ES2598961T3 - Derivados de ácido carbamoilmetoxiacético sustituido como inhibidores novedosos de NEP - Google Patents

Derivados de ácido carbamoilmetoxiacético sustituido como inhibidores novedosos de NEP Download PDF

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ES2598961T3
ES2598961T3 ES14155848.6T ES14155848T ES2598961T3 ES 2598961 T3 ES2598961 T3 ES 2598961T3 ES 14155848 T ES14155848 T ES 14155848T ES 2598961 T3 ES2598961 T3 ES 2598961T3
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alkyl
ethylamino
tetrazol
biphenyl
ylcarbamoyl
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Yuki Iwaki
Toshio Kawanami
Gary Michael Ksander
Muneto Mogi
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Novartis AG
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Abstract

Un compuesto de la fórmula (I'):**Fórmula** en la que: X1 es OH, alquilo -O-C1-7, -NRaRb, alquilo-C1-7-NHS(O)2 o bencilo -NHS(O)2-, en la que Ra y Rb para cada evento son independientemente H o alquilo C1-7; R1 es H, alquilo C1-6 o arilo C6-10-alquilo-C1-6, en la que alquilo es sustituido opcionalmente con benciloxi, hidroxi o alcoxi C1-6; para cada evento, R2 es independientemente alcoxi C1-6, hidroxi, halógeno, alquilo C1-6, ciano o trifluorometilo; A2 es O; R4 es H o alquilo C1-6; A1 es un enlace o cadena de alquileno C1-3; R3 es un heteroarilo de 5 o 6 miembros, arilo C6-10 o cicloalquilo C3-7, en la que cada heteroarilo, arilo o cicloalquilo están opcionalmente sustituidos con uno o más grupos seleccionados independientemente del grupo consistente en alquilo C1-6, halógeno, haloalquilo C1-6, alcoxi C1-6, hidroxi, CO2H y alquilo C1-6CO2; R6 para cada evento es independientemente halógeno, hidroxi, alcoxi C1-7, alquilo C1-7 o halo- alquilo C1-7; o R4. A1- R3, junto con el nitrógeno al cual están unidos R4 y A1-R3, forman un heterociclilo con 4 a 7 miembros o un heteroarilo con 5 a 6 miembros, cada uno de los cuales está opcionalmente sustituido con uno o más grupos seleccionados independientemente del grupo consistente en alquilo C1-6, halógeno, halo alquilo C1-6, alcoxi C1-6, hidroxi, CO2H y alquilo C1-6 CO2; y m es 0 o un número entero de 1 a 5; s es 0 o un número entero de 1 a 4; o una sal del mismo farmacéuticamente aceptable.

Description

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secreción ácida gástrica, hiperreninemia, fibrosis quística, restenosis, diabetes tipo 2, síndrome metabólico, complicaciones diabéticas y aterosclerosis, disfunción sexual masculina y femenina.
Ejemplificación de la invención:
Se pretende que los siguientes ejemplos ilustren la invención y no debe interpretarse que son limitaciones de ella.
5 Las temperaturas son dadas en grados centígrados. Si no se menciona de otro modo, todas las evaporaciones son ejecutadas bajo presión reducida, típicamente entre aproximadamente 15 mm Hg y 100 mm Hg (= 20-133 mbar). La estructura de los productos finales, materiales intermedios y de partida es confirmada por métodos analíticos estándar, por ejemplo microanálisis y características espectroscópicas, por ejemplo MS, IR, RMN. Las abreviaturas usadas son aquellas convencionales en la técnica. Todos los materiales de partida, bloques de construcción,
10 reactivos, ácidos, bases, agentes de deshidratación, solventes, y catalizadores utilizados para la síntesis de los compuestos de la presente invención están bien sea disponibles comercialmente o pueden ser producidos por métodos de síntesis orgánica conocidos por alguien de destreza ordinaria en la técnica (Houben-Weyl 4ª edición 1952, Methods of Organic Synthesis, Thieme, volumen 21). Además, los compuestos de la presente invención pueden ser producidos por métodos de síntesis orgánica conocidos por alguien de destreza ordinaria en la técnica,
15 como se muestra en los siguientes ejemplos.
