SI21507A - Postopek za pripravo spojin z ace inhibitornim delovanjem - Google Patents

Postopek za pripravo spojin z ace inhibitornim delovanjem Download PDF

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Publication number
SI21507A
SI21507A SI200300123A SI200300123A SI21507A SI 21507 A SI21507 A SI 21507A SI 200300123 A SI200300123 A SI 200300123A SI 200300123 A SI200300123 A SI 200300123A SI 21507 A SI21507 A SI 21507A
Authority
SI
Slovenia
Prior art keywords
preparation
compounds
ace inhibitory
activated
inhibitory activity
Prior art date
Application number
SI200300123A
Other languages
English (en)
Inventor
Branko Jenko
Original Assignee
LEK farmacevtska dru�ba d.d.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by LEK farmacevtska dru�ba d.d. filed Critical LEK farmacevtska dru�ba d.d.
Priority to SI200300123A priority Critical patent/SI21507A/sl
Priority to SI200431600T priority patent/SI1628956T1/sl
Priority to PCT/SI2004/000021 priority patent/WO2004101515A1/en
Priority to EP04731808A priority patent/EP1628956B1/en
Priority to RU2005139158/04A priority patent/RU2377236C2/ru
Priority to US10/556,986 priority patent/US7671215B2/en
Priority to AT04731808T priority patent/ATE488498T1/de
Priority to DE602004030112T priority patent/DE602004030112D1/de
Publication of SI21507A publication Critical patent/SI21507A/sl

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

Podan je postopek za pripravo spojin z ACE inhibitornim delovanjem s formulo I, kjer imajo R1, R2 in R3 zgoraj navedeni pomen pri katerem karboksilno skupino stereospecifične amino kisline aktiviramo z reagenti iz skupine O-Benzotriazolil heksafluoro fosfatov ali tetrafluoro boratov v aprotičnih topilih in nato aktivirano kislino pretvorimo v peptid z aminom, primernim za sintezo ACE inhibitorjev.ŕ

