and evaporated on a rotary evaporator to give a semi-solid residue. Purification with isopropyl ether and filtration yields 7 g of crude product which is recrystallized from ethanol / water to give 5.5 g (83.8%) of white crystals, mp 156.5-158 ° C.
Analyse: Beregnet for ci6Hi9F3N2^2: 10 C 58,53, H 5,83, N 8,53.Analysis: Calculated for C 18 H 19 F 3 N 2 2: 10 C 58.53, H 5.83, N 8.53.
Fundet: C 58,81, H 5,89, N 8,58. _1Found: C, 58.81; H, 5.89; N, 8.58. _1
Eksempel 24 N-(3-Methyl-2-butenyl)-3-[3-(trifluormethyl)phenoxy]-1-15 -azetidincarboxamidExample 24 N- (3-Methyl-2-butenyl) -3- [3- (trifluoromethyl) phenoxy] -1-15-azetidine carboxamide
En opløsning af 3,6 g (0,022 mol) 1,1'-carbonyl--diimidazol i 100 ml tetrahydrofuran afkøles med ledningsvandbad og omrøres under nitrogen, medens 1,6 g (0,022 mol) 3-methyl-2-butenylamin tilsættes med sprøj-20 te og nål. Reaktionsblandingen omrøres i en time og behandles derpå med 6,2 g (0,02 mol) 3-[3-(trifluormethyl)-phenoxy]azetidin-oxalat efterfulgt i løbet af 0,5 time af 5 ml triethylamin, hvorefter omrøringen fortsættes i 72 timer. Reaktionsblandingen fortyndes med 500· ml is-25 vand og ekstraheres med 6 x 50 ml methylenchlorid. De kombinerede ekstrakter vaskes med vand, tørres over magnesiumsulfat og inddampes til en fast remanens på en roterende fordamper. Omkrystallisation fra ethanol/ vand giver 6 g hvide krystaller, smeltepunkt 143-144°C.A solution of 3.6 g (0.022 mol) of 1,1'-carbonyl-diimidazole in 100 ml of tetrahydrofuran is cooled with tap water bath and stirred under nitrogen while 1.6 g (0.022 mol) of 3-methyl-2-butenylamine is added with syringe and needle. The reaction mixture is stirred for one hour and then treated with 6.2 g (0.02 mole) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate followed by 0.5 hour of 5 ml of triethylamine, then stirring is continued. 72 hours. The reaction mixture is diluted with 500 ml of ice-25 water and extracted with 6 x 50 ml of methylene chloride. The combined extracts are washed with water, dried over magnesium sulfate and evaporated to a solid residue on a rotary evaporator. Recrystallization from ethanol / water gives 6 g of white crystals, mp 143-144 ° C.
30 Analyse: Beregnet for : C 58,53, H 5,83, N 8,53.Analysis: Calculated for: C, 58.53; H, 5.83; N, 8.53.
Fundet: C 58,46, H 5,86, N 8,69.Found: C 58.46, H 5.86, N 8.69.
35 3035 30
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DK 168422 BlDK 168422 Bl
Eksempel 25 (E) -N- (2-Butenyl) -3- [4- (trifluormethyl) phenoxy] -1-azeti-dincarboxamidExample 25 (E) -N- (2-Butenyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En blanding af 3,6 g (0,022 mol) 1,1'-carbonyl-5 -diimidazol og 1,6 g (0,022 mol) trans-crotylamin omrøres i en time, behandles derpå med 6,2 g (0,02 mol) 3— [4— - (trifluormethyl) phenoxy] azetidin-oxalat efterfulgt i løbet af 0,5 time af 5 ml triethylamin, idet omrøringen fortsættes i 16 timer. Den delvis krystallinske blanding 10 vaskes med 2 x 50 ml vand, tørres over magnesiumsulfat og inddampes på en roterende fordamper til en fast remanens på 14,2 g. Omkrystallisation fra methanol/vand giver 5,35 g (85,1%) fine hvide krystaller, smeltepunkt 157-158°C.A mixture of 3.6 g (0.022 mol) of 1,1'-carbonyl-5-diimidazole and 1.6 g (0.022 mol) of trans-crotylamine is stirred for one hour, then treated with 6.2 g (0.02 mol) 3 - [4- (trifluoromethyl) phenoxy] azetidine oxalate followed by 0.5 hour of 5 ml of triethylamine, stirring being continued for 16 hours. The partially crystalline mixture 10 is washed with 2 x 50 ml of water, dried over magnesium sulfate and evaporated on a rotary evaporator to give a solid residue of 14.2 g. Recrystallization from methanol / water gives 5.35 g (85.1%) of fine white crystals, mp 157-158 ° C.
15 Analyse: Beregnet for ^i5H]_7F3N2°2: C 57,32, H 5,45, N 8,91.Analysis: Calculated for [15H] -7F3N2 ° 2: C 57.32, H 5.45, N 8.91.
Fundet: C 57,47, H 5,49, N 9,00.Found: C 57.47, H 5.49, N 9.00.
Eksempel 26 20 (E) -N- (2-Butenyl) -3-[3- (trifluormethyl)phenoxy]-1-azeti- dincarboxamidExample 26 (E) -N- (2-Butenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En opløsning af 3,6 g (0,022 mol) l,l'-carbon-yldiimidazol i 60 ml methylenchlorid afkøles i isbad under omrøring under nitrogen, medens der tildryppes 1,6 g 25 (0,022 mol) trans-crotylamin. Efter opvarmning til omgi velsernes temperatur tilsættes på én gang 6,2 g (0,02 mol) 3-[3-(trifluormethyl)phenoxy]azetidin-oxalat efterfulgt i løbet af 0,25 time af 5 ml triethylamin, idet omrøringen forsættes i 72 timer. Reaktionsopløsningen vaskes 30 med 2 x 50 ml vand, tørres over magnesiumsulfat og inddampes på en roterende fordamper til en fast remanens på 7 g. Omkrystallisation fra methanol/vand giver 5,5 g let gult pulver. Endnu en omkrystallisation med trækulbehandling fra isopropylether giver 3,75 g (59,7%) 35 fine hvide krystaller, smeltepunkt 127-128°C.A solution of 3.6 g (0.022 mol) of 1,1'-carbon-yldiimidazole in 60 ml of methylene chloride is cooled in an ice bath while stirring under nitrogen while 1.6 g (0.022 mol) of trans-crotylamine is added dropwise. After heating to ambient temperature, 6.2 g (0.02 mol) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate is added at once, followed by 0.25 hours of 5 ml of triethylamine, stirring is continued. 72 hours. The reaction solution is washed with 2 x 50 ml of water, dried over magnesium sulfate and evaporated on a rotary evaporator to give a solid residue of 7 g. Recrystallization from methanol / water gives 5.5 g of slightly yellow powder. Another recrystallization with charcoal treatment from isopropyl ether gives 3.75 g (59.7%) of 35 fine white crystals, mp 127-128 ° C.
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31 DK 168422 B131 DK 168422 B1
Analyse: Beregnet for ci5Hi7F3N2°2: C 57/32, H 5,45, N 8,91.Analysis: Calculated for c15 H17 F3 N2 ° 2: C 57/32, H 5.45, N 8.91.
Pundet: C 57,35, H 5,47, N 8,94.Pound: C 57.35, H 5.47, N 8.94.
5 Eksempel 27 N-Phenyl-3-[3-(trifluormethyl)phenoxy]-1-azetidin-carbox-amidExample 27 N-Phenyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En omrørt opslæmning af 6,2 g (0,02 mol) 3—[3— -(trifluormethyl)phenoxy]azetidin-oxalat i 60 ml tetra-10 hydrofuran behandles med 5 ml triethylamin efterfulgt af 2,62 g (0,022 mol) phenylisocyanat, og omrøringen_fortsættes i 16 timer. Reaktionsblandingen fortyndes med vand, indtil en olie udskilles, som hurtigt størkner.A stirred slurry of 6.2 g (0.02 mol) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate in 60 ml of tetrahydrofuran is treated with 5 ml of triethylamine followed by 2.62 g (0.022 mol) phenyl isocyanate, and stirring is continued for 16 hours. Dilute the reaction mixture with water until an oil is separated, which solidifies rapidly.
Det vandige tetrahydrofuran dekanteres, og den faste re-15 manens omkrystalliseres ud fra ethanol/vand, hvilket giver 5,3 g (80,1%) hvide krystaller, smeltepunkt 137-138°C. Analyse: Beregnet for : C 60,71, H 4,50, N 8,33.The aqueous tetrahydrofuran is decanted and the solid residue is recrystallized from ethanol / water to give 5.3 g (80.1%) of white crystals, mp 137-138 ° C. Analysis: Calculated for: C, 60.71; H, 4.50; N, 8.33.
Fundet: C 60,81, H 4,47, N 8,35.Found: C, 60.81; H, 4.47; N, 8.35.
2020
Eksempel 28 N-Phenyl-3-[4-(trifluormethyl)phenoxy]-1-azetidin-carb-oxamidExample 28 N-Phenyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En omrørt opslæmning af 6,2 g (0,02 mol) 3-[4-25 -(trifluormethyl)phenoxy]azetidin-oxalat og 2,62 g (0,022 mol) phenylisocyanat i 60 ml tetrahydrofuran behandles med 5 ml triethylamin, og omrøringen fortsættes i 16 timer. Reaktionsblandingen fortyndes med vand, indtil en olie udskilles. Tetrahydrofuran/vand-delen dekanteres, 30 og remanensen størkner ved henstand. Omkrystallisation fra ethanol/vand giver 3,5 g (53,4%) fine hvide krystaller, smeltepunkt 174,5-176°C.A stirred slurry of 6.2 g (0.02 mol) of 3- [4-25 - (trifluoromethyl) phenoxy] azetidine oxalate and 2.62 g (0.022 mol) of phenyl isocyanate in 60 ml of tetrahydrofuran is treated with 5 ml of triethylamine, and stirring is continued for 16 hours. Dilute the reaction mixture with water until an oil is separated. The tetrahydrofuran / water portion is decanted, and the residue solidifies upon standing. Recrystallization from ethanol / water gives 3.5 g (53.4%) of fine white crystals, mp 174.5-176 ° C.
Analyse: Beregnet for : C 60,71, H 4,50, N 8,33.Analysis: Calculated for: C, 60.71; H, 4.50; N, 8.33.
