DK144565B - PROCEDURE FOR PREPARING 1-BENZOYL-2- (2,6,6-DICHLORPHENYLAMINO) -2-IMIDAZOLINE AND ITS SALTS - Google Patents
PROCEDURE FOR PREPARING 1-BENZOYL-2- (2,6,6-DICHLORPHENYLAMINO) -2-IMIDAZOLINE AND ITS SALTS Download PDFInfo
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- DK144565B DK144565B DK354376AA DK354376A DK144565B DK 144565 B DK144565 B DK 144565B DK 354376A A DK354376A A DK 354376AA DK 354376 A DK354376 A DK 354376A DK 144565 B DK144565 B DK 144565B
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- DK
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- Prior art keywords
- imidazoline
- benzoyl
- mmol
- dichlorophenylamino
- benzoylethylenediamine
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D233/44—Nitrogen atoms not forming part of a nitro radical
- C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Animal Behavior & Ethology (AREA)
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- Pharmacology & Pharmacy (AREA)
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Description
/ A ^ ( O1» (19) DANMARK Vfee i r^i/ A ^ (O1 »(19) DENMARK Vfee i r ^ i
02) FREMLÆGGELSESSKRIFT (11) 144565 B02) PRESENTATION WRITING (11) 144565 B
DIREKTORATET FOR PATENT- OG VAREMÆRKEVÆSENETDIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM
(21) Ansøgning nr. 35*3/Ί S (51) ,ntC,.3 q q? q 233/50 (22) Indleveringsdag 6. aug. 1976 (24) Løbedag 6. aug. 1976 (41) Aim. tilgængelig 26. mar. 1 977 (44) Fremlagt 29· tnar. 1982 (86) International ansøgning nr.(21) Application No. 35 * 3 / Ί S (51), ntC, .3 q q? q 233/50 (22) Filing day Aug 6 1976 (24) Race day 6 Aug. 1976 (41) Aim. available Mar 26 1 977 (44) Presented 29 years. 1982 (86) International application no.
(86) International indleveringsdag -(85) Videreførelsesdag (62) Stamansøgning nr.(86) International filing day - (85) Continuation day (62) Stock application no.
(30) Prioritet 25. pep. 1975# 7355/75, AT(30) Priority 25. pep. 1975 # 7355/75, AT
(71) Ansøger CHEMIE LINZ AKTIENGESELLSCHAFT, 4020 Linz, AT.(71) Applicant CHEMIE LINZ AKTIENGESELLSCHAFT, 4020 Linz, AT.
(72) Opfinder Rudolf Franzmair, AT.(72) Inventor Rudolf Franzmair, AT.
(74) Fuldmægtig Ingeniørfirmaet Hofman-Bang & Boutard.(74) Associate Engineer Hofman-Bang & Boutard.
(54) Fremgangsmåde til fremstilling af 1- benzoyl-2-(2',6'-dichlorphenyl= amino)-2-imidazolln og dens salte.(54) Process for the preparation of 1- benzoyl-2- (2 ', 6'-dichlorophenyl = amino) -2-imidazoline and its salts.
Fra de østriske patentskrifter nr. 248 428, 250 344 og 250 345 er det kendt, at 2-arylamino-2-imidazoliner, især forbindelsen 2- (2',61-dichlorphenylamino)-2-imidazolin, har en udpræget hy-potensiv virkning, som er parret med en sedativ virkning.From Austrian patents Nos. 248,428, 250,344 and 250,345, it is known that 2-arylamino-2-imidazolines, especially the compound 2- (2 ', 61-dichlorophenylamino) -2-imidazoline, have a pronounced high potency. effect, which is paired with a sedative effect.
ffl Fra det belgiske patentskrift nr. 741 947 kendes endvidere N- ^ aroylderivater af disse 2-arylamino-2-imidazoliner, f.eks. 2-Further, from Belgian Patent Specification No. 741,947 N-aroyl derivatives of these 2-arylamino-2-imidazolines, e.g. 2-
LfD N-benzoyl-(21,6'-dichlorpheny1)-amino-2-imidazolin, som ligele- J" des har denne hypotensive og samtidig sedative virkning. De opnås ved aroylering af de frie 2-arylamino-2-imidazoliner med de til- *LfD N-benzoyl- (21,6'-dichlorophenyl) -amino-2-imidazoline, which also has this hypotensive and simultaneously sedative effect. They are obtained by aroylating the free 2-arylamino-2-imidazolines with the to- *
OISLAND
2 144565 svarende syrechlorider af aromatiske carboxylsyrer, idet syreresten ombyttes med det til anilinnitrogenet bundne H.2 144565 corresponding to acid chlorides of aromatic carboxylic acids, the acid residue being exchanged with the H attached to the aniline nitrogen.
