SI8811325A8 - Process for the production of crystalline azithromycin dihydrate. - Google Patents
Process for the production of crystalline azithromycin dihydrate. Download PDFInfo
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Description
POSTUPAK ZA DOBIJANJE KRISTALNOG AZITROMICIN DIHIDRATA
Oblast tehnike
Ovaj pronalazak spada u oblast hemije i odnosi se na postupak za dobijanje vrednog novog oblika azitromicin (9-deoksi-9a-aza-9a-metil-9a-homoeritromicina A), odnosno njegovog nehigroskopnog oblika dihidrata. Prema MKP ovaj pronalazak ima oznaku:
Tehnički problem
Pošto prethodno izkristališe iz etanola i vode (npr. primer 3 iz U.S. 4,474,768, azitromicin se dobija kao higroskopni monohidrat (za detalje videti dobijanje 1 niže). Zbog svoje higroskopne prirode, veoma je teško dobiti i održati ga u obliku koji ima konstantni reproduktivni sadržaj vode. Posebno je teško rukovanje za vreme pripremanja pošto na višim nivoima relativne vlažnosti, koji se opšte uzev, traže da bi se izbegli elektrostatički problemi (npr. brzine protoka, stvaranje praha sa potencijalnom mogučnosti eksplodiranja), monohidrat nesmetano upija različite količine vode, koje zavise od vremena izlaganja i precizne vrednosti relativne vlažnosti (videti dobijanje 1 niže). Prema torne, tehnički problem je obezbediti postupak za dobijanje nehigroskopnog kristalnog azitromicin dihidrata. Ovi problemi su prevazidjeni sadašnjim pronalaskom stabilnog dihidratnog oblika koji je u suštini nehigroskopan pod uslovima relativne vlažnosti koje postoje pri formiranju azitromicina. ' ·_ 2---Stanje tehnike,
Azitromicin je U.S.A.N. (generičko ime) za 9-deokso-9a-aza-9a-metil-9a-homoeritromicin A, antibakterijsko jedinjenje širokog spektra izvedeno iz eritromicina A. Azitromicin je bio nezavisno pronadjen od Strane Bright-a, U.S. Patent 4,474,768 i Kobrehel-a et al., U.S. Patent 4,517,359. Naziv N-metil-11-aza-10-deokso-10-dihidroeritromicin A koristi se u ovim patentnima. Sadašnji sistematičniji naziv je baziran na proširenju prstena i zamenskoj nomenklaturi iz IUPAC nomenklatura organske hemije, 1979 izdanje Pergamon Press, 1979. pp. 68-70, 459, 500-503. Dobijanje azitromicina kao higroskopnog monohidrata opisuje se u U.S. 4,474,768 (u primeru 3)
Opis rešenja tehničkog problema
Sadašnji pronalazak odnosi se na postupak za dobijanje vrednog novog oblika azitromicina, odnosno kristalnog nehigroskopnog dihidrata, koji se dobija kristalizacijom iz tetrahidrofurana i alifatičnog (C^-C^) ugljovodonika u prisustvu najmanje dva molarna ekvivalenta vode.
Azitromicin ima formulu:
On je izveden iz eritromicina A bez uključivanja asimetričnih t
centara, pa stoga ima stereohemiju na svakom od ovih centara (*) identičnu sa onom od eritromicina A, Azitromicin, uključujuči ovaj dihidrat poseduje antibakterijsku aktivnost širokog spektra u lečenju prijemčivih bakterijskih infekcija kod sisara, uključujuči čoveka.
Izraz alifatični (C^-C^) ugljovodonik odnosi se na ugliovodonične rastvarače niže tačke ključanja, cesto na smese odgovarajučeg opsega tačaka ključania kao što su oni koji se uopšteno nazivaju pentan, heksan”, heksani, itd. ali koji takodje mogu biti supstancijalno čisti, npr. n-heksan, cikloheksan ili metilcikloheksan. Najpoželjniji ugljovodonični rastvarač je takozvani heksan, čija je tačka ključanja vrlo bliska onoj od čistog n-heksana.
