PT94778B - Processo para a preparacao de acido {r-(r*r*)}-2-(4-fluorfenil)-beta,delta-di- hidroxi-5-(1-metiletil)-3-fenil-4-{(fenilamino)-carbonil}-1h-pirrol-heptanoico, da sua lactona e sais e de composicoes farmaceuticas que os contem - Google Patents

Processo para a preparacao de acido {r-(r*r*)}-2-(4-fluorfenil)-beta,delta-di- hidroxi-5-(1-metiletil)-3-fenil-4-{(fenilamino)-carbonil}-1h-pirrol-heptanoico, da sua lactona e sais e de composicoes farmaceuticas que os contem Download PDF

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Publication number
PT94778B
PT94778B PT94778A PT9477890A PT94778B PT 94778 B PT94778 B PT 94778B PT 94778 A PT94778 A PT 94778A PT 9477890 A PT9477890 A PT 9477890A PT 94778 B PT94778 B PT 94778B
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Prior art keywords
fluorophenyl
final product
salt
methylethyl
pyrrole
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PT94778A
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PT94778A (pt
Inventor
Bruce David Roth
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Warner Lambert Co
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    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C07D207/327—Radicals substituted by 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—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 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Description

! ANTECEDENTES DA INVENÇÃO i
ι
As trans-(+)-5-(4-fluorofenil)-2-(l-metiletil)-N,4-difenil-1-/-2-(tetra-hidro-4-hidroxi-6-oxo-2H-piran-2- -il)etil_7-lH-piran-2-il)-etil_7-lH-pirrol-3-carboxamidas estão entre os compostos da Patente U.S. Ns 4,681,893 com utili ij dade como inibidores da biossintese do colesterol. Os composj tos ali referidos incluem globalmente 4-b.idroxipiran-2-onas e ί os seus derivados ácidos de anel aberto correspondentes.
i'
M.A.i
Verifica-se agora inesperadamente que o enantiómero contendo a forma R do ácido de anel aberto de trans-5- (4-fluorofenil)-2-(1-metiletil )-N, 4-dif enil-l-/”2- (t etrahidro-4-hidroxi-6-oxo-2H-piran-2-il)etil_7-lH-piran-2-il)etil_7· -lH-pirrol-3-carboxamida; isto é o ácido /_R-(R*,R*)__7-2-(4-fluorofenil)- ô -di-hidroxi-5-((1-metiletil)-3-fenil-4-/ (fenilamino)carbonil_7-lH-pirrol-l-heptanóico, proporciona uma inibição supreendente da biossíntese do colesterol.
i!
I? conhecido que a 3-hidroxi-3-metilglutaril coen . Si zima A (HMG-CoA) existe como 3R-estereoisómero. Adicionalmen ' íj te, como é mcètrado no estudo de uma série de ácidos 3,5-dihi í droxipentanóicos 5-substituídos por Stokker e col., em 3-H^ droxy-3-methylglutaryl-Coenzyme A Reductase Inhibitors. 1. i Structural Modification of 5-Substituted 3,5-DihydroxypentaI ί jj noic acids and Their Lactone Derivatives,” J, Med. Chem. j; 1985, 28, 347-358, essencialmente toda a actividade biológiί ca reside no trans diastereómero de (E)-é-/-2-(2,4-diclorofe.
nil)etenil__7-3,4,5 >6-tetrahidro-4-hidroxi-2H-piranona possuin do uma rotação positiva. Além disso, a configuração absoluta para o radical de ^-hidroxi- δ-lactona comum à mevinolina com a fórmula (la)
fe compactina com a fórmula (lb)
' é aparentemente necessária para a inibição de HMG-CoA redutja se. Este facto é referido por Lynch e col. em Synthesis of an HMG-CoA Reductase Inhibitor; A Diastereoselective Aldol í;
h Approach in Tetrahedron Letters, Vol. 28, Ns 13, pág. 1395( -1388 (1987) como a configuração 4R, 6R.
Si ι
í Contudo, o especialista comum não podia prever a j inibição inesperada da bissíntese do colesterol da presente ' invenção tendo em conta estas referências.
RESUMO DA INVENÇÃO [ Assim a presente invenção refere-se a um processo para a preparação de compostos consistindo em ácido /~Rj -(R*,R*)_7-2-(4-fluorofenil)- β,δ -di-hidroxi-5-((1-metilet il)-3-fenil-4-/~ (fenilamino)carbonil_7-lH-pirrol-l-hept anóico (composto com a fórmula I), dos seus sais farmaceuticamente aceitáveis e (2R-trans)-5-(4-fluorofenil)-2-(l-metiletil)-N,4-difenil-1-/. 2-(tetrahidro-4-hidroxi-6-oxo-2H-piran-2-il) etil_7-lH-pirrol-3-carboxamida (a forma de lactona do ácido
heptanóico ou composto com a fórmula II).