35 Fundet: C 60,91, H 4,53, N 8,35.Found: C, 60.91; H, 4.53; N, 8.35.
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32 DK 168422 B132 DK 168422 B1
Eksempel 29 trans-N,2-Dimethyl-3-[3-(trifluormethyl) phenoxy]-1-azeti-dlncarboxamidExample 29 trans-N, 2-Dimethyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinylcarboxamide
Til en omrørt opløsning af 6 g (0,015 mol) rå trans-5 -2-methyl-3-[3-(trifluormethyl)phenoxy]azetidin i 50 ml tetrahydrofuran tildryppes 0,94 g (0,3165 mol) methyliso-cyanat, og der omrøres i 16 timer under nitrogentæppe. Fortynding af reaktionsblandingen med vand giver en olie, der størkner. Efter dekantering af den vandige tetrahy-10 drofuranfase omkrystalliseres den faste remanens fra ethanol/vand, hvilket giver 3,95 g (91,4%) fine hvide krystaller, smeltepunkt 104,5-106°C.To a stirred solution of 6 g (0.015 mole) of crude trans-5 -2-methyl-3- [3- (trifluoromethyl) phenoxy] azetidine in 50 ml of tetrahydrofuran is added 0.94 g (0.3165 mole) of methyl isocyanate, and stirring for 16 hours under nitrogen blanket. Dilution of the reaction mixture with water gives an oil which solidifies. After decanting the aqueous tetrahydrofurfuran phase, the solid residue is recrystallized from ethanol / water to give 3.95 g (91.4%) of fine white crystals, mp 104.5-106 ° C.
Analyse: Beregnet for ci3Hi5F3N2°2! C 54,17, H 5,25, N 9,72.Analysis: Calculated for ci3Hi5F3N2 ° 2! C 54.17, H 5.25, N 9.72.
15 Fundet: C 54,50, H 5,29, N 9,71.Found: C 54.50, H 5.29, N 9.71.
Eksempel 30 trans-2-Methyl-3- [3- (trif luorme thyl) phenoxy] -1-azetidin-carboxamid 20 En blanding af 6 g (0,015 mol) rå trans-2-me- thyl-2-[3-(trifluormethyl)phenoxy]azetidin (renhed 56,6%, indeholder diphenylmethan) og 2,4 g (0,0225 mol) nitro-urinstof i 40 ml acetone behandles med 4 ml vand"og opvarmes derpå, indtil der fås en klar homogen opløsning.Example 30 trans-2-Methyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide A mixture of 6 g (0.015 mole) of crude trans-2-methyl-2- [3- (trifluoromethyl) phenoxy] azetidine (purity 56.6%, contains diphenylmethane) and 2.4 g (0.0225 mole) of nitro urea in 40 ml of acetone are treated with 4 ml of water "and then heated until a clear homogeneous resolution.
25 Reaktionsblandingen omrøres natten over, hvor den afkøles til omgivelsernes temperatur og fortyndes med vand, indtil en olie udskilles. Olien størkner og omkrystalliseres fra ethanol/vand, hvilket giver 4,3 g hvide pladelignende krystaller, smeltepunkt 117-118°C. Pro-30 duktet omkrystalliseres fra benzen, hvilket giver 3,35 g (96,8%) krystaller, smeltepunkt 118-119°C.The reaction mixture is stirred overnight, where it is cooled to ambient temperature and diluted with water until an oil is separated. The oil solidifies and recrystallizes from ethanol / water to give 4.3 g of white plate-like crystals, mp 117-118 ° C. The product is recrystallized from benzene to give 3.35 g (96.8%) of crystals, mp 118-119 ° C.
Analyse: Beregnet for ^ΐ2Η13^3Ν2^2: C 52,56, H 4,78, N 10,22.Analysis: Calculated for ΐ2Η13 Η 3Ν2 2 2: C 52.56, H 4.78, N 10.22.
Fundet: C 52,54, H 4,74, N 10,17.Found: C, 52.54; H, 4.74; N, 10.17.
3535
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33 DK 168422 B133 DK 168422 B1
Eksempel 31 trans-2-Methyl-N-(2-propenyl)-3-[3-(trifluormethyl)phen-oxy]-1-azetidincarboxamidExample 31 trans-2-Methyl-N- (2-propenyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide
En opløsning af 6 g (0,015 mol) rå trans-2-me-5 thyl-3-[3-(trifluormethyl)phenoxy]azetidin (56,6%) i 50 ml tetrahydrofuran behandles med 1,54 g (0,0165 mol) 2--propenylisocyanat på én gang og omrøres under nitrogentæppe i 16 timer. Reaktionsblandingen fortyndes med vand, indtil en olie udskilles. Olien krystalliserer ikke, og 10 efter 7 uger udrives den med 3 x 25 ml isopropylether.A solution of 6 g (0.015 mole) of crude trans-2-methyl-3- [3- (trifluoromethyl) phenoxy] azetidine (56.6%) in 50 ml of tetrahydrofuran is treated with 1.54 g (0.0165 mole) 2 - propenyl isocyanate at once and stirred under nitrogen blanket for 16 hours. Dilute the reaction mixture with water until an oil is separated. The oil does not crystallize and, after 7 weeks, it is rubbed off with 3 x 25 ml isopropyl ether.
De kombinerede triturater giver 400 mg hvide granulære krystaller (8,5%) , smeltepunkt 55-57°C.The combined triturates give 400 mg of white granular crystals (8.5%), mp 55-57 ° C.
Analyse: Beregnet for ci5Hi7F3N2°2: C 57,32, H 5,45, N 8,91.Analysis: Calculated for c15 H17 F3 N2 ° 2: C 57.32, H 5.45, N 8.91.
15 Fundet: C 57,36, H 5,50, N 8,97.Found: C 57.36, H 5.50, N 8.97.
Eksempel 32 3- (3-Chlorphenoxy) -N*-methyl-1-azetidincarboxamidExample 32 3- (3-Chlorophenoxy) -N * -methyl-1-azetidinecarboxamide
En opløsning af 0,01275 mol l-chlorcarbonyl-3-20 -(3-chlorphenoxy)azetidin i 20 ml tetrahydrofuran behand les med 4 ml (0,05 mol) 40% vandig methylamin og omrøres i 16 timer. Reaktionsblandingen fortyndes med vand, indtil en olie begynder at udskilles, og ekstraheres derpå med 3 x 50 ml benzen. De kombinerede ekstrakter tørres 25 over magnesiumsulfat og inddampes til et faststof, som omkrystalliseres fra benzen/ligroin, hvilket giver 1,2 g (40,0%) fine hvide krystaller, smeltepunkt 140-141°C. Analyse: Beregnet for cuHi3C1N2°2: C 54,89, H 5,44, N 11,64 30 Fundet: C 55,05, H 5,58, N 11,52.A solution of 0.01275 mol of 1-chlorocarbonyl-3-20 - (3-chlorophenoxy) azetidine in 20 ml of tetrahydrofuran is treated with 4 ml (0.05 mol) of 40% aqueous methylamine and stirred for 16 hours. The reaction mixture is diluted with water until an oil begins to separate and then extracted with 3 x 50 ml of benzene. The combined extracts are dried over magnesium sulfate and evaporated to a solid which is recrystallized from benzene / ligroin to give 1.2 g (40.0%) of fine white crystals, mp 140-141 ° C. Analysis: Calculated for cuHl3 ClN2 ° 2: C 54.89, H 5.44, N 11.64 Found: C 55.05, H 5.58, N 11.52.
Eksempel 33 3-(3-Chlorphenoxy)-N-(2-propenyl)-1-azetidincarboxamid En opløsning af 5,4 g (0,017 mol) 1-chlorcar-35 bonyl-3-(3-chlorphenoxy)azetidin i 20 ml tetrahydrofuran behandles med 2,3 g (0,04 mol) 2-propenylamin og omrøresExample 33 3- (3-Chlorophenoxy) -N- (2-propenyl) -1-azetidinecarboxamide A solution of 5.4 g (0.017 mole) of 1-chlorocarbonyl-3- (3-chlorophenoxy) azetidine in 20 ml tetrahydrofuran is treated with 2.3 g (0.04 mole) of 2-propenylamine and stirred
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34 DK 168422 B1 i 2 timer. Reaktionsopløsningen inddampes i vakuum til et rosa-beigefarvet faststof. Odrivning af faststoffet med vand giver efter filtrering 4,4 g råprodukt. Efter tørring omkrystalliseres faststoffet med trækulbehand-.5 ling fra 2% acetone/isopropylether, hvilket giver 1,7 g (37,5%) blegt beigefarvede krystaller, smeltepunkt 87-89°C.34 DK 168422 B1 for 2 hours. The reaction solution is evaporated in vacuo to a pink-beige solid. The filtration of the solid with water gives 4.4 g of crude product after filtration. After drying, the solid is recrystallized from charcoal treatment from 2% acetone / isopropyl ether to give 1.7 g (37.5%) of pale beige crystals, mp 87-89 ° C.
Analyse: Beregnet for C-^H^j-Cl^C^: C 58,54, H 5,67, N 10,50.Analysis: Calculated for C- HH ^ j-Cl ^C ^: C 58.54, H 5.67, N 10.50.
10 Fundet: C 58,48, H 5,72, N 10,49.Found: C, 58.48; H, 5.72; N, 10.49.
Eksempel 34 N-Methyl-3-(2-pyridinyloxy)-1-azetidincarboxamidExample 34 N-Methyl-3- (2-pyridinyloxy) -1-azetidine carboxamide
En 2 molær benzenopløsning af 40 ml (0,08 mol) 15 phosgen tilsættes til en suspension af 10 g finmalet kaliumcarbonat i 40 ml methylenchlorid. Blandingen omrøres i 15 minutter ved stuetemperatur, og der tilsættes 10 g (0,056 mol) 1-(1-phenylethyl)-3-(2rpyridyloxy)aze-tidin i 50 ml methylenchlorid under mild afkøling. Blan-20 dingen omrøres ved stuetemperatur i en time og inddampes på en roterende fordamper ved 25°C i 30 minutter. Remanensen behandles med 100 ml tetrahydrofuran og afkøles i isbad. Til den afkølede omrørte blanding tilsættes 20 ml 40% vandig methylamin. Blandingen omrøres i 20 25 minutter og deles mellem methylenchlorid og vand. Me-thylenchloridet tørres over natriumsulfat og inddampes. Remanensen krystalliseres fra benzen/ethanol og om-krystalliseres ' fra ethylacetat/isopropylalkohol. Udbyttet af den i overskriften nævnte forbindelse er 2,3 g 30 (14%), smeltepunkt 165-168°C.A 2 molar benzene solution of 40 ml (0.08 mol) of phosgene is added to a suspension of 10 g of finely ground potassium carbonate in 40 ml of methylene chloride. The mixture is stirred for 15 minutes at room temperature and 10 g (0.056 mol) of 1- (1-phenylethyl) -3- (2-pyridyloxy) azidine is added in 50 ml of methylene chloride under gentle cooling. The mixture is stirred at room temperature for one hour and evaporated on a rotary evaporator at 25 ° C for 30 minutes. The residue is treated with 100 ml of tetrahydrofuran and cooled in an ice bath. To the cooled stirred mixture is added 20 ml of 40% aqueous methylamine. The mixture is stirred for 20 minutes and partitioned between methylene chloride and water. The methylene chloride is dried over sodium sulfate and evaporated. The residue is crystallized from benzene / ethanol and recrystallized from ethyl acetate / isopropyl alcohol. The yield of the title compound is 2.3 g (14%), mp 165-168 ° C.
