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ME00928B - Novi postupak za sintezu agomelatina - Google Patents

Novi postupak za sintezu agomelatina

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Publication number
ME00928B
ME00928B MEP-2009-257A MEP25709A ME00928B ME 00928 B ME00928 B ME 00928B ME P25709 A MEP25709 A ME P25709A ME 00928 B ME00928 B ME 00928B
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formula
compound
synthesis
agomelatine
give
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MEP-2009-257A
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Jean-Pierre Lecouve
Christophe Hardouin
Nicolas Bragnier
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Servier Lab
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Publication of ME00928B publication Critical patent/ME00928B/me

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Abstract

Postupak za industrijsku sintezu jedinjenja formule (I) :

Description

Ovaj pronalazak se odnosi na novi postupak dobijanja kristalnog oblika V agomelatina, ili N-[2-(7-metoksi-1-naftil)etil]acetamida, formule (I):
Agomelatin ili N-[2-(7-metoksi-1-naftil)etil]acetamid, poseduje korisna farmakološka svojstva.
Ustvari, ima dvostruke osobenosti, da je sa jedne strane agonist receptora melatoninergičnog sistema, a sa druge strane je antagonist receptora 5-HT2C receptora. Ova svojstva mu daju aktivnost u centralnom nervnom sistemu i, preciznije, u lečenju opšte depresije, sezonskih afektivnih poremećaja, poremećaja spavanja, kardiovaskularnih patologija, patologija digestivnog sistema, nesanice i umora kao posledice vremenske razlike, poremećaja apetita i gojaznosti.
Agomelatin, njegova proizvodnja i njegova upotreba u terapeutske svrhe, opisani su u evropskom patentu EP 0 447 285.
U smislu farmaceutske vrednosti ovog jedinjenja, najvažnije je njegovo dobijanje sa odličnim stepenom čistoće i, naročito, u savršeno reproducibilnom obliku što ima vredne osobenosti omogućavanja njegovog skladištenja u dužim vremenskim periodima bez posebnih zahteva u smislu temperature, svetla, vlažnosti ili nivoa kiseonika.
Patentna prijava EP 1 752 443 opisuje dobro-definisan kristalni oblik agomelatina, kristalni oblik V, koji je opisan svojim dijagramom difrakcije X-zraka praška u nastavku, koji je izmeren upotrebom Siemens D5005 difraktometra (bakarna antikatoda) i izražen u granicama međupovršinske udaljenosti d, Braggovog ugla 2 teta i, relativnog intenziteta (izražen kao procenat u odnosu na najintenzivniju liniju):
Ovaj savršeno definisani kristalni oblik, koji se dobija na reproducibilan način, ima visoko vredne morfološke karakteristike sa, posebno, specifičnom oblasti površine koja je mnogo veća nego za druge opisane oblike. Ipak, poseduje stabilnost u toku vremena koja je prilično kratka i, u svim slučajevima, manja od 6 meseci.
Podnosilac je sada razvio novi postupak za dobijanje agomelatina u kristalnom obliku V na savršeno reproducibilan način, gde je njegova stabilnost tokom vremena povećana. Ovaj novi postupak, prema tome, omogućava dobijanje agomelatina u kristalnom obliku V sa svojstvima koja su kompatibilna sa njegovom farmaceutskom upotrebom. Koristi se da bi se omogućilo dobijanje oblika V samo takozvanim “visoko-energetskim” mlevenjem ili putem zasejavanja te strukturno čiste forme koja se dobije mlevenjem. Podnosilac je sada otkrio, neočekivano, da je moguće dobiti ovaj oblik putem sušenja raspršivanjem. Sušenje raspršivanjem je zapravo tehnika koja se uobičajeno koristi za dobijanje čvrstih čestica u malim veličinama. Često, nastali materijal bude amorfan (Amorphous State, Polymorphism in pharmaceutical industry, Ed. R. Hilfiker, Wiley-VCH VVeinheim 2006, Chapter X, p. 259-285, S. Petit and G. Coquerel). Suprotno tome, u ovom pronalasku sušenje omogućava dobijanje dobro definisane kristalne forme, oblika V, koja pored toga ima, međutim, mnogo bolju stabilnost u toku vremena.
