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US 2024/0400558 A1Published application
Processes and intermediates for synthesis of adagrasib
AssigneeMirati Therapeutics, Inc.
InventorsThomas Scattolin, Cheng Chen, Tawfik Gharbaoui, Yonghong Gan, Michal Achmatowicz, David Snead
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Abstract
The present invention relates to improved synthetic routes of synthesizing adagrasib. The invention also provides intermediates used in the provided synthetic routes.
Claims84
A method of synthesizing adagrasib, comprising either step (a) or step (a′), wherein the step (a) comprises:
- a) reacting a compound of the following structure:
- with a free base or a salt of a compound of the following structure:
- in the presence of a polar aprotic solvent and an organic or an inorganic base to produce a final compound of step (a) with the following structure:
- and
- wherein step (a′) comprises
- a′) reacting a compound of the following structure:
- with the compound of the following structure:
- in the presence of a polar aprotic solvent and a base to produce the compound of the following structure:
- and then
- reacting this compound with benzyl chloroformate in the presence of sodium carbonate, methyl tert-butyl ether (MTBE) and water to produce a final compound of step (a′) with the following structure:
7 more elements
A method of synthesizing adagrasib, comprising the step of reacting
- with 2-fluoroacrylic acid or alkali or metal salts of 2-fluoroacrylic acid with a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
A method of synthesizing adagrasib, comprising the steps of:
- reacting
- with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce
- and
- reacting
- with 2-fluoroacrylic acid or alkali or metal salts of 2-fluoroacrylic acid with a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
2 more elements
A method of synthesizing adagrasib, comprising the steps of:
- reacting
- with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce
- reacting
- with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce
- and
- reacting
- with 2-fluoroacrylic acid or alkali or metal salts of 2-fluoroacrylic acid with a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
4 more elements
A method of synthesizing adagrasib, comprising the steps of:
- reacting the free base of
- with
- in the presence of a palladium catalyst, a base, a phosphorous-based ligand, and an aprotic solvent to produce
- reacting
- with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce
- reacting
- with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce
- and
- reacting
- with 2-fluoroacrylic acid or alkali or metal salts of 2-fluoroacrylic acid with a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
7 more elements
A method of synthesizing adagrasib, comprising the steps of:
- reacting
- with an acid to remove a Boc protecting group to produce a salt or free base of
- reacting the salt or free base of
- with
- in the presence of a palladium catalyst, a base, a phosphorous-based ligand, and an aprotic solvent to produce
- reacting
- with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce
- reacting
- with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce
- and
- reacting
- with 2-fluoroacrylic acid or alkali or metal salts of 2-fluoroacrylic acid with a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
9 more elements
A method of synthesizing adagrasib, comprising the steps of:
- reacting
- with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a palladium catalyst, a base, a phosphorous-based ligand, and an aprotic solvent to produce:
- reacting
- with an acid to remove a Boc protecting group to produce a salt or free base of:
- reacting the salt or free base of
- with
- in the presence of a palladium catalyst, a base, a phosphorous-based ligand, and an aprotic solvent to produce
- reacting
- with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce
- reacting
- with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce
- and
- reacting
- with 2-fluoroacrylic acid or alkali or metal salts of 2-fluoroacrylic acid with a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
11 more elements
A method of synthesizing adagrasib, comprising the steps of:
- a) reacting a compound of the following structure:
- with a salt of a compound of the following structure:
- in the presence of a polar aprotic solvent and an organic or an inorganic base to produce a final compound of step (a) with the following structure:
- b) reacting the final compound of step (a) with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a palladium catalyst, a base, a phosphorous-based ligand, and an aprotic solvent to produce a final compound of step (b) with the following structure:
- c) reacting the final compound of step (b) with an acid to remove a Boc protecting group from the final compound of step (b) to produce a salt or free base of a final compound of step (c) with the following structure:
- d) reacting the salt or free base of the final product of step (c) with
- in the presence of a palladium catalyst, a base, a phosphorous-based ligand, and an aprotic solvent to produce a final compound of step (d) with the following structure:
- e) reacting the final compound of step (d) with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce a final compound of step (e) with the following structure:
