SI8010058A8 - Process for obtaining 6,7-dimethoxy-4-amino-2-/4-(2-furoyl) -piperazinyl/-quinazoline chlorohydrate of an antihypertensive effect - Google Patents

Process for obtaining 6,7-dimethoxy-4-amino-2-/4-(2-furoyl) -piperazinyl/-quinazoline chlorohydrate of an antihypertensive effect Download PDF

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SI8010058A8
SI8010058A8 SI8010058A SI8010058A SI8010058A8 SI 8010058 A8 SI8010058 A8 SI 8010058A8 SI 8010058 A SI8010058 A SI 8010058A SI 8010058 A SI8010058 A SI 8010058A SI 8010058 A8 SI8010058 A8 SI 8010058A8
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Prior art keywords
dimethoxy
piperazinyl
furoyl
quinazoline
amino
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SI8010058A
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Slovenian (sl)
Inventor
Erkki Juhani Honkanen
Aino Kyllikki Pippuri
Pekka Juhani Kairisalo
Heinrich Thaler
Maija Katriina Koivisto
Sirpa Anneli Tuomi
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Orion Yhtymae Oy
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Priority claimed from FI790320A external-priority patent/FI67699C/en
Application filed by Orion Yhtymae Oy filed Critical Orion Yhtymae Oy
Publication of SI8010058A8 publication Critical patent/SI8010058A8/en

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Description

1. Oblast tehnike1. Field of technology

Pronalazak je Iz oblasti organske hsmije, bliže heterociklične hemije. Prema Internacionalnoj klasifikaciji spada u grupu C07D 405/14.The invention is from the field of organic chemistry, closer to heterocyclic chemistry. According to the International Classification it belongs to group C07D 405/14.

u SF 76 3614. Uporsdjivanjem ovog postupka sa postupkom iz sadašnjeg pronalaska očigledno je da oba postupka koriste kao polazni inaterijal formule II, ali se clklizacija postiže različitim postupcima. Prema postupku iz sadašnjeg pronalaska prazosin hlorhidrat ae dobiva u dobrom prinosu (93-95%) I u veoma čietom obliku (čistoča 99,7-99,8%).in SF 76 3614. Comparing this process with the method of the present invention, it is obvious that both methods are used as the starting material of the formula II, but clisification is achieved by different methods. According to the process of the present invention, prazosin hydrochloride is obtained in good yield (93-95%) and in a very pure form (purity 99.7-99.8%).

2. Tehnički problem2. Technical problem

Pronalazak se odnosi na novi, poboljšani postupak za proizvodnju 6,7-dlmetokal-4-amlno-2-/4-(2-furoll)-1 · plperazlnil/hinazolln hlorhidrata, tj. prazosin hlorhidrata, formule:The invention relates to a novel, improved process for the production of 6,7-dlmethocal-4-amino-2- / 4- (2-furoyl) -1 · piperazinyl / quinazoline hydrochloride, i. prazosin hydrochloride, of the formula:

3. Stanje tehnike3. State of the art

Raniji postupci za dobivanje prezosina su opisani u sledečim patentima, na primer: US 5 511 836, NL 72 06067 i DT 2457911.Previous procedures for obtaining presosin have been described in the following patents, for example: US 5 511 836, NL 72 06067 and DT 2457911.

U praktičnem izvodjenju pomenutih postupaka sa, medjutim, javijaju mnoge tehničke teškoče. Osim toga, upotrebom ovih postupaka, prinos je prilično nizak i prečiščavanje proizvoda je teško. U postupku za dobivanje prazosina prema Finskom patentu SF 76 3614, nedostaci koji se javijaju u prethodnim postupcima su znatno otklonjeni a istovremeno je i prinos povečan.In the practical implementation of the said procedures, however, there are many technical difficulties. In addition, using these methods yields are quite low and product purification is difficult. In the process for obtaining the blanks according to Finnish Patent SF 76 3614, the disadvantages that have occurred in the previous processes have been significantly eliminated and at the same time the yield has been increased.

