CZ307821B6 - - Google Patents

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CZ307821B6
CZ307821B6 CZ2015493A CZ2015493A CZ307821B6 CZ 307821 B6 CZ307821 B6 CZ 307821B6 CZ 2015493 A CZ2015493 A CZ 2015493A CZ 2015493 A CZ2015493 A CZ 2015493A CZ 307821 B6 CZ307821 B6 CZ 307821B6
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formula
acid
reacting
protected
aminoadamantanecarboxylic
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CZ2015493A
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Jeffrey Robl
Richard Sulsky
David Augeri
David Magnin
Lawrence Hamann
David Betebenner
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Bristol Myers Squibb Co
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Description

Chráněná aminohydroxyadamantan karboxylová kyselina a způsob její přípravy
Oblast techniky
Tento vynález se týká chráněné aminohydroxyadamantan karboxylové kyseliny a způsobu její přípravy.
Dosavadní stav techniky
Při přípravě chráněné aminohydroxyadamantan karboxylové kyseliny podle tohoto vynálezu se vychází z adamantankarboxylové kyseliny, která je známá a je komerčně dostupná.
Podstata vynálezu
Předmětem tohoto vynalezu je chráněna aminohydroxyadamantan karboxylová kyselina vzorce I:
BOC-HN (I).
Dále je předmětem tohoto vynálezu způsob přípravy shora uvedené chráněné aminohydroxyadamantan karboxylové kyseliny, při kterém se na chráněnou aminoadamantankarboxylovou kyselinu vzorce 36
(36), působí manganistanem draselným v přítomnosti hydroxidu draselného.
Chráněná aminoadamantankarboxylová kyselina vzorce 36 se může připravit sérii reakčních kroků z komerčně dostupné adamantankarboxylové kyseliny. Konkrétně může být chráněná aminoadamantankarboxylová kyselina vzorce 36 připravena tak, že se adamantankarboxylové kyselina esterifikuje buď v refluxujícím methanolu v přítomnosti kyseliny chlorovodíkové nebo s použitím trimethylsilyldiazomethanu v systému diethylether/methanol, za vzniku methylesteru vzorce 30. Získaný ester vzorce 30 se redukuje pomoci L1AIH4 na alkohol vzorce 31, který následně podrobí Swemově oxidaci na odpovídající aldehyd vzorce 32. Aldehyd vzorce 32 se převede za asymetrických Streckerových podmínek s použitím kyanidu draselného, hydrogensiričitanu sodného a R-(-)-2-fenylglycinolu. Získaný nitril vzorce 33 se hydrolyzuje v silně kyselém prostředí s použitím 12M kyseliny chlorovodíkové v kyselině octové za vzniku karboxylové kyseliny vzorce 34. Chirální pomocné činidlo se odstraní katalytickou redukcí ve vodíkové atmosféře v okyseleném methanolu a s použitím Pearlmannova katalyzátoru, čímž se získá hydrochloridová sůl aminoadamantankarboxylové kyseliny vzorce 35, ve které se v dalším kroku aminoskupina ochrání ve formě íerc-butylkarbamátu za vzniku požadované chráněné
- 1 CZ 307821 B6 aminoadamantankarboxylové kyseliny vzorce 36, která dále reaguje s KM 11()4 ve vodném roztoku hydroxidu draselného a při zvýšené teplotě za vzniku sloučeniny vzorce I podle tohoto vynálezu.
V následujícím textu je popsán konkrétní příklad provedení způsobu podle předmětného vynálezu.
Příklady uskutečnění vynálezu
V příkladu jsou použity následující zkratky:
BOC íerc-butyloxykarbonyl
DMSO dimethylsulfoxid ekv. ekvivalent
MS hmotnostní spektrometrie
PTFE poly(tetrafluorethylen)
Příklad 1
Krok 1
(30)
Adamantankarboxylová kyselina (10,0 g, 55 mmol, 1 ekv.) se rozpustí ve směsi diethyletheru (160 ml) a methanolu (40 ml), k roztoku se přidá trimethylsilyldiazomethan (2,0M roztok v hexanu, 30 ml, 60 mmol, 1,1 ekv.) a směs se míchá po dobu tří hodin při teplotě místnosti.