A presente invenção também se refere a uma compo sição farmacêutica, útil como agente hipocolesterolémico, compreendendo uma quantidade hipocolesterolémica eficaz de £ eido /~R-(R*,R*)_7-2-(4-fluorofenil)-p,<$-di-hidroxi-5-((l-metiletil)-3-fenil-4-/”(fenilamino)carbonil_7-lH-pirrol-l-heptanóico, e seus sais farmaceuticamente aceitáveis ou áci do (2R-trans)-5-(4-fluorofenil)-2-(1-metiletil)-N,4-difenil—1—/ 2-(tetrahidro-4-hidroxi-6-oxo-2H-piran-2-il)etil_7-lH-pirrol-3-carboxamida, e um veículo farmaceuticamente aceita vel. Além disso, a presente invençSo refere também um proce£ so de tratamento de mamíferos, incluindo o homem, sofrendo de hipercolesterolemia por administração a esse mamífero de ι uma forma de dosagem da composição farmacêutica acima descri ta.
i
I
DESCRIÇÃO DETALHADA DA INVENÇÃO
Os sais farmaceuticamente aceitáveis da invenção !'i são os geralmente obtidos pela dissolução do ácido livre ou da lactona, preferivelmente da lactona, num solvente aquoso ou numa solução aquosa de álcool ou de outros solventes adequados com uma base adequada e isolando o sal pela evaporação da solução ou por reacção do ácido livre ou da lactona, ί Λ preferivelmente da lactona e da base num solvente orgânico j no qual o sal se separa directamente ou pode ser obtido pela i
concentração da solução.
!!
i.
! Na prática, a utilização da forma de sal conduz a utilizar a forma de ácido ou de lactona. Os sais farmaceuticamente aceitáveis adequados que estão dentro do âmbito da invenção são os derivados de bases tais como hidróxido de s_ó dio, hidróxido de potássio, hidróxido de lítio, hidróxido de cálcio, l-desoxi-2-(metilamino)-D-glucitol, hidróxido de mag nésio, hidróxido de zinco, hidróxido de alumínio, hidróxido
ferroso ou férrico, hidróxido de amónio ou aminas orgânicas tais como N-metil glue amin a, colina, arginina e produtos seine lhantes. Preferivelmente, os sais de lítio, cálcio, magnésio, alumínio e ferrosos ou férricos são preparados a partir de sal de sódio ou de potássio adicionando o reagente adequado a uma solução de sal de sódio ou potássio, isto é, a adição de cloreto de cálcio a uma solução de sal de sódio ou potássio de um composto com a fórmula I dará o seu sal de cálcio.
ácido livre pode ser preparado por hidrólise da forma de lactona com a fórmula II ou fazendo passar o sal através de uma resina de permuta catiónica (resina H+) e eva porando a égua.
A realização mais preferida da presente invenção é o sal de hemicálcio do ácido /“R-(R*,R*)_7-2-(4-fluorofenil)- β,δ -di-hidroxi-5-((l-metiletiD^-fenil-A-/-(fenilamino)carhonil_7-lH-pirroll-heptanóico.
Geralmente, os compostos I e II da presente inven ção podem ser preparados por (1) resolução do racemato, que é preparado pelos processos descritos na Patente U.S. Nb 4 681 893 que é aqui incorporada por referência, ou (2) sintese da forma quiral desejada começando pelos materiais de partida que são conhecidos ou facilmente preparados utilizan do processos análogos aos conhecidos.
Especificamente, a resolução do racemato pode ser conseguida como se mostra no Esquema I (em que Ph é feni lo) como segue:
II
Esquema
4·.
Fase B
1) Separado
2) NaOH
3) refluxo era tolueno
II i!
isómero /~R(R*R*)_7
NaOH
isómero / S(R*R*)_7
”trans racemato do Esquema I significa uma mistura dos seguintes compostos:
isómero / R(R*R*) 7 isómero /”S(R*R*) 7 ji As condições da Fase 1 e 2 do Esquema 1 são geral
P mente como descritas nos Exemplos 6 e 7 seguintes.
A sintese quiral é como se mestra no Bsquema 2 (em que Ph é fenilo) como segue:
Esquema 2
I!
1. THF-80—90°C
Ihr
2. AcOH
1.1 eq NaOMe ->
MeOH, -10 °C l6hrs
COgBu*
2. H202
/ú<_7p3 = + 18.07 (CHClg) ! Geralmente, as condições para o Esquema 2 são as apresentadas nos Exemplos 1-5 seguintes.
especialista reconhecerá que são possíveis alterações aos Esquemas 1 e 2 adequadas para a preparação dos ίί compostos da presente invenção.
í:
Os compostos de acordo com a presente invenção e especialmente o composto com a fórmula I inibem a biossínte’ se do colesterol como é confirmado pelo ensaio de escrutínio ρ de CSI referido na Patente U.S. Ns 4 681 893 que é tambám aqui incorporada agora como referência. Os dados obtidos com os ensaios de CSI para o composto com a fórmula I, o seu ei1 nantiómero que é o composto com a fórmula II e o racemato destes dois compostos são os seguintes:
_____^ί7Μ»?^«ιΒΜ»ΒΕ!!ϊΓίΒϊΒ33^·ί«.*ι-*·*“?-'ί'> ·»'' ,x
Composto isómero / R-(R*R*)_7 isómero /~S-(R*R*)_7 Racemato (micromoles/litro)
0.0044
0.44
0.045
Assim, a presente invenção refere-se também a uma composição farmacêutica preparada a partir do composto ;; com a fórmula I ou II ou dos seus sais farmaceuticamente aceitáveis.
