FI94339C - Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi - Google Patents
Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi Download PDFInfo
- Publication number
- FI94339C FI94339C FI903614A FI903614A FI94339C FI 94339 C FI94339 C FI 94339C FI 903614 A FI903614 A FI 903614A FI 903614 A FI903614 A FI 903614A FI 94339 C FI94339 C FI 94339C
- Authority
- FI
- Finland
- Prior art keywords
- formula
- compound
- pharmaceutically acceptable
- methylethyl
- fluorophenyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 21
- 150000003839 salts Chemical class 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 title claims description 10
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 title claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 title claims description 3
- WSRKLYQAZKDXKA-UHFFFAOYSA-N 7-pyrrol-1-ylheptanoic acid Chemical compound OC(=O)CCCCCCN1C=CC=C1 WSRKLYQAZKDXKA-UHFFFAOYSA-N 0.000 title 1
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- 150000001875 compounds Chemical class 0.000 claims description 43
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 11
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- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 5
- 239000011575 calcium Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
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- XCIMEFFZGKWCOT-UHFFFAOYSA-N 7-[3-phenyl-4-(phenylcarbamoyl)-2-propan-2-ylpyrrol-1-yl]heptanoic acid Chemical compound C=1N(CCCCCCC(O)=O)C(C(C)C)=C(C=2C=CC=CC=2)C=1C(=O)NC1=CC=CC=C1 XCIMEFFZGKWCOT-UHFFFAOYSA-N 0.000 claims description 2
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- HCPLPXQDAYFYCK-UHFFFAOYSA-N 7-[2-(phenylcarbamoyl)pyrrol-1-yl]heptanoic acid Chemical compound OC(=O)CCCCCCN1C=CC=C1C(=O)NC1=CC=CC=C1 HCPLPXQDAYFYCK-UHFFFAOYSA-N 0.000 claims 1
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- 239000000203 mixture Substances 0.000 description 31
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- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
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- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229960000816 magnesium hydroxide Drugs 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 1
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- XZPVPNZTYPUODG-UHFFFAOYSA-M sodium;chloride;dihydrate Chemical compound O.O.[Na+].[Cl-] XZPVPNZTYPUODG-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
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
- C07D207/30—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
Description
94339
Menetelmä farmaseuttisesti käyttökelpoisen [R-(R*,R*)]-2-(4-f luorifenyyli) -/3,S-dihydroksi-5- (l-metyylietyyli) -3-fenyyli-4-[(fenyyliamino)karbonyyli]-lH-pyrroli-l-heptaa-nihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi
Trans-(±)-5-(4-fluorifenyyli)-2-(l-metyylietyyli)-N,4-di-fenyyli-l-[2-tetrahydro-4-hydroksi-6-okso-2H-pyran-2-yy-li)etyyli]-lH-pyrroli-3-karboksamideja on esitetty US-pa-tentissa n:o 4,681,893 yhdisteinä, joita voidaan käyttää kolesteroli-biosynteesin inhibiittoreina. Siinä esitetyt yhdisteet käsittävät yleisesti 4-hydroksipyran-2-oneja ja niistä muodostettuja vastaavia avatun renkaan omaavia happoja.
Nyt on odottamatta todettu, että trans-5-(4-fluorifenyyli ) -2 - ( 1-metyy1ietyy1i)-N,4-difenyyli-1-(2-tetrahydro-4-hydr oks i- 6-okso-2H-pyran-2 -yy 1 i) etyyli ] - lij-pyrrol i-3 -kar-boksamidin avatun renkaan omaavan hapon R-muodon enantio-meeri, s.o. [R-(R*,R*) ]-2-(4-f luorifenyyli)-/3, δ-dihydrok-si-5-(l-metyylietyyli)-3-fenyyli-4-[(fenyyliamino)karbonyyli ]-lfi-pyrroli-l-heptaanihappo saa aikaan kolesterolin biosynteesin yllättävän inhibiition.
On tunnettua, että 3-hydroksi-3-metyyliglutaryyli-koent-: syymi A (HMG-CoA) esiintyy 3R-stereoisomeerinä. Lisäksi, kuten Stokker et ai. ovat osoittaneet 5-substituoitujen 3.5- dihydroksipentaanihappojen ryhmän tutkimuksessa artikkelissa "3-Hydroxy-3-methylglutaryl-Coenzyme A Reductase Inhibitors. 1. Structural Modification of 5-Substituted 3.5- Dihydroxypentanoic acids and Their Lactone Derivati- * ves" julkaisussa J. Med. Chem. 1985, 28, 347 - 358, olen naisesti koko biologinen aktiivisuus kuuluu positiivisesti kiertävän (E)-6-[2-(2,4-dikloorifenyyli)etenyyli]-3,4,5,6-tetrahydro-4-hydroksi-2H-pyranonin trans-diastereomeereil-le. Edelleen HMG-CoA-reduktaasin inhibiitioon tarvitaan ilmeisesti /3-hydroksi-5-laktoni-osan absoluuttista konfiguraatiota, joka osa on yhteinen kaavan (la) 2 Q A τ 7 Q 7 ‘τ o O 7 / HO—ί o · h3c' mukaiselle mevinoliinille ja kaavan (lb) W°
H0-< o H
mukaiselle kompaktiinille. Lynch et ai. ovat esittäneet tämän 4R,6R-konfiguraationa artikkelissa "Synthesis of an HMG-CoA Reductase Inhibitor; A Diastereoselective Aldol Approach" julkaisussa Tetrahedron Letters, Vol. 28, No.
13, s. 1385 - 1388 (1987).
Kuitenkaan alan ammattihenkilö ei voi ennakoida tämän keksinnön odottamatonta ja yllättävää kolesteroli-biosyntee-. sin inhibiitiota näiden julkaisujen perusteella.
Siten tämä keksintö saa aikaan yhdisteitä, jotka koostuvat [R-(R*,R*) ]-2-(4-fluorifenyyli) -/3,5-dihydroksi-5-((1-me-tyylietyyli)-3-fenyyli-4-[(fenyyliamino)karbonyyli]-1H-pyrroli-l-heptaanihaposta (kaavan I mukainen yhdiste) ja sen farmaseuttisesti hyväksyttävistä suoloista. Heptaani- 3 94339 hapon laktonimuoto on (2R-trans)5-(4-fluorifenyyli)-2-(1-metyy1ietyy1i)-N,4-d i fenyy1i-1[2-(tetrahydro-4-hydroks i- 6-okso-2H-pyran-2-yyli)etyyli]lH-pyrroli-3-karboksamidi (kaavan II mukainen yhdiste).