Description

POSTOPEK ZA PRIPRAVO SPOJIN Z ACEINHIBITORNIM DELOVANJEM
PODROČJE TEHNIKE
Izum spada v področje kemijske sinteze in se nanaša na postopek za pripravo spojin z ACE inhibitomim delovanjem
TEHNIČNI PROBLEM
Pri nekaterih substancah z ACE inhibitomim delovanjem so obstoječi postopki komplicirani v smislu uporabe reagentov in tehnologije. Izum omogoča hitro, selektivno in enostavno tvorbo ACE inhibitorjev.
STANJE TEHNIKE
Do zdaj znani postopki za sintezo ACE inhibitoijev v ključni fazi sinteze uporabljajo nekaj v literaturi znanih načinov za tvorbo peptidne vezi:
NCA (Fosgen, di ali tri fosgen, karbonil diimidazol)
Klortionil imidazol ali tionil diimidazol
Dicikloheksil karbodiimid /1-hidroksi benzotriazol
V EP 1 279 665 je opisan postopek za pripravo perindoprila s tvorbo NCA s pomočjo trifosgena. Reakcija daje dobre rezultate vendar zahteva delo s trifosgenom posebno pazljivost. V USP 4 914 214 je opisana sinteza perindoprila s kondenzacijo (2,S,3aS,7aS)-2-22 karboksiperhidro indola ( z zaščiteno karboksilno skupino) z N-((S)-l-karbetoksibutil)-(S)alaninom s pomočjo dicikloheksil karbodiimida in 1-hidroksi benzotriazola. Postopek daje dobre rezultate vendar je potrebna pazljiva izolacija zaradi stranskega produkta dicikloheksil sečnine, ki jo je težje popolnoma izločiti iz reakcijske zmesi. V SI 94 00 290 je opisana sinteza enalaprila s tvorbo peptidne vezi s tionil imidazolom. Reakcija daje zadovoljive rezultate vendar je potrebna striktna kontrola reakcijskih pogojev in absolutno brezvodni mediji, sicer so izkoridtki vprašljivi in so možne stranske reakcije ( tvorba diketopiperazida ipd).
OPIS REŠITVE PROBLEMA Z IZVEDBENIMI PRIMERI
Predmet izuma je postopek za pripravo ACE inhibitorjev s formulo :
R2O
ch3
ali njihove farmacevtsko sprejemljive adicijske soli
RI je lahko : H, alkil, fenil
R2 je lahko : H, alkil R3 je lahko
-N \
(CH2)n /
/
Z r4oocz n=l?2?3
X,Z~CH2, NH,S R4 - ll,Bz,M,Me,Pr,Bu
M=Li,Na,K,Ca ali
»llCOOBz označen s tem, da karbonilno skupino stereospecifične amino kisline
Ri
H
OH
RI, R2 kot zgoraj aktiviramo z reagenti iz serije substituiranih O-Benzotriazolil heksafluoro fosfatov ali tetrafluoro boratov v aprotičnih topilih in nato aktivirano kislino pretvorimo v peptid s primernim aminom iz serije HR3 pri čemer je R3 :
-N (CH2)n /
Z
R4OOC n=l,2,3
X,Z = CH2, NH.S R4 - H,Bz,M,Me,Pr,Bu
M-UNa,K,Ca ali
'IICOOBz
Nastali produkt nato po izolaciji po potrebi prevedemo v farmacevtsko sprejemljivo sol.
Topila primerna za ta tip reakcije so klorirani ogljikovodiki, ciklični ali aciklični ogljikovodiki, estri org. kislin (n.pr, etil acetat), skratka aprotična topila.
Izvedba reakcije je zelo enostavna in ne zahteva posebnih pogojev. Izredno pomembno je, da poteče izredno hitro v primeijavi z ostalimi metodami sinteze ACE inhibitoijev (v 15 minutah) in zaradi izredne selektivnost praktično brez stranskih produktov. Ključna reakcija tvorbe peptidne vezi poteče tako, da 15-30 minut pri sobni temperaturi v topilu mešamo v steheometričnem razmerju (ali z rahlim prebitkom katerekoli komponente) kislino, amin in reagent iz zgoraj omenjene serije. Nastali reakcijski zmesi dodamo vodo in produkt izoliramo s primernim topilom, v katerem je produkt topen. Po spiranju raztopine z vodo in uparenju topila dobimo surov produkt visoke optične in kemijske čistost v visokem izkoristku (8795%).
Reakcijska shema:
OH (R5)2N—c=N(R5)2 o
PF6 ali BF4
R5= Me,Et ali pirolidino
H
Ra
-7Izum ponazarjamo z naslednjimi primeri, ki opisujejo izum, vendar ga ne omejujejo :
Primer 1
V 20 ml MeCN med mešanjem pri sobni temperaturi dodamo 855 mg Benzilnega estra (2S,3aS,7aS)-2-karboksiperhidro indola, 651 mg N-((S)-l-karbetoksibutil)-(S)-alanina in 1137 mg 0-(Benzotriazal-1-H)-NXN\N'-tetrametiluroniumheksafluorofosfata. Po 30 minutah mešanja dodamo 50 ml nasičene raztopine NaCl in produkt ekstrahiramo z dvakrat po 35 ml etil acetata, Združene ekstrakte speremo s 70 ml vode, ki smo ji dodali 1 ml HCI cone. in nato še s 130 ml vode. Ekstrakt sušimo z Na2SO4 in uparimo pri 40 °C v vakuumu. Dobimo 1210 mg (87,8%) Benzil (2Sf3aS,7aS)-((2-(1-(etoksikarbonil)-(S)-butilamino)4S)-propionil)oktahidroindol-2-karboksilata (benzilni ester perindoprila).
Nastali produkt lahko po znanih metodah pretvorimo v prosto kislino in nato v farmacevtsko primerno sol.
Primer 2
2,79 g (S)-l-(N-(l-(etoksikarbonil)-3-fenilpropil)-L-alanina, 1,15 g L-Prolina v 100 ml MeCN in 5 ml DMF, dodamo 2,9 ml trietilamina in med mešanjem še 3,8 g O-iBenzotnazol-l-ilj-N.N.N^N’tetrametiluroniumheksafluorofosfata in mešamo 30 minut pri sobni temperaturi. Dodamo 300 ml nas. raztopine NaCl in ekstrahiramo z dvakrat po 100 ml etilacetata. Produkt izoliramo na enak način kot v primeru 1. Dobimo 3,55 g enalaprila, ki ga raztopimo v 100 ml etilacetata in mu dodamo raztopino 1,00 g maleinske kisline v 20 ml etilacetata. Po 30 minutah odfiltriramo kristale enalapril maleata in jih posušimo v vakuumu pri 40 °C. Dobimo 4,2g produkta (85,4% )