-2CZ 307821 B6
Těkavé podíly se odstraní na rotační odparce a produkt se čistí flash chromatografií na sloupci silikagelu (sloupec 5 x 15 cm) s elucí směsí 40 % dichlormethanu/hexany, čímž se získá 10,7 g (100 %) požadovaného esteru vzorce 30 ve formě bílé krystalické látky.
Krok 2
Methylester z kroku 1 (10,7 mg, 0,055 mmol, 1 ekv.) se rozpustí v bezvodém tetrahydrofuranu (150 ml), roztok se převede pod argonovou atmosféru a přidá se k němu roztok lithiumaluminiumhydridu (1M v tetrahydrofuranu, 69 ml, 69 mmol, 1,25 ekv.). Reakční směs se míchá po dobu 1,5 hodiny při teplotě místnosti, ochladí se na teplotu 0 °C a postupně se přidají voda (5,1 ml), 15% vodný roztok hydroxidu sodného (5,1 ml) a voda (10,2 ml). Reakční směs se míchá po dobu 15 minut při teplotě místnosti, suspenze se podrobí vakuové filtraci a pevné produkty se promyjí ethylacetátem (2x 100 ml). Filtrát se zahustí na rotační odparce a zbylá pevná látka se čistí flash chromatografií na sloupci silikagelu (sloupec 5 x 15 cm) s elucí směsí 10 % ethylacetátu/dichlormethan, čímž se získá 8,74 g (96 %) požadovaného alkoholu vzorce 31 ve formě bílé pevné látky.
Krok 3
V sušárně vysušená tříhrdlá baňka opatřená přikapávací nálevkou o objemu 125 ml se naplní v argonové atmosféře bezvodým dichlormethanem (150 ml) a bezvodým DMSO (10,3 ml, 0,145 mol, 2,5 ekv.) a ochladí se na teplotu -78 °C. Pomalu po kapkách se přidá oxalylchlorid (6,7 ml, 0,0768 mol, 1,32 ekv.) a reakční směs se míchá po dobu 15 minut, čímž se získá aktivovaný DMSO adukt. K tomuto aduktu se přidá roztok sloučeniny z kroku 2 (9,67 g, 58,2 mmol, 1 ekv.) v suchém dichlormethanu (75 ml) a reakční směs se míchá po dobu jedné hodiny. K bílé reakční směsi se přidá po kapkách triethylamin (40,5 ml, 0,291 mol, 5 ekv.). Po 30 minutách se chladicí lázeň odstraní a do reakční směsi se postupně přidají studený 20% vodný roztok dihydrogenfosforečnanu draselného (25 ml) a studená voda (150 ml). Reakční směs se míchá po dobu 15 minut při teplotě místnosti, zředí se diethyletherem (400 ml) a jednotlivé vrstvy se od sebe oddělí. Organická vrstva se promyje studeným 10% vodným roztokem dihydrogenfosforečnanu draselného (3x 150 ml) a nasyceným vodným roztokem chloridu sodného (100 ml). Organická fáze se vysuší (síranem sodným), přefiltruje se a zahustí se. Zbytek se čistí flash chromatografií na sloupci silikagelu (sloupec 5 x 10 cm) s elucí dichlormethanem, čímž se získá 9,40 g (98 %) požadovaného aldehydu vzorce 32 ve formě bílé pevné látky.