- f) reacting the final compound of step (e) with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce a final compound of step (f) with the following structure:
- and
- g) reacting the final compound of step (f) with 2-fluoroacrylic acid (or corresponding alkali or metal salts) with a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
8 more elements
A method of synthesizing adagrasib, comprising the steps of:
- a′) reacting a compound of the following structure:
- with the compound of the following structure:
- in the presence of a polar aprotic solvent and a base to produce the compound of the following structure:
- and then
- reacting this compound with benzyl chloroformate in the presence of sodium carbonate, methyl tert-butyl ether (MTBE) and water to produce a final compound of step (a′) with the following structure:
- b) reacting the final compound of step (a′) with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a palladium catalyst, a base, a phosphorous-based ligand, and an aprotic solvent to produce a final compound of step (b) with the following structure:
- c) reacting the final compound of step (b) with an acid to remove a Boc protecting group from the final compound of step (b) to produce a salt or free base of a final compound of step (c) with the following structure:
- d) reacting the salt or free base of the final product of step (c) with
- in the presence of a palladium catalyst, a base, a phosphorous-based ligand, and an aprotic solvent to produce a final compound of step (d) with the following structure:
- e) reacting the final compound of step (d) with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce a final compound of step (e) with the following structure:
- f) reacting the final compound of step (e) with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce a final compound of step (f) with the following structure:
- and
- g) reacting the final compound of step (f) with 2-fluoroacrylic acid (or corresponding alkali or metal salts) with a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
10 more elements
A method of synthesizing adagrasib comprising the steps of:
- a) reacting a compound of the following structure:
- with a fumarate salt of a compound of the following structure:
- in the presence of DIPEA and DMAc to produce a final compound of step (a) with the following structure:
- b) reacting the final compound of step (a) with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of Pd2(dba)3, (R)-BINAP, K3PO4, and 2-MeTHF to produce a final compound of step (b) with the following structure:
- c) reacting the final compound of step (b) with a hydrochloric acid and L-tartaric acid to remove a Boc protecting group from the final compound of step (b) to produce a L-tartrate salt of a final compound of step (c) with the following structure:
- d) reacting the free base of the final product of step (c) with
- in the presence of Pd2(dba)3, (R)-BINAP, K3PO4, and 2-MeTHF to produce a final compound of step (d) with the following structure:
- e) reacting the final compound of step (d) with p-toluenesulfonic acid in the presence of a acetone and 2-MeTHF to produce a final compound of step (e) with the following structure:
- f) reacting the final compound of step (e) with 2-mercaptoethanol in the presence of K3PO4 and DMAc to produce a final compound of step (f) with the following structure:
- and
- g) reacting the final compound of step (f) with the sodium salt of 2-fluoroacrylic acid in the presence of MeCN and propylphosphonic anhydride to produce adagrasib.
8 more elements
A method of synthesizing adagrasib comprising the steps of:
- a′) reacting a compound of the following structure:
- with a compound of the following structure:
- in the presence of DIPEA and DMAc to produce the compound of the following structure:
- and then
- reacting this compound with benzyl chloroformate in the presence of sodium carbonate, methyl tert-butyl ether (MTBE) and water to produce a final compound of step (a′) with the following structure:
- b) reacting the final compound of step (a′) with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of Pd2(dba)3, Xantphos, K3PO4, and 2-MeTHF to produce a final compound of step (b) with the following structure:
- c) reacting the final compound of step (b) with a hydrochloric acid and L-tartaric acid to remove a Boc protecting group from the final compound of step (b) to produce a L-tartrate salt of a final compound of step (c) with the following structure:
- d) reacting the free base of the final product of step (c) with
- in the presence of Pd2(dba)3, (R)-BINAP, K3PO4, and 2-MeTHF to produce a final compound of step (d) with the following structure:
- e) reacting the final compound of step (d) with p-toluenesulfonic acid in the presence of a acetone and 2-MeTHF to produce a final compound of step (e) with the following structure:
- f) reacting the final compound of step (e) with 2-mercaptoethanol in the presence of K3PO4 and DMAc to produce a final compound of step (f) with the following structure:
- and
- g) reacting the final compound of step (f) with the sodium salt of 2-fluoroacrylic acid in the presence of MeCN and propylphosphonic anhydride to produce adagrasib.
10 more elements
A compound selected from the group consisting of
Dependencies are inferred from the claim text.