Ejemplificación de la invención:
Ejemplos en los que A2 no es O, son ejemplos de referencia.
Abreviaturas:
br: amplio
bs: singlete amplio
Ac: Acetilo
Atm: atmósfera
Aq: acuoso
calcd: calculado
Bn: bencilo
Boc: tert-butoxicarbonil
d: doblete
dd: doblete de dobletes
DCM: diclorometano
DME: 1,4-dimetoxietano
DMF: N,N-dimetilformamida
DMSO: dimetilsulfóxido
DAD: detector de arreglo de diodos
DTT: ditiotreitol
EDTA: ácido etilendiamino tetra acético
ESI: ionización por electroatomización
Et y EtOAc: etilo y acetato de etilo
HATU: O-(7-azobenzotriazol-1-il)-1,1,3,3tetrametiluronio hexafluorofosfato
HOBt: 1-hidroxi-7-azabenzotriazol
HPLC: cromatografía líquida de alta presión HPLC-RT: cromatografía líquida de alta presión -tiempo de retención
LC y LCMS: cromatografía líquida y cromatografía líquida y espectrometría de masas
H: hora(s)
IR: infrarrojo
MeOH: metanol
MS: espectrometría de masas
m: multiplete
min: minutos
Me: metilo
m/z: relación masa a carga
M y mM: Molar y milimole(s)
Mg: miligramo
n.d.: no determinado
RMN: resonancia magnética nuclear
PMBCl: cloruro de para-metoxibencilo
Pr e iPr: propilo e isopropilo
ppm: partes por millón
Pd/C: Paladio sobre carbón
Ph: Fenilo
q: cuarteto
RP: fase inversa
RT: temperatura ambiente
s: singlete
t: triplete
TFA: ácido trifluoroacético
THF: tetrahidrofurano
23
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imagen23
Ejemplo 1-2
(S)-2-[(S)-2-(2’,5’-dicloro-bifen il-4-il)-1(1H-tetrazol-5-ilcarbamoil)-etilamino]propionato de tert –butilo Ácido (S)-2-((S)-1-tertbutoxicarbonil-etilamino)3(2’,5’-diclorobifenil-4-il)propiónico y 5-amino-1H-tetrazole 1.38 min (C) 505
Ejemplo 1-3
(S)-2-[(S)-2-bifenil-4-il-1-(1H-tetrazol-5ilcarbamoil)-etilamino]-propionato de etilo Acido (S)-3-bifenil-4-il-2-((S)1-etoxi carboniletilamino)propiónico y 5-amino-1H-tetrazole 1.55 min (A) 409
Ejemplo 1-4
(S)-2-[(S)-2-(5’-fluoro-2’-metoxibifenil-4-il)1-(1H-tetrazol-5-ilcarbamoil)-etilamino]propionato de tertbutilo Acido (S)-2-((S)-1-tertbutoxicarboniletilamino)-3-(5’fluoro-2’-metoxi-bifenil-4-il)propiónico y 5-amino-1H-tetrazole 1.27 min (C) 485
Ejemplo 1-5
5-[(S)-3-bifenil-4-il-2-((S)1tertbutoxicarboniletilamino)propionilamino]1H-pirazole-3-carboxilato de metilo Acido (S)-3-bifenil-4-il-2-((S)1tertbutoxicarboniletilamino)propiónico y 5-amino-1H-pirazole-3carboxilato de metilo 1.49 min (C) 493
26
Ejemplo 1-6
(S)-2-[(S)-2-(3’-clorobifenil-4-il)-1-(3hidroxiisoxazol-5-ilcarbamoil)-etilamino]propionato de ter-butilo Acido (S)-2-((S)-1-tertbutoxicarbonil-etilamino)-3-(3’clorobifenil-4-y l)-propiónico y 5-amino-isoxazol-3-ol 1.48 min (C) 486
Ejemplo 1-7