Analyse: Beregnet for c;lqhi3N302: C 57,96, H 6,32, N 20,28.Analysis: Calculated for C ;qH33NNO₂: C 57.96, H 6.32, N 20.28.
Fundet: C 57,93, H 6,34, N 20,12.Found: C 57.93, H 6.34, N 20.12.
3535
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35 DK 168422 B1DK 168422 B1
Eksempel 35 N-(2-Propenyl)-3-(2-pyridinyloxy)-1-azetidincarboxamid Til en omrørt suspension af 10 g (0,072 mol) fintmalet kaliumcarbonat i 90 ml methylenchlorid tilsæt-5 tes 32 ml (0,062 mol) 2 molær phosgen i benzen. Blandingen omrøres i 15 minutter, og der tilsættes 8 g (0,031 mol) 1-(1-phenylethyl)-3-(2-pyridyloxy)azetidin 1 50 ml methylenchlorid. Blandingen omrøres ved 25°C i 2 timer og inddampes på en roterende fordamper ved 25°C 10 i 30 minutter, og remanensen behandles med 100 ml tetra- hydrofuran. Den omrørte blanding afkøles i isbad^og der tildryppes 4 g (0,07 mol) allylamin. Efter omrøring i 30 minutter ved 25°C deles materialet mellem vand og methylenchlorid. Methylenchloridet tørres og inddampes.Example 35 N- (2-Propenyl) -3- (2-pyridinyloxy) -1-azetidinecarboxamide To a stirred suspension of 10 g (0.072 mol) of finely ground potassium carbonate in 90 ml of methylene chloride, 32 ml (0.062 mol) of 2 molar are added. phosgene in benzene. The mixture is stirred for 15 minutes and 8 g (0.031 mol) of 1- (1-phenylethyl) -3- (2-pyridyloxy) azetidine in 50 ml of methylene chloride are added. The mixture is stirred at 25 ° C for 2 hours and evaporated on a rotary evaporator at 25 ° C for 30 minutes and the residue is treated with 100 ml of tetrahydrofuran. The stirred mixture is cooled in an ice bath and 4 g (0.07 mol) of allylamine is added dropwise. After stirring for 30 minutes at 25 ° C, the material is partitioned between water and methylene chloride. The methylene chloride is dried and evaporated.
(bj 15 Remanensen chrcmatograferes på "Waters,,vv Prep-500 HPLC ved hjælp af en silicakolonne, og der elueres med .50% ethylacetat/hexan. Produktet krystalliseres to gange fra isopropylether. Udbyttet af den i overskriften nævnte forbindelse er 1,5 g (21%), smeltepunkt 72-76°C.(The residue is chromatographed on Waters, vv Prep-500 HPLC using a silica column and eluted with .50% ethyl acetate / hexane. The product is crystallized twice from isopropyl ether. The yield of the title compound is 1.5 g (21%), mp 72-76 ° C.
20 Analyse: Beregnet for ^i2H15IJ3°2: C 61,79, H 6,48, N 18,'01.Calcd. For C 21 H 15 Y 3 ° 2: C 61.79, H 6.48, N 18, '01.
Fundet: C 61,53, H 6,50, N 17,96.Found: C 61.53, H 6.50, N 17.96.
Eksempel 36 25 3_(2-pyridinyloxy) -1-azetidincarboxamidExample 36 3 (2-Pyridinyloxy) -1-azetidinecarboxamide
En 2 molær benzenopløsning af phosgen (32 ml, 0,062 mol) tilsættes til en omrørt suspension af 10 g finmalet kaliumcarbonat i 80 ml methylenchlorid. Blanr’ dingen omrøres i 15 minutter, og der tilsættes 8 g 30 (0,031 mol) 1-(1-phenylethyl)-3-(2-pyridyloxy)azetidin i 50 ml methylenchlorid. Blandingen omrøres i 35 minutter og inddampes på en roterende fordamper (25°C i 30 minutter). Remanensen behandles med 100 ml tetrahydro-furan, afkøles med isbad, og der tilsættes langsomt un-35 der kraftig omrøring 20 ml koncentreret ammoniumhydroxid. Blandingen omrøres i en time ved stuetemperatur ogA 2 molar benzene solution of phosgene (32 ml, 0.062 mol) is added to a stirred suspension of 10 g of finely ground potassium carbonate in 80 ml of methylene chloride. The mixture is stirred for 15 minutes and 8 g of 30 (0.031 mol) of 1- (1-phenylethyl) -3- (2-pyridyloxy) azetidine is added in 50 ml of methylene chloride. The mixture is stirred for 35 minutes and evaporated on a rotary evaporator (25 ° C for 30 minutes). The residue is treated with 100 ml of tetrahydrofuran, cooled with an ice bath and slowly stirred under vigorous stirring 20 ml of concentrated ammonium hydroxide. The mixture is stirred for one hour at room temperature and
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36 DK 168422 B1 deles mellem methylenchlorid og vand. Vandlaget ekstraileres 2 gange med methylenchlorid, og de kombinerede organiske lag inddampes. Remanensen krystalliseres fra benzen og omkrystalliseres fra isopropylg±her.36 DK 168422 B1 is split between methylene chloride and water. The water layer is extracted twice with methylene chloride and the combined organic layers are evaporated. The residue is crystallized from benzene and recrystallized from isopropylg ± here.
5 Udbyttet af den i overskriften nævnte forbindelse er 1,4 g, smeltepunkt 133-137°C.The yield of the title compound is 1.4 g, mp 133-137 ° C.
Analyse: Beregnet for cg®nN302: C 55,95, H 5,74, N 21,75.Analysis: Calculated for C c cNN30O₂: C 55.95, H 5.74, N 21.75.
Fundet: C 55,73, H 5,71, N 21,10.Found: C, 55.73; H, 5.71; N, 21.10.
1010
Eksempel 37 1-[3-[4-(Trifluormethyl)phenoxy]-l-azetidinylcarbonyl]--IH-imidazol 15 En blanding af 1,7 g (0,01 mol) 1,1'-carbony1- diimidazol i 50 ml tetrahydrofuran og 3 g (0,015 mol) 3--[4-(trifluormethy 1)phenoxy]azetidin omrøres i 6 timer. Reaktionsblandingen fortyndes med vand og ekstraheres med 3 x 50 ml methylenchlorid. Ekstrakterne giver efter 20 inddampning i vakuum en ravfarvet remanens, som opløses i 20 ml benzen og vaskes med fortyndet saltsyre og derpå med vand. Benzendelen inddampes, hvilket giver en halvfast rest, som, når den udrives med isopropylether, giver 1,4 g gråt materiale. Omkrystallisation fra 25 acetonitril giver 1,3 g (41,8%) fine grå krystaller, smeltepunkt 139-140°C.Example 37 1- [3- [4- (Trifluoromethyl) phenoxy] -1-azetidinylcarbonyl] -1H-imidazole A mixture of 1.7 g (0.01 mole) of 1,1'-carbonyl-diimidazole in 50 ml tetrahydrofuran and 3 g (0.015 mol) of 3- [4- (trifluoromethyl 1) phenoxy] azetidine are stirred for 6 hours. The reaction mixture is diluted with water and extracted with 3 x 50 ml of methylene chloride. After 20 evaporation in vacuo, the extracts give an amber residue which is dissolved in 20 ml of benzene and washed with dilute hydrochloric acid and then with water. The benzene portion is evaporated to give a semi-solid residue which, when triturated with isopropyl ether, gives 1.4 g of gray matter. Recrystallization from acetonitrile gives 1.3 g (41.8%) of fine gray crystals, mp 139-140 ° C.
Analyse: Beregnet for ci4Hi2F3N3^2: C 54,02, H 3,89, N 13,50.Analysis: Calculated for C 14 H 12 F 3 N 3 O 2: C 54.02, H 3.89, N 13.50.
Fundet: C 54,33, H 3,96, N 13,89.Found: C, 54.33; H, 3.96; N, 13.89.
3030
Eksempel 38 N-Methyl-3-phenoxy-l-azetidincarboxamidExample 38 N-Methyl-3-phenoxy-1-azetidinecarboxamide
Forbindelsen fremstilles ud fra methansulfona-tet af 3-phenoxyacetidin og methylisocyanat som beskre-35 vet i eksempel 1 i USA patentskrift nr. 4.226.861, smeltepunkt 139-141°C.The compound is prepared from the methanesulfonate of 3-phenoxyacetidine and methyl isocyanate as described in Example 1 of U.S. Patent No. 4,226,861, m.p. 139-141 ° C.
DK 168422 B1 37 O .DK 168422 B1 37 O.
Eksempel 39 N-Methyl-3-[4-(trifluormethyl)phenoxy]-1-azetidincarbox-amidExample 39 N-Methyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide
Forbindelsen fremstilles ud fra 3-[4-(triflu-5 ormethylphenoxy)azetidin og methylioscyanat som beskrevet i eksempel 3 i USA patentskrift nr. 4.226.861, smeltepunkt 154-157°C.The compound is prepared from 3- [4- (trifluoromethylphenoxy) azetidine and methylioscyanate as described in Example 3 of U.S. Patent No. 4,226,861, m.p. 154-157 ° C.
Eksempel 40 10 N-Methyl-3- [ 3- (trif luorme thyl) phenoxy] -1-azetidincarb- oxamidExample 40 N-Methyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide
Forbindelsen fremstilles ud fra 3-[3-(trifluorme thyl) phenoxy] azetidin og methylisocyanat som beskrevet i eksempel 4 i OSA patentskrift nr. 4.266.861, smel-15 tepunkt 145-147°C.The compound is prepared from 3- [3- (trifluoromethyl) phenoxy] azetidine and methyl isocyanate as described in Example 4 of OSA Patent No. 4,266,861, m.p. 145-147 ° C.
Eksempel 41 N-Methyl-3-[2-(trifluormethyl)phenoxy]-1-azetidincarb-oxamid 20 Forbindelsen fremstilles ud fra 3-[2-(triflu- ormethyl) phenoxy] azetidin og methylisocyanat som beskrevet i eksempel 5 i USA patentskrift nr. 4.226.861, smeltepunkt 134-136°C.Example 41 N-Methyl-3- [2- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide The compound is prepared from 3- [2- (trifluoromethyl) phenoxy] azetidine and methyl isocyanate as described in Example 5 of the United States Patent Application No. 4,226,861, m.p. 134-136 ° C.
