ES2602902T3 - Derivados aminopropiónicos sustituidos como inhibidores de neprilisina - Google Patents

Derivados aminopropiónicos sustituidos como inhibidores de neprilisina Download PDF

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Publication number
ES2602902T3
ES2602902T3 ES13151795.5T ES13151795T ES2602902T3 ES 2602902 T3 ES2602902 T3 ES 2602902T3 ES 13151795 T ES13151795 T ES 13151795T ES 2602902 T3 ES2602902 T3 ES 2602902T3
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7alkyl
condition
intermediary
acid
room temperature
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Gary Mark Coppola
Yuki Iwaki
Rajeshri Ganesh Karki
Toshio Kawanami
Gary Michael Ksander
Muneto Mogi
Robert Sun
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Novartis AG
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Novartis AG
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    • C07—ORGANIC CHEMISTRY
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    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings 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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Abstract

Un compuesto de Fórmula I':**Fórmula** o una sal farmacéuticamente aceptable del mismo, en donde: R1 es H, C1-7alquilo, hidroxi, C1-7alcoxi, halógeno,-SH,-S-C1-7alquilo o NRaRb; R2 para cada ocurrencia, es independientemente C1-7alquilo, halo, NO2, CN, C1-7alcanoilamino, C3-7cicloalquilo, hidroxi, C1-7alcoxi, haloC1-7alquilo,-NRaRb, C6-10arilo, heteroarilo o heterociclilo; en donde Ra y Rb para cada ocurrencia son independientemente H o C1-7alquilo; R3 es A1-C(O)X1; R5 10 es H, halo, hidroxi, C1-7alcoxi, halo, C1-7alquilo o halo-C1-7alquilo; y X y X1 son independientemente OH,-O-C1-7alquilo,-NRaRb,-NHS(O)2-C1-7alquilo,-NHS(O)2-bencilo o-O-C6-10arilo; en donde alquilo está opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente del grupo que consiste de C6-10arilo, heteroarilo, heterociclilo, C(O)NH2, C(O)NH- C1-6alquilo, y C(O)N(C1-6alquilo)2; B1 es-C(O)NH- o-NHC(O)-; A1 es un C1-7alquileno lineal o ramificado; el cual está opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente del grupo que consiste de halo, C3-7cicloalquilo, C1-7alcoxi, hidroxi, O-Acetato; en donde dos alquilo germinales pueden opcionalmente combinarse para formar un C3-7cicloalquilo; o A1 es un C1-7alquenileno lineal o ramifiado; o A1 es un C1-4alquileno lineal en donde uno o más átomos de carbono están reemplazados por un heteroátomo seleccionado de O, NRc; y A1 está opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente del grupo que consistente de halo y C1-7alquilo; en donde Rc para cada aparición, es independientemente H, C1-7alquilo,-C(O)-O-C1-7alquilo, o-CH2C(O)OH; y n es 0, 1, 2, 3, 4 o 5; en donde cada heteroarilo es un anillo aromático monocíclico o bicíclico que comprende de 5-10 átomos de anillo seleccionados de átomos de carbono y 1 a 5 heteroátomos, y cada heterociclilo es una unidad estructural monocíclica saturada o parcialmente saturada, pero no aromática que comprende 4-7 átomos de anillo seleccionados de átomos de carbono y 1-5 heteroátomos, en donde cada heteroátomo de un heteroarilo o un heterociclilo es seleccionado independientemente de O, N y S.

Description

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forma de un derivado, por ejemplo, en una forma protegida o en la forma de una sal, o un compuesto obtenible por el proceso de acuerdo con la invención se produce bajo las condiciones de proceso y se procesa adicionalmente in situ.
Todos los materiales de partida, bloques de la construcción, reactivos, ácidos, bases, agentes deshidratantes,
5 solventes y catalizadores utilizados para sintetizar los compuestos de la presente invención están, bien sea, disponibles comercialmente o pueden ser producidos por métodos de síntesis orgánica conocidos para una persona de experiencia normal en la técnica (Houben-Weil 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volumen 21).
Los compuestos de la invención de acuerdo con cualquiera de las Fórmulas I’ y I a IIIC se pueden preparar por el 10 procedimiento descrito en las siguientes secciones.
