DK164363B - 3,4-disubstituerede 1,2,5-thiadiazol-1-oxider - Google Patents

3,4-disubstituerede 1,2,5-thiadiazol-1-oxider Download PDF

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DK164363B
DK164363B DK268990A DK268990A DK164363B DK 164363 B DK164363 B DK 164363B DK 268990 A DK268990 A DK 268990A DK 268990 A DK268990 A DK 268990A DK 164363 B DK164363 B DK 164363B
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alkyl
reaction
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thiadiazole
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DK268990A
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Ronnie Ray Crenshaw
Aldo Antonio Algieri
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Squibb Bristol Myers Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
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    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Lubricants (AREA)

Description

i
DK 164363 B
Den foreliggende opfindelse angår hidtil ukendte 3,4-disubstitue-rede 1,2,5-thiadiazol-1-oxider, der er nyttige som udgangsforbindelser ved fremstillingen af de i dansk patentansøgning nr. 3718/80 (svarende til fremlæggelsesskrift nr. 160.611 B) omhandlede histamin H2-5 antagonister.
Disse histamin H2-antagonister, som er nyttige til behandling af sygdommen peptisk ulcer, har formlen (0)p 10 N N„
M
A-(CH-,) Z(CH_) NH \l
2 ni 2 n R
hvori 15 p betegner 1 eller 2, 1 2 3 R betegner hydroxy eller NR R , R og R hver især uafhængigt af hinanden betegner hydrogen, (lavere)- alkyl, (lavere)alkenyl, (lavere)alkynyl, cycl o(lavere)al kyl, cyclo- (lavere)alkyl(lavere)alkyl, hydroxy(lavere)al kyl, (lavere)alkoxy- 20 (lavere)alkyl, (lavere)alkylthio(lavere)alkyl, ami no(lavere)al kyl, (lavere)al kyl amino(lavere)al kyl, di(lavere)al kyl amino(lavere)al kyl, pyrrolidino(lavere)al kyl, piperidino(lavere)alkyl, morpholino(lavere)- alkyl, piperazino(lavere)alkyl, pyridyl(lavere)al kyl, amino, (lavere)- alkylamino, di(lavere)al kyl amino, 2,2,2-trifluorethyl, 2-fluorethyl, 25 hydroxy, (lavere)alkoxy, 2,3-dihydroxypropyl, cyano, cyano(lavere)- alkyl, amidino, (lavere)alkylamidino, A'-(CH2)m,Z'(CH2)n,-, phenyl, phenyl(lavere)al kyl, substitueret phenyl eller substitueret phenyl- (lavere)alkyl, hvori phenylringen kan indeholde en eller to substi- tuenter uafhængigt valgt blandt (lavere)al kyl, hydroxy, (lavere)alkoxy 30 og halogen eller en substituent valgt blandt methyl endi oxy, trifluor- 2 3 methyl og di(lavere)alkyl amino, under den forudsætning at R og R ikke begge er cyclo(lavere)alkyl, phenyl, substitueret phenyl, amino, (lavere)al kyl ami no, di(lavere)al kyl amino, hydroxy, (lavere)alkoxy, cyano, amidino, (lavere)alkylamidino eller A'-(CH2)m, Z'(CH2)n,-, eller 35 R^ og R^ betegner tilsammen -CH2CH2X(CH2)r-, r er et helt tal fra 1 til 3, inklusive, X betegner methyl en, svovl, oxygen eller N-R4 under den forudsætning, at når r er 1, er X methyl en, 4
DK 164363 B
