Process for making substituted quinazoline compounds

Patent metadata

Field	Value
Publication number	US-9890128-B2
Application number	US-201415102417-A
Country	US
Kind code	B2
Filing date	Dec 8, 2014
Priority date	Dec 12, 2013
Publication date	Feb 13, 2018
Grant date	Feb 13, 2018

Abstract

The present invention is directed to a process for making Substituted Quinazoline Compounds of formula (I): which are useful for the treatment and prophylaxis of HCMV infection. The present invention is also directed to compounds that are useful as synthetic intermediates for making the compounds of formula (I).

First claim

What is claimed is:

1. A process for making a compound of Formula (I):

wherein said process comprises contacting a compound of formula (viii):

or a salt thereof,
with a phase-transfer catalyst and a base, in a mixture of water and organic solvent A, for a time sufficient to form a compound of formula (I), wherein:
R 1 represents 0 to 3 phenyl group substituents, each independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, —CN, —OH and C 1 -C 6 alkoxy;
R 2 represents 0 to 3 phenyl group substituents, each independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, —CN, —OH and C 1 -C 6 alkoxy;
R 3 represents 0 to 3 phenyl group substituents, each independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, —CN, —OH and C 1 -C 6 alkoxy; and
R 4 is C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl,

wherein:
organic solvent A is selected from toluene, DCM, MTBE, 2-methyltetrahydrofuran, xylenes, ethyl acetate, isopropyl acetate, acetonitrile and mixtures thereof;
the base is selected from an alkali metal carbonate, an alkali metal hydrogen carbonate, an alkali metal bicarbonate, an alkali metal phosphate, an alkali metal hydrogen phosphate, an alkali metal hydroxide, a trialkylamine and an aromatic amine;

organic solvent A is selected from toluene, DCM, MTBE, 2-methyltetrahydrofuran, xylenes and mixtures thereof; and
the phase-transfer catalyst is a compound of formula (PT1) or (PT2):

wherein:
R a is selected from ethyl and vinyl,
R b is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl, —C 1-4 alkyl-aryl, —C 1-4 alkyl-(5 or 6-membered monocyclic heteroaryl) and C 1-4 alkyl-(9 or 10-membered bicyclic heteroaryl), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl and the aryl and heteroaryl portions of —C 1-4 alkyl-aryl, —C 1-4 alkyl-(5 or 6-membered monocyclic heteroaryl), and C 1-4 alkyl-(9 or 10-membered bicyclic heteroaryl), are optionally substituted with one to five substituents independently selected from R f ,
R c is selected from hydrogen, methoxy, halo, —CN, —NO 2 and —CF 3 ;
R d is selected from the group consisting of hydrogen, C(O)R, C(O)OR, CONRR′, and C 1-6 alkyl,
R e is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl, —C 1-4 alkyl-aryl, —C 1-4 alkyl-(5 or 6-membered monocyclic heteroaryl) and C 1-4 alkyl-(9 or 10-membered bicyclic heteroaryl), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl and the aryl and heteroaryl portions of —C 1-4 alkyl-aryl, —C 1-4 alkyl-(5 or 6-membered monocyclic heteroaryl), and C 1-4 alkyl-(9 or 10-membered bicyclic heteroaryl), are optionally substituted with one to five substituents independently selected from R f ,
each occurrence of R f is independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, aryl, C 1-4 alkoxy, hydroxy, CN, CO 2 R, CONRR′, SR, SO 2 R, SO 3 R, PR 2 , PO(OR) 2 , PO(OR) (NRR′), PO(NRR′) 2 , P(OR) 2 , P(OR)(NRR′), P(NRR′) 2 , SiRR′R″, B(OR) 2 , C(O)R, NRR′, NO 2 , and halogen,
each R, R′ and R″ is independently selected from the group consisting of, H, C 1-6 alkyl, hydroxyl, C 1-6 alkoxy, aryl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl, —CH 2 -aryl, —CH 2 -heteroaryl, and
each X and Y are independently anions selected from halide, OH, HSO 4 , SO 4 , BF 4 , SbF 6 , carboxylate, carbonate, hydrogen carbonate, NO 3 , sulfonate, hexafluorophosphate, phosphate, hydrogen phosphate and perchlorate.

