RS61436B1 - Proces za izradu derivata karbamoilpiridona i međuproizvoda - Google Patents

Proces za izradu derivata karbamoilpiridona i međuproizvoda

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Publication number
RS61436B1
RS61436B1 RS20210153A RSP20210153A RS61436B1 RS 61436 B1 RS61436 B1 RS 61436B1 RS 20210153 A RS20210153 A RS 20210153A RS P20210153 A RSP20210153 A RS P20210153A RS 61436 B1 RS61436 B1 RS 61436B1
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Serbia
Prior art keywords
methyloxy
methyl
compound
mixture
formula
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RS20210153A
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English (en)
Inventor
Huan Wang
Steven N Goodman
Douglas Mans
Matthew Kowalski
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Viiv Healthcare Co
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Publication of RS61436B1 publication Critical patent/RS61436B1/sr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • AIDS & HIV (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pyridine Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Opis
Polje pronalaska
[0001] Ovaj pronalazak se odnosi na međuproizvode za upotrebu u izradi derivata karbamoilpiridona koji su korisni kao inhibitori HIV integraze.
Poreklo pronalaska
[0002] Jedinjenja koja imaju aktivnost inhibitora HIV integraze su opisani u WO 2006/116764 (odgovarajući U.S. Serial No.11/919386 dodeljen Shionogi & Co. Ltd.). Jedinjenja su otkrivena kao derivati policikličnog karbamoilpiridona. Takođe su otkriveni procesi za njihovu izradu. Među primere ovih jedinjenja, uključeni su naredni derivati policikličnog karbamoilpiridona:
[0003] Otkriveni procesi za izradu ovih jedinjenja su vrlo zahtevni i uključuju čak 14 faza. Zbog toga bi bio napredak u tehnici da se nađu efikasniji načini za izradu ovih jedinjenja.
Kratak sadržaj pronalaska
[0004] Ovaj pronalazak obezbeđuje jedinjenje formule (IV)
gde je R alkil, aril ili benzil grupa.
[0005] U jednom aspektu, jedinjenje u skladu sa pronalaskom je 1-[2,2-bis(metiloksi)etil]-5-(metiloksi)-6-[(metiloksi)karbonil]-4-okso-1,4-dihidro-3-piridinkarboksilna kiselina.
[0006] Ovo otkriće obezbeđuje unapređeni proces za izradu sledećih jedinjenja:
[0007] U jednom aspektu, ovo otkriće obezbeđuje postupak koji uključuje dovođenje u kontakt metil 3-{[2,2-bis(metiloksi)etil]amino}-2-[(metiloksi)acetil]-2-propenoata (formula I):
sa oksalatnim estrom formule II:
u prisustvu M<+ ->OR, gde je R alkil, aril ili benzil grupa; a M<+>je katjon alkalnog metala; da se formira piridinon formule III:
[0008] U narednom aspektu, ovo otkriće obezbeđuje postupak koji uključuje selektivnu hidrolizaciju piridinona formule III:
gde je R alkil, aril ili benzil grupa
sa reagensom za selektivnu hidroilzaciju da se formira piridinon karboksilna kiselina formule IV gde je R alkil, aril ili benzil grupa:
uz selektivnost veću od 90%.
[0009] U trećem aspektu, ovo otkriće obezbeđuje postupak koji uključuje dovođenje u kontakt jedinjenja formule VII:
sa katjonom magnezijuma ili litijuma i nukleofilnim anjonom da se formira jedinjenje formule VIII:
[0010] U četvrtom aspektu, ovo otkriće obezbeđuje jedinjenje izabrano iz grupe koja se sastoji od:
[0011] U petom aspektu, ovo otkriće obezbeđuje proces koji uključuje dovođenje u kontakt jedinjenja formule IV gde je R alkil, aril ili benzil grupa:
sa sirćetnom kiselinom i katalitičkom količinom jake protične kiseline da se formira aldehid piridinon karboksilne kiseline formule V, gde je R alkil, aril ili benzil grupa:
[0012] Proces iz ovog otkrića je koristan za izradu jedinjenja sa inhibitornom aktivnošću na HIV integrazu.
