ES2551708T3 - Compuestos de 4-desdimetilamino tetraciclina - Google Patents

Compuestos de 4-desdimetilamino tetraciclina Download PDF

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ES2551708T3
ES2551708T3 ES10183340.8T ES10183340T ES2551708T3 ES 2551708 T3 ES2551708 T3 ES 2551708T3 ES 10183340 T ES10183340 T ES 10183340T ES 2551708 T3 ES2551708 T3 ES 2551708T3
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dedimethylamino
mmol
added
reaction
filtered
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Mark L. Nelson
Kwasi Ohemeng
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Paratek Pharmaceuticals Inc
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Paratek Pharmaceuticals Inc
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Abstract

Un compuesto de tetraciclina sustituido seleccionado del grupo que consiste de**Fórmula** y sales farmacéuticamente aceptables de los mismos.

Description

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E10183340
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30.0 mL de ácido sulfúrico concentrado se agrega a 1.00 g de 4-desdimetilamino sanciclina con agitación y la solución luego se enfría a 0° C. Se agrega 1.09g de N-yodosuccinimida en forma de porciones a la solución durante una hora y la mezcla de reacción se monitorea por HPLC y TLC. La mezcla de reacción se vierte en 250 mL de agua helada, y se extrae tres veces con n-butanol, y el solvente se elimina bajo presión reducida. El residuo crudo se purifica mediante HPLC preparativo proporcionando 7-yodosanciclina y 7,9-diiodosanciclina.
7,9-Bis(3,4-Metilenodioxifenil)-Sanciclina
imagen19
Esquema 20
0.74 mmol de 7,9-diyodo 4-desdimetilamino sanciclina (20C) y 8.3 mg (0.37 mmol) acetato de paladio se disuelven
10 en 25 ml de metanol, bajo una atmósfera de nitrógeno. La solución se calienta a 60° C. Después de agitación durante diez minutos se agrega 234 mg (2.22 mmol), carbonato de sodio seguido por 246 mg (1.48 mmol) de ácido 3,4-metilenodioxifenil borónico (20B). Después de que se completa la reacción, la mezcla de reacción se filtra a través de un lecho de celita y se concentra bajo presión reducida. Este producto crudo se purifica mediante cromatografía líquida preparativa utilizando una fase estacionaria C18 con un eluyente A: 0.1 % de TFA en agua y
15 eluyente B: 0.1 % de TFA en acetonitrilo.
7 Yodo 4-Desdimetilamino Sanciclina
Un gramo de 4-desdimetilamino sanciclina se disuelve en 25 mL de TFA (ácido trifluoroacético) que se enfría a 0 C (en hielo). Se agrega 1.2 equivalentes de N-yodosuccinimida (NIS) a la mezcla de reacción y se hace reaccionar durante cuarenta minutos. La reacción se elimina del baño helado y luego se deja reaccionar a temperatura 20 ambiente durante unas cinco horas adicionales. La mezcla luego se analiza mediante HPLC y TLC, se lleva a terminación mediante la adición en forma de etapas de NIS. Después de la terminación de la reacción, el TFA se elimina en vacío y 3 mL de MeOH se agrega para disolver el residuo. La solución metanólica luego se agrega lentamente a una solución rápidamente agitada de éter de dietilo para formar un precipitado. El isómero 7-yodo de sanciclina se purifica al tratar el producto de 7-yodo con carbón activado, se filtra a través de Celita, y se elimina
25 posteriormente el solvente en vacío para producir el compuesto isómero 7 como un sólido puro.
7-Tetrametilsililetinil-4-Desdimetilamino Sanciclina
imagen20
Esquema 21
A una solución de 10 mmol de trifluoroacetato de 7-yodo-4-desdimetilamino-sanciclina 500 mg de tetrakis30 trifenilfosfino-paladato, 500 mg yoduro de cobre (I), 100 mg de acetato de paladio y 30 mL de trietilamina se agrega 3 ml de trimetilsililacetileno. La mezcla de reacción se agita a temperatura ambiente durante dos horas luego se filtra
20
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E10183340
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7-Etil-4-desdimetilamino sanciclina (23B, 6.7 mmol, 3.2 g) se disuelve en 75 ml de ácido metanosulfónico a temperatura ambiente. Se agrega N-yodo succinimida (24B, 13.5 mmol, 3.05 g) durante dos horas en 6 porciones. Después de dos horas se agrega éter de dietilo, y el precipitado se filtra y se seca. El producto crudo se purifica mediante cromatografía líquida preparativa utilizando una fase estacionaria C18 con eluyente A: 0.1% de TFA en agua y eluyente B: 0.1% de TFA en acetonitrilo.
7-Etil-9-Ciclohexeniletinil-4-Desdimetilamino Sanciclina
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Esquema 25
A una solución de 7-etil-4-desdimetilamino sanciclina (1.13 mmol), 50 mg de tetrakis-trifenilfosfino-paladato, 50 mg
10 de yoduro de cobre (I), 10 mg de acetato de paladio y 3 ml de trietilamina se agrega 0.1 ml de ciclohexenil-acetileno. La mezcla de reacción se agita a 60° C durante una hora, se filtra a través de un lecho de celita y se concentra. El material seco se disuelve en metanol y se filtra. La solución luego se concentra y se purifica utilizando cromatografía líquida preparativa. La cromatografía líquida preparativa utiliza una fase estacionaria C18 con eluyente A: 0.1% de TFA en agua y eluyente B: 0.1% de TFA en acetonitrilo.