Det har nu vist sig, at der ved omsætning af 2,6-dichlorpheny1-isocyaniddihalogenider med N-benzoylethylendiamin opstår et ben-zoylderivat af 2-(2',61-dichlorphenylamino)-2-imidazolin med interessante farmakologiske egenskaber, hvilket derivat bærer benzoylresten, ikke ved anilinnitroqenet, men som det klart fremgår af syntesen, ved imidazolinnitrogenet. Denne fra dansk patentansøgning nr. 941/75 kendte forbindelse er en struktur-isomer af det i det belgiske patentskrift nr. 741 947 beskrevne benzoylderivat, hvilket kan bevises ved fysiske målinger af bl.a, blandingssmeltepunkt og pKa-værdi.It has now been found that upon reaction of 2,6-dichlorophenyl-isocyanide dihalides with N-benzoylethylenediamine, a benzoyl derivative of 2- (2 ', 61-dichlorophenylamino) -2-imidazoline with interesting pharmacological properties is produced, which derivative bears the benzoyl residue, not by the aniline nitrogen, but as is clearly evident from the synthesis, by the imidazoline nitrogen. This compound known from Danish Patent Application No. 941/75 is a structural isomer of the benzoyl derivative described in Belgian Patent No. 741,947, which can be proved by physical measurements of ia, mixture melting point and pKa value.
Opfindelsen angår således en fremgangsmåde til fremstilling af 1-benzoy1-2-(2',6'-dichlorphenylamino)-2-imidazolin med formlen σν<3 ...The invention thus relates to a process for the preparation of 1-benzoyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline of the formula σν <3 ...
'''''Cl cx° ,, ¥ C6H5 eller J, O___<1 _// \^!_ (Ib) '"ci <k> tø, eller af dens salte, og fremgangsmåden ifølge opfindelsen er ejendommelig ved, at et 2,6-dichlorphenylisoeyaniddihalogenid med den almene formel 3 144565 (S < hvori X betyder halogen, fortrinsvis chlor, omsættes med N-benzo-ylethylendiamin i et overfor reaktanterne inert opløsningsmiddel ved temperaturer fra 0 °C indtil kogepunktet for det anvendte opløsningsmiddel under tilsætning af syrebindende midler, hvorefter den opnåede forbindelse med formlen (la) henholdsvis (Ib) isoleres som den fri base eller salt med uorganiske eller organiske syrer.C6H5 or J, O ___ <1 _ // \ ^! _ (Ib) "" ci <k> thaw, or of its salts, and the process of the invention is peculiar in that a 2,6-dichlorophenylisoyanide dihalide of the general formula 3 (S of acid binding agents, after which the obtained compound of formula (Ia) and (Ib), respectively, is isolated as the free base or salt with inorganic or organic acids.
N-benzoylethylendiamin er kendt fra litteraturen og kan fremstilles ifølge Aspinall, J.Org.Chem. 6,895,899 (1941).N-benzoylethylenediamine is known from the literature and can be prepared according to Aspinall, J.Org.Chem. 6,895,899 (1941).
Omsætningerne kan i princippet gennemføres efter alle kendte metoder for acyleringsreaktioner med den begrænsning, at man kun anvender de opløsningsmidler og syrebindende midler, som ikke reagerer eller kun reagerer så langsomt med et aryliso-cyaniddichlorid med formlen II, at den ønskede omsætning ikke hæmmes eller kun i ringe grad hæmmes. Som opløsningsmiddel kan man anvende apolære eller kun lidt polære opløsningsmidler, f.eks. benzen, toluen, xylen, cyclohexan, halogenerede csrbonhy-drider som f.eks. methylenchlorid eller chloroform, ethere som f.eks. diethylether, tetrahydrofuran eller dioxan, og estere som f.eks. eddikesyreethylester; eller man kan anvende polære opløsningsmidler, f.eks. alkoholer, fortrinsvis med mere end 2 C-atomer, acetonitril, dimethylformamid eller dime-thylsulfoxid.The reactions can in principle be carried out according to all known methods of acylation reactions with the restriction that only the solvents and acid-binding agents which do not react or only react so slowly with an arylisocyanide dichloride of the formula II are used that the desired reaction is not inhibited or only to a small extent inhibited. As the solvent one can use apolar or slightly polar solvents, e.g. benzene, toluene, xylene, cyclohexane, halogenated csrbonic hydrides, e.g. methylene chloride or chloroform, ethers such as e.g. diethyl ether, tetrahydrofuran or dioxane, and esters such as e.g. acetic acid ethyl ester; or one can use polar solvents, e.g. alcohols, preferably having more than 2 C atoms, acetonitrile, dimethylformamide or dimethylsulfoxide.