Estas composições são preparadas da forma descri ta na Patente U.S. Na 4 681 893, que é aqui, portanto, também incorporada como referência.
I:
A presente invenção refere também a utilização de agentes hipolipidémicos ou hipocolesterolémicos. Os compostos da presente invenção utilizados nas composições farma cêuticas desta invenção são administrados a um paciente em i níveis de dosagem de entre 10 a 500 mg por dia o que para um
I i ser humano adulto normal com aproximadamente 70 kg de peso corpóreo correspondem a uma dosagem de 0,14 a 7,1 mg/kg de
1' , peso corporeo por dia. As dosagens podem ser preferivelmente de 0,5 a 1,0 mg/kg por dia.
H
A dosagem é preferivelmente administrada como ! forma de unidade de dosagem. A forma de unidade de dosagem j; para utilização oral ou parentérica pode variar ou ser ajustada de 10 a 500 mg, de preferência de 20 a 100 mg de acordo com a aplicação particular e a potência do ingrediente activo As composições podem, se desejado, também conter outros agen tes terapeuticamente activos. As determinações das dosagens óptimas para uma situação particular são fáceis para o espe1 cialista.
Os compostos com as fórmulas I e II e os seus sais farmaceuticamente aceitáveis são em geral equivalentes em actividade e utilidade como aqui demostrado.
Os exemplos seguintes descrevem os processos par ticulares para preparar os compostos de acordo com esta invenção. Estes exemplos não devem ser entendidos como limitan do o âmbito da invenção.
EXEMPLO 1
São adicionados gota a gota 285 ml de n-butil lí tio 2,2 M (em Hexano) a 92 ml de diisopropilamina em 300 ml de THP (tetrahidrofurano) a 5O-6O°C num frasco de uma boca de 1000 ml através de um funil de carga e em atmosfera de azo to. A solução amarela bem agitada é deixada aquecer para cer ca de -20°C. Em seguida é canulada numa suspensão de 99 g de S(+)-2-acetoxi-l,l,2-trifeniletanol em 500 ml de THP absoluto, contida num frasco de 3 bocas de 2 litros a -70°C. Quando a adição ficou completa, deixa-se a mistura reaccional aquecer para -10°C num período de 2 horas. Entretanto, é preparada uma suspensão de 0,63 mol de MgB^ deitando 564 ml (0,63 mol) de bromo numa suspensão de 15,3 g de magnésio (0,63 mol) em 500 ml de THP num frasco de 3 litros equipado com um condensador de refluxo, e um agitador superior. Quando se completa a adição, arrefece-se a suspensão de MgBrg para -78°C e a solução de enolato (castanho escura) é canulada pa.
ra a suspensão num período de 30 minutos. Continua-se a agita ção durante 60 minutos a -78°C. São adicionados em 30 minutos 150 g de 5-(4-fluorofenil)-2-(l-metiletil)-l-(3-oxopropil)-N,4-difenil-lH-pirrol-3-carboxamida em 800 ml de THP ab soluto; em seguida agita-se durante 90 minutos a -78°C, depois modera-se a reacção com 200 ml de AcOH a -78°C. Remove-se o produto para um banho frio, adicionam-se 500 ml de égua e concentra-se a mistura em vazio a 40-50°C. Adicionam-se 500 ml de EtOAc/Heptano 1:1 a suspensão amarelada e fil- 13 !A*eES»SBS2ÉS323S3ís·^
tra-se. 0 filtrado é bem lavado com HC1 0,5 N, em seguida vé rias vezes com égua e finalmente com EtOAc/Hexano (3:1) que !; foi arrefecido com gelo seco a -20°C. 0 produto cristalino | castanho claro (Exemplo IA) á seco num forno de vazio a 40°C. j' Obtêm-se 194 g.
produto IA é recristalizado de EtOAc a -10°C para se obterem 100 g de produto 1B e em seguida este produto é recristalizado de acetona/pentano para se obterem 90 g de produto 10. As éguas-mães são combinadas com as lavagens do material bruto e recristalizadas de EtOAc/Hexano. 33 g de produto 1B revelam o seguinte: HPLC (crornatografia líquida de alta pressão) : 97,4:2,17 de isómeros R,S a S,S. 28,5 g de produto IC revelam o seguinte: HPLC: 95,7:3,7. Os produtos 1B e IC combinados são recristalizados de CHCl^ MeOH 10:1, proporcionando um produto IP com um rendimento de 4β,7 g de cristais brancos.
As águas-mães da primeira lavagem aquosa são |í cristalizadas (EtOAc/Heptano) para se obterem 21,4 g do produto ID; HPLC: 71,56:25,52.