4. Opis rešenja4. Description of the solution

Sada je sa iznenadjenjem zapaženo da prinos prazosina, i istovremeno čistoča proizvoda, mogu da se značajno poboljšaju i dobivanje i postupci prečiščevanja mogu da se uproste, ako se gornja reakcija zatvaranja prstena hinazolina vrši uz veliki višak upotrebljenog amonijum hlorida, prema ovom pronalasku, umssto gasovitog amonijaka. U ovom slučaju, za izvodjenje reakcije nije potreban alkalni katalizator (natrijum amid itd.). Osim toga, željeni prazosin hlorhidrat se dobija direktno u reakciji, sa veoma dobrim prinosom (93-95%). Čistoča sirovog proizvoda je takodje veoma visoka, oko 99.5%. Željeni stepen čistoče (99.7 - 99.8%) se dobija proštom kristalizacijom ovog sirovog proizvoda. Ukupan prinos je u ovom slučaju 85-86%.It is now surprisingly observed that the leakage yield, and at the same time the product purity, can be greatly improved and the preparation and purification processes can be simplified if the above quinazoline ring closure reaction is carried out with a large excess of the ammonium chloride used according to the present invention, rather than gaseous of ammonia. In this case, an alkaline catalyst (sodium amide, etc.) is not required to perform the reaction. In addition, the desired prazosin chloride is obtained directly in the reaction, in a very good yield (93-95%). The purity of the crude product is also very high, about 99.5%. The desired degree of purity (99.7 - 99.8%) is obtained by simple crystallization of this crude product. The total yield in this case is 85-86%.

Postupak za dobijanje prazosin hlorhidrata prema pronalasku predstavlja veoma značajan napredak u odnosu na poznate postupke.The process for the preparation of prazosin hydrochloride according to the invention represents a very significant step forward in the art.

Polazno jedinjenje, metil-N-(3,4-dimetoksi-6-cijanofenil)-/4-(2furoil)-1-piperazinil/-tioformidat formule (II)Starting compound, methyl-N- (3,4-dimethoxy-6-cyanophenyl) - N - (4- (2-furoyl) -1-piperazinyl) -thioformidate of formula (II)

U postupku za dobivanje prazosina prema SF 76 3614, zatvaranje hinazolinskog prstena se vrši intramolekularno upotrebom, kao polaznog materijala, metil-N-(3,4-dimetoksi-6cijanofenil)-/4-(2-furoil)-1-piperazinil/tioformamidata, formule (II). Ovo jedinjenje reaguje sa amonijakom u formamidu, u prisustvu alkainog katalizatora kao što je natrijum amid, prema sledečoj reakcionoj formuli:In the process for the preparation of gaps according to SF 76 3614, quinazoline ring closure is carried out intramolecularly using methyl N- (3,4-dimethoxy-6-cyanophenyl) - 4- (2-furoyl) -1-piperazinyl / thioformamidate as starting material , of formula (II). This compound reacts with ammonia in formamide, in the presence of an alkane catalyst such as sodium amide, according to the following reaction formula:

N “ C IN “C I

SCHSCH

N - Ct/ 3N - Ct / 3

U ovom postupku, prinos prazosina je 40-50% sirovog proizvoda čistoče 95-97%. Posle toga se proizvod mora prevesti u hlorhidrat, koji ustvari predstavlja lek, i mora se kristalisavati nekoliko puta pre nego što se dobije zahtevana čistoča za upotrebu u medicini (99.7-99.8%). Pritom ukupan prinos opada na oko 35%.In this process, the void yield is 40-50% of the crude product with a purity of 95-97%. Thereafter, the product must be converted to the hydrochloride, which is in fact a drug, and must crystallize several times before obtaining the required purity for medical use (99.7-99.8%). The overall yield drops to around 35%.

Najbliži ranije poznat postupak za dobivanje prazosina opisan je zagreva se na povišenoj temperaturi od 100 do 140°C, poželjno oko 120°C, u toku 15-20 sati, sa velikim viškom amonijum hlorida, u polarnom rastvaraču kao što je formamid, uz dovodjenje gasovitog azota.The closest previously known process for the preparation of gaps is described to be heated at an elevated temperature of 100 to 140 ° C, preferably about 120 ° C, for 15-20 hours, with a large excess of ammonium chloride, in a polar solvent such as formamide, by feeding of gaseous nitrogen.

Praktično izvodjenje reakcije i separacija i prečiščavanje proizvoda su veoma uproščeni. Osim toga, upotreba natrijum amida, sa kojim je teško raditi u velikim količinama, ovde je izbegnuta.Practical reaction and separation and purification of the product are very simplified. In addition, the use of sodium amide, which is difficult to handle in large quantities, is avoided here.