Abreviaturas:
ATP: 5’-trifosfato de adenosina
AS: Aldosterona Sintasa
Alloc: aliloxicarbonilo
BOC: carboxi butilo terciario
BOP: hexafluorofosfato de benzotriazol1iloxi)tris(dimetilamino) fosfonio
BINAP: 2,2’-bis(difenil fosfino)-1,1’-binaftil racémico
br: ancho
bs: singlete ancho
Ac: Acetilo
Atm: atmósfera
Aq: acuoso
calcd: calculado
Bn: bencilo
Cbz: benciloxicarbonilo
Bu, i-bu y t-Bu: butilo, isobutilo y t-butilo
Pr e i-Pr: propilo e isopropilo
CDI: 1, 1’-carbonildiimidazol
COD: 1,5-ciclooctadieno
DBU: 1,8-diazabiciclo[5.4.0]undec-7-eno
DCC: 1,3-diciclohexilcarbodiimida
DIAD: azodicarboxilato de diisopropilo
DAST: trifluoruro de (dietilamino)azufre
d: doblete dd: doblete de dobletes
DCM: diclorometano
DIEA: dietilisopropilamina
DME: 1,4-dimetoxietano
DMF: N,N-dimetilformamida
DMSO: dimetilsulfóxido
DIPEA: N,N-diisopropiletilamina
DMAP: N,N-dimetilaminopiridina
Dppb: 1,2-bis(difenilfosfino)butano
Dppe: 1,2-bis(difenilfosfino) etano
DAD: detector de conjunto de diodos
DTT: ditiotreitol
DPPA: difenilfosforilazida
EDCI, EDIC: Clorhidrato de N-Etil-N’-(3dimetilaminopropil)carbodiimida
EDTA: ácido de etilendiamino tetraacético
ESI: ionización por electroaspersión
Et y EtOAc: etilo y acetato de etilo
EDC: Clorhidrato de N-Etil-N’-(3dimetilaminopropil)carbodiimida
HATU: O-(7-azobenzotriazol-1-il)-1,1,3,3tetrametiluroniohexafluorofosfato
HOBt: 1-hidroxi-7-azabenzotriazol
HPLC: cromatografía líquida de alta presión
LC y LCMS: cromatografía líquida y cromatografía líquida y espectrometría de masas
H: Hora(s)
HOAt: 1-hidroxi-7-azabezotriazole
IR: infrarrojo
LDA: diisopropilamida de litio
KHMDS: bis(trimetilsilil)amida de potasio
LHMDS: bis(trimetilsilil)amida de litio
18
(continuación)
LTA: tetraacetato de plomo
NHMDS: bis(trimetilsilil)amida de sodio
MeOD: metanol-d4
MeOH: metanol
MS: espectrometría de masas
m: multiplete
min: minutos
m/z: relación de masa a carga
Ms: mesilo
Me: metilo
M y mM: Molar y milimolar
Mg: miligramo
n.d.: no determinado
RMN: resonancia magnética nuclear
ppm: partes por millón
Pr e iPr: propilo e isopropilo
Ph: Fenilo
Pd/C: Paladio sobre carbono
PyBOP:benzotriazol-1-iloxi Tripirrolidinofosfoniohexafluorofosfato
RT: temperatura ambiente
PIDA: bis(trifluoroacetato) de yodobenceno
PIFA: diacetato de yodobenceno
PS: soportado por polímero
RP: fase reversa
s: singlete y t: triplete
Ts: tosilo
TFA: ácido trifluoroacético
THF: tetrahidrofurano
Tf: triflato
tBu: terc-butilo
TLC: cromatografía de capa fina
Tris·HCl: clorhidrato de aminotris(hidroximetil) metano
mL, mL y L: microlitro, mililitro y litro
TMS: Trimetilsililo
WSC: carbodiimida soluble en agua (N-Etil-N’-(3dimetilaminopropil)carbodiimida)
UV: ultravioleta
Los compuestos de la invención de la fórmula II se pueden preparar por hidrólisis de los intermedios A a C en donde X, X1, A1, R1, R2 y n tienen la definición de la Fórmula I o I', supra; y P1 y P2 son grupos protectores apropiado seleccionado de, pero no limitado a, metilo, etilo, isopropilo, terc-butilo, metoxibencilo o bencilo.
imagen17
Intermediario A Intermediario B
19
imagen18
imagen19
imagen20
imagen21
imagen22
imagen23
imagen24
imagen25
imagen26
imagen27
imagen28
imagen29
imagen30
imagen31
imagen32
imagen33
imagen34
imagen35
Ejemplo #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 1-3
Ácido (R)-5-(1-(3’-clorobifenil-4-il)-4-etoxi-4-oxobutan-2-ilamino)-5oxopentanoico imagen36 DIPEA, DCM, Temperatura ambiente 1.57 min. (A) 432.1
Ejemplo 1-4
Ácido (R)-5-(4-etoxi-1-(5’-fluoro-2’-metoxibifenil-4-il)-4-oxobutan-2ilamino)-5-oxopentanoico imagen37 DIPEA, DCM, Temperatura ambiente 0,93 min. (B) 446.3
Ejemplo 1-5
Ácido (R)-5-(1-(5’-cloro-2’-metoxibifenil-4-il)-4-etoxi-4-oxobutan-2-ilamino)5-oxopentanoico imagen38 DIPEA, DCM, Temperatura ambiente 1.14 min. (B) 462.5
(continuación) (continuación)
Ejemplo #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 1-6