(S)-2-[(S)-2-(3’-clorobifenil-4-il)-1-(1-metil1 H-tetrazol-5-ilcarbamoil)-etilamino]propionato de etilo Acido (S)-3-(3’-clorobifenil-4il)-2-((S)-1etoxicarboniletilamino)propiónico y 1-metil-1H-tetrazol-5-ilamine 1.12 min (C) 457
Ejemplo 1-8
(S)-2-[(S)-2-(3’-Clorobifenil-4-il)-1-(1Htetrazol-5-ilcarbamoil)-etilamino]-4fenilbutirato de etilo (S)-2-[(S)-1-carboxi-2-(3’clorobifenil-4-il)-etilamino]-4fenil-butirato de etilo y 5-amino-1H-tetrazole 1.47 min. (C) 533,4
Ejemplo 1-9
(S)-2-[(S)-2-(3’-Clorobifenil-4-il)-1-(1Htetrazol-5-ilcarbamoil)-etilamino]-butirato de tertbutilo (S)-2-[(S)-1-carboxi-2-(3’clorobifenil-4-il)-etilamino]butirato de tertbutilo y 5-amino-1H-tetrazole 1.27 (C) 485
27
imagen24
Ejemplo 112
(S)-3-benciloxi-2-[(S)-2-(3’-clorobifenil-4-il)1-(1H-tetrazol-5-ilcarbamoil)-etilamino]propionato de etilo Acido (S)-2-((S)-2-benciloxi-1etoxicarbonil-etilamino)-3-(3’-clorobifenil-4-il)-propiónico y 5-amino-1H-tetrazole 1.31 min (C) 549
Ejemplo 113
(S)-2-[(S)-2-(3’-clorobifenil-4-il)-1-(1Htetrazol-5-ilcarbamoil)-etilamino]-3metoxipropionato de etilo (S)-3-(3’-clorobifenil-4-il)-2-((S)-1etoxicarbonil-2-metoxi-etilamino)propiónico Y 5-amino-1H-tetrazole 1.29 min (A) 471

Ejemplo 1-14: (S)-2-[(S)-2-(3’-cloro-bifenil-4-il)-1-(1H-tetrazol-5-ilcarbamoil)-etoxi]-propionato de etilo
imagen25
A una solución de ácido (S)-3-(3’-cloro-bifeni)-4-il)-2-((S)-1-etoxicarbonil-etoxi)-propiónico (62 mg, 0.165 mmol) en
5 TF (5 ml) a temperatura ambiente, se añadieron 5-aminotetrazole (38.0 mg, 0.447 mmol), DIPEA (0.086 ml, 0.494 mmol) seguidos por 1,3-diisopropilcarbodiimida (0.060 ml, 0.387 mmol). Se agitó la reacción a temperatura ambiente por 3 horas. Se detuvo la reacción con salmuera y se realizó extracción con EtOAc. Se lavó con salmuera la capa orgánica combinada y se secó sobre sulfato de sodio anhidro, se filtró y se concentró. Tiempo de retención en HPLC = 0.99 minutos (condición C); MS (m+1) = 444.
10 Ejemplo 2-1: (S)-2-[(R)-2-(3’-cloro-bifenil-4-il)-1-(1H-tetrazol-5-ilcarbamoil)-etilamino]-propionato de etilo
imagen26
El isómero cis obtenido del procedimiento descrito en el Ejemplo 1-1 fue aislado mediante HPLC de fase inversa (columna Sunfire C-18, TFA 0.1% en H2O / CH3CN) para suministrar (S)-2-[(R)-2-(3’-cloro-bifenil-4-il)-1-(1H-tetrazol5-ilcarbamoil)-etilamino]-propionato de etilo; 1H RMN (400MHz, DMSO-d6) δ1.07 (t, 3H, J = 7.1 Hz), 1.12 (d, 3H, J =
15 6.8 Hz), 2.88 (dd, 1H, J = 8.1, 13.6 Hz), 3.04 (dd, 1H, J = 6.1, 13.6 Hz), 3.18-3.26 (m, 1H), 3.69-3.78 (m, 1H), 3.87
29
4.03 (m, 2H), 7.35 (d, 2H, J = 8.1 Hz), 7.37-7.42 (m, 1H), 7.47 (dd, 1H, J = 7.8, 7.8 Hz), 7.58-7.65 (m, 3H), 7.68-7.72 (m, 1H); MS: m/z (MH+) 443.