As águas-mães de 1B e IC são cristalizadas de I CHCl-j/MeOH/Heptano para se obterem 55,7 g de cristais bran: cos do produto 1G.
ί; 0 produto ID é recristalizado de CHCl^/MeOH para ' se obter o produto IH.
i
I :
Todas as éguas mães são combinadas, concentradas, e em seguida o resíduo é dissolvido numa mistura quente de CHCl^/MeOH 10:1, é colocado numa coluna de gel de sílica, e á eluído com EtOAc/Hexano 40:60. 0 material cristalizou da : coluna e o gel de sílica á extraído com CHGl^/MeOH e concenJ trado. A recristalização do resíduo com CHCl^/Heptano 3:1 ί produz 33,7 g de produto II.
ι As águas-mães de II são recristalizadas para se u obterem 18,7 g de produto 1K.
ii h As águas-mães de 1K são cristalizadas para se ob ‘I “ íi terem 6,3 g de produto IL.
Os produtos II, 1K e 11 são combinados e recrista !| lizados de CHCl^/Heptano para se obterem 48 g.
As águas-mães combinadas de II, 1K e 11 são conL centradas para se obterem 31 g de produto 1M.
produto IF apresenta os seguintes dados característicos:
Anal: IF n 229-230°C
Cale. Determ.
C: 77.84 77.14
H: 6.02 6.45
N: 3.56 3.13 | Estes dados são consistentes com a formula
EXEMPLO 2 i
ί Suspendem-se 162 g (0,206 M) dos produtos IP, 1G, ! ÍH e IL combinados do Exemplo 1 em 800 ml de uma mistura de
Metanol/THP (5:3)· Arrefece-se para 0°C e adicionam-se a 11,7 g de metóxido de sódio. A mistura é agitada até dissolução total, em seguida é colocada no congelador durante a noite.
1 A mistura reaccional é deixada aquecer para a temperatura am biente, arrefece-se com 15 ml de HOAc, em seguida concentra-se em vazio a 40°C para se obter o produto pretendido com a 1 fórmula seguinte:
, Adiciona-se o produto obtido a 500 ml de água e ' extrai-se duas vezes com EtOAc (300 ml). Lavam-se os extractos combinados com solução saturada de NaHCO^, solução salina, seca-se em sulfato de magnésio anidro, filtra-se e evapo ra-se o solvente. 0 resíduo é cromatográfado em gel de sílij ca utilizando como eluente uma mistura de EtOAc/Heptano (1:4) j; para se obterem 109 g de um óleo incolor que é recristalizado de EtgO/Heptano para se obterem:
73,9 g de um primeiro lote, cristais brancos 8,2 g de um segundo lote, cristais brancos.
ί | Os cristais apresentavam as seguintes proprieda·' I
p.f. 125-126°C, Ot^0 = 4.23° (1.17 M, CH^OH)
Calc. Determ.
des:
C: 72.76 H: 6.30 N: 5.30
72.51
6.23
5.06
Estes dados são consistentes com a fórmula
002Me
São dissolvidos 77 ml de diisopropilamina em 250 ml de THE num frasco de três bocas de 2000 ml equipado com um termómetro e um funil de carga. A mistura reaccional é mantida em azoto. A mistura reaccional é arrefecida para -42°C e ê adicionada gota a gota durante 20 minutos a 200 ml de t-butil litio 2,2 M (em hexano) e ó agitada durante 20 mi nutos antes de se adicionarem gota a gota 62 ml de acetato de t-butilo, dissolvidos em 200 ml de THE (durante cerca de 30 minutos). Esta mistura é agitada durante 30 minutos a -40°C, em seguida são adicionados 140 ml de n-butil litio 2,2 M durante 20 minutos. Quando a adição está completa, são
adicionados 81 g do produto do Exemplo 2 em 500 ml de THF ab soluto o mais rapidamente possível sem deixar a temperatura aumentar para valores superiores a -40°C. A agitação é conti nuada durante quatro horas a -70°C. A mistura reaccional é i:
em seguida aquecida com 69 ml do écido acético glacial e dei ’ xada aquecer para a temperatura ambiente. A mistura é concen
I — ! trada em vazio e o resíduo é retomado em EtOAc, lavado bem j com água, em seguida com NH^Cl saturado, NaHCOg (saturado), e finalmente com solução salina. A fase orgânica é seca em is MgSO^ anidro, filtrada e o solvente evaporado. Os dados de
RMN da reacção são consistentes com o material de partida mais o produto em quantidades iguais mais algum material na linha de base de CCF (cromatografia de camada fina). 0 material da linha de base de CCF é separado do material de parti da e o produto é extraído por extracção ácido/base. A fase organica é seca e concentrada em vazio para produzir 73 g.
I Os dados de RMN e CCF são consistentes com a fórmula
i i
g do produto bruto do Exemplo 3 são dissolvidos em 500 ml de THF absoluto e são adicionados 120 ml de
I trietil borano, seguidos de 0,7 g de ácido t-butilcarboxíli18
I!
co. Α mistura é agitada numa atmosfera seca durante 10 minuj tos e são adicionados 70 ml de metanol seguidos de 4,5 g de j borohidreto de sódio. A mistura é novamente agitada a -78°C ' durante seis horas. Em seguida deita-se devagar numa mistura ( 4:1:1 de gelo/30% H202/H20. Esta mistura é agitada durante toda a noite deixando-se em seguida aquecer para a temperatu : ra ambiente.