Preciznije, ovaj pronalazak se odnosi na novi postupak dobijanja agomelatina formule (I) u kristalnom obliku V, pri čemu se postupak odlikuje time da se rastvor agomelatina, koji je rastvoren u jednom ili dva rastvarača koja se mešaju u ma kom odnosu i čija je tačka ključanja manja od 120°C, atomizuje u sprej sušioniku.
Sušenje raspršivanjem je tehnika koja se uobičajeno koristi u oblastima poljoprivrede, prehrane i farmacije kako bi se osušio rastvor koji se raspršuje kroz vruć gas. U praksi, gas koji se koristi za sušenje rastvora je vazduh ali izvesni farmaceutski proizvodni postupci koriste organske rastvarače koji pak zahtevaju inertni gas kao gas za sušenje i na taj način se izbegavaju izvesni procesi razgradnje.
Postupci kristalizacije, koji su u skladu sa ovim pronalaskom, poželjno se izvode putem sušenja raspršivanjem. Još bolje, atomizacija u skladu sa pronalaskom se izvodi u skladu sa principom atomizacije putem raspršivača sa paralelnim strujnim tokom i poželjnije, sa ko-strujnim protokom, to jest, raspršenim rastvorom i protokom sušećeg gasa u istom smeru.
Pogodno, upotrebljeni gas je kompresovani vazduh ili inertni gas kao što je, na primer, azot.
Rastvarači koji imaju prednost u postupku koji je u skladu sa pronalaskom su: etanol, voda, izoprpoil etar, metanol, etil acetat ili aceton.
Minimalna koncentracija rastvora agomelatina koji se upotrebljava je 5 g/L a, poželjnije, koristi se rastvor od 10 g/L.
Pogodno, temperatura ulaza za postupak koji je u skladu sa pronalaskom je od 70°C do 120°C.
U procesu kristalizacije, koji je u skladu sa pronalaskom, moguće je upotrebiti agomelatin formule (I) koji se dobija ma kojim postupkom.
Primeri u nastavku ilustruju pronalazak ali ga ne ograničavaju ni na koji način.
Primer 1: Kristalni oblik V N-[2-(7-metoksi-1-naftil)etil]acetamida
10 g/L rastvora agomelatina u mešavini etanol/izopropil etra (50/50: v/v) unese se u atomizer BUCHI 190 tip Mini Spray Dryer. Temperatura ulaza komore za sušenje je 90°C, a temperatura izlaza je 66°C. Atomizirani prašak se dobija u crevu za sakupljanje i, opisuje se sledećim kristalografskim podacima:
1) dijagramom, koji se dobija upotrebom difraktometra Siemens D5005 sa opsegom ugla 3°-30° u granicama od 20, korak od 0. 04° i 4 s po koraku:
- kristalna struktura jedinične ćelije: monoklinska,
- parametri jedinične ćelije: a = 11. 967 Å, b = 17. 902 Å, c = 15. 423 Å, β = 124. 5°
- prostor grupe: P2|/n
- broj molekula u jediničnoj ćeliji: 8 (Z’=2)
- zapremina jedinične ćelije: Vjedinične ćelije=2720.0 Å3
2) sledeći dijagram difrakcije X-zraka praška, izmeren korišćenjem difraktometra Siemens D5005 (bakarna antikatoda) i izražen u granicama međupovršinske udaljenosti d, Braggovog ugla 2 teta i, relativnog intenziteta (izražen kao procenat u odnosu na najintenzivniju liniju):
Primer 2: Stabilnost tokom vremena kristalnog oblika V, dobijenog atomizacijom N-[2-(7-metoksi-1 -naftil)etil]acetamida
Uzorak od 1 g jedinjenja dobijenog u Primeru 1 je smešteno pod uobičajene uslove skladištenja: pritisak i temperatura sredine. Nakon 21 meseca, difraktogram uzorka koji je dobijen se nije promenio i zadržao je karakteristike dobijenog oblika V.