2 R betegner hydrogen, (lavere)al kyl, (lavere)alkenyl, (lavere)alkynyl, (lavere)alkanoyl eller benzoyl, m og m' er hver især uafhængigt af hinanden et helt tal fra 0 til 2, inklusive, 5 n og n' er hver især uafhængigt af hinanden et helt tal fra 2 til 4, inklusive, Z og V er hver især uafhængigt af hinanden svovl, oxygen eller methyl en, A og A' er hver især uafhængigt af hinanden phenyl, imidazolyl, thia-10 zolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl eller pyridyl, under den forudsætning at A og A' uafhængigt af hinanden kan indeholde en eller to substituenter, idet den første substituent er udvalgt blandt (lavere)alkyl, hydroxy, trifluormethyl, halogen, amino, hydroxymethyl, (lavere)alkoxy, 15 -(CH2>qN=C\T 09 -(CH2>qNR5R6 "^~NHR4 20 og den anden er udvalgt blandt (lavere)al kyl, hydroxy, trifluormethyl, halogen, amino, hydroxymethyl og (lavere)alkoxy, q er et helt tal fra 0 til 6, inklusive, begge R4 er uafhængigt af 4 hinanden som ovenfor defineret, eller de to R -grupper kan tilsammen betegne ethyl en, og 25 R^ og R® betegner hver især uafhængigt af hinanden hydrogen, (lavere)- alkyl, (lavere)alkenyl, (lavere)alkynyl, cyclo(lavere)al kyl eller phenyl, under den forudsætning at R og R ikke begge kan være cyclo- 5 6 (lavere)alkyl eller phenyl, eller R og R kan sammen med det nitrogen-atom, hvortil de er knyttet, betegne pyrrolidino, morpholino, piperi-30 dino, methylpiperidino, N-methylpiperazino eller homopiperidino, eller et ikke-toxisk, farmaceutisk acceptabelt salt, hydrat, sol vat eller li-oxid deraf.
De 3,4-disubstituerede 1,2,5-thiadiazol-l-oxider ifølge opfindelsen har den almene formel (II) 35
^ II
DK 164363B
3
O
M
5 / \ 7
k R
hvori R^ betegner halogen, lavere(alkoxy), lavere(alkylthio), phenoxy eller phenylthio, som kan indeholde 1 eller 2 substituenter udvalgt 10 blandt halogen, lavere(alkyl), lavere(alkoxy) og nitro. Forbindelsen 3,4-dimethoxy-l,2,5-thiadiazol-l-oxider er den mest foretrukne forbindelse ifølge opfindelsen.
Forbindelserne med formlen II, hvori begge betegner alkoxy, alkylthio, phenoxy, phenylthio eller substitueret phenylthio kan 15 fremstilles ved omsætning af dichlorforbindelsen med formlen VI med den passende alkanol, al kyl thiol, phenol, thiophenol eller substituerede thiophenol.
o 20
. ^ H
Jq/ \ 8
/S\ R O OR
N N
- H
cl Cl x' O
M
30 · R»S \r8' 8 IJ~h Note: R = ålkyl eller phenyl. 1 35 R = alkyl, phenyl eller substitueret phenyl.
DK 164363 B
4
Omsætningen udføres i et inert organisk opløsningsmiddel, såsom O o/ ether, dimethyl formamid, eller lignende. Når reaktanten R OH eller R SH er en væske, f.eks. methanol, ethanol, ethylmercaptan eller thiophenol, kan reaktionen udføres i et overskud af denne reaktant som et opløs-5 ningsmiddel.
Forbindelse VI kan fremstilles ud fra den kendte forbindelse 3,4-dihydroxy-l,2,5-thiadiazol-l-oxid [der selv fremstilles i henhold til fremgangsmåden beskrevet i Org. Prep. Proced., 1, 255 (1969)] ved den samme fremgangsmåde, der benyttes til fremstilling af det tilsvarende 10 dioxyd ud fra 3,4-dihydroxy-l,2,5-thiadiazol-l,l-dioxid [se J. Org.
Chem., 40, 2743 (1975)].
Alternativt kan forbindelserne ifølge opfindelsen med formlen Il-a fremstilles ved omsætning af en passende substitueret oxaldiimidatester med formlen IX med SC12 eller SgCl2 i et inert opløsningsmiddel, såsom 15 dimethyl formamid, til dannelse af den tilsvarende 3,4-disubstituerede 1,2,5-thiadiazol med formlen X, som derpå oxideres til det tilsvarende 1-oxid med formlen Il-a.