E adicionado CHCl^ (400 ml) e a mistura é repartida. A fase aquosa é extraída novamente com CHCl^, Os extractos orgânicos são combinados e bem lavados com H20 sté ' : não se encontrar nenhum peróxido. A fase orgânica é seca em MgSO^, filtrada e o solvente é evaporado.
resíduo é tratado por cromatografia rápida em jj gel de sílica, isto é, EtOAc/hexano 1:3 para produzir 51 g.
Ί ,i 0 produto é dissolvido em THE/MeOH e adicionado í a 100 ml am NaOH, em seguida é agitado durante quatro horas â temperatura ambiente. A solução ó concentrada à temperatui ra ambiente para remover o solvente orgânico, adicionada a il 100 ml de H20, e extraída com Et2O por duas vezes, A fase aii quosa é acidificada com HCl 1 N e extraída com EtOAc por : três vezes. As fases orgânicas combinadas são lavadas com
J ! Λ x í H20. A fase organica e seca com MgSO^ anidro, filtrada e o í! solvente é evaporado. 0 resíduo é retomado em 2 litros de to.
lueno e aquecido sob refluxo utilizando uma ratoeira de Dean ' -Stark durante 10 minutos.
ί, A mistura reaccional é deixada arrefecer para a j temperatura ambiente durante toda a noite. 0 refluxo é repe1 tido durante 10 minutos e arrefece-se durante 24 horas.
! 0 procedimento acima é repetido. A mistura reacii cional é deixada â temperatura ambiente durante os 10 dias ! seguintes, em seguida é concentrada para se obterem 51 g de uma espuma incolor.
Este produto é dissolvido em CHCl^ mínimo e cromatograf ado em gel de sílica eluindo com EtOAc/heptano (50: :50) para se obterem 23 g de material puro.
A cromatografia em gel de sílica em CHCl^/2-propanol (98,5:1,5) produziu 13,2 g.
Calc.
C: 73.31
H: 6.15
N: 5.18
EXEMPLO 5
' Preparação de 2R-trans-5-(4-fluorofenil)-2-(l-metiletil)-H,4j -difenil-1-/ 2-tetrahidro-4-hidroxi-6-oxo-2H-piran-2-iI)etil7
-ÍH/-pirrol-3-carboxamida produto do Exemplo 4 é recristalizado de EtOAc/ /hexano. A fracção 1 produz 8,20 g de 4A. As águas-mães pro duzem 4,60 g de 4B, HPLC de 4B revela que 100% do produto é o isómero /~R-(R*R*)_7. 4A á recristalizado para produzir ! 4,81 g de 4C. 4B á cromatografado em gel de sílica em CHCl^/ ί' /2-propanol para produzir 4,18 g de uma espuma incolor de 4D | revelando + 24,53° (0,53% em CHCl^). 40 é recristali ' zado e as águas-mães de 4C produzem 2,0 g que HPLC indica
100% do isómero R-trans de 2R-trans-5-(4-fluorofenil)-2-(1íí -metiletil)-N, 4-difenil-l-/~2-tetrahicLro-4-hidroxi-6-oxo-2H-piran-2-il)etil_7-lH-pirrol-3-carboxamida.
EXEMPLO 6 !
! Preparação de <X-metilbenzilamidas i
Uma solução do racemato, trans-( + )-5-(4-fluorofe. nil)-2-(1-metiletil)-N,4-difenil-l-/—2-tetrahidro-4-hidroxi! -6-oxo-2H-piran-2-ilo)etil_7-lH-pirrol-3-carboxamida, (30 g, 55,5 ml) em (R)-(+)- O(-metilbenzilamina (575 ml, 4,45 mol, ! 98% Aldrich) é agitada durante toda a noite à temperatura am biente.
A solução resultante é em seguida diluída com éter (2 1) e em seguida é bem lavada com HCl 2 M (4 x 500 ml), ; égua (2 x 500 ml) e solução salina (2 x 500 ml). 0 extracto λ i orgânico é em seguida seco em MgSO^, filtrado e concentrado > ί' em vazio para produzir 28,2 g das o(-metilbenzilaminas dias' tereoméricas como um sólido branco; p.f. 174,O-177°C. As oi-metilbenzilaminas são separadas dissolvendo 1,5 g da mistuí; ra em 1,5 ml de 98:1,9:0,1 CHClg:CflgOH:NH^OH (1000 mg/ml) e injectando numa coluna de HPLC preparativa (gel de sílica,
300 mm x 41,4 mm D.I.) por meio de uma seringa vedante a ga! ses e eluindo com a mistura do solvente acima referida. As i! fracções são recolhidas por monitor de UV. 0 diastereómero 1 elui a 41 minutos. 0 diastereómero 2 elui a 49 minutos. As fracções de corte central são recolhidas. Este procedimento é repetido por três vezes e as fracções semelhantes são combinadas e concentradas. 0 exame de cada por HPLC analítica indica que o diastereómero 1 é 99,84% é puro e o diastereóm£ ) ro 2 é 96,53% puro. Cada isómero é retomado em separado nos
Exemplos seguintes.