Claims (11)

1. Postupak za industrijsku sintezu jedinjenja formule (I) koji je naznačen time što reaguje 7-metoksi-1-naftol formule (II): koji se kondenzuje, u prisustvu paladijuma, po prevođenju hidroksi funkcije u odlazeću grupu, kao što je halogen, tozilat ili trifluorometansulfonatna grupa, sa jedinjenjem formule (ili) : CH2=CH-R (III), gde R predstavlja grupu: gde R' i R", koji mogu biti isti ili različiti, svaki predstavlja linearnu ili razgranatu (C1- C6)alkil grupu ili, R' i R" zajedno obrazuju (C2-C3)alkilenski lanac i formirani prsten se može spojiti sa fenil grupom, kako bi se dobilo jedinjenje sa formulom (IV): gde je R, kao što je prethodno definisano, koje se podvrgava katalitičkoj hidrogenaciji da bi se dobilo jedinjenje formule (V): gde je R, kao što je prethodno definisano, koje se podvrgava hidrolizi bazom ili kiselinom ili binarnim sistemom redukujuće sredstvo/kiselina kako bi se dobilo jedinjenje sa formulom (VI) ili njegova hidrohloridna so: koje se sukcesivno podvrgava dejstvu natrijum acetata i zatim sirćetnog anhidrida da bi se dobilo jedinjenje formule (I), koje se izoluje u čvrstom obliku.
2.Postupak za sintezu jedinjenja formule (I), kao u patentnom zahtevu 1, naznačen time što je jedinjenje formule (ili) N-vinilftalimid.
3.Postupak za sintezu jedinjenja formule (I), kao u patentnom zahtevu 1, naznačen time što je jedinjenje formule (ili) akrilamid.
4.Postupak za sintezu jedinjenja formule (I), kao u patentnom zahtevu 1, naznačen time što se kondenzacija jedinjenja formule (III) da bi se dobilo jedinjenje formule (IV) izvodi upotrebom paladijum tetrakis(trifenilfosfina).
5.Jedinjenje formule (IV), kao u patentnom zahtevu 1, za upotrebu je kao intermedijer u sintezi agomelatina.
6.Upotreba jedinjenja formule (IV), kao u patentnom zahtevu 5 u sintezi agomelatina.
7.Upotreba jedinjenja formule (ll), kao u patentnom zahtevu 1 u sintezi agomelatina.
8.Upotreba jedinjenja formule (V), kao u patentnom zahtevu 1 u sintezi agomelatina.
9.Postupak za sintezu agomelatina, kao u patentnom zahtevu 1, koji započinje od jedinjenja for ule (IV), naznačen time što se jedinjenje formule (IV) dobija sintetskim postupkom kao u bilo kom od patentnih zahteva 1 do 4.
10.Postupak za sintezu agomelatina, kao u patentnom zahtevu 1, koji započinje od jedinjenja formule (V), naznačen time što se jedinjenje formule (V) dobija sintetskim postupkom kao u bilo kom od patentnih zahteva 1 do 4.
11.Postupak za sintezu agomelatina, kao u patentnom zahtevu 1, koji započinje od jedinjenja formule (VI), naznačen time što se jedinjenje formule (VI) dobija sintetskim postupkom kao u bilo kom od patentnih zahteva 1 do 4.
MEP-2009-257A 2008-08-05 2009-08-03 Novi postupak za sintezu agomelatina ME00928B (me)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0804465A FR2934859B1 (fr) 2008-08-05 2008-08-05 Nouveau procede de synthese de l'agomelatine
EP09290606A EP2151428B1 (fr) 2008-08-05 2009-08-04 Nouveau procédé de synthèse de l'agomélatine

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ME00928B true ME00928B (me) 2012-06-20

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CN102229541A (zh) * 2010-09-17 2011-11-02 福建广生堂药业有限公司 阿戈美拉汀n-[2-(7-甲氧基萘-1-基)乙基]乙酰胺的制备方法
CN102531956B (zh) * 2010-12-21 2014-07-09 浙江九洲药业股份有限公司 用于制备阿戈美拉汀的中间体及相关制备方法
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EP2562151A1 (en) * 2011-08-25 2013-02-27 Dr. Reddy's Laboratories Ltd. Processes for the preparation of agomelatine and its intermediates
ITMI20121444A1 (it) 2012-08-27 2014-02-28 Procos Spa Processo per la produzione di agomelatine
WO2014072998A1 (en) 2012-11-07 2014-05-15 Cadila Healthcare Limited An improved process for preparation of agomelatine
WO2015076296A1 (ja) * 2013-11-20 2015-05-28 マナック株式会社 含臭素ｎ－フェニルジアクリルイミド誘導体及びその製造方法
FR3014434B1 (fr) * 2013-12-05 2015-12-25 Servier Lab Nouveau procede de synthese du 7-methoxy-naphtalene-1-carbaldehyde et application a la synthese de l'agomelatine
FR3014437B1 (fr) * 2013-12-05 2016-12-23 Servier Lab Nouveau procede de synthese de l'agomelatine
CN114394906A (zh) * 2022-03-24 2022-04-26 中孚药业股份有限公司 一种阿戈美拉汀中间体的制备方法
CN115872887B (zh) * 2022-12-30 2023-07-07 上海国创医药股份有限公司 一种阿戈美拉汀的制备方法

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