-3CZ 307821 B6
Krok 4
Aldehyd z kroku 3 (9,40 mg, 57 mmol, 1 ekv.) se suspenduje ve vodě (145 ml) a suspenze se ochladí na 0 °C. Ke směsi se přidají hydrogensiřičitan sodný (5,95 g, 57 mmol, 1 ekv.) kyanid draselný (4,0 g, 59 mmol, 1,04 ekv.) a roztok (R)-(-)fenylglycinolu (8,01 g, 57 mmol, 1 ekv.) v methanolu (55 ml). Reakční směs se míchá po dobu 2 hodin při teplotě místnosti a potom se zahřívá k varu pod zpětným chladičem po dobu 16 hodin. Směs se ochladí na teplotu místnosti a přidá se 200 ml ethylacetátu. Reakční směs se míchá po dobu 15 minut a jednotlivé vrstvy se od sebe oddělí. Vodná frakce se extrahuje ethylacetátem. Spojené ethylacetátové extrakty se promyjí solankou (50 ml), vysuší se nad bezvodým síranem sodným, přefiltrují se a filtrát se zahustí. Produkt se čistí flash chromatografií na sloupci silikagelu (sloupec 6,4 x 20 cm) s elucí směsí 20 % ethylacetátu/hexan, čímž se získá 11,6 g (37,4 mmol) (65 %) požadovaného (R,S) produktu vzorce 33 ve formě bílé pevné látky. MS m/e 311 (M + H)+.
Krok 5
Nitril vzorce 33 (5,65 g, 18 mmol) z kroku 4 se zahříváním ve směsi koncentrované kyseliny chlorovodíkové (120 ml) a octové kyseliny (30 ml) udržuje na teplotě 80 °C po dobu 18 hodin, načež se reakční směs ochladí v ledové lázni. Vakuovou filtraci vzniklé sraženiny se získá požadovaná kyselina vzorce 34 ve formě bílé pevné látky (5,21 g, 14 mmol, 78 %). MS m/e 330 (M + H)+.
Krok 6
-4CZ 307821 B6
Kyselina z kroku 5 (5,21 g, 14 mmol) se rozpustí v methanolu (50 ml) a kyselině octové (10 ml) a hydrogenuje se při tlaku vodíku 345 Pa v přítomnosti Pearlmanova katalyzátoru (20% hydroxid palladnatý, 1,04 g, 20 % hmotn.) po dobu 18 hodin. Reakční směs se přefiltruje přes PTFE membránový filtr a katalyzátor se promyje methanolem (3x 25 ml) . Filtrát se zahustí na rotační odparce, čímž se získá bílý produkt, který se bez dalšího čištění použije v kroku 7.
Krok 7
Surová sloučenina z kroku 6 (předpoklad 14 mmol) se v argonové atmosféře rozpustí v bezvodém dimethylformamidu (50 ml) a ponechá se reagovat v argonové atmosféře s uhličitanem draselným (5,9 g, 42 mmol, 3 ekv.) a di-terc-butyldikarbonátem (3,14 g, 14 mmol, 1 ekv.) při teplotě místnosti. Po 19 hodinách se dimethylformamid odstraní na rotační odparce a zbytek se dále zbaví zbytku rozpouštědla při sníženém tlaku. Zbytek se smísí s vodou (100 ml) a s diethyletherem (100 ml), vrstvy se od sebe oddělí a alkalická vodná fáze se promyje diethyletherem (2x 100 ml) k odstranění vedlejších produktů hydrogenolýzy. Vodná fáze se ochladí Na 0 °C, zředí se ethylacetátem (200 ml) a míchá se intenzivně za opatrného okyselování vodné fáze na hodnotu pH 3 pomocí 1N vodné kyseliny chlorovodíkové. Vrstvy se oddělí a vodná vrstva se extrahuje ethylacetátem (100 ml). Spojené ethylacetátové extrakty se promyjí solankou (50 ml), vysuší se (síranem sodným), přefiltrují se a filtrát se zahustí na rotační odparce. Zbytek se čistí flash chromatografií na sloupci silikagelu (sloupec 5 x 12 cm) s eluci směsi 5 % methanolu/ dichlormethan + 0,5 % kyseliny octové. K produktu se přidá hexan, čímž se získá 4,07 g (13 mmol, 92 %) požadované sloučeniny vzorce 36 ve formě bílé pěny. MS m/e 310 (M + H)+.
