DK157548B - PROCEDURE FOR PREPARING THE CRYSTALLINIC ALFA FORM OF THE HYDROCHLORIDE OF PRAZOSINCHLORIDE - Google Patents

iin

DK 157548 BDK 157548 B

Opfindelsen angår en særlig fremgangsmåde til fremstilling af den krystallinske α-form af hydrochloridet af prazosin, som er et trivialnavn for 4-amino-6,7-dimethoxy-2-[4-(2-furoyl)-l-piperazin-yl]quinazolin med formlen 1: 5 ELCCL .N. J N_CO_s' °\ tgThis invention relates to a particular process for the preparation of the crystalline α-form of the hydrochloride of prazosin, which is a trivial name for 4-amino-6,7-dimethoxy-2- [4- (2-furoyl) -1-piperazin-yl] quinazoline of formula 1: 5 ELCCL .N. J N_CO_s' ° \ tg

10 H^CiT10 H + CiT

«ί2 a-Formen af hydrochloridet af prazosin fremstilles ved fremgangs-15 måden ifølge opfindelsen, som er ejendommelig ved, at krystal vandet i et hydrat af prazosinhydrochlorid fjernes ved azeotropisk kogning af hydratet i dichlormetan og fjerne det frigjorte vand under anvendelse af vandudladere. Når alt vandet er fjernet, har man rent prazosinhydrochlorid af α-form tilbage.The form of the hydrochloride of prazosin is prepared by the method of the invention, which is characterized by removing the crystal water of a hydrate of prazosine hydrochloride by azeotropically boiling the hydrate in dichloromethane and removing the released water using water dischargers. When all the water is removed, pure α-form prazosin hydrochloride is left.

2020

Prazosin er kendt som et blodtryksænkende lægemiddel. I FI fremlæggelsesskrift nr. 62082 har man karakteriseret en krystal form af dette vandfrie hydrochlorid og benævnt det a-prazosinhydrochlorid.Prazosin is known as a blood pressure lowering drug. In FI Patent Specification No. 62082, a crystal form of this anhydrous hydrochloride has been characterized and termed the α-prazosin hydrochloride.

Det anføres, at α-formen bl.a. besidder den fordel fremfor andre 25 krystal former, at den har bedre stabilitet (se FI fremlæggelsesskrift nr. 62082 side 13). Fra ovennævnte publikation er det kendt at fremstille α-formen af hydrochloridet af prazosin ved at opvarme andre krystal former ved høj temperatur (100-200°) i et organisk opløsningsmiddel, specielt i en alkohol, der indeholder 5-7 30 carbonatomer.It is stated that the α-form i.a. possesses the advantage over other 25 crystal forms that it has better stability (see FI presentation no. 62082 page 13). From the above publication it is known to prepare the α-form of the hydrochloride of prazosin by heating other high temperature crystal forms (100-200 °) in an organic solvent, especially in an alcohol containing 5-7 carbon atoms.

Den i FI fremlæggelsesskrift nr. 62082 anførte fremgangsmåde til fremstilling af α-formen af hydrochloridet af prazosin har visse ulemper. Ved høje temperaturer kan prazosinet sønderdeles delvis, 35 hvilket kan forårsage urenheder i produktet og mindre udbytte. Der er også fare for, at man i stedet for a-forwen opnår et krystallinsk polymorft produkt, som benævnes γ-form (se FI fremlæggelsesskrift nr. 62082 side 5). Desuden kan det være besværligt at fjerne et højtkogende opløsningsmiddel fra produktet.The process disclosed in FI Publication No. 62082 for the preparation of the α-form of the hydrochloride of prazosin has certain disadvantages. At high temperatures, the prazosin may be partially decomposed, which may cause impurities in the product and less yield. There is also a danger that, instead of α-forwen, a crystalline polymorphic product, called γ-form, is obtained (see FI presentation no. 62082, page 5). In addition, removing a high boiling solvent from the product can be difficult.