Ovaj pronalazak se brzo izvodi. Azitromicin dobiven prema Bright ili Kobrehel et al. (navedeno iznad) u amorfnom obliku ili u obliku monohidrata (koji može sadržavati, zbog svoje higroskopnosti, više od jednog molarnog ekvivalenta vode) se rastvori u tetrahidrofuranu. Pošto potrebne temperature za početni stadijum ovoga procesa nisu kritične, temperature okoline se uglavnom primenjuju pri čemu se izbegava cena >· kostanja grejanja i hladjenja. Štaviše da bi se maksimalno povečao prinos i smanjio rastvarač, kao I cena koštanja rada i aparature, zapremina tetrahidrofurana se održava na minimumu, tj. na 2 litra rastvarača po kilogramu substrata. Nerastvorne nečistoče koje rogu biti prisutne u ovoj fazi se lako otklanjaju konvencionalnim metodama filtriranja.
Ako je potrebno, smesa se može obezbojiti aktivnim ugljem.
Po želji, visoko koncentrovana smesa se može razblažiti sa porcijom (C,.-C7)ugl jovodonika pre filtriranja, da bi se olaksalo rukovanje. Ako je sadržaj vode u dobivenom materijalu veči od jednog molarnog ekvivalenta, tj. približno 2 molarna ekvivalenta, poželjno je sušiti smesu kratko vreme preko i
-4agensa za sušenje kao što je ;'gSO , naročito ako se ugljo*x vodonični rastvarač dodaje pre filtriranja. Da bi se dobio kristalni dihidrat dodaje se voda dobivenom bistrom rastvoru u količini dovoljnoj da se obezbedi totalni sadržaj vode do nivoa koji odgovara dva molarna ekvivalenta, uopšteno bez premašivanja nivoa od oko 3-4 molarna ekvivalenta.
Nivo vode prisutan u sistemu se lako prati standardnom Karl Fischer-ovom filtracijom. Dodavanje vode je pračeno dodavanjem ugljovodoničnog rastvarača( ili više ugljovodoničnih rastvarača, ako je smesa prethodno razblažena pre filtriranja), što dovodi do kristalizacije željenog dihidratnog proizvoda. Ova faza postupka se može odviti na temperaturi okoline ( npr. 17-3O°C) ali da bi se olakšala početna kristalizacija poželjno^ se odvija na slabo povišenoj temperaturi (npr. 3O-4O°C). Totalna zapremina ugljovodoničnog rastvarača koja se koristi je uglavnom četiri puta zapremine tetrahidrofurana. Više zapremine ugljovodonika su zadovoljavajuče, ali se uglavnom izbegavaju u interesu smanjenja troškova. Kada se završi kristalizacija, proizvod se regenerise filtriranjem, obično posle perioda granulacije (tj.
3-24 sata) na sobnoj temperaturi. Proizvod se suši od organskih rastvarača u vakuumu (na 20-40° , poželjno na sobnoj temperaturi!. Da bi se izbegao gubife^k vode hidratacije isparljivi delovi i sadržaj vode se uglavnom prate za vreme sušenja, tako da nivo tetrahidrofurana i ugljovodonika padne na vrednost ispod 0.25% a sadržaj vode bude 0.3% od teorijskog (4.6%).
'-'K'
Azitromicin dihidrat se formulise i deje u lečenju prijemčivih bakterijskih infekcija kod ljudi prema metodi i u količinama koje su pretbodno bile opisane od strane Bright,
U.S. Patent 4,474,768, koji je gore naveden i čija je referenca data.
Sadažnji .pronalazak je ilustrovan primerima koji slede.
Ipak treba prihvatiti da ovaj pronalazak nije ograničen specifičnim detelj ima ovib primera.