li í EXEMPLO 7 ι
j Preparação da 2R-trans-5-(4-fluorofenil)-2-(l-metiletil)-N,4í -difenil-1-/ 2-(tetrahidro-4-hidroxi-6-oxo-2H-piran-2-il)etil_7-lH-pirrol-3-carboxamida
A uma solução etanólica (50 M) do diastereómero do Exemplo 6, /~3R-/“3R*(R*), 5R*_7_7-2-(4-fluorofenil)-/ (i>_7, /~5_7-di-hidroxi-5-(l-metiletil)-3-fenil-4-/— (fenil2B8ssSS5=hE£SXL,·
amino)carbonil_7-N-(l-feniletil-lH-pirrol-l-heptanamida, (os ’ centros hidroxi são amhos R) (1 g, 1,5 mmol) é adicionado
NaOH 1 N (3,0 ml, 3 mmol). A solução resultante é aquecida sob refluxo durante 48 horas.
A solução é arrefecida para a temperatura ambien te e concentrada em vazio. 0 resíduo é ressuspenso em égua e acidificado cautelosamente com HG1 6 Ν. A solução ácida resultante á extraída com acetato de etilo. 0 extracto orgâni, co á lavado com égua, solução salina, seco em MgSO^, filtrado e concentrado em vazio. Este resíduo é redissolvido em to, lueno (100 ml) e aquecido sob refluxo com remoção azeotrópi- ca de água durante três horas. Ele é arrefecido para a temp£ ratura ambiente e concentrado em vazio para produzir 1,2 g de um semi-sólido amarelo. A cromatografia rápida em gel de sílica eluindo com 40$ de EtOAc/hexano produz 0,42 g de um ; sólido branco que ainda contem impurezas. Ele á recromatogra 1 fado para se obterem 0,1 g de R,R, enantiómero, 2R-trans-5-(4-fluorofenil)-2-(l-metiletil)-N,4-difenil-l-/—2-(tetrahidro-4-hidroxi-6-oxo-2H-piran-2-il)etil_7-lH-pirrol-3-carboxa ! mida, essencialmente puro, sob a forma de uma espuma branca, ít 0 ensaio de HPLC revela que este material é 94,6$ quimicamen , te puro /flc_7 *· 0,51$ em CHCl^ = 25,5°. 0 pico à tempera ji tura ambiente á tentativamente atribuído a um diastereoisóme. ro desconhecido que resulta de 2$ de (S)-(-)-Of-metilbenzilamina presente na Oí-metilbenzilamina de Aldrich.
tl ii EXEMPLO 8
1'
1' Preparação de 2S-trans-5-(4-fluorofenil)-2-(l-metiletil)-N,4-difenil-1-/-2-(tetrahidro-4-hidroxi-6-oxo-2H-piran-2-il)h etil_7-lH-pirrol-3-carboxamida-(enantiómero S,S do composto
I | 11 1 1 l_ 11 II I 1 preparado no Exemplo 5
Efectuando o processo descrito no Exemplo 7 no diastereómero 2 produziram-se 0,6 g de um sólido espumoso que foi cromatográfado rapidamente em gel de sílica. A eluição com 50% de EtOAc/hexano produziu 0,46 g de enantiómero S,S de 2S-trans-5-(4-fluorofenil)-2-(l-metiletil)-N,4-difenil-l-/”~2-(tetrahidro-4-hidroxi-6-oxo-2H-piran-2-il )etil_7-lH-pirrol-3-carboxamida, essencialmente puro, sob a forma de uma espuma branca. 0 ensaio de HPLC revelou que este mate rial era 97,83% quimicamente puro /CV__7 : 0,51% em CHClg= = - 24,8°.
í[ EXEMPLO 9 ji i Hidrólise da lactona química com a fórmula II ' A uma solução da lactona em THP à temperatura am : biente, é adicionada uma solução de hidróxido de sódio em égua. A mistura é agitada durante duas horas HPLC: 99,65% í (produto); 0,34 (lactona de partida). A mistura é diluída • com 3 1 de água, extraída com acetato de etilo (2 x 11) e acidificada para pH x 4 por adição de 37 ml de ácido cloríi drico 5N. A fase aquosa é extraída com porções de 2 x 1,5 1 ji de acetato de etilo. Os extractos de acetato de etilo combinados são lavados com 2 χ 1 1 de água, solução salina e secos, e produziram após filtração a solução de acetato de eti lo do ácido livre requerido. Esta solução é utilizada directa ) ) mente na fracção do sal de N-metilglucamina.
!
ι· Os extractos de acetato de etilo da solução sali
I na-água foram concentrados para se obterem 15,5 g de um sóli hí do branco.