Claims (4)

  1. PATENTNI ZAHTEVKI
    1. Postopek za pripravo spojin z ACE inhibitornim delovanjem s formulo :
    Ra
    In njihovih farmacevtsko sprejemljivih soli kjer imajo R1-R3 naslednje pomene :
    RI je lahko : H, alkil, fenil
    R2 je lahko : H, alkil
    R3 je lahko:
    /Xx
    -N (CH2)n
    R4OOC n-1,2,3 = CH2, NH,S R4 = H,Bz,M,Me,Pr,Bu
    M=Li,Na,K,Ca ali
    Η
    Η ilCOOBz označen s tem, da karboksilno skupino amino kisline s formulo aktiviramo z reagenti iz skupine substituiranih O-Benzotriazolil heksafluoro fosfatov ali tetrafluoro boratov v aprotičnih topilih in nato aktivirano kislino pretvorimo v peptid s primernim aminom iz serije HR3 pri Čemer je R3 :
    /x\
    -N (CH2)n \ /
    R4OOC n« 1,2,3
    X,Z CH2, NH,S
    R4 - H,BzMMe,Pr,Bu
    M=Li,Na,K,Ca
    -10ΑΟ ali
    Η llCOOBz
    H in nato dobljene produkte po potrebi pretvorimo v farmacevtsko sprejemljive soli.
  2. 2. Postopek za pripravo spojin z ACE inhibitomim delovanjem kot v zahtevku št. 1 s tem, daje amino kislinaN-((S)-l-karbetoksibutil)-(S)-alanin.
  3. 3. Postopek za pripravo spojin z ACE inhibitomim delovanjem kot v zahtevku Št. 1 s tem, daje aminBenzilni ester(2S,3aS,7aS)-2-karboksiperhidro indola.
  4. 4. Postopek za pripravo spojin z ACE inhibitomim delovanjem kot v zahtevku št. 1 s tem, da je reagent za tvorbo peptidne vezi iz serije substituiranih O-Benzotriazolil heksafluoro fosfatov O-(Benzotriazol-1 -il)-NN,N',N'-tetrametiluroniumheksafluorofosfat.
SI200300123A 2003-05-16 2003-05-16 Postopek za pripravo spojin z ace inhibitornim delovanjem SI21507A (sl)

Priority Applications (8)