Se prepararon los siguientes compuestos usando un procedimiento similar al ejemplo 1-1 y 2-1 con intermedios apropiados:
# de ejemplo
Producto Intermediarios HPLC-RT (condición) MS (M+1)
Ejemplo 22
(S)-2-[(R)-2-(2’,5’-dicloro-bifen il-4-il)-1-(1Htetrazol-5-ilcarbamoil)-etilamino]-propionato de tert–butilo Acido (S)-2-((S}-1-tertbutoxicarboniletilamino)-3-(2’,5’diclorobifenil-4-il)-propiónico y 5-amino-1H-tetrazole 1.38 min (C) 505
Ejemplo 23
(S)-2-[(R)-2-(3’-clorobifenil-4-il)-1-(3-hidroxiisoxazol-5-ilcarbamoil)-etilamino]-propionato de etilo Acido (S)-2-((S)1-tertbutoxicarboniletilamino)-3-(3’clorobifenil-4-y l)-propiónico y 5-amino-isoxazol-3-ol 1.46 min (C) 486
Ejemplo 24
(S)-2-[(R)-2-(3’-clorobifenil-4-il)-1-(1-metil-1 H-tetrazol-5-ilcarbamoil)-etilamino]propionato de etilo Acido (S)-3-(3’-clorobifenil-4-il)-2((S)-1-etoxicarboniletilamino)propiónico y 1-metil-1H-tetrazol-5-ilamine 1.16 min (C) 457

Ejemplo 3-1: Ácido (S)-2-[(S)-2-(3’-cloro-bifenil-4-il)-1-(1H-tetrazol-5-ilcarbamoil)-etilamino]-propiónico
30
imagen27
# de ejemplo
Producto Material de inicio Condición de hidrólisis HPLC-RT (condición) MS (M+1)
Ejemplo 3-3
imagen28 TFA, trietilsilano, DCM,tempe ratura ambiente 1.30 min. (A) 449
Ácido (S)-2-[(R)-2-(2’,5’-diclorobifeni)-4-il)-1-(1Htetrazol-5-ilcarbamo il)-etilamino]-propiónico
(S)-2-[(R)-2-(2’,5’-dicloro-bifen il4-il)-1-(1Htetrazol-5-ilcarbamo il)etilamino]-propionato de tert butilo
Ejemplo 3-4
imagen29 LiOH 1M, NaOH aq 2M, EtOH, temperatura ambiente 1.28 min. (B) 381
Acido (S)-2-[(S)-2-bifenil-4-il-1-(1Hbifenil-4-il-1-(1Htetrazol-5ilcarbamoil)-etilamino]-propiónico
(S)-2-[(S)-2-bifenil-4-il-1-(1Htetrazol-5-ilcarbamoil)-etilamino]propionato de etilo
TFA,
Ejemplo 3-5
trietilsilano, DCM, temperatura 1.19 min. (A) 429
Acido (S)-2-[(S)-2-(5’-fluoro-2’metoxibifenil-4-il)-1-(1Htetrazol-5ilcarbamoil)-etilamino]-propiónico
(S)-2-[(S)-2-(5’-fluoro-2’metoxibifenil-4-il)-1-(1H-tetrazol5-ilcarbamoil)-etilamino]propionato de tert-butilo ambiente
NaOH 2M
aq, EtOH,
Ejemplo 3-6
Acido 5-[(S)-3-bifenil-4-il-2-((S)-1carboxietilamino)-propionilamino]1H-pirazole-3-carboxílico 5-[(S)-3-Bifenil-4-il-2-((S)-1-tertbutoxicarboniletilamino)propionilamino]-1H-pirazole-3carboxilato de metilo temperatura ambiente. Seguido por TFA, DCM, temperatura ambiente 1.26 min. (B) 423
32
# de ejemplo
Producto Material de inicio Condición de hidrólisis HPLC-RT (condición) MS (M+1)