Tämän keksinnön mukaisesti valmistetuista yhdisteistä voidaan valmistaa myös farmaseuttinen koostumus, jota voidaan käyttää hypokolesteroleemisenä aineena ja joka käsittää hypokolesteroleemisesti vaikuttavan määrän [R-(R*,R*)]-2-(4-f luorifenyyli) -/9, δ—dihydroksi-5- (1-metyylietyyli) -3-fenyyli-4-[(fenyyliamino)karbonyyli]-lH-pyrroli-l-heptaa-nihappoa tai sen farmaseuttisesti hyväksyttäviä suoloja ja farmaseuttisesti hyväksyttävää kantoainetta. Edelleen tämän keksinnön mukaisesti valmistettuja yhdisteitä voidaan käyttää menetelmässä hyperkolesterolemiaa sairastavien nisäkkäiden, mukaanlukien ihmisen hoitamiseksi, missä menetelmässä tällaiselle nisäkkäälle annetaan yllä selitetyn farmaseuttisen koostumuksen annostusmuoto.
Tämä keksintö koskee siten menetelmää kaavan I mukaisten yhdisteiden valmistamiseksi, kuten oheisissa vaatimuksissa on esitetty.
Farmaseuttisesti hyväksyttäviä suoloja ovat sellaiset, jotka on tavallisesti muodostettu liuottamalla vapaa happo tai laktoni, etenkin laktoni vesipitoiseen tai vesipitoiseen alkoholiliuottimeen tai muihin sopiviin liuottimiin sopivan emäksen kanssa ja eristämällä suola haihduttamalla liuos tai saattamalla vapaa happo tai laktoni, etenkin laktoni ja emäs reagoimaan orgaanisessa liuottimessa, jos-sa suola erottuu suoraan tai se voidaan saada konsentroimalla liuos.
Käytännössä suolamuodon käyttö merkitsee happo- tai lakto-nimuodon käyttöä. Keksinnön puitteissa sopivia farmaseut- . tisesti hyväksyttäviä suoloja ovat sellaiset, jotka on « ί 4 94339 muodostettu emäksistä, kuten natriumhydroksidista, kalium-hydroksidista, litiumhydroksidista, kalsiumhydroksidista, l-deoksi-2-(metyyliamino)-D-glusitolista, magnesiumhydroksidista, sinkkihydroksidistä, aluminiumhydroksidistä, rauta(II)- tai rauta(III)-hydroksidista, ammoniumhydroksi-dista tai orgaanisista amiineista, kuten N-metyyliglu-kamiinista, koliinista, arginiinista tai vastaavasta. Litium-, kalsium-, magnesium-, aluminium- ja rauta(II)- ja rauta(III)-suolat valmistetaan edullisesti natrium- tai kaliumsuolasta lisäämällä sopivaa reagenssia natrium- tai kaliumsuolan liuokseen, s.o. kalsiumkloridin lisäys kaavan I mukaisen yhdisteen natrium- tai kaliumsuolan liuokseen tuottaa sen kalsiumsuolan.
Vapaa happo voidaan valmistaa hydrolysoimalla kaavan II mukainen laktonimuoto tai ohjaamalla suola kationinvaihto-hartsin (H+-hartsin) läpi ja haihduttamalla vesi.
Tämän keksinnön edullisin suoritusmuoto on [R-(R*,R*)]-2-(4-f luorifenyyli) -0,6-dihydroksi-5- (1-me tyyli etyyli) -3-fenyyli-4-[(fenyyliamino)karbonyyli]-lH-pyrroli-l-heptaa-nihappo-hemikalsiumsuola.
Tavallisesti yhdisteet I ja II voidaan valmistaa (1) erot-: tamalla rasemaatti, joka on valmistettu US-patentissa n:o 4,681,893 esitettyjen menetelmien mukaisesti, joka patentti on tässä viitejulkaisuna, tai (2) syntetisoimalla haluttu kiraalinen muoto lähtöaineista, jotka ovat tunnettuja tai valmistetaan helposti käyttämällä tunnettuja menetelmiä vastaavia menetelmiä.
• ·
Etenkin rasemaatin erotus voidaan suorittaa kaaviossa 1 (jossa Ph on fenyyli) esitetyllä tavalla seuraavasti: 5 94339
Kaavio 1 r
I O
p ? XX? H
[ N^s'^r'RV'^' N^Ph
Phs^J I I Phfflipv H I
\ I V ( CH>
PhHN a 0 / ^ r
q \\ 4 H2N'-|'''I>h vaihe A
f 013 F
R I
trans-rasemaatti
O
OH OH 0 V['k Nvl^ph
PhHN^>>V H^T
T \ f CH)
0 R
Vaihe B
1) Erotus
2) NaOH
3) Kuumennus palautus jäähdyttäen tolueenissa HO ν./'Ύ'0 ΗΟ'θ/^γ ° X^O ίγ° 'T0UO. ''Op
Ph CONHPh ph COKHPh [R(R«R*1]isomeeri (S (R*R*) ) isomeeri
NaOH J Na0H
COjNa COjNa V-OH /-08 S-OB V-0»
Ph^^CONHPh P hCOKHPh 6 94339
Kaavion 1 "trans-rasemaatti" tarkoittaa seuraavien ΗΟ,,,^Ο
Ph CONHPh Ph CONHPh [R(R1R1)]isomeeri [S (R1R1)]isomeeri yhdisteiden seosta.
Kaavion I vaiheen 1 ja 2 olosuhteet ovat yleisesti, kuten on esitetty esimerkeissä 6 ja 7.