Application Number Priority Date Filing Date Title
SI200300123A SI21507A (sl) 2003-05-16 2003-05-16 Postopek za pripravo spojin z ace inhibitornim delovanjem
SI200431600T SI1628956T1 (sl) 2003-05-16 2004-05-07 Postopek za pripravo spojin z ACE inhibitornim delovanjem
PCT/SI2004/000021 WO2004101515A1 (en) 2003-05-16 2004-05-07 A process for the preparation of compounds having an ace inhibitory action
EP04731808A EP1628956B1 (en) 2003-05-16 2004-05-07 A process for the preparation of compounds having an ace inhibitory action
RU2005139158/04A RU2377236C2 (ru) 2003-05-16 2004-05-07 Способ получения соединений, обладающих апф ингибиторной активностью
US10/556,986 US7671215B2 (en) 2003-05-16 2004-05-07 Process for the preparation of compounds having an ace inhibitory action
AT04731808T ATE488498T1 (de) 2003-05-16 2004-05-07 Verfahren zur herstellung von ace hemmern
DE602004030112T DE602004030112D1 (de) 2003-05-16 2004-05-07 Verfahren zur herstellung von ace hemmern

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
SI200300123A SI21507A (sl) 2003-05-16 2003-05-16 Postopek za pripravo spojin z ace inhibitornim delovanjem

Publications (1)

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SI21507A true SI21507A (sl) 2004-12-31

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Application Number Title Priority Date Filing Date
SI200300123A SI21507A (sl) 2003-05-16 2003-05-16 Postopek za pripravo spojin z ace inhibitornim delovanjem
SI200431600T SI1628956T1 (sl) 2003-05-16 2004-05-07 Postopek za pripravo spojin z ACE inhibitornim delovanjem

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Country Status (7)

Country Link
US (1) US7671215B2 (sl)
EP (1) EP1628956B1 (sl)
AT (1) ATE488498T1 (sl)
DE (1) DE602004030112D1 (sl)
RU (1) RU2377236C2 (sl)
SI (2) SI21507A (sl)
WO (1) WO2004101515A1 (sl)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008079266A2 (en) * 2006-12-21 2008-07-03 Wyeth Synthesis of pyrrolidine compounds
US20090076126A1 (en) * 2007-09-17 2009-03-19 Protia, Llc Deuterium-enriched enalapril
CN102498098A (zh) 2009-07-16 2012-06-13 艾博特公司 作为群多普利中间体的(2S，3aR，7aS)-八氢-1H-吲哚羧酸的合成方法
ES2670854T3 (es) * 2012-10-10 2018-06-01 Piramal Enterprises Limited Un proceso mejorado para la preparación de perindoprilo intermedio

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL4915C (sl) 1913-08-18
FR2620709B1 (fr) * 1987-09-17 1990-09-07 Adir Procede de synthese industrielle du perindopril et de ses principaux intermediaires de synthese
US5864040A (en) 1996-01-11 1999-01-26 American Home Products Corporation Benzimidazole phosphono-amino acids
GB9710612D0 (en) 1997-05-23 1997-07-16 Glaxo Group Ltd Synthesis of acridine derivatives
AU2001239469A1 (en) 2000-03-31 2001-10-08 Pfizer Products Inc. Novel piperazine derivatives
GB2375762B (en) 2001-05-21 2003-10-01 Fermenta Biotech Ltd Stereospecific synthesis of 2-hydroxy-4-phenyl-butyric acid esters
US7214769B2 (en) 2001-05-23 2007-05-08 The Curators Of The University Of Missouri Method for inverse solid phase synthesis of peptides
AR036187A1 (es) 2001-07-24 2004-08-18 Adir Un proceso para la preparacion de perindopril, compuestos analogos y sus sales, compuesto intermediario 2,5-dioxo-oxazolidina y proceso para preparar un intermediario
GB0119795D0 (en) 2001-08-14 2001-10-03 Smithkline Beecham Plc Novel process

Also Published As

Publication number Publication date
DE602004030112D1 (de) 2010-12-30
WO2004101515A1 (en) 2004-11-25
ATE488498T1 (de) 2010-12-15
US7671215B2 (en) 2010-03-02
RU2377236C2 (ru) 2009-12-27
RU2005139158A (ru) 2007-06-27
EP1628956B1 (en) 2010-11-17
SI1628956T1 (sl) 2011-03-31
EP1628956A1 (en) 2006-03-01
US20070072919A1 (en) 2007-03-29

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