Ácido (R)-4-(1-(2’-cloro-5’-fluorobifenil-4-il)-4-etoxi-4-oxobutan-2-ilamino)4-oxobutanoico imagen39 DIPEA, DCM, Temperatura ambiente 0,97 min. (B) 436.2
Ejemplo 1-7
Ácido (R)-4-(4-etoxi-1-(3’-fluorobifenil-4-il)-4-oxobutan-2-ilamino)-4oxobutanoico imagen40 DIPEA, DCM, Temperatura ambiente 1.23 min. (B) 402.0
Ejemplo 1-8
Ácido (R)-4-(4-(benciloxi)-1-(3’-clorobifenil-4-il)-4-oxobutan-2-ilamino)-4oxobutanoico imagen41 DIPEA, DCM, Temperatura ambiente 1.37 min. (B) 480,2
Ejemplo #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 1-9
imagen42 imagen43 Piridina, Temperatura ambiente 1.32 min. (C) 490,2
Ejemplo 1-10
imagen44 imagen45 DIPEA, DCM, Temperatura ambiente 1.52 min. (B) 506.4
=
=
=
imagen46
imagen47
= =
imagen48
imagen49
Ejemplo #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 1-18
Metil éster del ácido (2S,3R)-3-(3-Carboxi-propionilamino)-4-(3’-cloro-bifenil-4il)-2-hidroxi-butírico Metil éster del ácido (2R,3R)-3-(3-Carboxi-propionilamino)-4-(3’-cloro-bifenil-4il)-2-hidroxi-butírico Intermediario 50 Et3N, DCM 1.29 min. (A) 420,0
(continuación) (continuación) (continuación) (continuación)
Ejemplo #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 1-19
Metil éster del ácido (2S,3R)-3-(3-Carboxi-propionilamino)-4-(3’-cloro-bifenil-4il)-2-metoxi-butírico Metil éster del ácido (2R,3R)-3-(3-Carboxi-propionilamino)-4-(3’-cloro-bifenil-4il)-2-metoxi-butírico Intermediario 51 DIPEA, DCM 1.21 min. (A) 434.2
Ejemplo #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 1-20
Etil éster del ácido (2S,3R)-3-(3-Carboxi-propionilamino)-4-(3’-cloro-bifenil-4-il)2-metoxi-butírico Intermediario 52 DIPEA, DCM 1.57 min. (A) 448.3
Etil éster del ácido (2R,3R)-3-(3-Carboxi-propionilamino)-4-(3’-cloro-bifenil-4-il)2-metoxi-butírico
Ejemplo #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 1-21
Metil éster del ácido (2S,3R)-3-(3-Carboxi-propionilamino)-4-(3’-cloro-bifenil-4il)-2-fluoro-butírico Metil éster del ácido (2R,3R)-3-(3-Carboxi-propionilamino)-4-(3’-cloro-bifenil-4il)-2-fluoro-butírico Intermediario 53 Et3N, DCM 0,83 min. (B) 422.1
Ejemplo 1-22
Etil éster del ácido (R)-3-(3-Carboxi-propionilamino)-4-(3’-cloro-bifenil-4-il)-2metil-butírico Nuevo intermediario 54 Et3N, DCM 0,98 min. (B) 432
Ejemplo #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 1-23
Etil éster del ácido (R)-3-(2-Carboximetoxi-acetilamino)-4-(3’-cloro-bifenil-4-il)butírico imagen50 Et3N, DCM 0,75 min. (B) 434
==
imagen51
imagen52
imagen53
imagen54
= =
imagen55
= =
imagen56
imagen57
Ejemplo #
Producto Material de partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 3-2
6-(1-(3’-clorobifenil-4-il)-4-etoxi-4-oxobutan2-ilamino)-6-oxohexanoato de (R)-metilo imagen58 EDCI, HOAt, DIPEA, DMF, temperatura ambiente 1,40 min (B) 460,5
Ejemplo 3-3
4-(3’-clorobifenil-4-il)-3-(4-etoxi-4oxobutanamido) butanoato de (R)-bencilo imagen59 EDCI, HOAt, DIPEA, DMF, temperatura ambiente 1,56 min (B) 508,3
Ejemplo 3-4
5-(4-(benciloxi)-1-(3’-clorobifenil-4-il)-4oxobutan-2-ilamino)-5-oxopentanoato de (R)etilo imagen60 EDCI, HOAt, DIPEA, DMF, temperatura ambiente 1,57 min (B) 522,4
(continuación)
Ejemplo #
Producto Material de partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 3-5
4-(1-(3’-cloro-3-fluorobifenil-4-il)-4-etoxi-4oxobutan-2-ilamino)-4-oxobutanoato de tercbutilo imagen61 EDCI, HOAt, DMF, temperatura ambiente 1,46 min (B) 492,5
imagen62
==
imagen63
imagen64
=
=
imagen65
== =
imagen66
==
=
imagen67
Ejemplo #
Producto Material de partida Condición HPLC-RT (condición) MS (M+1)
Ejemplo 4-4
Ácido (R)-2-(tert-butoxicarbonil(2-(1-(3’-cloro bifenil-4-il)-4-etoxi-4-oxobutan-2-ilamino)-2oxoetil)amino)acético imagen68 EDCI, HOAt, DIPEA, DMF, temperatura ambiente 1,53 min (A) 533.2
Ejemplo 4-5
Ácido 4-(3’-clorobifenil-4-il)-3-(4-etoxi-4oxobutanamido) butanoato de (R)-butanoico imagen69 EDCI, HOAt, DIPEA, DMF, temperatura ambiente 1,00 min (B) 416,1