20 R80 OR8 r80 .OR8 \ / SC1_ \ / [Λΐ Forbindelse C—iC,--1^, Tf Λ // W ΟΓ S2C12 i \ 25 HN «Η \ /
O
IX
X
30
O
Oxaldiimidatesterne med formlen IX, hvori R betegner methyl, ethyl, n-propyl, isopropyl, n-butyl og n-pentyl, er kendte, og fremstillingen deraf er beskrevet i Chem. Ber., 107, 3121 (1974). Til-
O
svarende forbindelser, hvori R betegner phenyl, eventuelt substitueret 35 med (lavere)al kyl, (lavere)alkoxy, halogen eller nitro, kan fremstilles
O
ved en lignende fremgangsmåde. Forbindelser med formlen X, hvori R betegner methyl eller ethyl, er beskrevet i J. Org. Chem., 40, 2749 (1975).
DK 164363 B
5 I litteraturen er det beskrevet, at 1,2,5-thiadiazolkernen er følsom over for oxidation, at oxidation af thiadiazoler med persyrer sædvanligvis ledsages af ring-destruktion og dannelse af sulfation, og at forsøg på at fremstille 1,2,5-thiadiazol-1,1-dioxid ved pereddike-5 syreoxidation af basisringen resulterer i ring-spaltning. Det har nu overraskende vist sig, at 3,4-disubstituerede 1,2,5-thiadiazol-1--oxiderne med formlen VII let kan fremstilles i godt udbytte ved oxidation af den tilsvarende 3,4-disubstituerede 1,2,5-thiadiazol med formlen X med en persyre, såsom m-chlorperbenzoesyre, i et inert 10 opløsningsmiddel, såsom chloroform.
Der er nu fundet en særlig elegant fremgangsmåde, hvorved en forbindelse med formlen Il-a kan fremstilles i en én-trins-omsætning direkte ud fra en forbindelse med formlen IX ved omsætning af sidstnævnte med thionylchlorid.
A «* '\_X
>< ri
XNH
20 o ix II_a
Denne omsætning udføres i et inert organisk opløsningsmiddel, 25 såsom methylenchlorid, chloroform, eller lignende. Skønt reaktionen kan udføres uden tilsætning af en base som et syrebindende middel, foretrækkes det at tilsætte ca. to ækvivalenter af en base til fjernelse af det HC1, der dannes under omsætningen. Der opnås derved højere udbytter af forbindelse Il-a. Egnede baser inkluderer uorganiske baser, såsom 30 natriumcarbonat, kaliumcarbonat, natriumbicarbonat og kaliumbicarbonat, og organiske baser, såsom triethylamin, pyridin, og lignende. Denne fremgangsmåde eliminerer ikke blot et trin, men den er meget mere økonomisk, forsåvidt som den undgår anvendelsen af dyre oxideringsmidler, såsom m-chlorperbenzoesyre. Reaktionen kan udføres ved en 35 temperatur på fra ca. -20° til ca. 25°, og fortrinsvis ved ca. 0° til ca. 10°. Den nedenfor anførte procedure belyser fremstillingen, ved
O
denne fremgangsmåde, af forbindelsen med formlen Il-a, hvori R betegner methyl.
DK 164363 B
6
Illustrativ procedure 3,4-dimethoxv-l,2,5-thiadiazol-l-oxid
En opløsning af dimethyloxaldiimidat (4,0 g, 34,5 mmol) og pyridin 5 (5,71 ml, 5,58 g, 70,6 mmol) i 8 ml CHgCl2 sattes dråbevis til en kold opløsning af thionylchlorid (2,61 ml, 4,25 g, 34,7 mmol) i 18 ml CHgClg under en nitrogenstrøm med en sådan hastighed, at reaktionstemperaturen forblev mellem 0 og 15°. Efter omrøring ved omgi vel sestemperatur i 20 minutter vaskedes reaktionsblandingen med to 11 ml portioner vandig 10 0,055N HC1. Den vandige fase ekstraheredes med to 20 ml portioner CHgClg» £>9 den kombinerede organiske fase tørredes og inddampedes til tørhed under reduceret tryk. Den faste remanens omkrystalli seredes fra isopropyl al kohol til dannelse af 3,0 g af titel forbi ndel sen, smp. 137-139°.