Kada se koriste amonijak i natrijum amid, reakcija se odvija u alkalnoj sredini, kada se javlja izvesno premeštanje furoil grupa, prisutnih u prazosinskom prstenu sa formil grupama pod uticajem formamida koji se koristi kao rastvarač. S druge strane, amonijum hloridni rastvor je slabo kiseo i pomenuta izmena se teško javlja. Potpuna eliminacija pomenutih nečistoča,obrazovanje pri niškim koncentracijama, se pokazalo kao veoma teško u praksi.When ammonia and sodium amide are used, the reaction takes place in an alkaline medium, when a certain displacement of the furoyl groups present in the form of the solvent-formyl formyl group is present in the void ring. On the other hand, the ammonium chloride solution is poorly acidic and the aforementioned alteration is difficult to occur. The complete elimination of these impurities, education at low concentrations, has proven to be very difficult in practice.

Metil-N-(3,4-dimetoksi-6-cijanofenil)-/4-(2-furoil)-1piperazinii/tioformamidat (ll) se može dobiti sa prinosom od 7075% reakcijom 3,4-dimetoksi-6-aminobenzonitrila sa metil jodidom na način koji je opisan u Finskom patentu SF 76 3613.Methyl-N- (3,4-dimethoxy-6-cyanophenyl) - N- (4- (2-furoyl) -1piperazinyl / thioformamidate (11) can be obtained in 7075% yield by reaction of 3,4-dimethoxy-6-aminobenzonitrile with methyl iodide as described in Finnish Patent SF 76 3613.

---41498--- 41498

Pronalazak je ilustrovan sledečim primerom:The invention is illustrated by the following example:

6,7-dimetoski-4-amino-2-/4-(2-furoil)-1-piperazinil/hinazolin hlorhidrat6,7-dimethoxy-4-amino-2- / 4- (2-furoyl) -1-piperazinyl / quinazoline chloride

275 g (0.66 mola) metil-N-(3,4-dimetoksi-6-cijanofenll)-/4-(2furoil)-1-piperazinil/tioformamidata je rastvoreno u 3000 ml formamida, I uz mešanje je dodato 1375 g (25.7 mola) amonijum hlorida. Posle toga reakciona smeša je zagrevana tokom 15-20 h na 120°C, uz mešanje i dovodjenje gasovitog azota da bi se uklanjao proizvedeni metan tiol (može se absorbovati rastvorom natrijum hipohlorida). Dobiveni prazosln hlorhidrat postepeno kristališe iz reakcione smeše. Pošto je reakcija prestala, u smešu se dodaje 3-4 kg leda. Proizvod se procedi, ispere hladnom vodom i acetonom i osuši. Prinos 254259 g (93-95%). Čistoča 99.5% (Hromatografija pod visokim pritiskom). Proizvod kristališe iz oko 10 lit. smeše vode i etanola (15:50). Prinos 232-235 g (85-86%). Čistoča 99.7-99.8% (Hromatografija pod visokim pritiskom). IR, NMR i maseni spektar proizvoda su identični sa odgovarajučim spektrima prazosin hlorhidrata koji je proizveden postupcima opisanim u ranijoj literaturi.275 g (0.66 mol) of methyl-N- (3,4-dimethoxy-6-cyanophenyl) - [4- (2furoyl) -1-piperazinyl] thioformamidate was dissolved in 3000 ml of formamide, and 1375 g (25.7) was added with stirring. mole) ammonium chloride. Subsequently, the reaction mixture was heated at 120 ° C for 15-20 h, stirring and introducing gaseous nitrogen to remove the methane thiol produced (it could be absorbed by sodium hypochlorite solution). The resulting blank hydrochloride gradually crystallized from the reaction mixture. After the reaction has ceased, 3-4 kg of ice are added to the mixture. The product was washed, washed with cold water and acetone and dried. Yield 254259 g (93-95%). Purity 99.5% (High Pressure Chromatography). The product crystallizes from about 10 lit. water / ethanol mixture (15:50). Yield 232-235 g (85-86%). Purity 99.7-99.8% (High Pressure Chromatography). The IR, NMR, and mass spectra of the product are identical to the corresponding spectra of prazosin hydrochloride produced by the methods described in the previous literature.

pritiskom). Proizvod kristališe iz oko 10 lit. smeše vode i etanola (15:50). Prinos 232-235 g (85-86%). Čistoča 99.7-99.8% (Hromatografija pod visokim pritiskom). IR, NMR i maseni spektar proizvoda su identični sa odgovarajučim spektrima prazosin hlorhidrata koji je proizveden postupcima opisanim u ranijoj literaturi.pressing). The product crystallizes from about 10 lit. water / ethanol mixture (15:50). Yield 232-235 g (85-86%). Purity 99.7-99.8% (High Pressure Chromatography). The IR, NMR, and mass spectra of the product are identical to the corresponding spectra of prazosin hydrochloride produced by the methods described in the previous literature.