imagen70
(continuación)
imagen71
imagen72
(continuación)
Ejemplo
Producto Material de partida Condición HPLC-RT MS
de hidrólisis
(condición) (M+1)
NaOH
Ejemplo 5-16
acuoso, THF, MeOH, temperatura ambiente 1.44 min. (H) 386.2
Ácido (R)-4-(1-carboxi-3-(3’metoxibifenil-4-il)propan-2ilamino)-4-oxobutanoico
Ejemplo 2-14
NaOH
Ejemplo 5-17
acuoso, THF, MeOH, temperatura ambiente 0.49 min. (B) 381.1
Ácido (R)-4-(1-carboxi-3-(3’cianobifenil-4-il)propan-2-ilamino)4-oxobutanoico
Ejemplo 2-15
NaOH
Ejemplo 5-18
acuoso, THF, MeOH, temperatura ambiente 1.02 min. (B) 408.1
Ácido (R)-4-(1-carboxi-3-(3’-cloro5’-fluorobifenil-4-il)propan-2ilamino)-4-oxobutanoico
Ejemplo 2-16
NaOH
Ejemplo 5-19
acuoso, THF, MeOH, temperatura ambiente 0.53 min. (B) 424.0
Ácido (R)-4-(1-carboxi-3-(2’(trifluorometil)bifenil-4-il)propan-2ilamino)-4-oxobutanoico
Ejemplo 2-17
NaOH
Ejemplo 5-20
Ácido (R)-4-(1-carboxi-3-(2’cianobifenil-4-il)propan-2-ilamino)4-oxobutanoico Ejemplo 2-18 acuoso, THF, MeOH, temperatura ambiente 1.11 min. (A) 381.1
imagen73
imagen74
=
=
=
=
imagen75
imagen76
Condición de hidrólisis
LCMS-RT (condición) MS (M+1)
NaOH acuoso, MeOH, temperatura ambiente
1.52 min. (D) 420.1
NaOH acuoso, MeOH, temperatura ambiente
1.42 min. (D) 390.2
NaOH acuoso, MeOH, temperatura ambiente
1.53 min. (D) 420.2
NaOH acuoso, MeOH, temperatura ambiente
1.26 min. (A) 389.3
imagen77
(continuación) (continuación)
Ejemplo #
Producto Material de partida Condición de hidrólisis LCMS-RT (condición) MS (M+1)
Ejemplo 5-29
ÁcidoR-4-(1-carboxi-3-(3’-trifluorometoxi)bifenil-4-il)propan-2ilamino)-4-oxobutanoico imagen78 NaOH acuoso, MeOH, temperatura ambiente 1.57 min. (D) 440.1
Ejemplo 5-30
ÁcidoR-4-(1-carboxi-3-(2’-trifluorometoxi)bifenil-4-il)propan-2ilamino)-4-oxobutanoico imagen79 NaOH acuoso, MeOH, temperatura ambiente 1.41 min. (D) 440.0
Ejemplo 5-31
ÁcidoR-4-(1-carboxi-3-(2’-hidroxibifenil-4-il)propan-2ilamino)-4-oxobutanoico imagen80 NaOH acuoso, MeOH, temperatura ambiente 1.16 min (D) 373.2
Ejemplo 5-32
ÁcidoR-4-(1-carboxi-3-(2’,3’-difluoro-6’-metoxibifenil-4il)propan-4-ilamino)-4-oxobutanoico imagen81 NaOH acuoso, MeOH, temperatura ambiente 1.34 min. (D) 422.2
Ejemplo #
Producto Material de partida Condición de hidrólisis LCMS-RT (condición) MS (M+1)
Ejemplo 5-33
ÁcidoR-4-(1-carboxi-3-(3-fluoro-metoxibifenil-4-il)propan-2ilamino)-4-oxobutanoico imagen82 NaOH acuoso, MeOH, temperatura ambiente 1.29 min (D) 404.1
Ejemplo 5-34
ÁcidoR-4-(1-carboxi-3-(4-piridina-2’-il)fenil)propan-2-ilamino)4-oxobutanoico imagen83 NaOH acuoso, MeOH, temperatura ambiente 1.43 min. (D) 356.2
Ejemplo 5-35
ÁcidoR-4-(1-carboxi-3-(3’,5’-difluoro-2’-metoxibifenil-4il)propan-2-ilamino)-4-oxobutanoico imagen84 NaOH acuoso, MeOH, temperatura ambiente 1.42 min (D) 422.0
-
imagen85
=
imagen86
7.62 (m, 2H), 7.71 (m, 1 H), 12.07 (s, 1 H). Ejemplo 9-1: Síntesis del ácido (R)-4-(1-carboxi-3-(3'-clorobifenil-4-il)propan-2-ilamino)-4-oxobutanoico
imagen87
A una solución del ácido (R)-4-(1-(bifenil-4-il)-4-etoxi-4-oxobutan-2-ilamino)-4-oxobutanoico (110 mg, 0,263 Mmol) en THF (2 ml) y metanol (0,2 ml), se le añade solución acuosa 1 M de NaOH (1,053 ml, 1,053 mmol) a temperatura ambiente. Después de agitar durante 1 hora, la reacción se detiene con HCl acuoso 0,1 M, y la solución se diluye 10 con DCM (15 ml) y se deja agitar durante 1,5 horas. El sólido precipitado se recoge en un embudo, se lava con agua, DCM, heptano y luego DCM en ese orden, y se seca a presión reducida para producir el ácido (R)-4-(1carboxi-3-(3'-clorobifenil-4-Il)propan-2-ilamino)-4-oxobutanoico (66 mg). Tiempo de retención de HPLC = 0,87 minutos (condición B); MS (m + 1) = 390,0; 1H NMR (400 MHz, CD3OD) δ ppm 2.39 -2.55 (m, 6 H) 2.86 (A de ABX, Jab = 13.6 Hz, Jax = 7.6 Hz, 1 H) 2.92 (B de ABX, Jab = 13.6 Hz, Jbx = 6.2 Hz, 1 H) 4.42 -4.49 (m, 1 H) 7.30 -7.34 (m, 3