Kiraalinen synteesi on esitetty kaaviossa 2 (jossa Ph on fenyyli) seuraavasti: · 7 94339
Kaavio 2 F Γ Ί JL Μσ*4
v _ , 1. THF-80—90eC
Ο Θθ·' Ph', Q _lhr
ηΎ ? ♦ 2-lc0H
T"" N^ Ph
PhNHC'^1^ L J
0 /V (2)
F F
(^j) 1.1 eq NaOMe
I OH 0 ph -1-“ ον. I »H
PhN<A ^ X JL JL OH MeOH -10‘C Ph>A COjMe
' 1 Ph /^V
PhNHOC I Ph PhNHOC I
(3 J (4) 73% <3) 78%
F
0 JL
X^OBu1 8 eq O 1. B(Et)3 , NaBH4 - I °H 0 ——~~~ "
Ph^J | | t 2. H202 -30--4 0®C ^χ^*\χ^ν^Οθ2Βυ 5hrs JUs*/
PhNHOC I
(5) 78%
F
F 1 ; 6 V Λ
Ph. T f f . 2. Toi. -H20*| Ph^A ^11 V\ ^\xAv^*\^C02But -- Γ N o o A=v PhNHOC''^!
PhNHOC Ίί ^ (7, 57% (6,83% [«]"-♦ 18.07 (CHC1,) 94339 δ
Kaavion 2 olosuhteet ovat yleisesti, kuten on esitetty esimerkeissä 1-5.
Alan ammattihenkilö tunnistaa kaavioiden 1 ja 2 muunnelmia, jotka ovat sopivia tämän keksinnön mukaisten yhdisteiden valmistamiseksi.
Tämän keksinnön mukaisesti valmistetut yhdisteet ja etenkin kaavan I mukainen yhdiste inhiboivat kolesterolin biosynteesin, kuten on havaittu CSI-seulonta-analyysissä, joka on esitetty US-patentissa n:o 4,681,893, joka on tässä samoin viitteenä. Yhdisteen I, sen enantiomeerin yhdisteen II, ja näiden kahden yhdisteen rasemaatin CSI-arvot ovat seuraavat:
Yhdiste Ic50 (μ™00!!3/!) [R-(R*,R*)]-isomeeri 0,0044 [S-(R*,R*)]-isomeeri 0,44 rasemaatti 0,045
Farmaseuttiset koostumukset, jotka sisältävät keksinnön mukaisesti valmistettuja yhdisteitä, valmistetaan US-patentissa n:o 4,681,893 esitetyllä tavalla, joka patentti on siten jälleen tässä viitteenä.
» Tämän keksinnön mukaisesti valmistettuja yhdisteitä voidaan käyttää hypolipideemisinä tai hypokolesteroleemisinä aineina. Farmaseuttisessa menetelmässä käytettäviä tämän keksinnön mukaisesti valmistettuja yhdisteitä annetaan po-i tilaalle 10 - 500 mg/päivä, jolloin n. 70 kg painavan nor maalin täysikasvuisen annostuksena on 0,14 - 7,1 mg/kg päivää kohden. Annostukset voivat olla edullisesti 0,5 - 1,0 mg/kg/päivä.
Annostus annetaan edullisesti yksikköannostusmuodossa.
Oraalisesti tai parenteraalisesti käytettävä yksikköannos- li 9 94339 tusmuoto voi olla 10 - 500 mg, edullisesti 20 - 100 mg erityisen antomuodon ja aktiivisen aineen tehon mukaisesti. Koostumukset voivat haluttaessa sisältää myös muita aktiivisia terapeuttisia aineita. Alan ammattihenkilö osaa määrittää optimaaliset annostukset erityistä tilannetta varten.
Kaavan I ja II mukaiset yhdisteet ja niiden farmaseuttisesti hyväksyttävät suolat ovat yleensä samanarvoisia aktiivisuuden suhteen, kuten tässä on esitetty.
Seuraavat esimerkit havainnollistavat erityisiä menetelmiä tämän keksinnön mukaisten yhdisteiden valmistamiseksi.
Näitä esimerkkejä ei tule kuitenkaan pitää keksinnön piiriä rajoittavina.
Esimerkki l 285 ml 2,2 M n-butyylilitiumia (heksaanissa) lisätään ti-poittain 92 ml:aan di-isopropyyliamiinia 300 ml:ssa THF:ää -50 - -60eC:ssa 1000 ml:n yksikaulaisessa pullossa tiputus-suppilon kautta ja typpiatmosfäärissä. Hyvin sekoitetun keltaisen liuoksen annetaan lämmetä n. -20°C:seen. sitten se kanyloidaan suspensioon, jossa on 99 g S(+)-2-asetoksi- 1,1,2-trifenyylietanolia 500 ml:ssa absoluuttista THF:ää ja joka on 2 l:n 3-kaulaisessa pullossa ja pidetään -70eC: ssa. Lisäyksen päätyttyä reaktioseoksen annetaan lämmetä -10°C:seen 2 tunnin kuluessa. Tällä välin valmistetaan suspensio, jossa on 0,63 moolia MgBr2:ta, lisäämällä tipoit-tain 564 ml (0,63 moolia) bromia suspensioon, jossa on 15,3 g magnesiumia (0,63 moolia) 500 ml:ssa THF:ää ja joka on 3 l:n pullossa, joka on varustettu palautusjäähdytti-mellä ja ylhäällä olevalla sekoittimella. Kun tämä on päättynyt, MgBr2-suspensio jäähdytetään -78°C:seen ja enolaat-tiliuos (tummanruskea) kanyloidaan suspensioon 30 minuutin : kuluessa. Sekoittamista jatketaan 60 minuutin ajan -78°C:ssa.
94339 10 k
Sitten lisätään 150 g 5-(4-fluorifenyyli)-2-(l-metyyli-etyyli)-1-(3-oksopropyyli)-N,4-difenyyli-lH~pyrroli-3-kar-boksamidia 800 ml:ssa absoluuttista THF:ää tipoittain 30 minuutin kuluessa. Sitten sekoitetaan 90 minuutin ajan -78°C:ssa, sitten reaktio sammutetaan 200 ml:11a AcOH:ta -78°C:ssa. Tämä poistetaan jäähdytyshauteeseen, lisätään 500 ml H20:ta ja seos konsentroidaan tyhjössä 40 -50°C:ssa. Kellertävään lietteeseen lisätään 500 ml EtOAc:n ja heptaanin l:l-seosta ja sitten suodatetaan. Suodos pestään perusteellisesti 0,5 N HClrllä, sitten useita kertoja H20:lla ja lopuksi EtOAc/heptaanilla (3:1), joka oli jäähdytetty kuivajäällä -20°C:seen. Vaaleanruskea kiteinen tuote (esimerkki IA) kuivatetaan tyhjöuunissa 40°C:ssa.