Reaktionen kan gennemføres såvel homogent som heterogent. Ued heterogen gennemførelse af reaktionen egner sig som syrebindende midler især vandige natrium- eller kaliumhydroxidopløsninger eller NaH; ved homogen gennemførelse af reaktionen er natrium- 4 U4565 eller kaliumalkoholater velegnede.The reaction can be carried out both homogeneously and heterogeneously. Without heterogeneous conducting of the reaction, as acid binding agents, especially aqueous sodium or potassium hydroxide solutions or NaH are suitable; by homogeneous execution of the reaction, sodium 4 U4565 or potassium alcoholates are suitable.
Da den ifølge fremgangsmåden opnåede forbindelse er en svag base, må det foretrækkes at arbejde på den måde, at reaktionsproduktet i givet fald efter inddampning og optagelse i et inert opløsningsmiddel såsom benzen eller methylenchlorid, ekstraheres med en fortyndet syre, fortrinsvis med IN saltsyre, hvorefter de saltsure ekstrakter gøres basiske, hvorved den omhandlede forbindelse udfælder som krystaller. Efter filtrering omkrystalliseres der fra et egnet opløsningsmiddel, f.eks. isopropanol, acetonitril, ethylacetat, benzen eller toluen, hvorefter forbindelsen foreligger i stor renhed.Since the compound obtained by the process is a weak base, it is preferable to work in such a way that the reaction product, after evaporation and uptake in an inert solvent such as benzene or methylene chloride, is extracted with a dilute acid, preferably with 1N hydrochloric acid, after which the hydrochloric acid extracts are made basic, thereby precipitating the compound as crystals. After filtration, a suitable solvent is recrystallized, e.g. isopropanol, acetonitrile, ethyl acetate, benzene or toluene, after which the compound is in high purity.
Omsætningen gennemføres ved en temperatur på mellem 0 °C og kogepunktet for det anvendte opløsningsmiddel, fortrinsvis mellem +10 og +50 °C. Reaktionstiden kan med fordel andrage fra nogle få timer indtil 24 timer.The reaction is carried out at a temperature of between 0 ° C and the boiling point of the solvent used, preferably between +10 and +50 ° C. The reaction time may advantageously range from a few hours to 24 hours.
Overraskende, og ikke til at forudse, har det således vist sig, at et amidnitrogen, som det foreligger i N-benzoylethylendia-min, også reagerer ved brug af milde acyleringsmetoder, som f.eks. ved brug af Schotten Baumanns reaktion, hvor det let reagerer med et halogen i ary1isoeyaniddihalogenidet.Surprisingly, and not foreseeably, it has been found that an amide nitrogen, as present in N-benzoylethylenediamine, also reacts using mild acylation methods such as e.g. using Schotten Baumann's reaction, where it readily reacts with a halogen in the aryl isoyanide dihalide.
Forbindelsen med formlen la henholdsvis Ib er et ensartet, godt krystalliserende produkt. Strukturen af disse forbindelser kan for så vidt ikke bestemmes entydigt, da det må stå åbent, om den dobbelte binding sker i imidazolinringen (la) eller exo-cyclisk (Ib). Den omhandlede forbindelse har meget interessante farmaceutiske egenskaber. Den har endog en lige så god blodtryksænkende virkning som den kendte forbindelse, der i stedet for benzoylgruppen indeholder hydrogen, og som det ved anilin-nitrogenet substituerede benzoylderivat, der beskrives i belgisk patentskrift nr. 741 947; den sedative virkningskomponent er imidlertid væsentligt mindre udpræget. Ued anvendelse af den omhandlede forbindelse som hypotensivt middel bortfalder derfor 144565 5 den træthed, der ellers indtræder som en ubehagelig bivirkning.The compound of formula 1a and 1b, respectively, is a uniform, well crystallizing product. The structure of these compounds cannot be unambiguously determined as it must be open whether the double bond occurs in the imidazoline ring (1a) or exocyclic (1b). The compound in question has very interesting pharmaceutical properties. It even has as good a blood pressure lowering effect as the known compound containing hydrogen instead of the benzoyl group and as the benzoyl derivative substituted by the aniline nitrogen described in Belgian Patent No. 741,947; however, the sedative effect component is significantly less pronounced. Therefore, without using the subject compound as a hypotensive agent, the fatigue which otherwise occurs as an unpleasant side effect lapses.