Ejemplo 3-7
Acido (S)-2-[(S)-2-(3’-cloro-bifenil-4il)-1-(3-hidroxiisoxazol-5-ilcarbamoil)etilamino]-propiónico (S)-2-[(S)-2-(3’-cloro-bifenil-4-il)1-(3-hidroxiisoxazol-5-ilcarba moil)-etilamino]-propionato de tert-butilo TFA, trietilsilano, DCM, temperatura ambiente 1.30 min. (A) 430
Ejemplo 3-8
Acido (S)-2-[(R)-2-(3’-cloro-bifenil-4il)-1-(3-hidroxiisoxazol-5-ilcarbamoil)etilamino]-propiónico (S)-2-[(R)-2-(3’-cloro-bifenil-4-il)1-(3-hidroxiisoxazol-5-ilcarba moil)-etilamino]-propionato de tert-butilo TFA, trietilsilano, DCM, temperatura ambiente 1.40 min. (A) 430
NaOH 2M
Ejemplo 3-9
aq, EtOH, temperatura 1.16 min. (A) 429
ambiente
Acido (S)-2-{2-(3’-clorobifenil-4-il)-1
(S)-2-{2-(3’-clorobifenil-4-il)-1
[metil-(1Htetrazol-5-il)-carbamoil]
[metil-(1Htetrazol-5-il)
etilamino}-propiónico
carbamoil]-etilamino}-propionato
de etilo
NaOH aq,
Ejemplo 3-10
2M, EtOH, temperatura 1.38 min. (A) 429
ambiente
Acido (S)-2-[(S)-2-(3’-cloro-bifenil-4il)-1-(1-metil-1Htetrazol-5ilcarbamoil)-etilamino]-propiónico
(S)-2-[(S)-2-(3’-cloro-bifenil-4-il)1-(1-metil-1H-tetrazol-5ilcarbamoil)-etilamino]-propionato etilo
NaOH 2M
Ejemplo 3-11
aq, EtOH, temperatura 1.43 min. (A) 429
ambiente
Acido (S)-2-[(R)-2-(3’-cloro-bifenil-4il)-1-(1-metil-1Htetrazol-5ilcarbamoil)-etilamino]-propiónico
(S)-2-[(R)-2-(3’-cloro-bifenil-4-il)1-(1-metil-1H-tetrazol-5ilcarbamoil)-etilamino]-propionato de etilo
33
# de ejemplo
Producto Material de inicio Condición de hidrólisis HPLC-RT (condición) MS (M+1)
NaOH aq
Ejemplo 3-12
2M, EtOH, temperatura 0.82 min. (C) 505
ambiente
Acido (S)-2-[(S)-2-(3’-cloro-bifenil-4
(S)-2-[(S)-2-(3’-cloro-bifenil-4-il)
il)-1-(1H-tetrazol-5-ilcarbamoil)
1-(1Htetrazol-5-ilcarbamoil)
etilamino]-4-fenil-butírico
etilamino]-4-fenil-butirato de etilo
Ejemplo 3-13
Acido (S)-2-[(S)-2-(3’-cloro-bifenil-4il)-1-(1H-tetrazol-5-ilcarbamoil)-etilo amino]-butírico (S)-2-[(S)-2-(3’-cloro-bifenil-4-il)1-(1Htetrazol-5-ilcarbamoil)etilamino]-butirato de tertbutilo TFA, DCM, temperatura ambiente 0.42 min. (C) 429
NaOH 2M
Ejemplo 3-14
aq, EtOH, temperatura 1.25 min. (A) 491
ambiente
Acido (S)-2-[(S)-2-(3’-cloro-bifenil-4
2-[2-(3’-cloro-bifenil-4-il)-1-(1 H
il)-1-(1H-tetrazol-5-ilcarbamoil)
tetrazol-5-ilcarbamoil)-etilamino]
etilamino]-3-fenil-propiónico
3-fenilpropionato de etilo
NaOH 2M
Ejemplo 3-15
aq, EtOH, temperatura 1.28 min. (A) 491
ambiente
