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NZ751139B2 - Processes for the preparation of an apoptosis-inducing agent - Google Patents
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NZ751139B2 - Processes for the preparation of an apoptosis-inducing agent - Google Patents

Processes for the preparation of an apoptosis-inducing agent Download PDF

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Publication number
NZ751139B2
NZ751139B2 NZ751139A NZ75113914A NZ751139B2 NZ 751139 B2 NZ751139 B2 NZ 751139B2 NZ 751139 A NZ751139 A NZ 751139A NZ 75113914 A NZ75113914 A NZ 75113914A NZ 751139 B2 NZ751139 B2 NZ 751139B2
Authority
NZ
New Zealand
Prior art keywords
compound
formula
tert
butyl
combining
Prior art date
Application number
NZ751139A
Other versions
NZ751139A (en
Inventor
Jufang Barkalow
Jeanchristophe Califano
Vincent S Chan
Alan C Christensen
Timothy A Grieme
Yiyin Ku
Mathew M Mulhern
Yuming M Pu
Jean Christophe Califano
Yi Yin KU
Yu Ming M Pu
Original Assignee
Abbvie Ireland Unlimited Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbvie Ireland Unlimited Company filed Critical Abbvie Ireland Unlimited Company
Publication of NZ751139A publication Critical patent/NZ751139A/en
Publication of NZ751139B2 publication Critical patent/NZ751139B2/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/38—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings
    • C07C47/457—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

Provided herein is a process for the preparation of an apoptosis-inducing agent (A1), and chemical intermediates thereof. Also provided herein are novel chemical intermediates related to the process provided herein.

Description

PROCESSES FOR THE PREPARATION OF AN APOPTOSIS-INDUCING AGENT This application is a divisional of New Zealand Patent Application No. 711315 (national phase of ) and claims the benefit of United States Provisional Application No. 61/780,621, filed 13 March 2013, and United States Provisional Application No. 61/947,850, filed 4 March 4, 2014, each of which is hereby incorporated by reference herein in its entirety.
FIELD Provided herein are processes for the preparation of an apoptosis-inducing agent, and chemical intermediates thereof. Also provided herein are novel chemical intermediates related to the processes provided herein.
BACKGROUND 4-( 4-{[2-( 4-chlorophenyl)-4,4-dimethylcyclohexenyl]methyl} piperazinyl)- N-( {3-nitro[ ( tetrahydro-2H-pyranylmethyl)amino ]phenyl} sulfonyl)( 1 H- pyrrolo[2,3-b ]pyridinyloxy)benzamide (hereafter, "Compound 1 ") and 4-( 4-{[2-( 4- chlorophenyl)-4,4-dimethylcyclohexenyl]methyl} piperazinyl)-N-( {3-nitro[ (1R,4R)-[ 4-hydroxymethylcyclohexyl ]methyl)amino ]phenyl} sulfonyl)( 1 H- pyrrolo[2,3-b ]pyridinyloxy )benzamide (hereafter, "Compound 2") are each potent and selective Bcl-2 inhibitors having, inter alia, antitumor activity as apoptosis-inducing agents.
Compound 1 has the formula: Compound 2 has the formula: Compound 1 is currently the subject of ongoing clinical trials for the treatment of chronic lymphocytic leukemia. U.S. Patent Publication No. 2010/0305122 describes Compound 1, Compound 2, and other compounds which exhibit potent binding to a Bcl-2 family protein, and pharmaceutically acceptable salts thereof. U.S. Patent Publication Nos. 2012/0108590 and 2012/0277210 describe pharmaceutical compositions comprising such compounds, and methods for the treatment of neoplastic, immune or autoimmune diseases comprising these compounds. U.S. Patent Publication No. 2012/0129853 describes methods for the treatment of systemic lupus erythematosus, lupus nephritis or Sjogren’s Syndrome comprising these compounds. U.S. Patent Publication No. 2012/0157470 describes pharmaceutically acceptable salts and crystalline forms of Compound 1. The disclosures of U.S. 2010/0305122; 2012/0108590; 2012/0129853; 2012/0157470 and 2012/0277210 are hereby incorporated by reference herein in their entireties.
SUMMARY [0006a] In a first aspect of the invention, there is provided a compound of the formula: [0006b] In a second aspect of the invention, there is provided a process for the preparation of the compound of formula (D): wherein the process comprises: (25907089_1):AXG (x) combining a compound of formula (B): (B); with a compound of formula (C): (C), wherein R is tert-butyl, and a tert-butoxide salt in an organic solvent to provide the compound of formula (D). [0006c] In a third aspect of the invention, there is provided a compound of the formula: [0006d] In a fourth aspect of the invention, there is provided a process for the preparation of the compound of formula (3): wherein the process comprises: (y) combining a compound of formula (B): (B); with a compound of formula (C): (25907089_1):AXG (C), wherein R is tert-butyl, and a tert-butoxide salt in an organic solvent to provide the compound of formula (D): (D), wherein R is tert-butyl; (z) combining the compound of formula (D), wherein R is tert-butyl; with a compound of formula (I): (I), a source of palladium, a tert-butoxide salt, and a phosphine ligand in an aprotic organic solvent to provide the compound of formula (3).
Provided herein are processes for the preparation of compounds of formula A1: (A1), wherein R is selected from and .
Also provided herein are compounds of the formulae: (25907089_1):AXG