15 7-Yodo-9-t-Butil-4-Desdimetilamino Sanciclina
imagen23
Esquema 26
9-t-butil-4-desdimetilamino sanciclina (26A, 1.13 g, 2 mmol) se disuelve en 5 ml de ácido metanosulfónico (0.448, 2 mmol). Se agrega N-yodosuccinimida (26B) a temperatura ambiente durante una hora en cuatro porciones. El 20 producto (26C) se precipita con éter de dietilo, se filtra y se utiliza en otra reacción sin purificación adicional.
7-(2-Metoxi-5-Dimetilaminometilfenil)-9-t-Butil-4-Desdimetilamino Sanciclina
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Esquema 27
7-Yodo-9-t-butil-4-desdimetilamino sanciclina (26B, 710 mg, 1.0 mmol) y acetato de paladio (22.4 mg, 0.1 mmol) se
25 disuelven en 25 ml de metanol bajo una atmósfera de nitrógeno. Se agregan carbonato de cesio (3.25 g, 10 mmol) y ácido 2-metoxi-5-dimetilaminometilfenil-borónico (27B, 0.435 g, 0.15 mmol). La mezcla de reacción se agita a 60 °C durante dos horas y luego se filtra a través de un lecho de celita y se concentra bajo presión reducida. El producto
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E10183340
28-10-2015
crudo se purifica mediante cromatografía líquida preparativa utilizando una fase estacionaria C18 en eluyente A: 0.1% de TFA en agua y eluyente B: 0.1% de TFA en acetonitrilo.
Ejemplo de referencia 3: Preparación de compuestos de 4-desdimetilamino tetraciclina 9-sustituida
Preparación de 9-yodo 4-desdimetilamino minociclina
A 200 ml de 97% de ácido metanosulfónico se agrega lentamente, a temperatura ambiente, en forma de porciones
[56.56 mM] de sal de clorhidato de 4-desdimetilamino minociclina. La solución oscura luego se agita a temperatura ambiente mientras que se agrega [38 g; 169.7 mM] de N-yodosuccinimida, en seis porciones iguales durante un tiempo de 3.0 horas. La reacción se monitorea a través de LC analítico, observando la desaparición del material de partida.
La reacción se detiene lentamente en 2L de agua enfriada con hielo que contiene [17.88 g; 1134.1 mM] de tiosulfato de sodio con agitación rápida. Este enfriamiento se agita durante aproximadamente 30 minutos a temperatura ambiente. La capa acuosa luego se extrae con 6x200ml de acetato de etilo antes la capa acuosa se vertió sobre
[259.8 g; 3.08 M] de hidrógeno carbonato de sodio que contiene 300 ml de n-butanol. Las fases se separan y la fase acuosa se extrae con 4x250ml de n-butanol. Las fracciones orgánicas se combinan y se lavan con 3x250ml de agua y una vez con 250 ml de solución salina saturada. La fase orgánica resultante se reduce hasta sequedad bajo presión reducida. El residuo se suspende en metanol (~ 600 ml) y el gas HCl anhidro se burbujea en esta mezcla hasta que ocurre la solución. Esta solución se reduce hasta sequedad bajo presión reducida. Los filtrados se reducen a sequedad bajo presión reducida. El material resultante se tritura con 300 ml de éter de metilo y t-Butilo se aísla mediante filtración. Este material se vuelve a disolver en 300 ml de metanol y se trata con 0.5 g de carbón de madera, se filtra y los filtrados se reducen hasta sequedad bajo presión reducida. El material es de nuevo en forma de polvo bajo metil t-butil éter, aislado mediante filtración por succión y se lava adicionalmente con éter, y finalmente con hexanos. El material se seca al vacío para dar el producto.
Procedimiento general para la preparación de Compuestos de 9-alquinil 4-desdimetilamino minociclina
1 mmol de 9-yodo 4-desdimetilamino minociclina, 50 mg de tetrakis trifenilfosfinato paladato, 12 mg de acetato de paladio, 32 mg de yoduro de cobre (I) se disuelven/suspenden en 10 ml de acetonitrilo. Se agregan 2 a 5 mL de trietilamina y 3 a 5 mmol de derivado de alquinil 4-desdimetilamino minociclina. La mezcla de reacción se agita vigorosamente entre temperatura ambiente a 70° C. El tiempo de reacción es 2-24 horas. Cuando la reacción se completa la suspensión oscura se filtra a través de un lecho de celita y se concentra. El producto crudo se purifica mediante HPLC prep. Las fracciones combinadas se concentran y toman en ~1 ml de metanol. Se agrega ~3 ml de HCl metanol saturado, y el producto se precipita con éter.
Procedimiento General para la Preparación de Compuestos de 9-Aril 4-Desdimetilamino Minociclina
0.15 mmol de 9-yodo 4-desdimetilamino minociclina, PdOAc (3.2mg), 229 µl de Na2CO3 2M y 2 equivalentes de ácido fenil borónico se disuelven/suspenden en 10 ml de metanol. El matraz de reacción se purga con argón y la reacción se corren durante un mínimo de cuatro horas o hasta que el monitoreo de HPLC muestra el consumo del material de partida y/o la aparición de productos. La suspensión se filtra a través de celita, y se somete a purificación mediante HPLC prep sobre una columna de divinilbenceno.
9-(4-Trifluorometoxifenilureido)-Metil Minociclina
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Esquema 28
23
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Claims (1)

  1. imagen1
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