EXEMPLO 10
Sal de Cálcio do Sal de Sódio e/ou Lactona
Dissolve-se uma mole de lactona (540,6 g) em 5 1 de MeOH; após dissolução adiciona-se 1 1 de HgO. Durante a agitação é adicionado um equivalente de NaOH e segue-se por
HPLC até 2% ou menos de lactona e ester de metilo do dioláci do permanecerem (não se pode usar um excesso de NaOH, porque í Ca(0H)2 irá formar uma adição de CaCl2). Carrega-se NaOH como solução cáustica (51,3 ml, 98 eq.) ou como pastilhas ,i (39,1 g, 98 eq.).
j 0 procedimento acima referido é representado da forma seguinte:
p.m. = 540.6 g
1:1 íi EtOAc, Hexano ! h2o
->
Lavagem
Após o fim da hidrólise, adicionam-se 10 1 de H2O, em seguida lava-se tudo pelo menos duas vezes com tuna mistura 1:1 de EtOAc/hexano. Cada lavagem deve conter 10 1
cada de EtOAc/hexano. Se o sal de sódio for puro, adicionam-se 15 1 de MeOH. Se for impuro e/ou tiver cor, adicionam-se
100 g de carvão G-60, agita-se durante duas horas e filtra-se em supercel. Lava-se com 15 1 de MeOH. Efectua-se uma de. terminação de p/vol % na mistura reaocional por HPLC, para de. teiminar a quantidade exacta de sal na solução.
ij ' Dissolve-se 1 eq. ou um pequeno excesso de il CaClg.SHgO (73,5 g) em 20 1 de HgO. Aquecem-se a mistura reaccional e a solução de CaCl^ para 60°C. Adiciona-se lentaII mente a solução de CaCl2, com forte agitação. Após adição II completa, arrefece-se lentamente para 15°C e filtra-se. Lava I -se o bolo do filtro com 5 1 de H20. Seca-se a 50°C num forno de vazio.
j;
Pode recristalizar-se por dissolução em 4 1 de
EtOAc (50°C) filtrando em supercel, lavando com 1 1 de EtOAc, :i em seguida carregando 3 1 de hexano è solução a 50°C rxn.
procedimento acima referido e o seguinte:
h2o
p.m. = 580.6 g
EXEMPLO 11
H Tratamento da Solução de Acetato de Etilo do Ácido Livre da
Fórmula I com N-metilglucamina.
A uma solução do ácido livre da fórmula I (0,106 ί M) em acetato de etilo (3 1) é adicionada uma solução de N! -metilglucamina (20,3 g, 0,106 ml) em água-acetona (1:1) (120 ml, 120 ml) com forte agitação à temperatura ambiente.
A agitação é continuada durante 16 horas e a solução turva é ) ! concentrada em vazio para ^250 mp. É adicionado tolueno (1
1) e a mistura é concentrada para um sólido branco *vl00 g. 0 ; sólido é dissolvido em 1670 ml de acetona e filtrado num j frasco de três bocas equipado com um agitador mecânico e um i' termostato controlado por termómetro. 0 frasco e filtro são lavados com 115 ml de água-acetona (1:1) e a solução transpa rente é arrefecida lentamente. Obteve-se assim um precipita! do que é re-dissolvido por aquecimento para 65°C. A adição de mais 20 ml de água seguido de lavagem produziu um produto í cristalino que foi isolado por filtração. Os sólidos são lavados com 1200 ml de CHgCl e secos em vazio a 255°C para se obter um sólido branco. A análise deste material indica que . ele contem 4% de amina e também 0,4 % de acetona residual e
0,61 % de água. Os resultados analíticos são referidos da se.
j guinte maneira:
ι ί Ponto de fusão: 1O5-155°C (decomposição) ί Análise Esperada: C = 63.73; H = 6.95; N = 5.57;
F2 = 9.53
Análise Determ.: C = 62.10; H - 6.89; N - 5.34; F2
C = 61.92; H - 7.02; N = 5.38; F2
H20 = 0.47% (KF)
HPLC: MeOH, H20, THF (40; 550; 250)
Econosil: C18, 5μ , 25 CM 256 nm: 1.0 ml/min.
6-81 min.: 98.76%
Ret. Opt.: Γ<χ7 .b = -10.33° (c = 1.00, MeOH)
Solventes residuais: CHgCH = 0.26%
Titulações: HC104 (0.1 N) = 203.8%
Bu4N0H (0.1 N) = 98.5%
Outros sais preparados de maneira análoga aos processos adequadamente escolhidos dos Exemplos 10 e 11 acima referidos podem ser 0 sal de potássio, sal de hemimagnésio sal de hemizinco ou 0 complexo de l-desoxi-2-(metilamino)-D-glucitol do composto com a fórmula I.