15 H) 7.40 (t, J = 7.4Hz, 1 H) 7.51 -7.56 (m, 3 H) 7.60 (t, J = 1.8 Hz, 1 H).
Los siguientes compuestos se preparan usando un procedimiento similar al descrito en el ejemplo 9-1:
Ejemplo
Producto Material de partida Condición de HPLC-RT MS
#
hidrólisis (condición) (M+1)
Ejemplo 9-2
NaOH acuoso, THF, MeOH, 0,79 min (B) 404.1
temperatura ambiente
Ácido (R)-5-(1-carboxi-3-(3’-clorobifenil -4-il)propan-2-ilamino)-5-oxopentanoico
Ejemplo 9-3
imagen88 imagen89 NaOH acuoso, THF, MeOH, temperatura ambiente 0,65 min (B) 418.2
Ácido (R)-5-(1-carboxi-3-(5’-fluoro-2’metoxibifenil-4-il)propan-2-ilamino)-5oxopentanoico
Ejemplo 9-4
imagen90 imagen91 NaOH acuoso, THF, MeOH, temperatura ambiente 0,63 min (B) 434.3
Ácido (R)-5-(1-carboxi-3-(5’-cloro-2’metoxibifenil-4-il)propan-2-ilamino)-5oxopentanoico
imagen92
imagen93
(continuación)
Ejemplo
Producto Material de partida Condición de HPLC-RT MS
#
hidrólisis (condición) (M+1)
Ejemplo 9-15
imagen94 imagen95 NaOH acuoso, MeOH, temperatura ambiente 0,96 min (A) 420.1
(producto principal) Ácido (R)-3-(3Carboxipropionilamino)-4-(3’clorobifenil-4-il)-2-metoxi-butírico
imagen96
Ejemplo 9-16
imagen97 NaOH acuoso, MeOH, temperatura ambiente 1,07 min (A) 408.1
Ácido (R)-3-(3-Carboxipropionilamino)4-(3’-clorobifenil-4-il)-2-fluoro-butírico
imagen98
Ejemplo 9-17
imagen99 imagen100 NaOH acuoso, MeOH, temperatura ambiente 0,53 min (B) 404
Ácido (R)-3-(3-Carboxipropionilamino)4-(3’-clorobifenil-4-il)-2-metil-butírico
Ejemplo 9-18
imagen101 imagen102 NaOH acuoso, MeOH, temperatura ambiente 0,37 min (B) 406
Ácido (R)-3-(2-carboximetoxiacetilamino)-4-(3’-clorobifenil-4-il)-butírico
Ejemplo 9-2: 1H RMN (400 MHz, CD3OD) δ ppm 1.76 -1.83 (m, 2 H) 2.15 -2.21 (m, 4 H) 2.49 (A de ABX, Jab = 15.7 Hz, Jax = 7.3 Hz, 1 H) 2.53 (B de ABX, Jab = 15.7 Hz, Jbx = 6.1 Hz, 1 H) 2.83 (A de ABX, Jab = 13.6 Hz, Jax = 8.3 Hz, 1 H) 2.93 (B de ABX, Jab = 13.6 Hz, Jbx = 5.8 Hz, 1 H) 4.46 -4.53 (m, 1 H) 7.30 -7.33 (m, 3 H) 7.39 (t" J = 7.8 Hz, 1 H)
7.51 -7.55 (m, 3 H) 7.59 -7.60 (m, 1 H). Ejemplo 9-3: 1H RMN (400 MHz, CD3OD) δ ppm 1.77 -1.84 (m, 2 H) 2.16 -2.23 (m ,4 H) 2.39 -2.42 (m, 2 H) 2.49
81
imagen103
imagen104
imagen105
Ejemplo #
Producto Material de partida HPLC-RT (condición) MS (M+1)
Ejemplo 12-2
Ácido N-[(R)-1-(3’-cloro-bifenil-4-ilmetil)-3-oxo-3(propano-1-sulfonilamino)-propil]-succinámico imagen106 1,26 min (condición A) 495
Ejemplo 12-3
