Processes for the preparation of compounds

• US 20080058521A1
• Filed: 01/25/2007
• Published: 03/06/2008
• Est. Priority Date: 01/26/2006
• Status: Abandoned Application

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Dilley, Anja, Zhang, Mei-Yi, Blum, Cynthia, Pan, Sherry, Shah, Uresh, Sharma, Archana, Blum, David, Krishnan, Lalitha, Potoski, John, Wu, Yanzhong, Strong, Henry
• Application Number:
  US11/698,258
• Publication Number:
  US 20080058521A1
• Time in Patent Office: Days
• US Class Current: 544/331
• CPC Class Codes: C07D 213/61 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 333/70 attached in position 2
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention provides improved synthetic methods for the preparation of compounds that modulate proliferation or differentiation in a cell or tissue.

Claims

1-115. -115. (canceled)

116. A method for

A) the preparation of a compound of Formula D, or a salt thereof:

comprising treating a compound of Formula A, or a salt thereof, with a compound of Formula B, or a salt thereof;

under imine formation conditions,

wherein, as valence and stability permit,

Ar is a substituted or unsubstituted aryl or heteroaryl;

M, independently for each occurrence, represents a substituted or unsubstituted methylene group, NR⁴ (wherein R⁴ is H, substituted or unsubstituted alkyl, or an amine protecting group), O, S, S(O), or S(O)₂, selected such that no two heteroatoms are adjacent to each other;

n is an integer from 0-4;

Z is H, a substituted or unsubstituted aryl, carbocyclyl, heterocyclyl, or heteroaryl, or a nitro, cyano, or halogen;

R^a is H, substituted or unsubstituted alkyl or an amine protecting group; and

PG is H or an amine protecting group;

or

B) the preparation of a compound of Formula D, or a salt thereof;

comprising treating a compound of Formula C, or a salt thereof;

with an amine protecting group source under amine protection conditions,

wherein, as valence and stability permit,

M, R⁴, n, Ar, Z, and R^a are as defined in section A); and

PG is an amine protecting group;

or

C) the preparation of a compound of Formula E, or a salt thereof;

comprising treating a compound of Formula D, or a salt thereof;

with a reducing agent under imine reduction conditions,

wherein, as valence and stability permit,

M, R⁴, n, Ar, Z, PG, and R^a are as defined in section B);

or

D) the preparation of a compound of Formula G, or a salt thereof;

comprising treating a compound of Formula E, or a salt thereof, with a compound of Formula F, or a salt thereof;

under acylation conditions,

wherein, as valence and stability permit,

M, R⁴, n, Ar, Z, PG, and R^a are as defined in section B);

LG is a leaving group;

X is —

C(═

O)—

, —

C(═

S)—

, —

S(O₂)—

, —

S(O)—

, —

C(═

NCN)—

, or —

P(═

O)(OR)—

; and

Cy′

is a substituted or unsubstituted benzothiophene;

or

E) the preparation of a compound of Formula I, or a pharmaceutically acceptable salt thereof;

comprising subjecting a compound of Formula G, or a salt thereof;

to amine deprotection conditions,

wherein, as valence and stability permit,

M, R⁴, n, Ar, Z, PG, R^a, X, and Cy′

are as defined in section D);

or

F) the preparation of a compound of Formula B, or a salt thereof, wherein n is 0;

comprising treating a compound of Formula B1, or a salt thereof, with a compound of Formula B2, or a salt thereof;

under carbon-carbon bond-forming conditions,

wherein, as valence and stability permit,

Ar is as defined in section A);

Z is a substituted or unsubstituted aryl or heteroaryl;

X¹ is a halogen, triflate, or mesylate; and

the carbon bond-forming conditions comprise a catalytic amount of Pd(OAc)₂ or (Ph₃P)₂PdCl₂, a metal carbonate, ethanol or dimethoxyethane solvent, and water;

or

G) the preparation of a compound according to Formula A3, or a salt thereof;

comprising treating a compound of Formula A1, or a salt thereof, with a compound of Formula A2;

under carbamate forming conditions,

wherein, as valence and stability permit,

R′

is a substituted or unsubstituted alkyl;

or

H) the preparation of a compound of Formula A, or a salt thereof;

comprising treating a compound of Formula A4, or a salt thereof;

with an aldehyde under imine forming conditions followed by treating with an amine protecting group source under amine protecting conditions followed by treating with imine cleavage conditions,

wherein, as valence and stability permit,

R^a is substituted or unsubstituted alkyl, or an amine protecting group;

PG is as defined in section B); and

the imine formation conditions comprise an alkyl alcohol solvent;

or

I) the preparation of a compound of Formula C, or a salt thereof;

comprising treating a compound of Formula A4, or a salt thereof, with a compound of Formula B, or a salt thereof;

under imine formation conditions,

wherein, as valence and stability permit,

M, R⁴, n, Ar, and Z are as defined in section A); and

R^a is as defined in section H);

or

J) the preparation of a compound according to Formula E, or a salt thereof;

comprising treating a compound of Formula A, or a salt thereof, with a compound of Formula B, or a salt thereof;

under imine formation conditions followed by treating with a reducing agent under imine reduction conditions,

wherein, as valence and stability permit,

M, R⁴, n, Ar, Z, PG, and R^a are as defined in section B); and

the imine formation conditions comprise an alkyl alcohol solvent;

or

K) the preparation of a compound according to Formula I, or a pharmaceutically acceptable salt thereof;

comprising;

a) treating a compound of Formula A4, or a salt thereof, with a compound of Formula B, or a salt thereof;

under imine formation conditions to generate a compound of Formula C, or a salt thereof;

b) treating the compound of Formula C, or a salt thereof, with an amine protecting group source under amine protecting conditions to generate a compound of Formula D, or a salt thereof;

c) treating the compound of Formula D, or a salt thereof, with a reducing agent under imine reduction conditions to generate a compound of Formula E, or a salt thereof;

d) treating the compound of Formula E, or a salt thereof, with a compound of Formula F, or a salt thereof;

under acylation conditions to generate a compound of Formula G, or a salt thereof;

e) treating the compound of Formula G, or a salt thereof, under conditions that remove PG to prepare a compound of Formula I, or a pharmaceutically acceptable salt thereof,

wherein, as valence and stability permit,

M, R⁴, n, Ar, Z, X, PG, R^a, Cy′

, and LG are as defined in section D);

or

L) the preparation of a compound according to Formula I, or a pharmaceutically acceptable salt thereof;

comprising;

a) treating a compound of Formula A, or a salt thereof, with a compound of Formula B, or a salt thereof;

under imine formation conditions to generate a compound of Formula D, or a salt thereof;

b) treating the compound of Formula D, or a salt thereof, with a reducing agent under imine reduction conditions to generate a compound of Formula E, or a salt thereof;

c) treating the compound of Formula E, or a salt thereof, with a compound of Formula F, or a salt thereof;

under acylation conditions to generate a compound of Formula G, or a salt thereof;

d) treating the compound of Formula G, or a salt thereof, under conditions that remove PG to prepare a compound of Formula I, or a pharmaceutically acceptable salt thereof,

wherein, as valence and stability permit,

M, R⁴, n, Ar, Z, X, PG, R^a, Cy′

, and LG are as defined in section D).