15 Forbindelserne med formlen I kan fremstilles ud fra en forbindelse med formlen II ved forskellige alternative reaktionsforløb via adskillige typer af hidtil ukendte mellemprodukter.
LiIV lOHJOJ D
7
Reaktionsskema 1
O
/ S\
Forbindelse A(CH_) Z (CH_) NH_ N N
2 ni 2 n 2 , w yt " -^ M,
A(CH-) Z (CH-,) HH R
2 ni 2 n r9h r9h
V V
o o /s\ / s\ N H A(CH2)mZ(CH2)nNH2 Jj /—{ 9 : " / '9
p7 R A(CH-) Z(CH0) NH R
Λ 2 m 2 n XII la
DK 164363 B
8 9 2 3 I reaktionsskema 1 kan R betegne -NR R eller -NH(CH2)n,Z'(CH2)m/A'. Når A', V , m' og n' er det samme som A, Z, m og n, kan reaktionen naturligvis udføres i ét trin ved omsætning af forbindelsen med formlen II med to ækvivalenter af A(CH2)mZ(CH2)nNH2.
5 Mellemprodukterne med formlen XI er alle hidtil ukendte. Mellemprodukterne med formlen XII er hidtil ukendte. Omsætningerne udføres i et inert organisk opløsningsmiddel. Det har vist sig, at methanol er et hensigtsmæssigt og let tilgængeligt opløsningsmiddel. Reaktionstemperaturen er ikke kritisk. De fleste udgangsmaterialer er temmelig reaktive, 10 og det foretrækkes at udføre omsætningen ved en temperatur under stuetemperatur, f.eks. 0-10°. Med nogle mindre reaktive forbindelser er det hensigtsmæssigt at udføre omsætningen ved stuetemperatur. Undertiden er det ønskeligt senere at hæve reaktionsblandingens temperatur (f.eks. til 50-60°) for at fuldende omsætningen.
15
Reaklionsskema 2 O 1
Forbindelse , /S\
„ MCHjVICHjJhMIj h \ XT
-—> \\ //
A(CH2)mZ(CH2)nNH
^^/hoh
O
/ SX
M
A(CH2)mZ(CH2,nNH °H
Ib 9 I reaktionsskema 2 betegner M en metal kation, som fortrinsvis er K+, Li+ eller Na+. Reaktionsbetingelserne og opløsningsmidlerne er som beskrevet for reaktionsskema 1. Alle mellemprodukterne med formlen XI er hidtil ukendte forbindelser.
5
Reaktionsskema 3
Forbindelse
II
/r10H \HS(CH2)nHH2 C o
Μ M
R7 K10 HS(CH2)nNH R7 χΙν xm \ .
VS<CH2JnNH2 /oH
^ / '0 /s\
N H
w / ' „10
HS (CH-,) NH R
i n i A(CH2) X m \7 o
Xs \
N N
)-( A(CH-) S(CH_) NH R10 i m δ n
Ic
DK 164363 B
10 I reaktionsskema 3 betegner R*° -NR2R3 eller -NH(CH2)n,Z'- (CHJ.A', og X er en konventionel fraspaltelig gruppe. Egnede fra-c m η spaltelige grupper omfatter f.eks. fluor, chlor, brom, iod, -0-SR , 11 ^ hvori R betegner (lavere)alkyl (f.eks. methansulfonat), aryl eller 5 substitueret aryl (f.eks. benzensul fonat, p-brombenzensulfonat eller p-toluensulfonat), O^SF, acetoxy og 2,4-dinitrophenoxy. Af nemheds og økonomiske grunde foretrækkes det at anvende en forbindelse, hvori X betegner chlor. Reaktionsbetingelserne for fremstillingen af forbindelserne med formlerne XIII, XIV og XV er som beskrevet for reaktions-10 skema 1. Omsætningen af forbindelsen med formlen XV med AiCHg)^ kan udføres i et hvilket som helst inert organisk opløsningsmiddel, såsom en alkanol, acetonitril, dimethyl formamid, dimethyl sul foxid, acetone, og lignende. Det foretrækkes at udføre omsætningen i en alkanol, såsom methanol, ethanol eller isopropanol. Reaktionstemperaturen er ikke 15 kritisk; omsætningen kan udføres ved temperaturer på fra ca. 0° til ca.