Manglen af sedativ henholdsvis centralt dæmpende virkning kan let påvises ved konstatering af carotissinusrefleks hos en narkotiseret kanin efter indgivelse af den nævnte forbindelse i doser på 100 mikrogram/kg. Denne refleks er på den anden side næsten fuldstændig undertrykt ved indgivelse af den samme dosis 2-(2',6'-dichlorphenylamino)-2-imidazolin. Den manglende refleks kan også iagttages ved uændret væremåde hos vågne mus efter indgivelse af 5 eller 10 mg/kg l-benzoyl-2-(2',6'-dichlorphenylami-no)-2-imidazolin.The lack of sedative or centrally attenuating effect can easily be detected by the finding of carotissin reflex in an anesthetized rabbit after administration of said compound at doses of 100 micrograms / kg. This reflex, on the other hand, is almost completely suppressed by administration of the same dose of 2- (2 ', 6'-dichlorophenylamino) -2-imidazoline. The lack of reflex can also be observed by unchanged behavior in awake mice after administration of 5 or 10 mg / kg of 1-benzoyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline.
Forbindelsen med formlen la henholdsvis Ib er udmærket egnet til oral indgivning.The compound of formula Ia and Ib, respectively, is very suitable for oral administration.
Fremgangsmåden til fremstilling af denne forbindelse forklares nærmere ved hjælp af de følgende eksempler.The process for preparing this compound is explained in more detail by the following examples.
EKSEMPEL 1 1,64 g (10 mmol) N-benzoylethylendiamin opløses i 100 ml benzen, og der tilsættes 25 ml vand og opvarmes under kraftig omrøring til 50 °C; der tilsættes samtidig dråbevis en opløsning af 2,31 g (10 mmol) 2,6-dichlorpheny1 isocyaniddichlorid i 20 ml absolut benzen og 20 ml IN NaOH indenfor et tidsrum af 75 minutter. Efter 3 timers forløb efterrøres der ved 50 °C. Man nedkøler til stue temperatur, og faserne adskilles. Den vandige fase ekstraheres endnu engang med 100 ml benzen. De to benzenfaser blandes, og der vaskes med vand og ekstraheres 3 gange, hver gang med 75 ml IN saltsyre. De saltsure ekstrakter blandes, vaskes 1 gang med ether og. gøres basiske med N a £ C 0 ^ , hvorved der opnås 650 mg (19,4 %) rå l-benzoyl-2-(2',6'-dichlorphenylamino)-2-imidazolin.EXAMPLE 1 1.64 g (10 mmol) of N-benzoylethylenediamine is dissolved in 100 ml of benzene and 25 ml of water is added and heated to 50 ° C with vigorous stirring; at the same time, a solution of 2.31 g (10 mmol) of 2,6-dichlorophenyl isocyanide dichloride in 20 ml of absolute benzene and 20 ml of 1N NaOH is added dropwise over a period of 75 minutes. After 3 hours, stir at 50 ° C. One is cooled to room temperature and the phases are separated. The aqueous phase is extracted again with 100 ml of benzene. The two benzene phases are mixed and washed with water and extracted 3 times, each time with 75 ml of 1N hydrochloric acid. The hydrochloric acid extracts are mixed, washed once with ether and. is basified with N a C 0 O to give 650 mg (19.4%) of crude 1-benzoyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline.
Efter omkrystallisering fra isopropanol opnår man 480 mg produkt.After recrystallization from isopropanol, 480 mg of product is obtained.