25 Eksempel 42 N-Methyl-3- [2- (aminocarbonyl) phenoxy] -1-azetidincarboxamid Forbindelsen fremstilles ud fra 2-(3-azetidi-nyloxy)benzamid og methylisocyanat som beskrevet i eksempel 2 i USA patentskrift nr. 4.226.861, smeltepunkt 30 236-240°C.Example 42 N-Methyl-3- [2- (aminocarbonyl) phenoxy] -1-azetidinecarboxamide The compound is prepared from 2- (3-azetidyloxy) benzamide and methyl isocyanate as described in Example 2 of U.S. Patent No. 4,226,861. , mp 236-240 ° C.
Eksempel 43 N-Methyl-3- [3- (aminocarbonyl) phenoxy] -1-azetidincarboxamid Forbindelsen fremstilles ud fra 3-(3-azetidi-35 nyloxy)benzamid og methylisocyanat som beskrevet i eksempel 6 i USA patentskrift nr. 4.226.861, smeltepunkt 238-240°C.Example 43 N-Methyl-3- [3- (aminocarbonyl) phenoxy] -1-azetidinecarboxamide The compound is prepared from 3- (3-azetidinylxy) benzamide and methyl isocyanate as described in Example 6 of U.S. Patent No. 4,226,861. , mp 238-240 ° C.
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38 DK 168422 B138 DK 168422 B1
Eksempel 44 N-Methyl-3- [4- (aminocarbonyl) phenoxy] -1-azetidincarboxamid Forbindelsen fremstilles ud fra 4-(3-azetidinyl-oxy)benzamid og methylisocyanat som beskrevet i eksempel 5 7 i USA patentskrift nr. 4.226.861, smeltepunkt 208-210°C.Example 44 N-Methyl-3- [4- (aminocarbonyl) phenoxy] -1-azetidinecarboxamide The compound is prepared from 4- (3-azetidinyl-oxy) benzamide and methyl isocyanate as described in Example 57 in U.S. Patent No. 4,226,861. , mp 208-210 ° C.
Eksempel 45' 3- [3- (Tr if luorme thyl) phenoxy] -1-azetidincarboxamid 10 En blanding af 30,6 g (0,141-mol) 3-[3-(tri- fluormethyl)phenoxy]azetidin og 42 g (0,321 mol) nitro-urinstof (80%) i 500 ml acetone omrøres i 5 dage (5 dage er ikke nødvendigt, men fordelagtigt) ved stuetemperatur. Blandingen filtreres, og filtratet inddampes i 15 vakuum. Remanensen deles mellem 150 ml vand og 100 ml ethylacetat, og lagene adskilles. Det vandige lag vaskes med 100 ml ethylacetat. Ethylacetatlagene vaskes med 75 ml 5% vandig natriumhydroxidopløsning efterfulgt af 75 ml vand, tørres over natriumsulfat og inddampes 20 i vakuum. Den residuale olie krystalliseres fra e- thylalkohol/ethylacetat, hvilket giver 22 g (60%) hovedsagelig af den i overskriften nævnte forbindelse. To gange omkrystallisation fra ethylalkohol giver 9,9 g hvidt krystallinsk faststof, smeltepunkt 151-152,5°C.Example 45 '3- [3- (Trifluoromethyl) phenoxy] -1-azetidinecarboxamide A mixture of 30.6 g (0.141 mole) of 3- [3- (trifluoromethyl) phenoxy] azetidine and 42 g ( 0.321 mol) of nitro-urea (80%) in 500 ml of acetone is stirred for 5 days (5 days is not necessary but advantageous) at room temperature. The mixture is filtered and the filtrate is evaporated in vacuo. The residue is partitioned between 150 ml of water and 100 ml of ethyl acetate and the layers are separated. The aqueous layer is washed with 100 ml of ethyl acetate. The ethyl acetate layers are washed with 75 ml of 5% aqueous sodium hydroxide solution followed by 75 ml of water, dried over sodium sulfate and evaporated in vacuo. The residual oil is crystallized from ethyl alcohol / ethyl acetate to give 22 g (60%) of mainly the title compound. Twice recrystallization from ethyl alcohol gives 9.9 g of white crystalline solid, mp 151-152.5 ° C.
25 Analyse: Beregnet for cxihhF3N2®2: C 50,77, H 4,26, N 10,76.Calcd. For C 18 H 18 F 3 N 2 ® 2: C 50.77, H 4.26, N 10.76.
Fundet: C 50,90, Η·'.4,29, N 10,71.Found: C, 50.90, 4 · 4.24, N, 10.71.
Eksempel 46 30 N-Ethyl-3- [ 3- (trif luormethyl) phenoxy] -1-azetidincarboxamidExample 46 N-Ethyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide
Til en omrørt og afkølet (15-20°) opløsning af 0,024 mol 3-[3-(trifluormethyl)phenoxy]azetidin i 50 ml tør benzen tildryppes 1,99 g (0,028 mol) ethylisocyanat. Reaktionsblandingen omrøres ved stuetemperatur natten o-35 ver og fortyndes med 50 ml methylenchlorid. Opløsningen vaskes med 5% natriumhydroxid (2 x 50 ml) , 50 ml vand,To a stirred and cooled (15-20 °) solution of 0.024 mol of 3- [3- (trifluoromethyl) phenoxy] azetidine in 50 ml of dry benzene is added 1.99 g (0.028 mol) of ethyl isocyanate. The reaction mixture is stirred at room temperature overnight and diluted with 50 ml of methylene chloride. The solution is washed with 5% sodium hydroxide (2 x 50 ml), 50 ml water,
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39 DK 168422 B1 25 ml mættet natriumchlorid, tørres over natriumhydroxid og inddampes i vakuum. Remanensen på 9,6 g omkrystalliseres to gange fra ethylacetat/isopropylether, hvilket giver 5,4 g hvidt faststof, smeltepunkt 125-126°C.25 ml of saturated sodium chloride, dried over sodium hydroxide and evaporated in vacuo. The residue of 9.6 g is twice recrystallized from ethyl acetate / isopropyl ether to give 5.4 g of white solid, mp 125-126 ° C.
5 Analyse: Beregnet for ^i3H^5F3N2®2: C 54,16, H 5,24, N 9,72.Analysis: Calculated for C 13 H 5 F 3 N 2 ® 2: C 54.16, H 5.24, N 9.72.
Fundet: C 54,24, H 5,23, N 9,74.Found: C, 54.24; H, 5.23; N, 9.74.
Eksempel 47 10 N-(1-Methylethyl)-3-[3-(trifluormethyl)phenoxy]-1-azeti- dincarboxamidExample 47 N- (1-Methylethyl) -3- [3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
Til en omrørt og afkølet (10-20°C) opløsning af 9,0 g (0,042 mol) 3-[3-trifluormethyl)phenoxy]aceti-din i 100 ml tør methylenchlorid tildryppes 4,1 g (0,048 15 mol) isopropylisocyanat. Reaktionsblandingen omrøres ved stuetemperatur i 2 timer og fortyndes med 100 ml methylenchlorid. Opløsningen vaskes med 2 x 40 ml 5% natriumhydroxid, 50 ml vand, 50 ml mættet natriumchlorid, tørres (natriumsulfat) og inddampes i vakuum. Remanensen 20 krystalliseres fra ethylacetat, hvilket giver 7,6 g (60,6%). Omkrystallisation fra ethylacetat giver 5,0 g klare hvide nåle, smeltepunkt 150-151,5°C.To a stirred and cooled (10-20 ° C) solution of 9.0 g (0.042 mol) of 3- [3-trifluoromethyl) phenoxy] acetidine in 100 ml of dry methylene chloride is added 4.1 g (0.048 mol) of isopropyl isocyanate. . The reaction mixture is stirred at room temperature for 2 hours and diluted with 100 ml of methylene chloride. The solution is washed with 2 x 40 ml of 5% sodium hydroxide, 50 ml of water, 50 ml of saturated sodium chloride, dried (sodium sulfate) and evaporated in vacuo. The residue 20 is crystallized from ethyl acetate to give 7.6 g (60.6%). Recrystallization from ethyl acetate gives 5.0 g clear white needles, mp 150-151.5 ° C.
Analyse: Beregnet for ci4Hi7F3N2°2: C 55,62, H 5,68, N 9,27.Analysis: Calculated for C 14 H 7 F 3 N 2 O 2: C 55.62, H 5.68, N 9.27.
25 Fundet: C 55,77, H 5,68, N 9,22.Found: C, 55.77; H, 5.68; N, 9.22.
Eksempel 48 N-Propyl-3-[3-(trifluormethyl)phenoxy]-1-azetidincarbox-amid 30 Til en omrørt og afkølet (10-15°C) opløsning af 0,027 mol 3-[3-(trifluormethyl)phenoxy]azetidin i 100 ml tør benzen tildryppes 4,0 g (0,047 mol) n-propyl-isocyanat. Reaktionsblandingen omrøres ved stuetemperatur i 30 minutter. Benzenen vaskes med 50 ml fortyndet 35 natriumbicarbonat, 25 ml vand, 25 ml mættet natriumchlorid og tørres (natriumsulfat). Opløsningens volumen re-Example 48 N-Propyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide To a stirred and cooled (10-15 ° C) solution of 0.027 mol of 3- [3- (trifluoromethyl) phenoxy] azetidine 4.0 g (0.047 mol) of n-propyl isocyanate are dropped into 100 ml of dry benzene. The reaction mixture is stirred at room temperature for 30 minutes. The benzene is washed with 50 ml of dilute 35 sodium bicarbonate, 25 ml of water, 25 ml of saturated sodium chloride and dried (sodium sulfate). The volume of the solution
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40 DK 168422 B1 duceres til 50 ml, og der tilsættes 30 ml petroleumether, hvilket giver 6,5 g (81%) produkt. Omkrystallisatiou fra isopropylether/isopropylalkohol giver 6,0 g små hvide nåle, smeltepunkt 115-117°C.B1 is induced to 50 ml and 30 ml of petroleum ether is added to give 6.5 g (81%) of product. Recrystallization from isopropyl ether / isopropyl alcohol gives 6.0 g of small white needles, mp 115-117 ° C.
5 Analyse: Beregnet for C14H17F3N2°2: C 55,63, H 5,67, N 9,27.Analysis: Calculated for C 14 H 17 F 3 N 2 O 2: C 55.63, H 5.67, N 9.27.
Fundet: C 55,65, H 5,68, N 9,25.Found: C 55.65, H 5.68, N 9.25.