Ácido N-[(R)-1-(3’-cloro-bifenil-4-ilmetil)-3-oxo-3fenilmetanosulfonil aminopropil]-succinámico imagen107 1,34 min (condición A) 543
Ejemplo 12-4
Ácido N-[(R)-2-carbamoil-1-(3’-cloro-bifenil-4ilmetil)-etil]-succinámico imagen108 1,33 min (condición A) 389
imagen109
imagen110
(continuación)
Intermediario #
Producto Condición HPLC-RT (condición) MS (ES+; 100%)
Intermediario 2-3
3-(tert-butoxicarbonilamino)-4-(5’cloro-2’-metoxibifenil-4-il)butanoato de (R)-etilo Complejo de PdCl2(dppf).CH2Cl2, ácido 5cloro-2-metoxifenilborónico, Na2CO3 2M acuoso, tolueno, 95°C 1.58 min. (B) 348.1 (m-BOC+2)
Intermediario 2-4
3-(tert-butoxicarbonilamino)-4-(5’fluoro-2’-metoxibifenil-4-il)butanoato de (R)-etilo Complejo de PdCl2(dppf).CH2Cl2, ácido 5fluoro-2-metoxifenilborónico, Na2CO3 2M acuoso, tolueno, 95°C 1.42 min. (B) 332.2 (m-BOC+2)
Intermediario 2-5
3-(tert-butoxicarbonilamino)-4-(2’cloro-5’-fluorobifenil-4-il)butanoato (R)-etilo Pd(PPh3)4, ácido 2-cloro-5fluorofenilborónico, Na2CO3 2M acuoso, tolueno, 95 °C 1.49 min. (B) 336.1 (m-BOC+2)
Intermediario 2-6
3-(tert-butoxicarbonilamino)-4-(5’cloro-2’-fluorobifenil-4-il)butanoato de (R)-etilo Pd(PPh3)4, ácido 5-cloro-2fluorofenilborónico, Na2CO3 2M acuoso, DME, 95 °C 1.47 min. (B) 336.1 (m-BOC+2)
88
imagen111
CLOROFORMO-d) δ ppm 1.41 (s, 9 H) 1.47 (s, 9 H) 2.36 (A de ABX, Jab = 15.6 Hz, Jax = 6.2 Hz, 1 H) 2.44 (B de ABX, Jab = 15.5 Hz, Jbx = 5.45 Hz) 2.82-2.97 (m, 2 H) 4.15 (br s) 5.09 (br d) 7.6-7.35 (m, 3H) 7.41-7.45 (m, 2 H) 7.51-7.56 (m, 4 H).
Intermediario 5: 4-(4-bromofenil)-3-(tert-butoxicarbonilamino)butanoato de (R)-etilo
imagen112
5
A una suspensión de ácido (R)-4-(4-bromofenil)-3-(tert-butoxicarbonilamino)butanoico (9.98 g, 27.9 mmol) y NaHCO3
(4.68 g, 55.7 mmol) en DMF (45 mL) se agrega yoduro de etilo (6.75 mL, 84 mmol) a temperatura ambiente bajo nitrógeno. Después de agitar durante 71 horas, la mezcla de reacción es detenida con H2O (300 mL), y luego el sólido precipitado se recolecta y se lava con H2O (500 mL) para producir 4-(4-bromofenil)-3-(tert
10 butoxicarbonilamino)butanoato de (R)-etilo (10,25 g, 94%). Tiempo de retención de HPLC = 1.48 minutos (condición B); MS (ES+) = 329.9 (m-tBu+2); 286.0 (m-Boc+2; 100%); 1 H RMN (400 MHz, CLOROFORMO-d) δ ppm 1.27 (t, J =
7.2 Hz, 3 H) 1.40 (s, 9 H), 2.43 (A de ABX, Jab = 15.8 Hz, Jax = 5.7 Hz, 1 H) 2.50 (B de ABX, Jab = 15.8 Hz, Jbx = 5.4 Hz, 1 H) 2.74-2.90 (m, 2 H) 4.11 (br s) 4.15 (q, J = 7.1 Hz, 2 H) 5.04 (br d) 7.07 (d, J = 8.3 Hz, 2 H) 7.40-7.43 (m, 2 H).