Detaljan opis pronalaska
[0013] Niže data šema ilustruje opšti proces za izradu jedinjenja formule VIII, ((3S,11aR)-N-[(2,4-difluorofenil)metil]-6-hidroksi-3-metil-5,7-diokso-2,3,5,7,11,11aheksahidro[1,3]oksazolo[3,2-a]pirido[1,2-d]pirazin-8-karboksamid).
Šema:
[0014] U prethodno datoj šemi, 4-metoksiacetoacetat se dovodi u kontakt sa DMFDMA (N,N-dimetil-1,1-bis(metiloksi)metanaminom) pod uslovima dovoljnim da se formira metil 3-(dimetilamino)-2-[(metiloksi)acetil]-2-propenoat. Reakcijom ovog međuproizvoda sa aminoacetaldehidom dimetil acetala se dobija metil 3-{[2,2-bis(metiloksi)etil]amino}-2-[(metiloksi)acetil]-2-propenoat (I).
[0015] Jedinjenje I se nakon toga dovodi u kontakt sa oksalatnim estrom (II) u prisustvu M<+ ->OR da se formira piridinon (III). Svaki R je C1-C5-alkil, aril ili benzil grupa; M<+>je katjon alkalnog metala kao što su litijum, natrijum ili kalijum. Preferirano je da je katjon alkalnog metala litijum a R grupa oksalatnog estra je ista kao R grupa iz M<+ ->OR. Preferirano, R je C1-C5-alkil, posebno C1-C2-alkil grupa. Posebno preferirani oksalatni estri su dimetil etandioat i dietil etandioat. Posebno preferirani alkoksidi alkalnih metala su litijum metoksid i litijum etoksid. Preferirano, kada je oksalatni estar dimetil etandioat, alkoksid alkalnog metala je litijum metoksid. Preferirano, kada je oksalatni estar dietil etandioat, alkoksid alkalnog metala je litijum etoksid.
[0016] Piridinon (III) se selektivno hidrolizuje sa LiOH da se formira piridinon karboksilna kiselina (IV). Neočekivano, metil estar na položaju 5 piridinona (III) se hidrilizuje sa najmanje 90% selektivnosti u odnosu na estar na položaju 2.
[0017] Piridinon karboksilna kiselina (IV) se dovodi u kontakt sa sirćetnom kiselinom i katalitičkom količinom jake protične kiseline da se formira aldehid piridinon karboksilne kiseline (V). U primere odgovarajućih jakih protičnih kiselina spadaju metansulfonska kiselina, sumporna kiselina, toluen sulfonska kiselina i hlorovodonična kiselina. Aldehid (V) se nakon toga dovodi u kontakt sa (2S)-2-amino-1-propanolom da se formira ((3S,11aR)-3-metil-6-(metiloksi)-5,7-diokso-2,3,5,7,11,11a-heksahidro[1,3]oksazolo[3,2-a]pirido[1,2-d]pirazin-8-karboksilna kiselina) (VI).
[0018] Jedinjenje VI se pod uslovima udvajanja dovodi u kontakt sa 2.4-difluorobenzilaminom da se formira (3S,11aR)-N-[(2,4-difluorofenil)metil]-3-metil-6-(metiloksi)-5,7-diokso-2,3,5,7,1 1,11a-heksahidro[1,3]oksazolo[3,2-a]pirido[1,2-d)pirazin-8-karboksamid (VII).
[0019] Konačno, jedinjenje VII se demetiliše sa Luisovom kiselinom da se formira Produkt (3S,11aR)-N-[(2,4-difluorofenil)metil]-6-hidroksi-3-metil-5,7-diokso-2,3,5,7,11,11aheksahidro[1,3]oksazolo[3,2-a]pirido[1,2-d]pirazin-8-karboksamid (VIII). U primere odgovarajućih Luisovih kiselina spadaju soli magnezijuma i litijuma. Soli magnezijuma uključuju soli kao što su magnezijum hlorid, magnezijum bromid, magnezijum jodid i magnezijum sulfid. Soli litijuma uključuju soli kao što su litijum hlorid, litijum bromid, litijum jodid i litijum sulfid. Preferiran je litijum bromid.