Claims (10)

CLAIMS 1.:
1. A compound of the formula:
2. A process for the preparation of the compound of formula (D): wherein the process comprises: (x) combining a compound of formula (B): (B); with a compound of formula (C): (C), wherein R is tert-butyl, and a tert-butoxide salt in an organic solvent to provide the compound of formula (D).
3. The process of claim 2, wherein the compound of formula (C) is prepared according to the following steps: (a) combining a compound of formula (A): (25907089_1):AXG with RMgX in an aprotic organic solvent; wherein R is tert-butyl and X is C1, Br or I; and (b) combining tert-butyl chloroformate or di-tert-butyl dicarbonate with the product of step (a), to provide the compound of formula (C).
4. The process of claim 3, wherein step (b) comprises combining di-tert-butyl dicarbonate with the product of step (a), to provide the compound of formula (C).
5. A compound of the formula:
6. A process for the preparation of the compound of formula (3): wherein the process comprises: (y) combining a compound of formula (B): (B); with a compound of formula (C): (C), wherein R is tert-butyl, and a tert-butoxide salt in an organic solvent to provide the compound of formula (D): (25907089_1):AXG (D), wherein R is tert-butyl; (z) combining the compound of formula (D), wherein R is tert-butyl; with a compound of formula (I): (I), a source of palladium, a tert-butoxide salt, and a phosphine ligand in an aprotic organic solvent to provide the compound of formula (3).
7. The process of claim 6, wherein the source of palladium is Pd dba .
8. The process of claim 6 or claim 7, wherein the phosphine ligand is a compound of formula (J): (J).
9. The process of any one of claims 6 to 8, wherein the compound of formula (C) is prepared according to the following steps: (a) combining a compound of formula (A): with RMgX in an aprotic organic solvent; wherein R is tert-butyl and X is C1, Br or I; and (25907089_1):AXG (b) combining a tert-butyl chloroformate or a di-tert-butyl dicarbonate with the product of step (a), to provide the compound of formula (C).
10. The process of claim 9, wherein step (b) comprises combining di-tert-butyl dicarbonate with the product of step (a), to provide the compound of formula (C). AbbVie Inc. By the Attorneys for the Applicant SPRUSON & FERGUSON Per: (25907089_1):AXG
NZ751139A 2013-03-13 2014-03-12 Processes for the preparation of an apoptosis-inducing agent NZ751139B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201361780621P 2013-03-13 2013-03-13
US61/780,621 2013-03-13
US201461947850P 2014-03-04 2014-03-04
US61/947,850 2014-03-04
NZ711315A NZ711315B2 (en) 2013-03-13 2014-03-12 Processes for the preparation of an apoptosis-inducing agent

Publications (2)

Publication Number Publication Date
NZ751139A NZ751139A (en) 2020-10-30
NZ751139B2 true NZ751139B2 (en) 2021-02-02

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