Primer 1
Nehigroskopnl azitromicin dihidrat
Metoda A
Higroskopni monohidrat prema Dobivanju 1 (100 c; sadržaj vode«3.1 %), teftrahidrofuran (220 ml) i diatomejska zemlja (5 g) se dodaju u Erleramajerov sud mešaju 30 min. i filtriraju ispiranjem sa 20 ml tetrahidrofurana. Kombinovani filtrat i rastvor posle ispiranja se prebacuje u trolitarski balon sa okruglim dnom. Rastvor se jako mesa i dodaje se HjO (2.0 ml). Posle 5 minuta 1800 ml heksana se dodaje u toku pet minuta, uz produženo jako mešanje. Posle perioda granulacije od 18 časova, naslovni proizvod se regenerise filtracijom i ispiranjem sa 1x10 ml heksana, a zatim se suši u vakuumu do 4.6- 0.2% H^O po Karl Fiscfc^r-u , 89.5 g.
Metoda B
Higroskopnim monohidratom prema Dobivanju 1 (197.6 g) 1 i tetrahidrofuranom (430 ml.) se napuni reaktor i smesa se meša da bi se postigao mlečno beli rastvor. Dodaju se aktivni ugalj (10 g) i diatomejska zemlja (10 g) i smeša se meša minuta zatim se razblažuie sa 800 ml heksana i filtrira pod pritiskom preko diiatomejske zemlje sa 250 ml heksana za ispiranje. Kombinovani filtrat i isprani deo rastvora se razblažuje do 2500 ml sa heksanom i zagreva do 34°C.
Uz stalno mešanje, 24.7 ml Η2θ se dodaje. Smeša se hladi na sobnu temperaturu, granulira u toku 5 sati i regenerise se naslovni proizvod i suši kao u Metodi A, 177.8 g,
Dihidrat se izrazito topi na 126°C ( u toploj fazi 10°/minut); diferenciialna skanirajuča kalorimetrija (brzina zagrevanja 20°/minut) pokazuje endoterm na 127°C; termalna gravimetrijska analiza_(brzina zagrevanja 30°C/ minut) pokazuje 1,8% gubitka u masi na 100°C a 4.3% gubitka u masi na 150°C; IR (KBr) 3953, 3488, 2968, 2930, 2888,
2872, 2827, 2780, 2089,.1722, 1664, 1468, 1426, 1380,1359, 1344, 1326, 1318, 1282, 1270, 1252, 1187, 1167, 1157,
1123, | 1107 | , 1082, 1050, 1004, | 993, | 977, | 955, | 930, | 902, |
986, | 879, | 864, 833, 803, 794, | 775, | 756, | 729, | 694, | 671, |
661, | 637, | 598, 571, 526, 495, | 459, | 399, | 374, | 321, | i 207 cm”1 |
/alfa/p = -41.4° (c=l, CHClg).
Izračunata analiza za C3gH72N2°12 C, 58.14; H, 9.77; N, 3.57; OCH3, 3.95;
2H2O;
H90 4.59.
z »
Nadjena·
C, 58.62; H, 9.66; N,3.56; 0CH3, 4.11; H20, 4.49. Ekvivalent neutralizacije; (0.5N HCl u 1*1 CH3CN:H20):
Izračunato: 374.5 . Nadjene:393,4.
Uzorci dihidrata, slabo presušeni do sadržaja vode od 4.1% (manje od teorijskog) brzo su primili vodu na 33%, 75% ili 100% relativne vlažnostida bi se dostigao teorijski sadržaj vode (4.6%) za dihidrat. Na 33% i 75% relativne vlažnosti, sadržaj vode ostaje bitno konstanten najmanje 4 dana. Na 100% relativne vlažnosti, sadržaj vode se kasnije povišava na oko 5.2, gde ostaje suštinski konstantan, sledeča tri dana.
Uzorak istog dihidrata, održavan na 18% relativne vlažnosti postepeno je gubio vodu. Posle 4 dana sadržaj vode je 'Str.
bio 2.5% a posle 12 dana, 1.1%.