Acido (S)-2-[(R)-2-(3’-cloro-bifenil-4
2-[2-(3’-clorobifenil-4-il)-1-(1 H
il)-1-(1H-tetrazol-5-ilcarbamoil)
tetrazol-5-ilcarbamoil)-etilamino]
etilamino]-3-fenil-propiónico
3-fenilpropionato de etilo
NaOH 2M
Ejemplo 3-16
aq, EtOH, temperatura 1.35 min. (A) 521
ambiente
Acido (S)-3-benciloxi-2-[(S)-2-(3’-clorobifenil-4-il)-1-(1H-tetrazol-5ilcarbamoil)-etilamino]-propiónico
(S)-3-benciloxi-2-[(S)-2-(3’-clorobifenil-4-il)-1-(1H-tetrazol-5ilcarbamoil)-etilamino]-propionato de etilo
34
# de ejemplo
Producto Material de inicio Condición de hidrólisis HPLC-RT (condición) MS (M+1)
Ejemplo 3-17
Acido (S)-2-[(S)-2-(3’-cloro-bifenil-4il)-1-(1H-tetrazol-5-ilcarbamoil)etilamino]-3-metoxi-propiónico (S)-2-[(S)-2-(3’-cloro-bifenil-4-il)1-(1H-tetrazol-5-ilcarbamoil)etilamino]-3-metoxi-propionato de etilo NaOH 2M aq, EtOH, temperatura ambiente 0.93 min. (A) 445
Ejemplo 3-18
Acido (S)-2-[(S)-2-(3’-cloro-bifenil-4il)-1-(1H-tetrazol-5-ilcarbamoil)etoxi]-propiónico (S)-2-[(S)-2-(3’-cloro-bifenil-4-il)1-(1H-tetrazol-5-ilcarbamoil)etoxi]-propionato de etilo NaOH 2M aq, MeOH, temperatura ambiente 1.09 min (A) 416

Ejemplo 3-3: 1H RMN (400MHz, DMSO-d6+TFA-d) δ 1.48 (d, 3H, J = 7.1 Hz), 3.27 (dd, 1H, J = 8.8, 13.1 Hz), 3.47 (dd, 1 H, J = 6.1, 13.4 Hz), 4.03 (dd, 1 H, J = 7.1, 14.1 Hz), 4.47 (dd, 1H, J = 7.3, 7.3 Hz), 7.37-7.42 (m, 5H), 7.47 (dd, 1H, J = 2.8, 8.6 Hz), 7.58 (d, 1H, J = 8.6 Hz), 14.89 (bs, 1 H).
5 Ejemplo 3-4: 1H RMN (400MHz, DMSO-d6) δ 1.37 (d, 3H, J = 6.8 Hz), 3.20 (d, 2H, J = 6.3 Hz), 3.73-3.87 (bs, 1H), 4.25-4.38 (bs, 1H), 7.33-7.38 (m, 1H), 7.36 (d, 2H, J 8.1 Hz), 7.45 (dd, 2H, J = 7.4, 7.4 Hz), 7.60-7.66 (m, 4H).
Ejemplo 3-5: 1H RMN (400MHz, DMSO-d6) δ 1.35-1.43 (m, 3H), 3.20 (bs, 2H), 3.71 (s, 3H), 3.75-4.00 (m, 1 H), 4.36 (bs, 1H), 7.05-7.20 (m, 3H), 7.31 (d, 2H, J = 8.3 Hz), 7.45 (d, 2H, J = 8.3 Hz).
Ejemplo 3-6: 1H RMN (400MHz, DMSO-d6+TFA-d) δ 1.48 (d, 3H, J = 7.3 Hz), 3.22 (dd, 1H, J = 7.6, 13.6 Hz), 3.32 10 (dd, 1H, J = 6.6, 13.9 Hz), 3.96 (dd, 1H, J = 7.3, 14.4 Hz), 4.50 (dd, 1H, J = 7.3, 7.3 Hz), 6.97 (s, 1 H), 7.33-7.38 (m, 3H), 7.45 (t, 2H, J = 7.8 Hz), 7.61-7.67 (m, 4H).
Ejemplo 3-7: 1H RMN (400MHz, DMSO-d6) δ 1.37 (bd, 3H, J = 4.8 Hz), 3.09-3.26 (m, 2H), 3.67-3.90 (m, 1H), 4.10
4.37 (m, 1 H), 5.83 (s, 1H), 7.34 (d, 2H, J = 8.1 Hz), 7.40-7.45 (m, 1 H), 7.48 (dd, 1H, J = 7.8, 7.8 Hz), 7.61-7.66 (m, 1H), 7.66-7.73 (m, 3H).