200°C. Ved lave temperaturer er omsætningen langsom, medens høje temperaturer normalt fører til mindre rene produkter på grund af nedbrydning og dannelse af biprodukter. Det foretrækkes sædvanligvis at udføre omsætningen ved stuetemperatur. Omsætningen af forbindelsen med 20 formlen XV med AtCHg^X til dannelse af forbindelsen med formlen Ic udføres fortrinsvis i nærværelse af en base, som letter omsætningen ved at optræde som en syreacceptor. Egnede baser omfatter f.eks. NaOH, KOH,
LiOH, triethylamin, dimethyl anil in, natriumethoxid, og lignende. Hvor X betegner hydroxyl, kan omsætningen udføres i koncentreret mineralsyre, 25 f.eks. HC1. Alle mellemprodukter med formlen XIII, XIV og XV er hidtil ukendte forbindelser.
Fremstillingen af thiadiazol ifølge opfindelsen er beskrevet i eksemplet nedenfor.
30 Eksempel 3,4-dimethoxy-l,2,5-thiadiazol-l-oxid
En opløsning af 3,4-dimethoxy-l,2,5-thiadiazol (35,2 g, 24,1 mmol) (fremstillet i henhold til den i J. Org. Chem., 40, 2749 (1975) beskrevne fremgangsmåde) i 100 ml chloroform sattes i løbet af en periode på 3 35 minutter til en omrørt opløsning af m-chlorperbenzoesyre (50,7 g, 25,0 mmol, 85% prøve) i 900 ml chloroform ved 20° under anvendelse af et kølebad for at forhindre den exotermiske reaktion i at stige over 32°.
Efter omrøring i 3 timer ved omgivelsernes temperatur omsattes den 11 overskydende persyre med yderligere 2,0 g 3,4-dimethoxy-l,2,5-thiadiazol og omrørtes i 1 time. Den organiske opløsning ekstraheredes med to 300 ml portioner af en 1% opløsning af NaHCOg, vaskedes med 250 ml vand, tørredes og inddampedes under reduceret tryk til dannelse af 47,0 g af 5 produktet. Omkrystallisation fra isopropyl al kohol gav titel forbi ndel sen (34,0 g). En yderligere omkrystallisation fra isopropyl al kohol gav en analytisk prøve, smp. 135-137°.
Analyse for C^HgNgOgS:
Beregnet: C: 29,63, H: 3,72, N: 17,27, S: 19,77, 10 Fundet: C: 29,53, H: 3,75, N: 17,26, S: 19,83.

Claims (3)

1. En forbindelse med den almene formel o 5 /S\ N N M 7/ 7 R7 R 10 hvori hvert R7 betegner halogen, (lavere)alkoxy, (lavere)al kyl thi o phenoxy eller phenylthio, som kan indeholde 1 eller 2 substituenter udvalgt blandt halogen, (lavere)al kyl, (lavere)alkoxy og nitro.
2.
3,4-dimethoxy-l,2,5-thiadiazol-l-oxid. 15 20 25 30
DK268990A 1979-09-04 1990-11-09 3,4-disubstituerede 1,2,5-thiadiazol-1-oxider DK164363C (da)

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US7251779A 1979-09-04 1979-09-04
US7251779 1979-09-04
US11718280A 1980-01-31 1980-01-31
US11718280 1980-01-31
US16383180A 1980-06-07 1980-06-07
US16383180 1980-06-07

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DK269090A DK164700C (da) 1979-09-04 1990-11-09 3,4-disubstituerede 1,2,5-thiadiazol-1-oxider eller -1,1-dioxider
DK269190A DK164702C (da) 1979-09-04 1990-11-09 3,4-disubstituerede 1,2,5-thiadiazol-1-oxider eller -1,1-dioxider
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DK269090A DK164700C (da) 1979-09-04 1990-11-09 3,4-disubstituerede 1,2,5-thiadiazol-1-oxider eller -1,1-dioxider
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