Krok 8
Roztok manganistanu draselného (337 mg, 2,13 mmol, 1,1 ekv.) ve 2% vodném roztoku hydroxidu draselného (6 ml) se zahřeje na teplotu 60 °C, po částech se přidá sloučenina z kroku 7 (600 mg, 1,94 mmol, 1 ekv.) a teplota reakční směsi se zvýší na 90 °C. Po uplynutí 1,5 hodiny se reakční směs ochladí na 0 °C, přidá se ethylacetát (50 ml) a směs se opatrně okyselí na pH 3 pomoci 1M kyseliny chlorovodíkové. Vrstvy se oddělí a vodná vrstva se extrahuje ethylacetátem (50 ml). Spojené organické extrakty se promyjí solankou, vysuší se nad síranem sodným, přefiltrují se a zahustí. Zbytek se čistí flash chromatografií na sloupci silikagelu (sloupec 3,8 x 15 cm) s gradientovou eluci směsí 2 % (200 ml), 3 % (200 ml), 4 % (200 ml) a 5 % (500 ml) methanolu/dichlormethan + 0,5 % kyseliny octové. Po izolování se k produktu přidá hexan, čímž
-5CZ 307821 B6 se získá 324 mg (51 %) požadované sloučeniny vzorce I ve formě bílé pevné látky. MS m/e 326 (M+H)+.

Claims (3)

  1. PATENTOVÉ NÁROKY
    1. Chráněná aminohydroxyadamantankarboxylová kyselina vzorce I
    (I), kde BOC znamená íerc-butyloxykarbonyl.
  2. 2. Způsob přípravy sloučeniny vzorce I podle nároku 1, vyznačující se tím, že zahrnuje následující kroky:
    (a) reakci adamantankarboxylové kyseliny s trimethylsilyldiazomethanem za vzniku methylesteru adamantankarboxylové kyseliny vzorce 30
    (30);
    (b) reakci methylesteru adamantankarboxylové kyseliny vzorce 30 s lithiumaluminiumhydridem za vzniku 1-hydroxymethyladamantanu vzorce 31
    'OH (31);
    (c) reakci 1-hydroxymethyladamantanu vzorce 31 s aktivovaným aduktem dimethylsulf oxidu, vytvořeným reakcí dimethylsulfoxidu s oxalylchloridem, za vzniku adamantanaldehydu vzorce 32
    OHC (32);
    -6CZ 307821 B6 (d) reakci adamantanaldehydu vzorce 32 s kyanidem draselným a R-(-)-fenylglycinolem za vzniku adamantannitrilového derivátu vzorce 33
    (33);
    (e) reakci adamantannitrilového derivátu vzorce 33 s kyselinou chlorovodíkovou a kyselinou octovou za vzniku hydrochloridové soli fenylglycinadamantankarboxylové kyseliny vzorce 34
    (34);
    (f) reakci fenylglycinadamantankarboxylové kyseliny vzorce 34 s vodíkem, za vzniku odpovídající hydrochloridové soli aminoadamantankarboxylové kyseliny vzorce 35 (35);
    (g) reakci hydrochloridové soli aminoadamantankarboxylové kyseliny vzorce 35 s di-tercbutyldikarbonátem v argonové atmosféře, za vzniku chráněné aminoadamantan karboxylové kyseliny vzorce 36 (36);
    kde BOC znamená íerc-butyloxykarbonyl; a
    -7 CZ 307821 B6 (h) reakci chráněné aminoadamantankarboxylové kyseliny vzorce 36 s manganistanem draselným za vzniku chráněné aminohydroxyadamantankarboxylové kyseliny vzorce I
    (I), kde BOC znamená íerc-butyloxykarbonyl.
  3. 3. Chráněná aminoadamantankarboxylová kyselina vzorce 36
    (36), kde BOC znamená íerc-butyloxykarbonyl
    15 jako meziprodukt pro přípravu sloučeniny vzorce I podle nároku 1.
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