[0020] Alternativno, i u narednom aspektu ovog otkrića, jedinjenje V može da se dovede u kontakt sa (3R)-3-amino-1-butanolom da se formira jedinjenje formule VIa:
[0021] Jedinjenje VIa može pod uslovima udvajanja da reaguje sa 2,4-difluorobenzilaminom da se formira jedinjenje formule VIIa:
[0022] Jedinjenje VIIa može da se demetiliše sa MgXn ili LiXn (gde je X halid, na primer, Br, Cl, F ili I) da se formira jedinjenje VIIIa:
Primeri
[0023] Naredni primeri ilustruju proces iz ovog otkrića. Rastvarači i uslovi reakcije ne treba da ograniče okvir pronalaska. Početni materijali su poznati u tehnici i lako se izrađuju ili su komercijalno raspoloživi. Preferirano, hemikalije korišćene u primerima su nabavljene na tržištu (na primer od firme Aldrich®).
A. 1-[2,2-Bis(metiloksi)etil]-5-(metiloksi)-6-[(metiloksi)karbonil]-4-okso-1,4-dihidro-3-piridinkarboksilna kiselina
[0024] Smeša metil 4-metoksiacetoacetata (20 mL) i DMFDMA (24 mL) se meša 1.5 h na sobnoj temperaturi. Reaktivna smeša se razblaži sa MeOH (50 mL) i doda se aminoacetaldehid dimetil acetal (16.7 mL). Smeša se meša 1 h na sobnoj temperaturi, koncentruje i nakon toga razblaži sa MeOH (113 mL). Doda se dimetil oksalat (45.66 g) a nakon toga se u porcijama doda LiH (2.15 g) uz održavanje temperature reakcije ispod 25 °C. Sadržaj reakcije se zagreva 14 h na 40 °C. Reaktivna smeša se ohladi na -5 °C i doda se LiOH (14.82 g) uz održavanje temperature reakcije ispod 5 °C. Kada je dodavanje završeno, smeša se meša još 2 h na 3-5 °C. Reaktivna smeša se neutrališe sa vodenim rastvorom HCl (2 N, 367 mL), održavajući temperaturu reakcije ispod 5 °C. Po završenom dodavanju, doda se EtOAc (450 mL) i smeša se zagreje na 20 °C. Reaktivna smeša se filtrira i vodeni sloj se odbaci. Doda se voda (225 mL) i organski sloj se ukloni pod sniženim pritiskom. Produkt se sakupi filtriranjem i suši u vakuumskoj pećnici u toku noći na 50 °C. Produkt se dobija kao čvrsta supstanca.
B. (3S,11aR)-3-Metil-6-(metiloksi)-5,7-diokso-2,3,5,7,11,11aheksahidro[1,3]oksazolo[3,2-a]pirido[1,2-d]pirazin-8-karboksilna kiselina
[0025] 1-[2,2-bis(metiloksi)etil]-5-(metiloksi)-6-[(metiloksi)karbonil]-4-okso-1,4-dihidro-3-piridinkarboksilna kiselina (22.54 g) se rastvori u 220 mL CH3CN. Dodaju se HOAc (20 mL) i CH3SO3H (1.4 mL) na sobnoj temperaturi i smeša se zagreva 19.5 h na 58-65 °C. Polako se dodaje Alaninol (7.511g) u CH3CN (15 mL) i dobijena smeša se meša 18.5 h na 64 °C. Smeša se koncentruje a ostatak se ponovo rastvori u CH2Cl2(170 mL). Doda se HCl (1 N, 170 mL) i slojevi se razdvoje. Vodeni sloj se ekstrahuje sa CH2Cl2(170 mLx2) i organski slojevi se kombinuju i koncentruju. Doda se MeOH (50 mL) i dobijena smeša se ponovo koncentruje. Doda se MeOH (80 mL) i dobijena smeša se zagreva pod refluksom 4 h, postepeno ohladi na 20 °C i ostavi 15 h na 20 °C. Produkt se sakupi filtriranjem i suši pod vakuumom.