Saanto on 194 g.
Tuote IA kiteytetään uudelleen EtOAc:stä -10°C:ssa, jolloin saadaan 100 g tuotetta IB ja sitten kiteytetään uudelleen asetoni/pentaanista, jolloin saadaan 90 g tuotetta 1C. Emäliuos yhdistetään raa'an aineen pesusta ja kiteytetään uudelleen EtOAc/heksaanista. Tuotteen IB (33 g) HPLC: R,S-isomeerin suhde S,S-isomeeriin 97,4:2,17. Tuotteen 1C (28,5 g) HPLC: 95,7:3,7. Yhdistetty IB ja 1C kiteytetään uudelleen CHCl3:n ja MeOH:n 10:1-seoksesta, jolloin saadaan tuote 1F, jonka saanto on 48,7 g valkoista kidettä.
I ·
Ensimmäisen vesipesun emäliuos kiteytetään (EtOAc/heptaa-ni), jolloin saadaan 21,4 g tuotetta ID: HPLC: 71,56:25,52.
; Tuotteiden IB ja 1C emäliuos yhdistetään ja kiteytetään uudelleen CHCl3:n, MeOH:n ja heptaanin seoksesta, jolloin saadaan 55,7 g tuotteen 1G valkoisia kiteitä.
ID kiteytetään uudelleen CHCl3/MeOH:sta, jolloin saadaan tuote 1H.
94339 11
Kaikki emäliuos yhdistetään, sitten konsentroidaan ja jäännös liuotetaan kuumaan CHCl3:n ja MeOH:n 10:l-seok-seen, laitetaan piihappogeelipylväälle ja eluoidaan EtOAc:n ja heksaanin 40:60-seoksella. Aine kiteytyy pylväällä ja piihappogeeli uutetaan CHCl3/MeOH:11a ja konsentroidaan. Jäännöksen uudelleenkiteytys CHCl3/heptaanis-ta (3:1) tuottaa 33,7 g tuotetta 11.
Tuotteen 11 emäliuos kiteytetään uudelleen, jolloin saadaan 18,7 g tuotetta 1K.
Tuotteen 1K emäliuos kiteytetään, jolloin saadaan 6,3 g tuotetta IL.
II, 1K, IL yhdistetään ja kiteytetään uudelleen CHCl3/hep-taanista, jolloin saadaan 48 g.
Tuotteiden li, 1K ja IL yhdistetty emäliuos konsentroidaan, jolloin saadaan 31 g tuotetta IM.
Tuote 1F omaa seuraavat arvot:
Analyysi: 1F, sp. 229 - 230°C: laskettu: C 77,84, H 6,02, N 3,56 saatu: C 77,14, H 6,45, N 3,13.
Nämä arvot ovat yhtäpitäviä kaavan 1 4 i 12 94339
F
p
Ph OH 1
Ph. 1 I Λ. .OH
Ίγ" >co2 X
Ν «Ph ^=5/ Ph
PhNHCO I
kanssa.
Esimerkki 2 162 g (0,206 M) esimerkin l yhdistettyjä tuotteita IF, 1G, 1H ja IL suspendoidaan 800 ml:aan metanolin ja THF:n 5:3-seosta. Jäähdytetään 0°C:seen ja lisätään 11,7 g:aan nat-riummetoksidia. Seosta sekoitetaan, kunnes kaikki on liuennut, sitten se laitetaan pakastimeen yön ajaksi.
Reaktioseoksen annetaan lämmetä huoneen lämpötilaan, reaktio sammutetaan 15 ml:11a HOAc:tä, sitten seos konsentroidaan tyhjössä 40eC:ssa, jolloin saadaan odotettu tuote seuraavasti:
F
O
| OH
.C02Me : 0 L** ^ v
PhNHC1^] Tämä tuote lisätään 500 ml:aan H20:ta ja uutetaan kahdesti EtOAc:llä (300 ml). Yhdistetyt uutteet pestään kylläste-... tyllä NaHC03:lla, suolaliuoksella, kuivatetaan vedettömän 94339 13 magnesiumsulfaatin päällä, suodatetaan ja liuotin haihdutetaan. Jäännös kromatografoidaan piihappogeelillä käyttämällä eluenttina EtOAcrn ja heptaanin l:4-seosta, jolloin saadaan 109 g väritöntä öljyä, joka kiteytetään uudelleen Et20/heptaanista, jolloin saadaan 73,9 g:n ensimmäinen erä valkoisia kiteitä ja 8,2 g:n toinen erä valkoisia kiteitä. Kiteet omaavat seuraavat arvot: sp. 125 - 126°C, [a]D20 = 4,23® (1,17 M, CH3OH).
Analyysi: laskettu: C 72,76, H 6,30, N 5,30 saatu: C 72,51, H 6,23, N 5,06.
Nämä arvot ovat yhtäpitäviä kaavan
F
O
I OH
Ph N C02Me
PhNHCO*I
kanssa.
Esimerkki 3 77 ml di-isopropyyliamiinia liuotetaan 250 ml:aan THF:ää 2000 ml:n kolmikaulaisessa pullossa, joka on varustettu ·♦ lämpömittarilla ja tiputussuppilolla. Reaktioseos pidetään typpiatmosfäärissä. Seos jäähdytetään -42°C:seen ja lisätään tipoittain 20 minuutin kuluessa 200 ml:aan 2,2 H n-butyylilitiumia (heksaanissa) ja sekoitetaan 20 minuutin ajan ja sitten lisätään tipoittain 62 ml t-butyyliasetaat-tia, joka on liuotettu 200 ml:aan THF:ää (n. 30 minuutin v kuluessa). Tätä seosta sekoitetaan 30 minuutin ajan i 14 94339 -40°C:ssa, sitten lisätään 140 ml 2,2 M n-butyylilitiumia 20 minuutin kuluessa. Lisäyksen päätyttyä 81 g esimerkin 2 tuotetta 500 ml:ssa THF:ää lisätään mahdollisimman nopeasti antamatta lämpötilan nousta yli -40°C:een. Sekoittamista jatketaan 4 tunnin ajan -70°C:ssa. Reaktio sammutetaan sitten 69 ml:11a jääetikkaa ja sitten seoksen annetaan lämmetä huoneen lämpötilaan. Seos konsentroidaan tyhjössä ja jäännös otetaan EtOAc:hen, pestään perusteellisesti vedellä, sitten kyllästetyllä NH4Cl:llä, NaHC03:lla (kyllästetty) ja lopuksi suolaliuoksella. Orgaaninen kerros kuivatetaan vedettömän MgS04:n päällä, suodatetaan ja liuotin haihdutetaan. Reaktion NMR on yhtäpitävä lähtöaineen + tuotteen n. yhtä suurina määrinä + TLC:n perusviivalla olevan pienen ainemäärän kanssa. TLC:n perusviivan aine erotetaan lähtöaineesta ja tuote uutetaan happo/emäs-uu-tolla. Orgaaninen faasi kuivatetaan ja konsentroidaan tyhjössä, jolloin saadaan 73 g tuotetta. NMR ja TLC ovat yhtäpitäviä kaavan
F
p I OH o 0
PhNHCO'^] kanssa.