Claims (1)

  1. - 1· Processo para a preparação de ácido /—R-(R*,R*)_7-2-(4-fluorfenil)- φ, £ -di-hidroxi-5-(1-metiletil)-3-fenil-4-/ (fenilamin oí-carbonil_7-lH-pirrol-l-heptanoico ou (2R-trans)-5-(4-fluorfenil)-2-(1-metiletil)-N,4-dif enil-l-/~2-(tetra-hidro-4-hidroxi-6-oxo-2H-piran-2-il)-etil_7-lH-pirrol-3-carboxamida e dos seus sais farmaceuticamente aceitáveis, caracterizado por
    a) se resolver o racemato ou
    b) se sintetizar a forma quiral pretendida.
    - 2fl Processo de acordo com a reivindicação 1, caracterizado por se obter o ácido /”R-(R*R*)_7-2-(4-fluorfenil)- -di-hidroxi-5-(1-metiletil)-3-fenil-4-/~(fenilamino)-carbonil__7-lH-pirrol-l-hept anoic o.
    - 3a Processo de acordo com a reivindicação 1, caracterizado por se obter como produto final a (2R-trans)-5-(4-f luorf enil )-2- (1-metiletil)-N, 4-dif enil-l-/~”2- (tetra-hidro-4-hidroxi-6-oxo-2H-piran-2-il)-etil_7-lH-pirrol-3-carboxami da.
    - 4a Processo de acordo com a reivindicação 1, caracterizado por se obter como produto final o sal de monossódio do composto de acordo com a reivindicação 2.
    X
    - 5a Processo de acordo com a reivindicação 1, caracterizado por se obter como produto final o sal monopotássio do composto de acordo com a reivindicação 2.
    - 6B Processo de acordo com a reivindicação 1, caracterizado por se obter como produto final o sal de hemicálcio do composto de acordo com a reivindicação 2.
    - 7» Processo de acordo com a reivindicação 1, caracterizado por se obter como produto final o sal de N-metil-glucamina do composto de acordo com a reivindicação 2.
    - 8» Processo de acordo com a reivindicação 1, caracterizado por se obter como produto final o sal de hemimagnásio do composto de acordo com a reivindicação 2.
    Processo de acordo com a reivindicação 1, caracterizado por se obter como produto final o sal de hemizinco do composto de acordo com a reivindicação 2.
    I
    - 10 fi Processo de acordo com a reivindicação 1, caracterizado por se obter como produto final uma mistura de 1-de.
    soxi-l-(metilamino)-D-glucitol com o composto de acordo com a reivindicação 2.
    - 29 11«
    Processo para a preparação de composições farma- cêuticas para o tratamento de hipercolesterolemia, caracteri ί zado por se incorporar uma quantidade hipocolesterolémica de um composto de acordo com a reivindicação 1, numa substância farmaceuticamente aceitáveis.
    A requerente reivindica a prioridade do pedido norte-americano apresentado em 21 de Julho de 1989, sob o nú h mero de série 384,187.
PT94778A 1989-07-21 1990-07-20 Processo para a preparacao de acido {r-(r*r*)}-2-(4-fluorfenil)-beta,delta-di- hidroxi-5-(1-metiletil)-3-fenil-4-{(fenilamino)-carbonil}-1h-pirrol-heptanoico, da sua lactona e sais e de composicoes farmaceuticas que os contem PT94778B (pt)

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IE20040325A1 (en) 2004-06-30
NO174709C (no) 1994-06-22
KR910002794A (ko) 1991-02-26
GEP20043167B (en) 2004-02-10
ES2153332T3 (es) 2005-03-01
ZA905742B (en) 1992-03-25
DK1061073T3 (da) 2004-10-25
ATE270274T1 (de) 2004-07-15
CA2021546A1 (en) 1991-01-22
NO903251D0 (no) 1990-07-20
ATE207896T1 (de) 2001-11-15
AU5972490A (en) 1991-01-24
DK0409281T3 (da) 2002-02-25
KR0167101B1 (ko) 1999-01-15
ES2167306T3 (es) 2002-05-16
GR20010300002T1 (en) 2001-02-28
JPH0358967A (ja) 1991-03-14
NO174709B (no) 1994-03-14
IE902659A1 (en) 1991-02-27
ES2153332T1 (es) 2001-03-01
NZ234576A (en) 1992-12-23
FI903614A0 (fi) 1990-07-18
SG46495A1 (en) 1998-02-20
EP0409281A1 (en) 1991-01-23
EP0409281B1 (en) 2001-10-31
FI94339B (fi) 1995-05-15
EP1061073B1 (en) 2004-06-30
DE69034153D1 (de) 2004-08-05
JP2007197460A (ja) 2007-08-09
JP2007137903A (ja) 2007-06-07
DE69034153T2 (de) 2005-07-14
EP1061073A1 (en) 2000-12-20
NO903251L (no) 1991-01-22
DE69033840T2 (de) 2002-05-16
JP2007137904A (ja) 2007-06-07
FI94339C (fi) 1995-08-25
PT94778A (pt) 1991-03-20
JP2003201236A (ja) 2003-07-18
USRE40667E1 (en) 2009-03-17
JP2002234871A (ja) 2002-08-23
US5273995A (en) 1993-12-28
AU628198B2 (en) 1992-09-10
JP3506336B2 (ja) 2004-03-15
CA2021546C (en) 1997-04-29

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