[0026] C. (3S11aR)-N-[(2,4-Difluorofenil)metil]-3-metil-6-(metiloksi)-5,7-diokso-2,3,5,7,11,11a-heksahidro[1,3]oksazolo[3,2-a]pirido[1,2-d]pirazin-8-karboksamid
[0027] (3S,11aR)-3-Metil-6-(metiloksi)-5,7-diokso-2,3,5,7,11,11aheksahidro[1,3]oksazolo[3,2-a]pirido[1,2-d]pirazin-8-karboksilna kiselina (3.00 g) i 1,1’-karbonildiimidazol (CDI) (2.15 g) se suspenduju u 1,2-dimetoksietanu (DME) (30 mL).
Smeša se zagreva 1 h na 80 °C. Dobijeni rastvor se ohladi na 20 °C, nakon toga tretira sa 2,4-difluorobenzilaminom (1.45 mL). Nakon 1 h mešanja, smeša se neutrališe sa vodom (30 mL) i DME se ukloni pod sniženim pritiskom. Produkt se sakupi filtriranjem i suši u vakuumskoj pećnici u toku noći na 50 °C. Produkt se dobija kao čvrsta supstanca.
D. (3S,11aR)-N-[(2,4-Difluorofenil)metil]-6-hidroksi-3-metil-5,7-diokso-2,3,5,7,11,11a-
1
heksahidro[1,3]oksazolo[3,2-a]pirido[1,2-d]pirazin-8-karboksamid
[0028] (38,11aR)-N-[(2,4-Difluorofenil)metil]-3-metil-6-(metiloksi)-5,7-diokso-2,3,5,7,11,11a-heksahidro[1,3]oksazolo[3,2-a]pirido[1,2-d)pirazin-8-karboksamid (193.1 mg) se rastvori u CH3CN (4 mL) i doda se MgBr2(206.3 mg). Smeša se zagreva 2 h na 50 °C i neutrališe sa HCl (0.2 N, 10 mL). Smeša se razblaži sa CH2Cl2i pH dalje podesi na ~1.
Vodeni sloj se ekstrahuje sa CH2Cl2(10 mLx2). Kombinovani organski slojevi se suše i koncentruju da se dobije produkt.
[0029] Alternativno, demetilacija može da se izvrši sa LiBr: (3S,11aR)-N-[(2,4-Difluorofenil)metil]-3-metil-6-(metiloksi)-5,7-diokso-2,3,5,7,11,11aheksahidro[1,3]oksazolo[3,2-a]pirido[1,2-d]pirazin-8-karboksamid (8.609 g) se rastvori u THF (90 mL) i doda se LiBr (3.942 g). Smeša se zagreva 12 h pod refluksom i neutrališe sa H2SO4(0.5 M, 94.467 g). Dobijena suspenzija se meša 2 h na 20 °C i filtrira. Čvrsti produkt se ponovo suspenduje u smeši voda-THF (50 mL-50 mL) na 20 °C u toku 2 h. Produkt se sakupi filtriranjem, ispere sa smešom voda-THF (1-1, 30 mL) i suši pod vakuumom da se dobije produkt.

Claims (2)

  1. Patentni zahtevi 1. Jedinjenje formule (IV)
    naznačeno time što je R alkil, aril ili benzil grupa.
  2. 2. Jedinjenje u skladu sa patentnim zahtevom 1, naznačeno time što je to 1-[2,2-bis(metiloksi)etil]-5-(metiloksi)-6-[(metiloksi)karbonil]-4-okso-1,4-dihidro-3-piridinkarboksilna kiselina. Izdaje i štampa: Zavod za intelektualnu svojinu, Beograd, Kneginje Ljubice 5
RS20210153A 2010-03-23 2011-03-22 Proces za izradu derivata karbamoilpiridona i međuproizvoda RS61436B1 (sr)

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US31642110P 2010-03-23 2010-03-23
EP17165935.2A EP3260457B1 (en) 2010-03-23 2011-03-22 Process for preparing carbamoylpyridone derivatives and intermediates

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