Eksempel 49 10 N-Butyl-3-[3-(trifluormethyl)phenoxy]-1-azetidincarboxamid En opløsning af 18,9 g (0,05 mol) rå 3-’[3-(trifluormethyl) phenoxy]azetidin (indeholder en ækvimolær mængde diphenylmethan) i 100 ml isopropylether omrøres under nitrogen, medens der langsomt tilsættes 4,96 g (0,05 mol) 15 N-butylisocyanat. Den klare reaktionsopløsning bliver varm at føle på, og efter 20 minutter begynder et hvidt krystallinsk faststof at udfælde. Efter omrøring i 16 timer fjernes faststoffet ved filtrering, vaskes med frisk isopropylether og lufttørres, hvilket giver 8 g 20 blegt beigefarvede krystaller, smeltepunkt 108-109°C.Example 49 N-Butyl-3- [3- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide A solution of 18.9 g (0.05 mol) of crude 3- - [3- (trifluoromethyl) phenoxy] azetidine (contains a equimolar amount of diphenylmethane) in 100 ml of isopropyl ether is stirred under nitrogen while slowly adding 4.96 g (0.05 mole) of N-butyl isocyanate. The clear reaction solution becomes warm to the touch and after 20 minutes a white crystalline solid begins to precipitate. After stirring for 16 hours, the solid is removed by filtration, washed with fresh isopropyl ether and air dried to give 8 g of 20 pale beige crystals, mp 108-109 ° C.
Analyse: Beregnet for C15H19F3N2°2: C 56,95, H 6,05, N 8,86.Analysis: Calculated for C 15 H 19 F 3 N 2 O 2: C 56.95, H 6.05, N 8.86.
Fundet: C 56,78, H 6,06, N 8,83.Found: C 56.78, H 6.06, N 8.83.
25 Eksempel 50 N-Ethyl-3-[4-(trifluormethyl)phenoxy]-1-azetidincarboxamid En opløsning af 6,5 g (0,03 mol) rå 3-[4-(trifluormethyl) phenoxy] azetidin i 50 ml isopropylether omrøres under nitrogentæppe, medens der tildryppes 2,85 g 30 (0,04 mol) ethylisocyanat. Efter omrøring i 2 timer ved omgivelsernes temperatur begynder et faststof at udfælde, og efter 4 timer opsamles faststoffet ved filtrering, hvilket giver 3,7 g beigefarvet produkt, smeltepunkt 94-96°C. Genoparbejdning af filtratet giver kun spor af y-35 derligere produkt. Produktet omkrystalliseres fra isopropylether/hexan (behandlet med trækul), hvilket gi-Example 50 N-Ethyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide A solution of 6.5 g (0.03 mol) of crude 3- [4- (trifluoromethyl) phenoxy] azetidine in 50 ml of isopropyl ether stirred under nitrogen blanket while dropping 2.85 g (0.04 mole) of ethyl isocyanate. After stirring for 2 hours at ambient temperature, a solid begins to precipitate and after 4 hours the solid is collected by filtration to give 3.7 g of beige colored product, mp 94-96 ° C. Reprocessing of the filtrate gives only traces of γ-35 additional product. The product is recrystallized from isopropyl ether / hexane (treated with charcoal) to give
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41 DK 168422 B1 ver 2,61 g (30%) produkt, smeltepunkt 109-110°C.41 2. 16 g (30%) of product, mp 109-110 ° C.
Analyse: Beregnet for ci3Hi5F3N2°2: C 54,17, H 5,25, H 9,72.Analysis: Calculated for C 13 H 15 F 3 N 2 O 2: C 54.17, H 5.25, H 9.72.
Fundet: C 54,40, H 5,33, H 9,89.Found: C 54.40, H 5.33, H 9.89.
55
Eksempel 51 N-Butyl-3-[4-(trifluormethyl)phenoxy-l-azetidincarboxamid En opløsning af 6,5 g (0,03 mol) rå 3-[4-(tri-fluormethyDphenoxy]azetidin i 50 ml isopropylether om-10 -øres under nitrogentæppe, medens der tildryppes 4 g (0,04 mol) n-butylisocyanat. Reaktionen er let eksoter-misk, og efter 30 minutter udskilles et faststof. Faststoffet opsamles ved filtrering efter 3 timer, hvilket giver 3,85 g krystallinsk produkt, smeltepunkt 135-136°C.Example 51 N-Butyl-3- [4- (trifluoromethyl) phenoxy-1-azetidinecarboxamide A solution of 6.5 g (0.03 mol) of crude 3- [4- (trifluoromethylphenoxy] azetidine in 50 ml of isopropyl ether The reaction is lightly exothermic and after 30 minutes a solid is separated, the solid is collected by filtration after 3 hours to give 3.85 g. crystalline product, mp 135-136 ° C.
15 Efter 24 timer fås endnu en portion krystaller på 1,5 g, smeltepunkt 132-134°c. De to fraktioner kombineres og omkrystalliseres ud fra cyclohexan, hvilket giver 3,6 g produkt (38%), smeltepunkt 136-137°C.After 24 hours another portion of crystals of 1.5 g, m.p. 132-134 ° C is obtained. The two fractions are combined and recrystallized from cyclohexane to give 3.6 g of product (38%), mp 136-137 ° C.
Analyse: Beregnet for ci5Hi9F3N2°2: 20 C 56,96, H 6,05, N 8,86.Analysis: Calculated for c15 H19 F3 N2 ° 2: C 56.96, H 6.05, N 8.86.
Fundet: C 57,12, H 6,13, N 8,93.Found: C 57.12, H 6.13, N 8.93.
Eksempel 52 N-Propyl-3- [4-(trifluormethyl)phenoxy]-1-azetidincarb-25 oxamidExample 52 N-Propyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide
En opløsning af 8,7 g (0,04 mol) rå 3-[4-(tri-fluormethyl)phenoxy]azetidin i 75 ml isopropylether omrøres under nitrogentæppe, medens der tildryppes 4,3 g (0,05 mol) n-propylisocyanat. Efter omrøring i 2 timer 30 dannes der kun spor af krystallinsk bundfald i reaktionsblandingen, og efter omrøring i 18 timer giver filtrering kun 1,1 g produkt, smeltepunkt 112-114°C. Filtratet inddampes i vakuum, hvilket giver en mørk ravfarvet remanens. Efter 3 dage kan der kun fås 1,3 g yderligere 35 råprodukt fra isopropylether/hexan. Alle reaktionsprodukterne opløses i chloroform og chromatograferes 42 DK 168422 B1A solution of 8.7 g (0.04 mole) of crude 3- [4- (trifluoromethyl) phenoxy] azetidine in 75 ml of isopropyl ether is stirred under nitrogen blanket while 4.3 g (0.05 mole) of n- propylisocyanate. After stirring for 2 hours, only traces of crystalline precipitate form in the reaction mixture, and after stirring for 18 hours, filtration yields only 1.1 g of product, mp 112-114 ° C. The filtrate is evaporated in vacuo to give a dark amber residue. After 3 days, only 1.3 g of additional crude product from isopropyl ether / hexane can be obtained. All the reaction products are dissolved in chloroform and chromatographed
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på en silicagelkolonne på 200 g. Eluering med chloroform giver en rødlig præfraktion, som kasseres. Elue-ringen forandres til 2% ethylacetat/chloroform, derpå til 4% ethylacetat og endelig til 2% methanol/chloroform.on a silica gel column of 200 g. Chloroform elution gives a reddish fraction which is discarded. The elution is changed to 2% ethyl acetate / chloroform, then to 4% ethyl acetate and finally to 2% methanol / chloroform.
5 Alle fraktionerne kombineres og inddampes, hvilket giver 4,1 g hvidt faststof. Omkrystallisation fra cyclohexan giver 2,86 g (23,6%) fint hvidt krystallinsk produkt, smeltepunkt 119-120°C.5 All the fractions are combined and evaporated to give 4.1 g of white solid. Recrystallization from cyclohexane gives 2.86 g (23.6%) of fine white crystalline product, mp 119-120 ° C.
Analyse: Beregnet for C,.H.-F-N-O«: 10 C 55,63, H 5,67, N 9,27.Analysis: Calculated for C, H-F-N-O: C, 55.63; H, 5.67; N, 9.27.
Fundet: C 55,50, H 5,77, N 9,19. -Found: C, 55.50; H, 5.77; N, 9.19. -
Eksempel 53 3_[4_(Trifluormethyl)phenoxy]-1-azetidincarboxamid 15Example 53 3 - [4 - (Trifluoromethyl) phenoxy] -1-azetidine carboxamide 15
En opløsning af 9,6 g (0,025 mol) 3-[4-(tri-fluormethyl)phenoxy]azetidin 56,66% (indeholder diphenyl-methan) i 50 ml acetone behandles med 4,22 g (0,045 mol) ni trourinstof og 5 ml vand. Blandingen opvarmes på en varmeplade, indtil der fås en klar opløsning, og får så 20 lov at køle af til omgivelsernes temperatur i løbet af de næste 4 timer. Reaktionsblandingen fortyndes med 200 ml isvand, og en olie udskilles (diphenylmethan), som opløses i 30/60 petroleumether og fraskilles. Ved henstand dannes et fint hvidt bundfald i den vandige opløs-25 ning. Filtrering giver 3,6 g fine hvide krystaller, smeltepunkt 176-178°C. Efter tørring under 0,5 mm Hg-vakuum ved 80°C reduceres produktets vægt til 3,1 g (47,7%), smeltepunkt 178-179°C.A solution of 9.6 g (0.025 mole) of 3- [4- (trifluoromethyl) phenoxy] azetidine 56.66% (containing diphenylmethane) in 50 ml of acetone is treated with 4.22 g (0.045 mole) of nine nitrogen. and 5 ml of water. The mixture is heated on a hot plate until a clear solution is obtained, and then allowed to cool to ambient temperature over the next 4 hours. The reaction mixture is diluted with 200 ml of ice water and an oil is separated (diphenylmethane) which is dissolved in 30/60 petroleum ether and separated. Upon standing, a fine white precipitate is formed in the aqueous solution. Filtration gives 3.6 g of fine white crystals, mp 176-178 ° C. After drying under 0.5 mm Hg vacuum at 80 ° C, the weight of the product is reduced to 3.1 g (47.7%), mp 178-179 ° C.
Analyse: Beregnet for : 30 C 50,74, H 4,26, N 10,77.Analysis: Calculated for: C, 50.74; H, 4.26; N, 10.77.
Fundet: C 50,72, H 4,24, N 10,72.Found: C, 50.72; H, 4.24; N, 10.72.