Esimerkki 4 - · · 73 g esimerkin 3 raakatuotetta liuotetaan 500 ml:aan absoluuttista THF:ää ja sitten lisätään 120 ml trietyyliboraa-nia ja tämän jälkeen 0,7 g t-butyylikarboksyylihappoa.
Seosta sekoitetaan kuivassa atmosfäärissä 10 minuutin ... ajan, jäähdytetään -78°C: seen ja lisätään 70 ml metanolia 94339 15 ja sitten 4,5 g natriumboorihydridiä. Seosta sekoitetaan jälleen -78°C:ssa 6 tunnin ajan. Sitten se kaadetaan hitaasti jään, 30%:isen H202:n ja H20:n 4:1:1-seokseen. Tätä seosta sekoitetaan yön yli ja sitten sen annetaan lämmetä huoneen lämpötilaan.
CHCl3:a (400 ml) lisätään ja seos jaetaan. Vesikerros uutetaan jälleen CHCl3:lla. Orgaaniset uutteet yhdistetään ja pestään perusteellisesti H20:lla, kunnes ei voida havaita enää yhtään peroksidia. Orgaaninen kerros kuivatetaan MgS04:n päällä, suodatetaan ja liuotin haihdutetaan.
Jäännös käsitellään pikakromatografiällä (flash chromatography) piihappogeelillä käyttämällä eluenttina EtOAc:n ja heksaanin l:3-seosta, jolloin saadaan 51 g tuotetta.
Tuote liuotetaan THF:n ja MeOH:n seokseen ja lisätään 100 ml:aan NaOH:ta ja sitten sekoitetaan 4 tunnin ajan huoneen lämpötilassa. Liuos konsentroidaan huoneen lämpötilassa orgaanisen liuottimen poistamiseksi, lisätään 100 ml:aan H20:ta ja uutetaan Et02:lla kahdesti. Vesikerros tehdään happamaksi 1 N Helillä ja uutetaan EtOAc:llä 3 kertaa. Yhdistetyt orgaaniset kerrokset pestään H20:lla. Orgaaninen kerros kuivatetaan vedettömällä MgS04:llä, suodatetaan ja liuotin haihdutetaan. Jäännös otetaan 2 l:aan tolueenia ja kuumennetaan palautusjäähdyttäen käyttämällä Dean-Stark-loukkua 10 minuutin ajan.
Reaktioseoksen annetaan jäähtyä huoneen lämpötilaan yön :· aikana. Kuumennetaan uudelleen palautusjäähdyttäen 10 mi nuutin ajan ja sitten annetaan jäähtyä 24 tunnin kuluessa.
Yllä esitetty toimenpide toistetaan. Reaktioseos jätetään huoneen lämpötilaan seuraavien 10 päivän ajaksi, sitten se konsentroidaan, jolloin saadaan 51 g väritöntä vaahtoa.
16 94339 Tämä tuote liuotetaan minimimäärään CHCl3:a ja kromatogra-foidaan piihappogeelillä eluoimalla EtOAc:n ja heptaanin 50:50-seoksella, jolloin saadaan 23 g puhdasta ainetta.
Kromatografia piihappogeelillä CHCl3/2-propanolissa (98,5:1,5) tuottaa 13,2 g tuotetta.
Laskettu: C 73,31, H 6,15, N 5,18.
Esimerkki 5 2R-trans-5-(4-fluorifenyyli)-2-(l-metyylietyyli)-fi,4-di-f enyyli-l-[ 2 - (tetrahydr o-4 -hydroksi-6-okso-2H-pyran-2-yy-li)etyyli]-lH-pyrroli-3-karboksamidin valmistus
Esimerkin 4 tuote kiteytetään uudelleen EtOAc/heksaanista.
Fraktio 1 tuottaa 8,20 g yhdistettä 4A. Emäliuos tuottaa 4,60 g yhdistettä 4B. Yhdisteen 4B HPLC osoittaa tuotteen olevan 100%:isesti [R-(R*,R*)]-isomeeri. 4A kiteytetään uudelleen, jolloin saadaan 4,81 g yhdistettä 4C. 4B kroma-tografoidaan piihappogeelillä CHCl3/2-propanolissa, jolloin saadaan 4,18 g yhdisteen 4D väritöntä vaahtoa, jonka [a]D23 = 24,53° (0,53 % CHCl3:ssa). 4C kiteytetään uudelleen ja yhdisteen 4C emäliuos tuottaa 2,0 g. HPLC osoit- .·, taa, että se on 100%:isesti R-trans-isomeeri, 2R-trans- • « 5-(4-fluorifenyyli)-2-(1-metyylietyyli)-N,4-difenyyli-l-[2-(tetrahydro-4-hydroks i-6-okso-2H-pyran-2-yy1i)etyyli]-lH-pyrroli-3-karboksamidi.
Esimerkki 6 : Diastereomeeristen a-metyylibentsyyliamidien valmistus
Rasemaatin, trans-(±)-5-(4-fluorifenyyli)-2-(l-metyyli-etyyli)-N,4-difenyyli-l-[2-(tetrahydro-4-hydroksi-6-okso-2H-pyran-2-yyli)etyyli]-lH-pyrroli-3-karboksamidin (30 g, 55,5 ml), liuosta (R)-(+)-a-metyylibentsyyliamiinissa (575 ... ml, 4,45 moolia, 98 % Aldrich) sekoitetaan yön ajan huo neen lämpötilassa.
