Chemical Process for the Synthesis of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline

Patent metadata

Field	Value
Publication number	US-2016185754-A1
Application number	US-201514805816-A
Country	US
Kind code	A1
Filing date	Jul 22, 2015
Priority date	Sep 30, 2005
Publication date	Jun 30, 2016
Grant date	—

Abstract

The present invention relates to chemical processes for the manufacture of certain quinazoline derivatives, or pharmaceutically acceptable salts thereof. The invention also relates to processes for the manufacture of certain intermediates useful in the manufacture of the quinazoline derivatives and to processes for the manufacture of the quinazoline derivatives utilising said intermediates. In particular, the present invention relates to chemical processes and intermediates useful in the manufacture of the compound 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline.

First claim

1 .- 8 . (canceled)

9 . A process for the manufacture of a compound of the Formula VI:

wherein R 1 is an acid labile protecting group
from a compound of the Formula VII:

which process comprises the steps of:
(g) reacting the compound of the Formula VII with a suitable chlorinating agent in the presence of a suitable base and a suitable solvent, wherein the reaction is carried out by:
(g-1) adding a mixture of the compound of the Formula VII and the base in the solvent to a mixture of the chlorinating agent in the solvent at a temperature in the range of from 60 to 90° C. over a period of about 60 minutes; or
(g-2) adding the chlorinating agent to a mixture of the compound of the Formula VII and the base in the solvent at ambient temperature over a period of about 15 minutes and then heating the reaction mixture over a period of about 90 minutes to a temperature in the range of from 70 to 90° C. and stirring the reaction mixture at that temperature for about 1 hour; or
(g-3) adding the chlorinating agent to a mixture of the compound of the Formula VII and the base in the solvent at a temperature in the range of from 60 to 110° C over a period of about 15 minutes,

to form a compound of the Formula VIII:

(h) reacting the compound of the Formula VIII with 4-bromo-2-fluoroaniline in situ in the presence of the solvent used in step (g) to form the compound of the Formula VI as a hydrochorde salt

and whereafter the compound of the Formula VI obtained in the form of the hydrochloride salt optonally may be converted into the free base or into the form of an alternative salt.

10 . The process according to claim 9 , wherein steps (g) and (h) are both conducted in toluene.

11 . The process according to claim 9 , wherein the chlorinating agent used in step (g) is phosphorus oxychloride.

12 . The process according to claim 9 , wherein the base used in step (g) is selected from the group consisting of triethylamine and N,N-diisopropylethylamine.

13 . The process according to claim 9 , further comprising the step (i) of isolating the compound of the Formula VI.

14 . A process for the manufacture of 7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline, a compound of the Formula IX:

from a compound of the Formula VII:

wherein R 1 is an acid labile protecting group,
which process comprises the steps of converting the compound of the Formula VII to a compound of the Formula VI:

by conducting a process according to claim 9 ; and
(j) removing R 1 from the compound of the Formula VI in situ in the presence of the solvent used in steps (g) and (h) to form the compound of the Formula IX or a salt thereof;
and whereafter the compound of the Formula IX obtained in the form of the free base may be converted into a salt form and the compound of the Formula IX obtained in the form of a salt optionally may be converted into the free base or into the form of an alternative salt.

15 . The process according to claim 14 , wherein R 1 is benzyl and in step (j) the benzyl group is removed in situ by reaction with trifluoroacetic acid at a temperature in the range of from 60 to 80° C.

16 . The process according to claim 14 wherein R 1 is benzyl and the benzyl group is removed in the presence of trifluoroacetic acid and the compound of Formula IX is converted into a trifluoroacetic acid salt by addition of potassium hydroxide or the addition of sodium hydroxide and water.

17 . A process for the manufacture of 7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline, a compound of the Formula IX:

from a compound of the Formula VII:

which process comprises the steps of converting the compound of the Formula VII to a compound of the Formula VI:

by conducting a process according to claim 13 ; and
(k) removing R 1 from the compound of the Formula VI to form the compound of the Formula IX or a salt thereof;
and whereafter the compound of the Formula IX obtained in the form of the free base may be converted into a salt form and the compound of the Formula IX obtained in the form of a salt optionally may be converted into the free base or into the form of an alternative salt.

18 . The process according to claim 17 , wherein R 1 is benzyl and in step (k) the benzyl group is removed by reaction with a suitable hydrogenation agent.

19 . A process for the manufacture of 7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline, a compound of the Formula X:

from a compound of the Formula VII:

which process comprises converting the compound of the Formula VII to a compound of the Formula IX:

by conducting a process according to claim 14 ; and
(l) reacting the compound of the Formula IX with a compound of the Formula II:

in the presence of a suitable base to provide a compound of the Formula X or a salt thereof;

and whereafter the compound of the Formula X obtained in the form of the free base may be converted into a salt form and the compound of the Formula X obtained in the form of a salt optionally may be converted into the free base or into the form of an alternative salt.

20 . The process according to claim 19 , wherein the base used in step (l) is selected from sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

21 . The process according to claim 19 , further including the step (m) of isolating the compound of the Formula X.

22 . A process for the manufacture of 7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline, a compound of the Formula X:

from 7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline, a compound of the Formula IX:

which process comprises the steps of:
(l) reacting the compound of the Formula IX with a compound of the Formula II:

Assignees

• Astrazeneca Ab

Inventors

• Blixt Jorgen
• Golden Michael David
• Hogan Philip John
• Martin David Michael Glanville
• Montgomery Francis Joseph
• Patel Zakariya
• Pittam John David
• Sependa George Joseph
• Squire Christopher John
• Wright Nicholas Cartwright Alexander

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P17/06

  Antipsoriatics · CPC title