3535
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43 DK 168422 B143 DK 168422 B1
Eksempel 54 N-(l-Methylethyl)-3-[4-(trifluormethyl)phenoxy]-1-azetidin-carboxamidExample 54 N- (1-Methylethyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En omrørt opslæmning af 6,2 g (0,02 mol) 3— £4— 5 -(trifluormethyl)phenoxy] azetidin-oxalat i 60 ml tetra- hydrofuran behandles med 1,8 g (0,022 mol) 1-methylethyl-isocyanat, og efter 0,5 time tilsættes 5 ml triethylamin.A stirred slurry of 6.2 g (0.02 mol) of 3- [4- (trifluoromethyl) phenoxy] azetidine oxalate in 60 ml of tetrahydrofuran is treated with 1.8 g (0.022 mol) of 1-methylethyl isocyanate , and after 0.5 hour, 5 ml of triethylamine is added.
Der fås en klar gul opløsning, som omrøres i 18 timer og derpå behandles med 10 ml vand, hvilket giver 5,3 g (87,7%) 10 bleggule krystaller, smeltepunkt 151-152°C.A clear yellow solution is obtained, which is stirred for 18 hours and then treated with 10 ml of water to give 5.3 g (87.7%) of 10 pale yellow crystals, mp 151-152 ° C.
Analyse; Beregnet for C14H17F3N2°2: C 55,63, H 5,67, N 9,27.Analysis; Calcd for C 14 H 17 F 3 N 2 O 2: C 55.63, H 5.67, N 9.27.
Fundet; C 55,80, H 5,71, N 9,24.found; C, 55.80; H, 5.71; N, 9.24.
15 Eksempel 55 N-(1,1-Dimethylethyl·)-3-[4-(trifluormethyl)phenoxy]-1--azetidincarboxamidExample 55 N- (1,1-Dimethylethyl) -3- [4- (trifluoromethyl) phenoxy] -1 - azetidinecarboxamide
En omrørt opslæmning af 6,2 g (0,02 mol) 3— £4— -(trifluormethyl)phenoxy]azetidin-oxalat i 60 ml tetra-20 hydrofuran behandles med 2 g (0,022 mol) 1,1-dimethyle-thylisocyanat, og efter 0,5 time tilsættes 5 ml triethylamin. Reaktionen bliver hurtigt en bleggul opløsning, som omrøres i 18 timer og derpå behandles med 10 ml vand. Efter 20 minutter fraskilles tetrahydrofuran-25 delen, tørres over magnesiumsulfat og inddampes på en roterende fordamper. Den faste remanens omkrystalliseres fra isopropylether, hvilket giver 5 g (79,0%) fine hvide krystaller, smeltepunkt 145-146°C.A stirred slurry of 6.2 g (0.02 mol) of 3- [4- (trifluoromethyl) phenoxy] azetidine oxalate in 60 ml of tetrahydrofuran is treated with 2 g (0.022 mol) of 1,1-dimethylethyl isocyanate and after 0.5 hour 5 ml of triethylamine is added. The reaction quickly becomes a pale yellow solution, which is stirred for 18 hours and then treated with 10 ml of water. After 20 minutes, the tetrahydrofuran portion is separated, dried over magnesium sulfate and evaporated on a rotary evaporator. The solid residue is recrystallized from isopropyl ether to give 5 g (79.0%) of fine white crystals, mp 145-146 ° C.
Analyse; Beregnet for ci5HigF3N2°2: 30 C 56,96, H 6,05, N 8,86.Analysis; Calcd. For c15 HigF3 N2 ° 2: 30 C 56.96, H 6.05, N 8.86.
Fundet: C 56,97, H 6,15, N 8,86.Found: C 56.97, H 6.15, N 8.86.
35 44 DK 168422 B135 44 DK 168422 B1
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Eksempel 56 N-(2-Methylpropyl)-3"[3-(trifluormethyl)phenoxy]-1-azeti-dincarboxamidExample 56 N- (2-Methylpropyl) -3 "[3- (trifluoromethyl) phenoxy] -1-azetidine carboxamide
En omrørt opløsning af 3,6 g (0,022 mol) 1,1'-5 -carbonyldiimidazol i 100 ml methylenchlorid under nitrogen behandles med 1,6 g (0,022 mol) 2-methylpropyla-min (tilsættes via sprøjte og nål gennem en væg anbragt i reaktionskolbens ene hals). Efter omrøring i en time tilsættes på én gang 6,2 g (0,02 mol) 3-[3-(trifluorme-10 thyl)phenoxy]azetidin-oxalat efterfulgt i løbet af 30 minutter af 5 ml triethylamin, og omrøringen fortsættes i 18 timer. Reaktionsblandingen vaskes med 2 x 25 ml vand, tørres over magnesiumsulfat og inddampes i vakuum, hvilket giver 13 g rå fast remanens. Omkrystallisationt 15 fra ethanol/vand giver 5,9 g produkt med en lyserød tone. Endnu en omkrystallisation fra cyclohexan giver 4,8 g fine hvide krystaller, smeltepunkt 124-125°C. Oparbejdning på ny af filtraterne giver 1,2 g yderligere beige-farvede krystaller. Samlet produktudbytte er 75,6% af 20 det teoretiske.A stirred solution of 3.6 g (0.022 mol) of 1,1'-5-carbonyldiimidazole in 100 ml of methylene chloride under nitrogen is treated with 1.6 g (0.022 mol) of 2-methylpropylamine (added via syringe and needle through a wall placed in one neck of the reaction flask). After stirring for one hour, 6.2 g (0.02 mole) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate are added at one time followed by 5 minutes of 5 ml of triethylamine and stirring is continued for 18 hours. The reaction mixture is washed with 2 x 25 ml of water, dried over magnesium sulfate and evaporated in vacuo to give 13 g of crude solid residue. Recrystallization from ethanol / water gives 5.9 g of product with a pink tone. Another recrystallization from cyclohexane gives 4.8 g of fine white crystals, mp 124-125 ° C. Reprocessing of the filtrates gives 1.2 g of additional beige colored crystals. Overall product yield is 75.6% of the theoretical.
Analyse: Beregnet for : C 56,96, H 6,05, N 8,86.Analysis: Calculated for: C 56.96, H 6.05, N 8.86.
Fundet: C 57,01, H 6,11, N 8,88.Found: C 57.01, H 6.11, N 8.88.
25 Eksempel 57 N- (1, lr>Dimethylethyl) -3- [ 3- (trif luormethyl) phenoxy] -1-a-zetidincarboxamidExample 57 N- (1,1r> Dimethylethyl) -3- [3- (trifluoromethyl) phenoxy] -1-a-zetidine carboxamide
En omrørt opslæmning af 6,2 g (0,02 mol) 3-[3--(trifluormethyl)phenoxy]azetidin-oxalat i 60 ml tetra-30 hydrofuran behandles med 2 g (0,02 mol) 1,1-dimethylethyl-isocyanat efterfulgt i løbet af 30 minutter af 5 ml tri-ethylamin. Den klare opløsning, som dannes, omrøres i 18 timer. Reaktionsblandingen behandles med 10 ml vand, og efter 20 minutter fraskilles tetrahydrofuran-35 delen, tørres over magnesiumsulfat og inddampes på en roterende fordamper. Den faste remanens omkrystalliseresA stirred slurry of 6.2 g (0.02 mol) of 3- [3- (trifluoromethyl) phenoxy] azetidine oxalate in 60 ml of tetrahydrofuran is treated with 2 g (0.02 mol) of 1,1-dimethylethyl -isocyanate followed over 30 minutes by 5 ml of triethylamine. The clear solution which is formed is stirred for 18 hours. The reaction mixture is treated with 10 ml of water and after 20 minutes the tetrahydrofuran portion is separated, dried over magnesium sulfate and evaporated on a rotary evaporator. The solid residue is recrystallized
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45 DK 168422 B1 fra ethanol/vand, hvilket giver 5f8 g (91,7%) fine hvide krystaller, smeltepunkt 105-107°C.451 from ethanol / water to give 5f8 g (91.7%) of fine white crystals, mp 105-107 ° C.
Analyse: Beregnet for ci5Hi9F3N2°2: C 56,96, H 6,05, N 8,86.Analysis: Calculated for c15 H19 F3 N2 ° 2: C 56.96, H 6.05, N 8.86.
5 Fundet: C 56,95, H 6,14, N 8,92.Found: C, 56.95; H, 6.14; N, 8.92.
Eksempel 58 N- (2-Methylpropyl) -3- [4- (tr if luorme thyl) phenoxy] -1-azeti-dincarboxamid 10 En omrørt opløsning af 3,6 g (0,022 mol) 1,1- -carbonyldiimidazol i 100 ml methylenchlorid under nitrogen behandles med 1,6 g (0,022 mol) 2-methylpropylamin (tilsat via en sprøjte og kanyle gennem en væg anbragt i reaktionskolbens ene hals) . Efter omrøring i en time 15 tilsættes på én gang 6,2 g (0,02 mol) 3-[4-(trifluorme-thyl) phenoxy] azetidin-oxalat efterfulgt i løbet af 30 minutter af 5 ml triethylamin, og omrøringen fortsættes i 18 timer. Reaktionsblandingen vaskes med 2 x 25 ml vand, tørres over magnesiumsulfat og inddampes i vakuum.Example 58 N- (2-Methylpropyl) -3- [4- (trifluoromethyl) phenoxy] -1-azetidine carboxamide A stirred solution of 3.6 g (0.022 mol) of 1,1-carbonyldiimidazole in 100 ml of methylene chloride under nitrogen is treated with 1.6 g (0.022 mole) of 2-methylpropylamine (added via a syringe and cannula through a wall placed in one neck of the reaction flask). After stirring for one hour, 6.2 g (0.02 mole) of 3- [4- (trifluoromethyl) phenoxy] azetidine oxalate are added at one time followed by 5 minutes of 5 ml of triethylamine and stirring is continued for 1 hour. 18 hours. The reaction mixture is washed with 2 x 25 ml of water, dried over magnesium sulfate and evaporated in vacuo.
20 Den faste remanens omkrystalliseres fra ethanol/vand, hvilket giver 5,4 g (85,4%) bleggule krystaller.The solid residue is recrystallized from ethanol / water to give 5.4 g (85.4%) of pale yellow crystals.
Analyse: Beregnet for ci5H]_9F3N2°2: C 56,96, H 6,05, N 8,86.Analysis: Calculated for C15 H18 F3 N2 O2: C 56.96, H 6.05, N 8.86.
Fundet: C 57,02, H 6,08, N 8,82.Found: C 57.02, H 6.08, N 8.82.