94339 17
Saatu liuos laimennetaan sitten eetterillä (2 1) ja pestään perusteellisesti 2 M Helillä (4 x 500 ml), vedellä (2 x 500 ml) ja suolaliuoksella (2 x 500 ml). Orgaaninen uute kuivatetaan sitten MgS04:n päällä, suodatetaan ja konsentroidaan tyhjössä, jolloin saadaan 28,2 g diastereomeerisiä a-metyylibentsyyliamideja valkoisena kiintoaineena, sp.
174,0 - 177°C. α-metyylibentsyyliamidit erotetaan liuottamalla 1,5 g seosta 1,5 ml:aan CHCl3:n, CH3OH:n ja NH4OH:n 98:1,9:0,1-seosta (1000 mg/ml) ja injektoimalla prepara-tiivisen HPLC-pylvään päälle (piihappogeeli, 300 mm x 41,4 mm I.D.) kaasunpitäväliä ruiskulla ja eluoimalla yllä esitetyllä liuotinseoksella. Fraktiot kerätään UV-monitoril-la. Diastereomeeri 1 eluoituu 41 minuutissa. Diastereomee-ri 2 eluoituu 49 minuutissa. Keskifraktiot kerätään. Tämä toimenpide toistetaan 3 kertaa ja samanlaiset fraktiot yhdistetään ja konsentroidaan. Jokaisen tutkiminen analyyttisellä HPLC:llä osoittaa, että diastereomeeri 1 on 99,84%:sesti puhdas ja diastereomeeri 2 on 96,53%:sesti puhdas. Kumpikin isomeeri otetaan erikseen seuraaviin esimerkkeihin.
Esimerkki 7 2R-trans-5-(4-fluorifenyyli)-2-(1-metyylietyyli)-N,4-dife-nyyli-l-[2-(tetrahydro-4-hydroksi-6-okso-2H-pyran-2-yyli)-etyyli)-ΙΗ-pyrro1i-3-karboksamid in valmistus
Esimerkin 6 diastereomeerin 1, [3R-[3R*(R*),5R*]]-2-(4-fluorifenyyli) -[0], [5]-dihydroksi-5- (1-metyylietyyli) -3-fenyyli-4-[(fenyyliamino)karbonyyli]-N-(1-fenyylietyyli)-lH-pyrroli-l-heptaaniamidin (hydroksikeskukset ovat molemmat R) (1 g, 1,5 mmoolia) etanoliseen liuokseen (50 M) lisätään 1 N NaOHita (3,0 ml, 3 mmoolia). Saatua liuosta kuumennetaan palautusjäähdyttäen 48 tunnin ajan.
Liuos jäähdytetään huoneen lämpötilaan ja konsentroidaan \ tyhjössä. Jäännös suspendoidaan uudelleen veteen ja teh- 18 94339 dään varovasti happamaksi 6 N HCl:llä. Saatu hapan liuos uutetaan etyyliasetaatilla. Orgaaninen uute pestään vedellä, suolaliuoksella, kuivatetaan MgS04:n päällä, suodatetaan ja konsentroidaan tyhjössä. Tämä jäännös liuotetaan uudelleen tolueeniin (100 ml) ja sitä kuumennetaan palautus jäähdyttäen 3 tunnin ajan poistamalla vesi atseotroop-pisesti. Tämä jäähdytetään huoneen lämpötilaan ja konsentroidaan tyhjössä, jolloin saadaan 1,2 g keltaista puoli-kiinteää ainetta. Pikakromatografia piihappogeelillä eluoimalla 40%:isella EtOAc/heksaanilla tuottaa 0,42 g valkoista kiintoainetta, joka sisältää edelleen epäpuhtauksia. Tämä kromatografoidaan uudelleen, jolloin saadaan 0,1 g olennaisesti puhdasta R,R-enantiomeeriä, 2R-trans- 5-(4-fluorifenyyli)-2-(1-metyylietyyli)-N,4-difenyyli-l-[2-(tetrahydro-4-hydroksi-6-okso-2H-pyran-2-yyli)etyyli]-lH-pyrroli-3-karboksamidia valkoisena vaahtona. HPLC osoittaa, että tämä aine on 94,6%:isesti kemiallisesti puhdasta, [a]D23: 0,51 % CHCl3:ssa = 25,5°. Piikki huoneen lämpötilassa = 53,46 minuuttia on kokeellisesti osoitettu tuntemattomaksi diastereomeeriksi, joka johtuu 2 %:sta (S)-(-)-α-metyylibentsyyliamiinia, joka on läsnä Aldrichin a-metyylibentsyyliamiinissa.
\ Esimerkki 8 2S-trans-5- (4-f luorif enyyli) -2- (1-metyylietyyli) -Ji, 4-dif e-nyyli-1-[2-(tetrahydro-4-hydroksi-6-okso-2H-pyran-2-yyli)-etyyli]-l|i-pyrroli-3-karboksamidin valmistus (esimerkissä 5 valmistetun yhdisteen S,S-enantiomeeri ;: Suoritettaessa esimerkissä 7 selitetty menetelmä diaste- reomeerillä 2 saadaan 0,6 g vaahtomaista kiintoainetta, joka pikakromatografoidaan piihappogeelillä. Eluointi 50%:isella EtOAc/heksaanilla tuottaa 0,46 g olennaisesti puhdasta S,S-enantiomeeriä, 2S-trans-5-(4-fluorifenyyli)-2 - (1 -metyy 1 ietyy li) -Ji, 4-dif enyy li-1-[ 2-(t etr ahydr o-4 -hyd-roksi-6-okso-2H-pyran-2-yyli)etyyli]-lH-pyrroli-3-karboks- 9 4339 19 amidia valkoisena vaahtona. HPLC osoittaa, että tämä aine on 97,83%:isesti kemiallisesti puhdasta. [a]D23 = 0,51 % CHCl3;ssa = -24,8°.