Dobijanje 1
Higroskopni azitromicin monohidrat
Suštinski prateči postupak metilovanjar. Kobrehel et al., U.S. Patent 4,517,359; i postupak kristalizacije Bright-a, U.S. Patent 4,474,768; 9-deokso-9a-aza-9a-homoeritromicin A (prethodno nazvan ll-aza-10-deokso-10-dihidroeritromicin A; 100 g, 0.218 mol) se rastvori uz mešanje u 400 ml CHCl^ . Mravlja kiselina (98%; 10.4 ml, 0.436 mola) i formaldehid (37%; 16.4 ml, 0.349 mola) se dodaju u toku 4-5 minuta, i reakciona smesa se zagreva na temperaturi refluktovanja 20 sati. Smesa se.hladi do sobne temperature, razblažuje sa 400 ml H^O i podešava na pH 10.5 sa 50% NaOH. Vodeni sloj je bio odvojen i ekstrahovan sa 2x100 ml svežeg CHCl^. Organski slojevi su kombinovani, upareni na vakuumu do 350 ml dva puta razblaženi sa 450 r,l etanola i ponovo upareni do 350 ml, i najzad razblaženi sa 1000 ml H^O u toku 1 sata sa pauzama od po 15 minuta, pošto kaša počne da se •avl‘a posle dodavanja od 250 ml h^O, Naslovni proizvod je regeneriscn filtracijom i osušen na vazduhu pri 50°C u toku 24 sata, 85 g , t.t. 136°C; diferencijalna termalna analiza (brzina zagrevanja 20°C/minut) pokazuje endoterm na 142°C; termalna gravimetrijska analiza (brzina zagre-5 vanja 30°C/minut) pokazuje 2.6% gubitka u masi na 100°C i 4.5% gubitka u masi na 150°C; sadržaj vode 3.92 %; sadržaj etanola 1.09%.
Izračunata analiza za C33H72N2°12 (kor^9°vana za sadržaj vode i etanola)·
C, 58.46; H, 9.78; N, 3.74; Alkoksi, 4.67.
Nadjena; C, 58.40; H, 9.29; N, 3.50; Alkoksi, 4.52.
Uzorak monohidrata (sa sadržajem vode od 3.2%) je bio izložen na 18% relativne vlažnosti 14 dana. Uzorak je izgubio vodu prvih 24 časa da bi se dobio monohidrat sa teorijskim sadržajem vode od 2.35%. Sadržaj vode je ostao sušting^i konstantan 14 dana a vrednost od 2.26% je bila zabeležena u toku 14 dana.
Na 33% relativne vlažnosti sadržaj vode u uzorku istog monohidrata se brzo popeo na 5.6% na kome se suštinski čvrsto održao najmanje tri dana. Slično, na 75% i 100% relativne vlažnosti, sadržaj vode se brzo povečavao ali je sada održavan čak na visokom nivou, 6.6% i 7.2%, najmanje 3 dana.
Claims (3)
1. Postupak za dobijanje kristalnog azitromicin dihidrata, naznačen time, što se vrši kristalizacija azitromicina formule:
iz smeše tetrahidrofurana i (C -C )alifatičnog ugljovodonika, najpoželjnije u
O f odnosu 1:4, u prisustvu najmanje 2 molarna ekvivalenta vode, na temperaturi od sobne do 4O°C.
2. Postupak prema zahtevu 1, naznačen time, što je ugljovodonik heksan
3. Postupak prema zahtevu 1-3, naznačen time, što se kristalizacija odvija na slabo povišenoj temperaturi od 30 - 40°C.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US1987/001612 WO1989000576A1 (en) | 1987-07-09 | 1987-07-09 | Azithromycin dihydrate |
YU1325/88A YU45075B (en) | 1987-07-09 | 1988-07-08 | Process for obtaining crystalline azitromycine dihydrate |
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Publication Number | Publication Date |
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SI8811325A8 true SI8811325A8 (en) | 1996-12-31 |
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SI8811325A SI8811325A8 (en) | 1987-07-09 | 1988-07-08 | Process for the production of crystalline azithromycin dihydrate. |
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US5912331A (en) * | 1991-03-15 | 1999-06-15 | Merck & Co., Inc. | Process for the preparation of 9-deoxo-9(Z)-hydroxyiminoerythromycin A |
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US5189159A (en) * | 1992-04-02 | 1993-02-23 | Merck & Co., Inc. | 8a-AZA-8a-homoerythromycin cyclic iminoethers |
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US5332807A (en) * | 1993-04-14 | 1994-07-26 | Merck & Co., Inc. | Process of producing 8A- and 9A-azalide antibiotics |
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