2525
Eksempel 59 3-(3-Chlorphenoxy)-1-azetidincarboxanidExample 59 3- (3-Chlorophenoxy) -1-azetidinecarboxanide
En opløsning af 5,4 g (0,017 mol) 1-chlorcar-bonyl-3-(3-chlorphenoxy)azetidin i 20 ml tetrahydrofuran 30 behandles med 3 ml ammoniumhydroxid og omrøres i en time. Reaktionsblandingen inddampes i vakuum til 4 g vådt faststof, som omkrystalliseres efter tørring fra benzen, hvilket giver 1,5 g hvidt krystallinsk pulver, smeltepunkt 163-164,5°C. Udbyttet beregnet ud fra l-(2-phenyl-35 ethyl)azetidinforbindelsen er 38,9%.A solution of 5.4 g (0.017 mol) of 1-chlorocarbonyl-3- (3-chlorophenoxy) azetidine in 20 ml of tetrahydrofuran is treated with 3 ml of ammonium hydroxide and stirred for one hour. The reaction mixture is evaporated in vacuo to 4 g of wet solid which is recrystallized after drying from benzene to give 1.5 g of white crystalline powder, mp 163-164.5 ° C. The yield calculated from the 1- (2-phenyl-35-ethyl) azetidine compound is 38.9%.
46 DK 168422 B146 DK 168422 B1
OISLAND
Analyse: Beregnet for C10HllC1N2O2'· C 52,991 H 4,89, N 12,36.Analysis: Calculated for C 10 H 11 ClN 2 O 2 · C 52.991 H 4.89, N 12.36.
Fundet: C 52,99, H 4,91, N 12,32.Found: C, 52.99; H, 4.91; N, 12.32.
5 Eksempel 60 3-(3-Fluorphénoxy)-N-methyl-l-azetidincarboxamidExample 60 3- (3-Fluorophenoxy) -N-methyl-1-azetidine carboxamide
En omrørt blanding af 5,4 g (0,02 mol) 3-(3--fluorphenoxy)azetidin-oxalat og 1,7 g (0,022 mol) me-thylisocyanat i 20 ml tetrahydrofuran behandles med 5 ml 10 triethylamin, hvorefter omrøringen fortsættes i 3 timer.A stirred mixture of 5.4 g (0.02 mol) of 3- (3-fluorophenoxy) azetidine oxalate and 1.7 g (0.022 mol) of methyl isocyanate in 20 ml of tetrahydrofuran is treated with 5 ml of triethylamine, then the stirring continue for 3 hours.
Reaktionen fortyndes med vand, og det opnåede fine krystallinske bundfald opsamles ved filtrering og tørres ved 60°C under vakuum, hvilket giver 3 g (66,9%) produkt, smeltepunkt 155-156°C.The reaction is diluted with water and the obtained fine crystalline precipitate is collected by filtration and dried at 60 ° C under vacuum to give 3 g (66.9%) of product, mp 155-156 ° C.
15 Analyse: Beregnet for cnHi3FN2°2: C 58,92, H. 5,84, N 12,49.Analysis: Calculated for C11 H13 FN2 O2: C, 58.92, H. 5.84, N, 12.49.
Fundet: C 58,93, H 5,91, N 12,26.Found: C, 58.93; H, 5.91; N, 12.26.
Eksempel 61 20 3-(3-Fluorphenoxy) -N-methyl-l-azetidincarboxamidExample 61 3- (3-Fluorophenoxy) -N-methyl-1-azetidine carboxamide
Til en omrørt opslæmning af 0,38 g (0,02 mol) 60% natriumhydrid. som mineraloliesuspension i 10 ml tør dime-thylformamid tildryppes under nitrogen 1,12 g (0,01 mol) 3-fluorphenol i 20 ml dimethylformamid. Efter en time 25 opvarmes blandingen ved 90°C i 20 minutter, hvorpå der tilsættes 2,1 g (0,01 mol) N-methyl-3-[-(methansulfonyl)-oxy]-1-azetidincarboxamid som faststof. Derpå omrøres reaktionsblandingen ved 90°C i 8 timer. Reaktionsblandingen afkøles ved tilsætning af isvand og fortyndes så 30 yderligere til 200 ml med vand og ekstraheres med 3 x 50 ml methylenchlorid. Der fås mindre end 1 g olie efter inddampninger af ekstrakterne. Ekstraktion med 4 x 50 ml benzen giver kun spor af produkt. Massespektrum (Cl) viser det forventede p+1 ved 225 m/e. Produktet størkner 35 ved henstand og omkrystalliseres fra methanol/vand, DK 168422 B1 47 o hvilket giver 650 mg (29,0% flagelignende sølvagtige krystaller, smeltepunkt 165-158°C.To a stirred slurry of 0.38 g (0.02 mol) of 60% sodium hydride. As a mineral oil suspension in 10 ml of dry dimethylformamide, 1.12 g (0.01 mole) of 3-fluorophenol in 20 ml of dimethylformamide is added dropwise. After one hour, the mixture is heated at 90 ° C for 20 minutes, then 2.1 g (0.01 mole) of N-methyl-3 - [- (methanesulfonyl) oxy] -1-azetidinecarboxamide is added as a solid. Then, the reaction mixture is stirred at 90 ° C for 8 hours. The reaction mixture is cooled by the addition of ice water and then further diluted to 200 ml with water and extracted with 3 x 50 ml of methylene chloride. Less than 1 g of oil is obtained after evaporation of the extracts. Extraction with 4 x 50 ml benzene gives only traces of product. Mass spectrum (CI) shows the expected p + 1 at 225 m / e. The product solidifies on standing and recrystallized from methanol / water, yielding 650 mg (29.0% flag-like silvery crystals, mp 165-158 ° C).
Analyse: Beregnet for cnHi3FN2°2: C 58,92, H 5,84, N 12,49.Analysis: Calculated for C11 H13 FN2 O2: C 58.92, H 5.84, N 12.49.
5 Pundet: C 58,93, H 5,91, N 12,42.5 Pounds: C 58.93, H 5.91, N 12.42.
Anti-angst-prøve. Den prøvescreeningsmetode, der benyttes, til at vise positiv anti-angst-resultat, er en modifikation af Vogel-konfliktprøven, som er base-10 ret på chock-undertrykt drikkeadfærd hos rotter, beskrevet af J.R. Vogel m.fl. i Psychopharmacology 21,__l-7 (1971). Den anvendte metode er som følger: Prøvere ference- og kontrolpræparater indgives intraperitonealt i fysiologisk saltvandsopløsning, 0,5% vandig methylcel-15 lulose eller andet afhængigt af en opløselighed i en sådan koncentration, at det indgivne volumen er 5 ml/kg. Prøvepræparatets indledende screeningsdosis er i reglen 100 mg/kg, og referencepræparatet ("Diazepam") er 5 mg/kg.Anti-anxiety test. The sample screening method used to show positive anti-anxiety results is a modification of the Vogel Conflict Test, which is based on the shock-suppressed drinking behavior of rats, described by J.R. Vogel et al. in Psychopharmacology 21, __ l-7 (1971). The method used is as follows: Sample ference and control preparations are administered intraperitoneally in physiological saline solution, 0.5% aqueous methyl cellulose or otherwise depending on a solubility at such a concentration that the volume administered is 5 ml / kg. The initial screening dose of the sample is usually 100 mg / kg and the reference preparation ("Diazepam") is 5 mg / kg.
Før indgift holdes rotter 2 pr. bur og undvæ-20 rer vand i 48 timer og fordeles derefter tilfældigt i behandlingsgrupper på 5. Føde er tilgængelig ad libitum.Prior to administration, rats are maintained at 2 pr. cages and evacuates water for 48 hours and is then randomly assigned to treatment groups of 5. Food is available ad libitum.
30 minutter efter indgift anbringes hver rotte for sig i et plexiglasbur, der måler 18 cm i bredden, 13 cm i højden og 29,5 cm i længden og er forsynet med et gittergulv 25 af rustfrit stål. Buret dækkes med et plastlåg med huller for at lette indførelse af en vandflaske (30 ml plastcentr i fugeglas) .med gummiprop og metaldrikkerør. Et "Drinkometer"-kredsløb (Omniteck Electronics, Inc., 3000 Cortona Road, Columbus, Ohio 43204) forbindes med drik-30 kerøret og apparatets gittergulv, så at rotten slutter en strømkreds, hver gang den slikker på røret. Metoden går ud på at lade rotten finde drikkerøret og slikke 20 gange (som vist på "Drinkometer" digitalaflæsning), før forsøget påbegyndes. Rotter, der ikke opfylder dette 35 kriterium, kasseres. En forsøgsrunde på tre minutter indledes med et chok på 0,25 milliampere ved det 20.30 minutes after administration, each rat is placed individually in a plexiglass cage measuring 18 cm in width, 13 cm in height and 29.5 cm in length and provided with a stainless steel grating floor 25. The cage is covered with a plastic lid with holes to facilitate the insertion of a water bottle (30 ml plastic center in sealing glass) with rubber stopper and metal drinking pipe. A "Drinkometer" circuit (Omniteck Electronics, Inc., 3000 Cortona Road, Columbus, Ohio 43204) is connected to the beverage tube and the appliance's grille floor so that the rat closes a circuit every time it licks the tube. The method involves letting the rat find the drinking tube and licking 20 times (as shown on the "Drinkometer" digital reading) before starting the experiment. Rats that do not meet this criterion are discarded. A three-minute trial begins with a shock of 0.25 milliamps at the 20th.
OISLAND
48 DK 168422 B1 slik. Rotter, der fortsætter med at drikke, bliver udsat for et chok for hvert efterfølgende 20. slik. Det samlede antal chok under forsøgsrunden noteres på følgende måde: 5 totalt antal slik . , _ . . . , , -2q- +1= samlet antal chok48 DK 168422 B1 candy. Rats that continue to drink are subjected to a shock for each subsequent 20th candy. The total number of shocks during the trial round is noted as follows: 5 total number of sweets. , _. . . ,, -2q- + 1 = total number of shocks
Statistisk analyse udføres ved hjælp af Dunn's flerdobbelte sammenligningsprøve beskrevet af O.J. Dunn, Technometrics 6(3), 241-252 .(1964). Det gennemsnitlige 10 antal chok, som kontrolgruppen oplever, sammenlignes med dem, som hver præparatbehandlede gruppe kommer ud for. Signifikans sættes ved P<0,1. Jo højere det samlede antal chok er sammenlignet med kontrolgruppen, jo mere aktiv er forbindelsen. Aktive forbindelser kan derpå af-15 prøves på lignende måde ved nedsatte doser. Eksempelvis er en foretrukken forbindelse, forbindelsen ifølge eksempel 16, dvs. N-cyclopropyl-3-[4-(trifluormethyl)phenoxy]--1-azetidincarboxamid, aktiv ved en så lav dosis som 10 mg/kg, hvor det samlede antal chok, der fås, beregnet i 20 sammenligning med kontrolgruppen, er 14/4,6 (P = 0,03) sammenlignet med ca. 12-15/4 for "Diazepam". De opnåede forsøgsresultater fremgår af nedenstående tabel.Statistical analysis is performed using Dunn's multiple comparison test described by O.J. Dunn, Technometrics 6 (3), 241-252 (1964). The average number of shocks experienced by the control group is compared to those experienced by each preparation group. Significance is set at P <0.1. The higher the total number of shocks compared to the control group, the more active the connection. Active compounds can then be tested similarly at reduced doses. For example, a preferred compound is the compound of Example 16, i. N-cyclopropyl-3- [4- (trifluoromethyl) phenoxy] -1-azetidinecarboxamide, active at a dose as low as 10 mg / kg, with the total number of shocks obtained calculated in comparison with the control group being 14 / 4.6 (P = 0.03) compared with ca. 12-15/4 for "Diazepam". The test results obtained are shown in the table below.