15 Los siguientes intermediarios se preparan usando el procedimiento similar al descrito en el intermediario 5:
Intermediario #
Producto Condición HPLC-RT (condición) MS (ES+; 100%)
Intermediario 5-2
4-(4-bromofenil)-3-(tertbutoxicarbonilamino)butanoato de (R)-bencilo BnBr, NaHCO3, DMF, Temperatura ambiente 1.56 min. (B) 348 (m-BOC+2)
Intermediario 5-3
Propil éster del ácido (R)-4-(4-Bromo-fenil)-3tert-Butoxicarbonilamino-butírico yoduro de npropilo, NaHCO3, DMF, Temperatura ambiente 1.47 min. (B) 400 (m+1)
Intermediario 5-4
Butil éster del ácido (R)-4-(4-Bromo-fenil)-3-tertButoxicarbonilamino-butírico Yoduro de nbutilo, NaHCO3, DMF, Temperatura ambiente 1.55 min. (B) 414 (m+1)
90
(continuación)
Intermediario #
Producto Condición HPLC-RT (condición) MS (ES+; 100%)
Intermediario 5-5
5-metil-2-oxo-[1,3]dioxol-4-ilmetil éster del ácido (R)-4-(4-Bromo-fenil)-3-tert-butoxicarbonilaminobutírico K2CO3, DMF, Temperatura ambiente 1.28 min. (B) 470 (m+1)
Intermediario 5-6
Dimetilcarbamoil metil éster del ácido (R)-4-(4Bromo-fenil)-3-tert-butoxicarbonilamino-butírico K2CO3, DMF, Temperatura ambiente 1.65 min. (B) 444 (m+1)
Intermediario 5-7
2-morfolin-4-il-etil éster del ácido (R)-4-(4Bromo-fenil)-3-tert-butoxicarbonilamino-butírico K2CO3, DMF, Temperatura ambiente 1.19 min. (B) 471 (m+1)
Intermediario 5-2: 4-(4-bromofenil)-3-(tert-butoxicarbonilamino)butanoato de (R)-bencilo
imagen113
5 A una suspensión de ácido (R)-4-(4-bromofenil)-3-(tert-butoxicarbonilamino)butanoico (5.02 g, 14.01 mmol) y NaHCO3 (3.53 g, 42.0 mmol) en DMF (20 mL) se agrega Bromuro de bencilo (5.10 mL, 42 mmol) a temperatura ambiente bajo nitrógeno. Después de agitar durante 46 horas, la reacción se diluye con H2O (200 mL), y luego el sólido precipitado se recolecta y se lava con H2O (500 mL) y luego con heptano (200 ml) para producir 4-(4bromofenil)-3-(tert-butoxicarbonilamino)butanoato de (R)-bencilo (5.61 g, 89%). Tiempo de retención de HPLC = 1.56
10 minutos (condición B); MS (ES+) = 392.1 (m-tBu+2); 348.1 (m-Boc+2; 100%); 1 H RMN (400 MHz, CLOROFORMOd) δ ppm 1.39 (s, 9 H) 2.48 (A de ABX, Jab = 15.9 Hz, Jax = 5.6 Hz, 1 H) 2.54 (B de ABX, Jab = 15.9 Hz, Jbx = 5.3 Hz, 1 H) 2.72-2.88 (m, 2 H) 4.11 (br s, 1 H) 5.02 (br s, 1 H) 5.10 (A de AB, J = 12.1 Hz, 1 H) 5.16 (A de AB, J = 12.1 Hz, 1 H) 7.00 (d, J = 8.1 Hz, 2 H) 7.34-7.39 (m, 7 H).
Intermediario 6: Ácido (R)-3-(bifenil-4-ilmetil)-4-(3-metoxi-3-oxopropilamino)-4-oxobutanoico
91
imagen114
imagen115
imagen116
imagen117
imagen118
imagen119
Intermediario #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Intermediario 16-2
Clorhidrato de 3-amino-4-(bifenil-4-il)butanoato de (R)-etilo Intermediario 2 HCl 4M/1,4-dioxano 0,89 min. (B) 284.1
Intermediario 16-3
Clorhidrato de 3-amino-4-(3’-fluorobifenil-4-il)butanoato de (R)-etilo Intermediario 2-2 HCl 4M/1,4-dioxano 0,94 min. (B) 302.1
Intermediario 16-4
Clorhidrato de 3-amino-4-(5’-cloro-2’-metoxibifenil-4-il)butanoato de (R)-etilo Intermediario 2-3 HCl 4M/1,4-dioxano 0,94 min. (B) 348.2
Intermediario 16-5
Clorhidrato de 3-amino-4-(5’-fluoro-2’-metoxibifenil-4-il)butanoato de (R)-etilo Intermediario 2-4 HCl 4M/1,4-dioxano 1.38 min. (A) 332.2
(continuación)
Intermediario #
Producto Material de Partida Condición HPLC-RT (condición) MS (M+1)
Intermediario 16-6
Clorhidrato de 3-amino-4-(2’-cloro-5’-fluorobifenil-4-il)butanoato de (R)-etilo Intermediario 2-5 HCl 4M/1,4-dioxano 0,93 min. (B) 336.1
Intermediario 16-7
3-amino-4-(3’-clorobifenil-4-il)butanoato de (R)-bencilo Intermediario 17-2 HCl 4M/1,4-dioxano 1.20 min. (B) 380,2
Intermediario 16-8
3-amino-4-(5’-cloro-2’-fluorobifenil-4-il)butanoato de (R)-etilo Intermediario 2-6 HCl 4M/1,4-dioxano 0,88 min. (B) 336.1
imagen120
Intermediario #
Producto Condición HPLC-RT (condición) MS (ES+; 100%)
Intermediario 17-2
3-(tert-butoxicarbonilamino)-4-(3’clorobifenil-4-il)butanoato de (R)bencilo Pd(PPh3)4, ácido 3clorofenilborónico, Na2CO3 2M acuoso, tolueno, 95 °C 1.74 min. (B) 380,2 (m-BOC+2)