Esimerkki 9
Kaavan II mukaisen kemiallisen laktonin hydrolyysi
Huoneen lämpötilassa olevaan laktonin liuokseen THF:ssä lisätään natriumhydroksidin liuos vedessä. Seosta sekoitetaan 2 tunnin ajan. HPLC: 99,65 (tuote); 0,34 (lähtölak-toni). Seos laimennetaan 3 1:11a vettä, uutetaan etyyliasetaatilla (2x11) ja tehdään happamaksi pH-arvoon 4 lisäämällä 37 ml 5N kloorivetyhappoa. Vesipitoinen kerros uutetaan 2 x 1,5 l:n annoksilla etyyliasetaattia. Yhdistetyt etyyliasetaattiuutteet pestään 2x1 1:11a vettä, suolaliuosta ja kuivatetaan, jolloin saadaan etyyliasetaatti-liuoksen suodattamisen jälkeen vapaa happo. Tätä liuosta käytetään suoraan N-metyyliglukamiini-suolan fraktiossa.
Suolaliuos-vedestä saadut etyyliasetaattiuutteet konsentroidaan, jolloin saadaan 15,5 g kellertävää kiintoainetta.
Esimerkki 10
Kalsiumsuola natriumsuolasta ja/tai laktonista
Liuotetaan 1 mooli laktonia (540,6 g) 5 Iraan MeOH:ta ja liukenemisen jälkeen lisätään 1 1 H20:ta. Sekoittaen lisätään yksi ekvivalentti NaOH:ta ja seurataan HPLC:llä, kunnes jäljelle jää 2 % tai vähemmän laktonia ja diolihapon metyyliesteriä (ei voida käyttää NaOH:n ylimäärää, koska Ca(OH)2 muodostaa CaCl2:n addition). Lisätään NaOH:ta kaustisena (51,3 ml, 98 ekv.) tai pelletteinä (39,1 g, 0,98 ekv.).
Yllä oleva menetelmä voidaan osoittaa seuraavasti: 94 339 0 20 ‘
Ph p .90 eq. NaOH
0' ,NS -► H Ph MeOH, H20 5 : 1 m.w.= 540.6 g
OH OH O
EtOAc, heksaani /—v h?°— F~H@^ty<
Ph,c.
O .N, H Ph
Hydrolyysin päätyttyä lisätään 10 1 H20:ta ja sitten pestään vähintään 2 kertaa EtOAc:n ja heksaanin l:l-seoksel-la. Jokainen pesu sisältää 10 1 sekä EtOAc:tä että heksaa-nia. Jos natriumsuola on puhdas, lisätään 15 1 MeOH:ta.
Jos se on epäpuhdas ja/tai se sisältää väriä, lisätään 100 g G-60-hiiltä, sekoitetaan 2 tunnin ajan ja suodatetaan Supercelin läpi. Pestään 15 1:11a MeOH:ta. Suoritetaan paino/tilav.-%-määritys reaktioseoksessa HPLC:llä suolan tarkan määrän määrittämiseksi liuoksessa.
«
Liuotetaan 1 ekvivalentti tai pieni ylimäärä CaCl2*2H20:ta (73,5 g) 20 l:aan H20:ta. Kuumennetaan sekä reaktioseos että CaCl2-liuos 60°C:seen. Lisätään hitaasti sekoittaen voimakkaasti CaCl2-liuosta. Lisäyksen päätyttyä jäähdyte-: tään hitaasti 15°C:seen ja suodatetaan. Pestään suodatus- kakku 5 1:11a H20:ta. Kuivatetaan 50°C:ssa tyhjöuunissa.
Voidaan kiteyttää uudelleen liuottamalla 4 l:aan EtOAc:tä (50°C), suodattamalla Supercelin läpi, pesemällä 1 1:11a EtOAc:tä, sitten lisäämällä 3 1 heksaania 50°C:iseen . liuokseen.
94339 21
Yllä selitetty menetelmä voidaan esittää seuraavasti: oh oh o / \ JL JL Jk / OH OH O \ F~\0) C ) C 1/2 eq.CaCli ' 2H20 /f_/qV__/N\_/ ° ^
Ph °,C'K' H’° \ I
\ €KX* / ·.«.· S80.6 g \ / ' m.w.- 1155.4 g ' 2
Esimerkki 11
Kaavan I mukaisen vapaan hapon etyyliasetaattiliuoksen käsittely N-metyyliglukamiinilla
Kaavan I mukaisen vapaan hapon liuokseen (0,106 M) etyyliasetaatissa (3 1) lisätään voimakkaasti sekoittaen huoneen lämpötilassa liuos, jossa on N-metyyliglukamiinia (20,3 g, 0,106 M) veden ja asetonin l:l-seoksessa (120 ml, 120 ml). Sekoittamista jatketaan 16 tunnin ajan ja sitten samea liuos konsentroidaan tyhjössä (- 250 sp.). Lisätään to-lueenia (11) ja seos konsentroidaan valkoiseksi kiintoaineeksi (- 100 g). Kiintoaine liuotetaan 1670 ml:aan aseto-nia ja suodatetaan kolmikaulaiseen pulloon, joka on varustettu mekaanisella sekoittimella ja termostaatti-säätöi-sellä lämpömittarilla. Pullo ja suodatin pestään 115 ml:11a veden ja asetonin l:l-seosta ja kirkas liuos jäähdytetään hitaasti. Näin saadaan sakka, joka liuotetaan uu- : delleen kuumentamalla takaisin 65°C:seen. Lisätään edel- « leen 20 ml vettä ja pestään, jolloin saadaan kiteinen tuote, joka eristetään suodattamalla. Kiintoaineet pestään 1200 ml:lla CH3Cl:ää ja tyhjökuivatetaan 255°C:ssa, jolloin saadaan valkoinen kiintoaine. Tämän aineen analyysi osoittaa, että se sisältää 4 % amiinia samoin kuin 0,4 % “ jäämäasetonia ja 0,67 % vettä. Analyyttiset tulokset ovat seuraavat: 22 94339 sulamispiste: 105 - 155°C (hajaantuen) laskettu analyysi: C 63,73, H 6,95, N 5,57, F2 9,53 saatu analyysi: 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, 5 μ, 25 cm 256 nm: 1,0 ml/min.