DK 157548 BDK 157548 B

22

Det er uventet blevet observeret, at ren α-form af prazosinhydro-chlorid kan fremstilles med kvantitativt udbytte og meget simpelt ved, at vand fjernes fra prazosinhydrochloridets hydrat eller vandholdige hydrat ved azeotropisk destillation sammen med dichlor-5 metan, og det frigjorte vand fjernes under anvendelse af en vandudlader. Herved konstateredes det, at der udelukkende dannedes α-formen af prazosinhydrochlorid. Produktet identificeredes på basis af dets IR-spektrum.It has been unexpectedly observed that pure α-form of prazosine hydrochloride can be produced in quantitative yield and very simply by removing water from the hydrate or aqueous hydrate of the prazosin hydrochloride by azeotropic distillation together with dichloromethane and removing the released water under using a water dispenser. Hereby it was found that only the α-form of prazosin hydrochloride was formed. The product was identified on the basis of its IR spectrum.

10 Fremgangsmåden ifølge opfindelsen er først og fremmest fordelagtig på grund af den lave temperatur (ca. 42°C). En yderligere fordel er, at dichlormetan er et billigt, let regenererbart og til industriel brug særligt hensigtsmæssigt opløsningsmiddel. Der er ikke blevet observeret forurening i forbindelse med fremgangmåden ifølge opfin-15 del sen.The process according to the invention is first and foremost advantageous because of the low temperature (about 42 ° C). A further advantage is that dichloromethane is an inexpensive, easily regenerable and especially suitable solvent for industrial use. No contamination has been observed in connection with the method of the invention.

Følgende eksempler illustrerer opfindelsen.The following examples illustrate the invention.

Eksempel 1 20 228 g (0,5 mol) Dihydrat af prazosinhydrochlorid (fremstillet ifølge den i FI fremlæggelsesskrift nr. 67699 anførte fremgangsmåde) opslæmmedes i 2200 ml dichlormetan. Til reaktionskarret blev der tilsluttet en vandudlader, og blandingen kogtes under tilbageløb 25 (ca. 42°C), til der ikke mere blev udskilt vand (ca. 4-6 timer). Bundfaldet filtreredes fra, og det tilbageværende dichlormetan afdampedes under nedsat tryk. Der opnåedes 210 g (100% af det teoretiske) prazosinhydrochlorid (sønderdelingspunkt 280-282°, IR (KBr): 3319, 3226, 3077, 2857, 1634, 1597, 1481, 1468, 1425, 1280, 30 794, 763, 751, 721, 717, 675 cm"*). IR-spektret er identisk med det i beskrivelsen til FI fremlæggelsesskrift nr. 67699 beskrevne spektrum for a-formen.Example 1 20 228 g (0.5 mol) Dihydrate of prazosin hydrochloride (prepared according to the method of FI, No. 67699) was suspended in 2200 ml of dichloromethane. To the reaction vessel was added a water discharger and the mixture was refluxed (about 42 ° C) until no more water was separated (about 4-6 hours). The precipitate was filtered off and the remaining dichloromethane was evaporated under reduced pressure. 210 g (100% of theory) of prazosine hydrochloride was obtained (decomp. 280-282 °, IR (KBr): 3319, 3226, 3077, 2857, 1634, 1597, 1481, 1468, 1425, 1280, 30 794, 763, 751 , 721, 717, 675 cm ")). The IR spectrum is identical to the spectrum of the α-form described in FI Publication No. 67699.

Eksempel 2 35 300 g Ikke-tørret, fra vandholdigt medium filtreret, og med vand vasket prazosinhydrochlorid (indeholdende 30% vand ifølge Karl Fischers bestemmelsesmetode) opslæmmedes i 2200 ml dichlormetan og behandledes på samme måde som i eksempel 1. Der opnåedes 210 g (100%EXAMPLE 2 35 300 g of non-dried, filtered from aqueous medium and water-washed prazosine hydrochloride (containing 30% water according to Karl Fischer's method of determination) were slurried in 2200 ml of dichloromethane and treated in the same manner as in Example 1. 210 g (100 g) was obtained. %

DK 157548BDK 157548B

3 af det teoretiske) a-prazosinhydrochlorid.3 of the theoretical α-prazosin hydrochloride.

5 10 15 20 25 30 355 10 15 20 25 30 35