Claims (2)

PATENTNI ZAHTEVIPATENT REQUIREMENTS 1. Postupak za dobivanje 6,7-dimetoksl-4-amlno-2-/4-(2-furoil)1-piperazinil/hinazolln hlorhidrata (sa antihipertenzivnlm efektom) formule:1. A process for the preparation of 6,7-dimethoxy-4-amino-2- [4- (2-furoyl) 1-piperazinyl / quinazoline hydrochloride (with antihypertensive effect) of the formula: nhj.rci naznačen time, što se polazno jedinjenje metii-N-(3,4dimetoksi-6-oijanofenil)-/4-(2-furoil)-1-piperazinil/-tloformidat formule (II)characterized in that the starting compound is methyl-N- (3,4-dimethoxy-6-oiophenyl) - [4- (2-furoyl) -1-piperazinyl] -thloformidate of formula (II) 6,7-dimetoksi-4-amino-2-/4-(2-furoil)-1-piperazinil/hinazolin hlorhidrat6,7-dimethoxy-4-amino-2- [4- (2-furoyl) -1-piperazinyl] quinazoline chloride 275 g (0.66 mola) metil-N-(3,4-dimetoksi-6-cijanofenil)-/4-(2furoil)-1-piperazinil/tioformamidata je rastvoreno u 3000 ml formamida, i uz mešanje je dodato 1375 g (25.7 mola) amonijum hlorida. Posle toga reakciona smeša je zagrevana tokom 15-20 h na 120°C, uz mešanje i dovodjenje gasovitog azota da bi se uklanjao proizvedeni metan tiol (može se absorbovati rastvorom natrijum hipohlorita). Dobiveni prazosin hlorhidrat postepeno kristališe iz reakcione smeše. Pošto je reakcija prestala, u smešu se dodaje 3-4 kg leda. Proizvod se procedi, ispere hladnom vodom i acetonom i osuši. Prinos 254259 g (93-95%). Čistoča 99.5% (Hromatografija pod visokim zagreva na povišenoj temperaturi od 100-140°C, prvenstveno 120°C u toku 15-20 sati sa velikim viškom amonijum hlorida u polarnom rastvaraču kao što js formamld, uz dovodjenje gasovitog azota.275 g (0.66 mol) of methyl-N- (3,4-dimethoxy-6-cyanophenyl) - [4- (2furoyl) -1-piperazinyl] thioformamidate was dissolved in 3000 ml of formamide, and 1375 g (25.7) was added with stirring. mole) ammonium chloride. Thereafter, the reaction mixture was heated at 120 ° C for 15-20 h, stirring and introducing gaseous nitrogen to remove the methane thiol produced (it could be absorbed by sodium hypochlorite solution). The resulting prazosin hydrochloride gradually crystallized from the reaction mixture. After the reaction has ceased, 3-4 kg of ice is added to the mixture. The product was washed, washed with cold water and acetone and dried. Yield 254259 g (93-95%). Purity 99.5% (High-temperature chromatography at an elevated temperature of 100-140 ° C, preferably 120 ° C for 15-20 hours with a large excess of ammonium chloride in polar solvent such as formamld, with the addition of gaseous nitrogen. 2. Postupak prema zahtevu 1 .naznačen t i m e, što ss amonijum hlorid, koristi u količini od 30-40 mola NH4CI na 1 mol jedinjenja formule (II).2. A process according to claim 1, wherein ss ammonium chloride uses in an amount of 30-40 moles of NH 4 Cl per 1 mole of the compound of formula (II).
SI8010058A 1979-01-31 1980-01-10 Process for obtaining 6,7-dimethoxy-4-amino-2-/4-(2-furoyl) -piperazinyl/-quinazoline chlorohydrate of an antihypertensive effect SI8010058A8 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FI790320A FI67699C (en) 1979-01-31 1979-01-31 PROCEDURE FOR THE FRAMSTATION OF AV 6,7-DIMETOXY-4-AMINO-2- (4- (2-FUROYL) -1-PIPERAZINYL) QUINAZOLINE HYDROCHLORIDE WITH BLODTRYCKSSAENKANDE VERKAN
YU58/80A YU41498B (en) 1979-01-31 1980-01-10 Proces for obtaining 6,7-dimethoxy-4-amino-2-(4-(2-furoyl)-1-piperazinyl)-guinazoline chlorohydrate of an antihypertensive effec

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SI8010058A8 true SI8010058A8 (en) 1997-02-28

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