Smeltepunkt = 160 - 162 °C.Melting point = 160 - 162 ° C.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT735575A AT339897B (en) | 1975-09-25 | 1975-09-25 | PROCESS FOR PREPARING THE NEW 1-BENZOYL-2- (2 ', 6'-DICHLOROPHENYLAMINO) -2-IMIDAZOLINE AND THE SALT THEREOF |
| AT735575 | 1975-09-25 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK354376A DK354376A (en) | 1977-03-26 |
| DK144565B true DK144565B (en) | 1982-03-29 |
| DK144565C DK144565C (en) | 1982-09-13 |
Family
ID=3595222
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK354376A DK144565C (en) | 1975-09-25 | 1976-08-06 | METHOD OF PREPARING 1-BENZOYL-2- (2 ', 6'-DICHLORPHENYLAMINO) -2-IMIDAZOLINE AND ITS SALTS |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS5239675A (en) |
| AT (1) | AT339897B (en) |
| BG (1) | BG35040A3 (en) |
| CA (1) | CA1062267A (en) |
| CH (1) | CH601253A5 (en) |
| CS (1) | CS196324B2 (en) |
| DD (1) | DD126907A1 (en) |
| DK (1) | DK144565C (en) |
| ES (1) | ES451829A1 (en) |
| FI (1) | FI63752C (en) |
| NL (1) | NL7608971A (en) |
| NO (1) | NO145274C (en) |
| PL (1) | PL100503B1 (en) |
| PT (1) | PT65438B (en) |
| RO (1) | RO69914A (en) |
| SE (1) | SE439010B (en) |
| SU (1) | SU604488A3 (en) |
| YU (1) | YU39360B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MTP837B (en) * | 1977-11-07 | 1979-10-22 | Hoffman La Roche And Co Aktien | Derivatives 2 finino-imidazolidire |
| DE2811847A1 (en) | 1978-03-17 | 1979-09-20 | Lentia Gmbh | NEW ARYLAMINOIMIDAZOLINE DERIVATIVES, THEIR PRODUCTION AND USE AS MEDICINAL PRODUCTS |
| DE3200258A1 (en) * | 1982-01-07 | 1983-07-21 | Lentia GmbH Chem. u. pharm. Erzeugnisse - Industriebedarf, 8000 München | SUBSTITUTED 1-BENZOYL-2-PHENYLIMINO IMIDAZOLIDINE, THE ACID ADDITION SALTS THEREOF, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THE SAME |
-
1975
- 1975-09-25 AT AT735575A patent/AT339897B/en not_active IP Right Cessation
-
1976
- 1976-07-05 CH CH859676A patent/CH601253A5/en not_active IP Right Cessation
- 1976-07-12 FI FI762025A patent/FI63752C/en not_active IP Right Cessation
- 1976-07-12 NO NO762439A patent/NO145274C/en unknown
- 1976-07-21 BG BG7633815A patent/BG35040A3/en unknown
- 1976-07-27 YU YU1848/76A patent/YU39360B/en unknown
- 1976-07-28 RO RO7687139A patent/RO69914A/en unknown
- 1976-08-04 PT PT65438A patent/PT65438B/en unknown
- 1976-08-06 DK DK354376A patent/DK144565C/en not_active IP Right Cessation
- 1976-08-12 NL NL7608971A patent/NL7608971A/en not_active Application Discontinuation
- 1976-08-25 SE SE7609391A patent/SE439010B/en not_active IP Right Cessation
- 1976-08-27 CA CA259,993A patent/CA1062267A/en not_active Expired
- 1976-09-21 SU SU762399518A patent/SU604488A3/en active
- 1976-09-22 JP JP51113178A patent/JPS5239675A/en active Granted
- 1976-09-23 DD DD194962A patent/DD126907A1/xx unknown
- 1976-09-23 PL PL1976192594A patent/PL100503B1/en unknown
- 1976-09-24 CS CS766199A patent/CS196324B2/en unknown
- 1976-09-24 ES ES451829A patent/ES451829A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| NO762439L (en) | 1977-03-28 |
| CH601253A5 (en) | 1978-06-30 |
| RO69914A (en) | 1981-06-30 |
| NO145274C (en) | 1982-02-17 |
| CA1062267A (en) | 1979-09-11 |
| JPS5239675A (en) | 1977-03-28 |
| ATA735575A (en) | 1977-03-15 |
| SE439010B (en) | 1985-05-28 |
| ES451829A1 (en) | 1977-11-01 |
| FI63752B (en) | 1983-04-29 |
| FI63752C (en) | 1983-08-10 |
| PT65438B (en) | 1978-02-09 |
| JPS5333592B2 (en) | 1978-09-14 |
| PT65438A (en) | 1976-09-01 |
| SE7609391L (en) | 1977-03-26 |
| NL7608971A (en) | 1977-03-29 |
| SU604488A3 (en) | 1978-04-25 |
| YU39360B (en) | 1984-10-31 |
| FI762025A (en) | 1977-03-26 |
| BG35040A3 (en) | 1984-01-16 |
| NO145274B (en) | 1981-11-09 |
| DK144565C (en) | 1982-09-13 |
| DD126907A1 (en) | 1977-08-17 |
| AT339897B (en) | 1977-11-10 |
| DK354376A (en) | 1977-03-26 |
| PL100503B1 (en) | 1978-10-31 |
| YU184876A (en) | 1982-06-30 |
| CS196324B2 (en) | 1980-03-31 |
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| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |