Process for the manufacture of 6-alkynyl-pyridine derivatives

Patent metadata

Field	Value
Publication number	US-11053237-B2
Application number	US-201716301213-A
Country	US
Kind code	B2
Filing date	May 17, 2017
Priority date	May 19, 2016
Publication date	Jul 6, 2021
Grant date	Jul 6, 2021

Abstract

The application includes a description of novel intermediates, of new manufacturing steps resulting in a novel and improved process for producing the intermediates and the final compounds, i.e., 6-alkynyl-pyridine derivatives. The intermediates of the invention are useful to produce 6-alkynyl-pyridine derivatives, which compounds are useful for the treatment of cancer.

First claim

The invention claimed is:

1. A process for the synthesis of a compound of formula

comprising the step of
preparing the compound of formula

according to a process comprising the steps of:
obtaining the compound of formula

by reacting 5,6-dibromo-pyridin-2-yl-amine with a 1,1-dialkoxy-N,N-dialkylmethyl-amine of the formula (R z O) 2 —CHN(R a ,R b ), wherein R z is a —C 1-3 alkyl group;
and reacting the compound of formula

with a compound of formula

reacting the resulting compound of formula (III)

with a compound of formula

wherein
A is one of the following two fused rings:

each optionally substituted with a —C 1-3 alkyl group;
R 1 is selected from hydrogen, —C 1-3 alkyl and halogen;
R 2 is selected from hydrogen, —C 1-3 alkyl and halogen;
R 3 is selected from —C 1-3 alkyl and pyridyl optionally substituted with —C 1-3 alkyl or —O—C 1-3 alkyl;
X is halogen;
R a and R b are the same or different selected from —C 1-4 alkyl and —CH 2 -phenyl.

2. A process for the synthesis of a compound of formula

wherein
A is one of the following two fused rings:

each optionally substituted with a —C 1-3 alkyl group;
R 1 is selected from hydrogen, —C 1-3 alkyl and halogen;
R 2 is selected from hydrogen, —C 1-3 alkyl and halogen;
R 3 is selected from —C 1-3 alkyl and pyridyl optionally substituted with —C 1-3 alkyl or —O—C 1-3 alkyl;
comprising the steps of
preparing the compound of formula

according to the process of claim 1 ;
wherein
R a and R b are the same or different selected from —C 1-4 alkyl and —CH 2 -phenyl;
deprotecting the compound of formula II to form a compound of formula

forming a compound of formula

by coupling a compound of formula M with 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid, wherein the 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid is racemic, (S)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid or (R)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid;
deprotecting the compound of formula

to obtain the compound of formula

3. The process according to claim 1 , further comprising the steps of
cyclizing a compound of formula

to obtain a compound of formula

and, optionally,
further reacting compound of formula (J) to obtain a compound of formula

wherein
Y − is Br − or Cl − ;
R 1 is selected from hydrogen, —C 1-3 alkyl and halogen;
R 2 is selected from hydrogen, —C 1-3 alkyl and halogen;
R 3 is —CH 2 —C 1-2 alkyl;
R 4 is selected from hydrogen and C 1-2 alkyl;
X is halogen.

4. The process of claim 1 , wherein
R 1 is selected from hydrogen, —C 1-3 alkyl and
R 2 is selected from hydrogen, —C 1-3 alkyl and
R 3 is selected from —C 1-3 alkyl and pyridyl optionally substituted with —C 1-3 alkyl or —O—C 1-3 alkyl.

5. A compound of formula (II)

wherein
A is one of the following two fused rings:

each optionally substituted with a —C 1-3 alkyl group;
R 1 is selected from hydrogen, —C 1-3 alkyl and halogen;
R 2 is selected from hydrogen, —C 1-3 alkyl and halogen;
R 3 is selected from —C 1-3 alkyl and pyridyl optionally substituted with —C 1-3 alkyl or —O—C 1-3 alkyl;
R a and R b are the same or different selected from —C 1-4 alkyl and —CH 2 -phenyl;
or a salt thereof.

6. A compound or a salt thereof according to claim 5 selected from among

Assignees

• Boehringer Ingelheim Int

Inventors

• Lu Guanghua
• Huchler Guenther
• Krueger Thomas
• Pangerl Michael
• Santagostino Marco
• Desrosiers Jean-Nicolas

Classifications

• C07D217/24

  Oxygen atoms · CPC title

• C07D213/74 Primary

  Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D213/73

  Unsubstituted amino or imino radicals · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title