Intermediario 17-3
Propil éster del ácido (R)-3-tertButoxicarbonilamino-4-(3’clorobifenil-4-il)-butírico Pd(PPh3)4, ácido 3clorofenilborónico, Na2CO3 2M acuoso, tolueno, 95 °C 1.66 min. (B) 432 (m+1)
Intermediario 17-4
Butil éster del ácido (R)-3-tertButoxicarbonilamino-4-(3’-clorobifenil-4-il)-butírico Pd(PPh3)4, ácido 3clorofenilborónico, Na2CO3 2M acuoso, tolueno, 95 °C 1.73 min. (B) 446 (m+1)
Intermediario 17-5
5-metil-2-oxo-[1,3]dioxol-4-ilmetil éster del ácido (R)-3-tertButoxicarbonilamino-4-(3’clorobifenil-4-il)-butírico Pd(OAc)2, diciclohexil-(2’,6’dimetoxi-bifenil-2-il)-fosfano, ácido 3-clorofenilborónico, K3PO4, tolueno, 95 °C 1.53 min. (B) 502 (m+1)
Intermediario 17-6
dimetilcarbamoil metil éster del ácido (R)-3-tertButoxicarbonilamino-4-(3’clorobifenil-4-il)-butírico Pd(PPh3)4, ácido 3clorofenilborónico, K3PO4, DMF, 95 °C 1.51 min. (B) 475 (m+1)
101
imagen121
imagen122
imagen123
imagen124
imagen125
imagen126
imagen127
imagen128
imagen129
imagen130
imagen131
imagen132
imagen133
mezcla de reacción se acidifica con HCl 1 M y se extrae con EtOAc. La capa orgánica se lava con salmuera, se seca sobre Na2SO4 y se concentra in vacuo. A una solución de este residuo en DMF (2 mL) se agregan metilsulfonamida (85 mg, 0,897 mmol), EDC (172 mg, 0,897 mmol), HOAt (98 mg, 0,718 mmol), y Et3N (0,125 mL, 0,897 mmol). Después de ser agitada a temperatura ambiente durante la noche, la mezcla de reacción se diluye con EtOAc, se 5 lava con HCl 1 M y salmuera. La capa orgánica se seca sobre Na2SO4 y se concentra. El residuo se purifica por cromatografía de columna instantánea (sílica gel, eluyente: DCM/MeOH al 10% en DCM = 100:0 a 0:100) para producir tert-butil éster del ácido [(R)-1-(3’-cloro-bifenil-4-ilmetil)-3-metanosulfonilamino-3-oxo-propil]-carbámico (244 mg). Tiempo de retención de HPLC = 1.30 minutos (condición B); MS (m+1) = 467; 1 H RMN (400 Mz, DMSO-d6) δ ppm 1.30 (s, 9 H), 2.41-2.48 (m, 2 H), 2.70-2.78 (m, 2 H), 3.18 (s, 3 H), 3.99-4.11 (m, 1 H), 7.28 (d, 2 H, J = 8.34 Hz),
10 7.38-7.44 (m, 1 H), 7.48 (t, 1 H, J =7.83 Hz), 7.59-7.66 (m, 3 H), 7.69 (s, 1 H).
Los siguientes compuestos se preparan usando un procedimiento similar al descrito en el ejemplo 53-1:
Ejemplo
Producto Reactivo HPLC-RT (condición) MS (M+1)
Ejemplo 53-2
imagen134 imagen135 1.22 min. (condición B) 496
Ejemplo 53-3
imagen136 imagen137 1.33 min. (condición B) 544
Ejemplo 53-4
imagen138 NH4Cl 1.17 min. (condición B) 389
Intermediario 54-1: etil éster del ácido (R)-3-[2-(tert-butoxicarbonil-etoxicarbonilmetil-amino)-propionilamino]-4-(3’clorobifenil-4-il)-butírico
imagen139
A una suspensión de sal de TFA del ácido 2-(tert-butoxicarbonil-etoxicarbonilmetil-amino)-propiónico (197 mg, 0,714 mmol) en THF (10 ml) a temperatura, ambiente se agrega EDCI (219 mg, 1.142 mmol) y HOBT (164 mg, 1.071 mmol). La mezcla se agita a temperatura ambiente durante 10 minutos y luego se agrega una solución de etil éster del ácido (R)-3-amino-4-(3’-cloro-bifenil-4-il)-butírico (202 mg, 0,571 mmol) en THF y TEA (0,199 ml, 1.428 mmol). La
20 mezcla se agita a temperatura ambiente. HPLC en fase reversa [30 a 90% de ACN-H2O (TFA al 0,1%) durante 10 minutos mediante columna de fenilo de X-Bridge] da el compuesto del título (290 mg, rendimiento del 71%). LCMS (condición B): 575 (M+1): tiempo de retención = 1.52 minutos.
115
imagen140

Claims (1)

  1. imagen1
    imagen2
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CO6470847A2 (es) 2012-06-29
CL2011002990A1 (es) 2012-08-31
TWI445530B (zh) 2014-07-21
ZA201108222B (en) 2012-07-25
CA2763572C (en) 2017-10-17
ES2602826T3 (es) 2017-02-22
JO2962B1 (en) 2016-03-15
AU2010251967A1 (en) 2011-12-08
DK2435409T3 (da) 2014-10-27
EP2594557B1 (en) 2016-08-10
EP2594556B1 (en) 2016-08-10
EP2435409B1 (en) 2014-08-13

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