25 30 35 DK 168422 B1 4925 30 35 DK 168422 B1 49
TabelTable
Dosis IP Behandlet/KontrolDose IP Treated / Control
Eks. nr. mg/kg Chock 5 - 7 50 (PO) 2,3/2,0 8 100 (PO) 7,8/1,0 56,2 (PO) 3,2/1,0 10 9 100 (PO) 1/6/1,8 10 56,2 (PO) 8,4/1,1* 31,6 (PO) 6,0/1,2 15 11 200 (PO) 1,75/1,25 12 56,2 10,2/2,6 31.5 6,8/5,4 20 13 56,2 10,2/2,6 31.6 18,8/2,2 14 31,6 18,0/4,8 25 17,8 14,6/4,8 15 16 17,8 13,0/3,8 30 10,0 14,2/4,6 17 18 56,2 10,5/2,4 35 31,6 15,0/2,4 17,8 4,6/2,4 20 10,0 6,6/2,4 40 22 31 56,2 12,4/4,2 37 100 (PO) 2,2/1,2 45 38 39 50 40 45 56,2 (PO) 3,2/1,2 31,6 (PO) 2,0/1,2 55 *Gennemsnit af to eller flere værdier 50 DK 168422 B1Ex. No. mg / kg Shock 5 - 7 50 (PO) 2.3 / 2.0 8 100 (PO) 7.8 / 1.0 56.2 (PO) 3.2 / 1.0 10 9 100 (PO) 1/6 / 1.8 10 56.2 (PO) 8.4 / 1.1 * 31.6 (PO) 6.0 / 1.2 15 11 200 (PO) 1.75 / 1.25 12 56.2 10.2 / 2.6 31.5 6.8 / 5.4 20 13 56.2 10.2 / 2.6 31.6 18.8 / 2.2 14 31.6 18.0 / 4.8 25 17.8 14.6 / 4.8 15 16 17.8 13.0 / 3.8 30 10.0 14.2 / 4.6 17 18 56.2 10.5 / 2.4 35 31.6 15 , 0 / 2.4 17.8 4.6 / 2.4 20 10.0 6.6 / 2.4 40 22 31 56.2 12.4 / 4.2 37 100 (PO) 2.2 / 1 , 2 45 38 39 50 40 45 56.2 (PO) 3.2 / 1.2 31.6 (PO) 2.0 / 1.2 55 * Average of two or more values 50 DK 168422 B1
Farmaceutiske præparater til behandling af angsttilstande.Pharmaceuticals for the treatment of anxiety disorders.
De aktive forbindelser til behandling af angst hos mennesker og pattedyr indgives i form af et farmaceutisk præparat indeholdende mindst én af forbindelserne med formlen 5 I kombineret med en farmaceutisk bærer eller ekscipiens. Forbindelserne foreligger således i et terapeutisk præparat, der er egnet til oral, rectal, parenteral, subcutan, in-tramuskulær, intraperitoneal eller intravenøs indgift. Således kan f.eks. præparaterne til oral indgift foreligge i 10 form af eliksirer, kapsler, tabletter eller overtrukne tabletter indeholdende bærere, der er almindelig anvendt inden for pharmacien. Egnede tabletekscipienser omfatter lactose, kartoffel- og majsstivelse, talkum, gelatine, stearin- og kiselsyre, magnesiumstearat og polyvinylpyrrolidon.The active compounds for the treatment of anxiety in humans and mammals are administered in the form of a pharmaceutical composition containing at least one of the compounds of Formula 5 in combination with a pharmaceutical carrier or excipient. Thus, the compounds are present in a therapeutic composition suitable for oral, rectal, parenteral, subcutaneous, intramuscular, intraperitoneal or intravenous administration. Thus, e.g. the oral preparations are in the form of elixirs, capsules, tablets or coated tablets containing carriers commonly used in the field of pharmacology. Suitable tablet excipients include lactose, potato and corn starch, talc, gelatin, stearic and silicic acid, magnesium stearate and polyvinylpyrrolidone.
15 Til parenteral indgift kan bærere omfatte en steril, parenteralt acceptabel væske, f.eks. vand eller arachisolie indeholdt i ampuller.For parenteral administration, carriers may comprise a sterile, parenterally acceptable fluid, e.g. water or arachis oil contained in ampoules.
I præparater til rectal indgift kan bæreren omfatte en suppositoriebase, f.eks. kakaosmør eller glycerid.In rectal administration preparations, the carrier may comprise a suppository base, e.g. cocoa butter or glyceride.
20 Præparaterne kan med fordel tilberedes som doserings enheder, idet hver enhed er indrettet til at give en fastsat dosis aktive stoffer. Tabletter, overtrukne tabletter, kapsler, ampuller og suppositorier er eksempler på foretrukne doseringsformer. Det er kun nødvendigt, at den aktive be-25 standdel udgør en effektiv mængde, dvs., således at en passende effektiv dosis vil være i overensstemmelse med den anvendte doseringsform. De nøjagtige individuelle doseringer samt den daglige dosering bestemmes naturligvis i overensstemmelse med medicinske standardprincipper under tilsyn af 30 en læge eller dyrlæge.The compositions can advantageously be prepared as dosage units, each unit being adapted to provide a fixed dose of active substances. Tablets, coated tablets, capsules, ampoules and suppositories are examples of preferred dosage forms. It is only necessary that the active ingredient constitute an effective amount, i.e., that a suitably effective dose will be in accordance with the dosage form used. The exact individual dosages as well as the daily dosage are, of course, determined in accordance with standard medical principles under the supervision of a physician or veterinarian.
En effektiv daglig dosering med forbindelser med formlen I som antiangstmidler anslås at være ca. 1-10 mg/kg/-dag legemsvægt baseret på data opnået ved dyreforsøg.An effective daily dosage of compounds of formula I as anti-anxiety agents is estimated to be approx. 1-10 mg / kg / day body weight based on data obtained from animal studies.
3535
Claims (8)
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US70663285A | 1985-02-28 | 1985-02-28 | |
US70663285 | 1985-02-28 |
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DK90186D0 DK90186D0 (en) | 1986-02-27 |
DK90186A DK90186A (en) | 1986-08-29 |
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DK90186A DK168422B1 (en) | 1985-02-28 | 1986-02-27 | Use of a 3-aryloxyazetidine carboxamide or carbothioamide or a pharmaceutically acceptable acid addition salt thereof for the preparation of a pharmaceutical composition for the treatment of anxiety states |
DK36893A DK170270B1 (en) | 1985-02-28 | 1993-03-29 | Use of a 3-phenoxyazetidine carboxamide for the preparation of a pharmaceutical composition for the treatment of muscle tension and / or muscle plasticity |
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DK36893A DK170270B1 (en) | 1985-02-28 | 1993-03-29 | Use of a 3-phenoxyazetidine carboxamide for the preparation of a pharmaceutical composition for the treatment of muscle tension and / or muscle plasticity |
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JP (1) | JPH0699386B2 (en) |
AU (1) | AU599312B2 (en) |
CA (1) | CA1294274C (en) |
DK (2) | DK168422B1 (en) |
ES (1) | ES8802300A1 (en) |
GR (1) | GR860531B (en) |
IL (1) | IL77995A (en) |
IN (1) | IN162808B (en) |
NZ (1) | NZ215312A (en) |
PH (1) | PH25525A (en) |
PT (1) | PT82118B (en) |
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DE3641343A1 (en) * | 1986-12-03 | 1988-06-16 | Hoechst Ag | CARBAMOYLIMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS FUNGICIDES |
AU2009220974B2 (en) * | 2008-03-04 | 2013-10-24 | Vernalis (R&D) Ltd. | Azetidine derivatives |
CN113754541A (en) * | 2020-06-02 | 2021-12-07 | 深圳湾实验室 | Micromolecule inhibitor targeting EB virus nuclear antigen protein, preparation method and application thereof |
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US4226861A (en) * | 1978-04-18 | 1980-10-07 | A. H. Robins Company, Inc. | N-Lower-alkyl 3-phenoxy-1-azetidinecarboxamides |
IL68699A (en) * | 1982-08-19 | 1986-08-31 | Robins Co Inc A H | 3-phenoxy-1-azetidine-carboxamides,their preparation and pharmaceutical compositions containing them |
US4505907A (en) * | 1982-09-02 | 1985-03-19 | A. H. Robins Company, Inc. | N-Formyl and N-hydroxymethyl-3-phenoxy-1-azetidinecarboxamides |
US4594189A (en) * | 1983-07-06 | 1986-06-10 | A. H. Robins Company, Inc. | Process for preparing 3-phenoxy-1-azetidines and carboxamide derivatives |
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1986
- 1986-02-10 IN IN90/MAS/86A patent/IN162808B/en unknown
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- 1986-02-21 AU AU53888/86A patent/AU599312B2/en not_active Ceased
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- 1986-02-26 PH PH33452A patent/PH25525A/en unknown
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- 1986-02-27 DK DK90186A patent/DK168422B1/en not_active IP Right Cessation
- 1986-02-27 ES ES552472A patent/ES8802300A1/en not_active Expired
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ZA861215B (en) | 1986-10-29 |
DK36893A (en) | 1993-03-29 |
GR860531B (en) | 1986-06-24 |
PT82118B (en) | 1988-07-01 |
PT82118A (en) | 1986-03-01 |
AU5388886A (en) | 1986-09-04 |
DK90186A (en) | 1986-08-29 |
JPS61205254A (en) | 1986-09-11 |
DK90186D0 (en) | 1986-02-27 |
DK170270B1 (en) | 1995-07-24 |
ES8802300A1 (en) | 1987-05-01 |
IL77995A (en) | 1989-06-30 |
PH25525A (en) | 1991-07-24 |
JPH0699386B2 (en) | 1994-12-07 |
DK36893D0 (en) | 1993-03-29 |
IN162808B (en) | 1988-07-09 |
AU599312B2 (en) | 1990-07-19 |
NZ215312A (en) | 1990-02-26 |
CA1294274C (en) | 1992-01-14 |
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B1 | Patent granted (law 1993) | ||
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