15 Ejemplo 3-8: 1H RMN (400MHz, DMSO-d6) δ 1.19-1.39 (m, 3H), 3.05-3.218 (m, 2H), 3.30-4.25 (m, 2H), 5.83 (s, 1 H), 7.33 (d, 2H, J = 8.3 Hz), 7.40-7.44 (m, 1 H), 7.48 (dd, 1H, J = 7.8, 7.8 Hz), 7.61-7.73 (m, 4H).
Ejemplo 3-9: 1H RMN (400MHz, DMSO-d6) δ 1.48-1.57 (m, 3H), 3.05-3.47 (m, 2H), 3.728/3.31 (s32, total 3H), 4.02
4.21 (m, 1H), 5.61-5.82 (m, 1H), 7.06-7.27 (m, 1H), 7.34-7.76 (m, 7H).
Ejemplo 3-10: 1H RMN (400MHz, DMSO-d6) δ 1.35-1.43 (m, 3H), 3.13-3.34 (m, 2H), 3.35-3.95 (m, 1H), 3.73 (s, 20 3H), 4.08-4.45 (m, 1H), 7.39-7.45 (m, 3H), 7.49 (dd, 1H, J = 7.8, 7.8 Hz), 7.62-7.75 (m, 4H).
Ejemplo 3-11: 1H RMN (400MHz, DMSO-d6) δ 1.32-1.42 (m, 3H), 3.13-3.34 (m, 2H), 3.35-3.95 (m, 1H), 3.73 (s, 3H), 4.02-4.36 (m, 1H), 7.37-7.45 (m, 3H), 7.49 (dd, 1H, J = 7.8, 7.8 Hz), 7.61-7.74 (m, 4H).
Ejemplo 3-12: 1H RMN (400 MHz, DMSO-d6) δ ppm 1.67 -1.90 (m, 2 H), 2.59 (t, J=7.7 Hz, 2 H), 2.96 (dd, J=13.6,
7.3 Hz, 1 H), 3.07 (dd, J=13.6, 7.1 Hz, 1 H), 3.11 -3.17 (m, 1 H), 3.78 (t, J=7.1 Hz, 1 H), 7.07 -7.18 (m, 5 H), 7.33
25 (d, J=8.3 Hz, 2 H), 7.37 -7.42 (m, 1 H), 7.46 (t, J=8.0 Hz, 1 H), 7.61 (d, J=8.3 Hz, 3 H), 7.68 (t, J=1.8 Hz, 1 H), 12.02 (br. s., 1 H), 15.89 (br. s., 1H).
Ejemplo 3-13: 1H RMN (400 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.5 Hz, 3 H), 1.67 -1.80 (m, 2 H), 3.08 -3.27 (m, 2
35
imagen30
imagen31
imagen32
# de Intermediario
Intermediario Reactivo HPLC-RT (condición) MS (M+1)
Intermediario 3
Acido (S)-3-bifenil-4-il-2-((S)-1-etoxi carbonil-etilamino)-propiónico Ácido fenilborónico fue usado en cambio del ácido 3-clorofenilboronico en el paso 1 0.71 min (C) 342
Intermediario 4
Acido (S)-2-((S)-1-tert-butoxicarboniletilamino)-3-(5’-fluoro-2’metoxibifenil-4-il)-propiónico Se usó ácido 2-metoxi-5-fluorofenilborónico en cambio del ácido 3clorofenilborónico en el paso 1 1.07 min (C) 418
Intermediario 5
(S)-3-Bifenil-4-il-2-((S)-1tertbutoxicarboniletilamino)-propionic acid Se usó ácido fenilborónico en cambio del ácido 3-clorofenilborónico en el paso 1 1.05 min (C) 370
Intermediario 6
(S)-2-[(S)-1-carboxi-2-(3’-clorobifenil4-il)-etilamino]-4-fenil-butirato de etilo Se usó (R)-2-hidroxi-4-fenil-butirato de etilo en cambio del (R)2-hidroxipropionato de tert-butilo en el paso 3’ 1.39 min (C) 466
Intermediario 7
(S)-2-[(S)-1-carboxi-2-(3’-clorobifenil4-il)-etilamino]-butirato de tert-butilo Se usó (R)-2-hidroxi-butirato de tertbutilo en cambio del (R)-2-hidroxipropionato de tert-butilo en el paso 3' 1.15 min (C) 418
Intermediario 8
Acido (S)-3-(3’-cloro-bifenil-4-il)-2-( (S)-1-etoxicarbonil-2-feniletil amino)propiónico Se usó (R)-2hidroxi-3-fenilpropionato de etilo en cambio del (R)2-hidroxi-propionato de tert-butilo en el paso 3' 1.27 min (C) 452