6-81 min.: 98,76 %
Opt. ret.: [<x]*b = -10,33° (c = 1,00, MeOH) jäämäliuottimet: CH2CH = 0,26 % titraatiot: HC104 (0,1 N) = 203,8 %
BuNOH (0,1 N) = 98,5 %
Muita suoloja, jotka valmistetaan vastaavalla tavalla kuin esimerkeissä 10 ja 11, voivat olla kaliumsuola, hemimagne-siumsuola, hemisinkkisuola tai kaavan I mukaisen yhdisteen l-deoksi-2-(metyyliamino)-D-glusitolikompleksi.
I!
Claims (5)
1. Menetelmä farmaseuttisesti käyttökelpoisen [R-(R*,R*)]~ 2-(4-f luorifenyyli) -/3,5-dihydroksi-5- (1-me tyyli e tyyli) -3-fenyyli-4-[(fenyyliamino)-karbonyyli]-lH-pyrroli-l-heptaa-nihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi, tunnettu siitä, että A, 1) käsitellään kaavan F [6) HO XX ro il \ o mukainen trans-rasemaatti kaavan + h2nXp*« /r : ( ch, R mukaisella yhdisteellä, yhdisteiden valmistamiseksi, joiden kaava on 94339 F ph^J^ OH OH o I N'^^'^^Rv'v^'''rvv^''^n Pb PhHN\^w *χΓ Il \ f OHj ° .x^ R + F Φ _. ] OH OH O ΡΗ^Α II phHN H^T » \ f C»3 O R 2. käsitellään yhdisteitä vahvalla emäksellä, 3. palautuskeitetään vaiheen 2 tuote, ja 4. käsitellään vaiheen 3 erotettua tuotetta jolloin saadaan [R-(R*,R*)]-2-(4-fluorifenyyli)-β,5-dihydroksi-5-(1-metyy-lietyyli)-3-fenyyli-4-[(fenyyliamino)-karbonyyli]-lH-pyr-roli-l-heptaanihappo ja sen farmaseuttisesti hyväksyttävät suolat, tai B, 1) käsitellään kaavan • · II 94339 F 0} Ph O PhNHC'^'W •I I O I mukainen yhdiste kaavan (2) ..Mg1' ® O Ph \ T^Ph L Ph mukaisella yhdisteellä, minkä jälkeen käsitellään etikkaha-polla kaavan (3) F 0} OH O Ph fh^y***\ Τ’ Π JL· , Ph PhNHOC O) mukaisen yhdisteen saamiseksi, 2. käsitellään vaiheen 1) kaavan (3) mukainen yhdiste pienellä ylimäärällä natriummetoksidia kaavan (4) 94339 F φ Ph i °H n'^^s^x^vv-^COjMc PhNHOC'''^5^/ (4) mukaisen yhdisteen saamiseksi, 3. käsitellään vaiheen 2 kaavan (4) mukainen yhdiste suurella ylimäärällä o- kaavan (5) F φ I OH o C02Bu' PhNHOC''^V (5) mukaisen yhdisteen valmistamiseksi, ja 4. käsitellään vaiheen 3 kaavan (5) mukainen yhdiste trietyyliboraanilla ja sen jälkeen natriumboorihydridillä metanolissa, minkä jälkeen lisätään vetyperoksidia jolloin : saadaan [R-(R1,R1) ]-2-(4-fluorifenyyli)-/3,5-dihydroksi-5- * · « (1-metyylietyyli)-3-fenyyli-4-[(fenyyliamino)-karbonyyli]-lH-pyrroli-l-heptaanihappo ja sen farmaseuttisesti hyväksyttävät suolat.
2. Patenttivaatimuksen 1 mukainen menetelmä, tunnet-.· t u siitä, että valmistetaan yhdiste, joka on [R(R1,R1)]~ li 94339 2- (4-f luorifenyyli) -/3,5-dihydroksi-5- ((1-metyylietyyli) -3-fenyyli-4-[ (fenyyliamino)karbonyyli]-lH-pyrroli-l-heptaa-nihappo.
3. Patenttivaatimuksen 1 mukainen menetelmä, tunnet-t u siitä, että valmistetaan patenttivaatimuksen 2 mukaisen yhdisteen mononatriumsuola.
4. Patenttivaatimuksen 1 mukainen menetelmä, tunnet-t u siitä, että valmistetaan patenttivaatimuksen 2 mukaisen yhdisteen hemikalsiumsuola siten että heptaanihappo tai sen suola saatetaan reagoimaan kalsiurosuolan muodostavan aineen kanssa.
5. Patenttivaatimuksen 1 mukainen menetelmä, tunnet-t u siitä, että valmistetaan patenttivaatimuksen 2 mukaisen yhdisteen N-metyyliglukamiinisuola. 1 94339
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US38418789A | 1989-07-21 | 1989-07-21 | |
| US38418789 | 1989-07-21 |
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| FI903614A0 FI903614A0 (fi) | 1990-07-18 |
| FI94339B FI94339B (fi) | 1995-05-15 |
| FI94339C true FI94339C (fi) | 1995-08-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI903614A FI94339C (fi) | 1989-07-21 | 1990-07-18 | Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi |
Country Status (20)
| Country | Link |
|---|---|
| US (2) | US5273995A (fi) |
| EP (2) | EP0409281B1 (fi) |
| JP (6) | JP3506336B2 (fi) |
| KR (1) | KR0167101B1 (fi) |
| AT (2) | ATE270274T1 (fi) |
| AU (1) | AU628198B2 (fi) |
| CA (1) | CA2021546C (fi) |
| CY (1) | CY2357B1 (fi) |
| DE (3) | DE1061073T1 (fi) |
| DK (2) | DK0409281T3 (fi) |
| ES (2) | ES2153332T3 (fi) |
| FI (1) | FI94339C (fi) |
| GE (1) | GEP20043167B (fi) |
| GR (1) | GR20010300002T1 (fi) |
| IE (1) | IE902659A1 (fi) |
| NO (1) | NO174709C (fi) |
| NZ (1) | NZ234576A (fi) |
| PT (1) | PT94778B (fi) |
| SG (1) | SG46495A1 (fi) |
| ZA (1) | ZA905742B (fi) |
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| JP2023543565A (ja) | 2020-09-29 | 2023-10-17 | ラボラトリオス シラネス、エセ．ア．デ セ．べ． | 脂質異常症及び心血管疾患の処置及び予防のためのスタチン類及びフィブラート類の薬学的配合物 |
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1990
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1991
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2002
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