Intermediario 9: [1-(4-metoxi-bencil)-1H-tetrazol-5-il]-metil-amina
39
imagen33
A una suspensión de 5-amino-1H-tetrazole (1.50 g, 17.6 mmol) en DMF (30 mL) se añadieron Cs2CO3 (8.62 g, 26.4 mmol) y PMBCI (2.90 g, 18.5 mmol). Después de agitar a 60°C por 3 horas, se enfrió la mezcla de reacción hasta temperatura ambiente y se diluyó con EtOAc. Se lavó la mezcla con H2O y salmuera, se secó sobre Na2SO4, y se 5 concentró bajo presión reducida. Se diluyó el residuo con DCM y se colectó el precipitado resultante mediante filtración para dar 1-(4-metoxi-bencil)-1H-tetrazol-5-ilamina (0.625 g). 1H RMN (400MHz, DMSO-d6) δ 3.73 (s, 3H),
5.27 (s, 2H), 6.78 (s, 2H), 6.92 (d, 2H, J = 8.8 Hz), 7.21 (d, 2H, J = 8.8 Hz).
A continuación, a una suspensión de 1-(4-metoxi-bencil)-1H-tetrazol-5-ilamina (600 mg, 2.92 mmol) en MeOH (10 mL) se añadieron paraformaldehído (132 mg, 4.39 mmol) y metóxido de sodio (632 mg, 25 % en peso en MeOH). 10 Se realizó reflujo a la mezcla por 30 min hasta que la suspensión se convirtió en una solución clara. Se enfrió la mezcla hasta temperatura ambiente y se añadió en porciones borohidruro de sodio (332 mg, 8.77 mmol). Se realizó reflujo nuevamente a la mezcla de reacción por 15 min. Después de enfriar hasta temperatura ambiente, se detuvo la reacción con H2O. Se diluyó la mezcla con EtOAc, se concentró parcialmente y se lavó con salmuera. Se secó la capa orgánica sobre Na2SO4 y se concentró bajo presión reducida. El residuo fue purificado por cromatografía en 15 columna de gel de sílice (eluyente: MeOH 10% en DCM) para dar [1-(4-metoxi-bencil)-1H-tetrazol-5-il]-metil-amina
(0.63 g). 1H RMN (400MHz, CDCl3) δ 3.00 (d, 3H, J = 5.3 Hz), 3.61 (bs, 1H), 3.82 (s, 3H), 5.25 (s, 2H), 6.91 (d, 2H, J = 8.8 Hz), 7.16 (d, 2H, J = 8.8 Hz); MS: m/z (MH+) 220.
Se prepararon los siguientes intermediarios usando un procedimiento similar al del intermediario 1 o intermediario 2 con reactivos apropiados:
# de Intermediario
Intermediario Reactivo HPLC-RT (condición) MS (M+1)
Intermediario 9
Acido (S)-2-((S)-2-benciloxi-1etoxicarbonil-etilamino)-3-(3’-clorobifenil-4-il)-propiónico Se usó (R)-3-benciloxi-2-hidroxipropionato de etilo en cambio del (R)-2-hidroxi-propionato de etilo en el paso 3 1.41min (C) 482
Intermediario 10
Acido (S)-3-(3’-cloro-bifenil-4-il)-2-((S)1-etoxicarbonil-2-metoxietilamino)propiónico Se usó (R)-2-hidroxi-3-metoxipropionato de etilo en cambio del (R)-2-hidroxi-propionato de etilo en el paso 3 0.56min (C) 496

Intermediario 11: ácido (S)-3-(3’-cloro-bifenil-4-il)-2-((S)-1-etoxicarbonil-etoxi)-propiónico
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