2. The process of claim 1 , further comprising the step of making the compound of formula (viii)

wherein said process comprises the steps:
(A) contacting a compound of Formula (v):

with a dehydrating agent and a base in an organic solvent B, for a time sufficient to provide an intermediate compound of Formula (vi):

and
(B) contacting the intermediate compound of formula (vi) with a compound of formula (vii):

in the presence of a base, in a mixture of water and organic solvent B′, for a time sufficient to provide a compound of formula (viii), wherein organic solvents B and B′ are each independently selected from ethyl acetate, isopropyl acetate, THF, 2-methyltetrahydrofuran, DCM, benzene, toluene, xylene, chlorobenzene, acetonitrile and dioxane.

3. The process of claim 2 , further comprising the step of contacting the formed compound of formula (viii) with an acid, in a mixture of water and an organic solvent C for a time sufficient to form the corresponding acid salt of the compound of formula (viii), wherein organic solvent C is selected from toluene, DCM, MTBE, 2-methyltetrahydrofuran, xylenes, ethyl acetate, isopropyl acetate, acetonitrile and mixtures thereof, to provide the corresponding acid salt of the compound of formula (viii).

4. The process of claim 1 , wherein said process is conducted at a temperature in a range of from about −10° C. to about 30° C.

5. The process of claim 4 , wherein:
said process is conducted at a temperature in a range of from about −5° C. to about 10° C.;
the base used is selected from K 2 CO 3 , KHCO 3 , Na 2 CO 3 , NaHCO 3 , Na 3 PO 4 , Na 2 HPO 4 , NaH 2 PO 4 , K 3 PO 4 , K 2 HPO 4 and KH 2 PO 4 ; and
the phase transfer catalyst used is selected from:

6. The process of claim 1 , wherein the phase transfer catalyst used is:

7. The process of claim 2 , wherein:
Step A is conducted at a temperature in a range of from about 20° C. to about 45° C.;
the dehydrating agent used in step A is selected from PCl 5 , POCl 3 , P 2 O 5 and oxalyl chloride;
the base used in step A is selected from a trialkylamine, a pyridine and an imidazole;
Step B is conducted at a temperature in a range of from about 20° C. to about 45° C.; and
the base used in step B is selected from an alkali metal carbonate, an alkali metal hydrogen carbonate, an alkali metal bicarbonate, an alkali metal phosphates an alkali metal hydrogen phosphate, an alkali metal hydroxide, a trialkylamine and an aromatic amine.

8. The process of claim 7 , wherein:
the base used in step A is selected from quinoline, 1-methyl imidazole, 2-picoline, pyridine, 2,6-di-tert-butylpyridine, 2,6-di-tert-butyl-4-methyl pyridine, 2,4-dimethylpyridine, 2,4,6-trimethyl pyridine, triethylamine and diisopropylethylamine; and
the base used in step B is selected from K 2 CO 3 , KHCO 3 , Na 2 CO 3 , NaHCO 3 , Na 3 PO 4 , Na 2 HPO 4 , NaH 2 PO 4 , K 3 PO 4 , K 2 HPO 4 and KH 2 PO 4 .

9. The process of claim 3 ,

Assignees

• Luzung Michael
• Humphrey Guy
• Xiang Bangping
• Belyk Kevin M
• Dalby Stephen Mark
• Schwab Wilfried
• Klenke Burkhard
• Moody Tom
• Brown Gareth
• Merck Sharp & Dohme
• Aicuris Anti Infective Cures Gmbh

Inventors

• Luzung Michael
• Humphrey Guy
• Xiang Bangping
• Belyk Kevin M
• Dalby Stephen Mark
• Schwab Wilfried
• Klenke Burkhard
• Moody Tom
• Brown Gareth

Classifications

• B01J31/0232

  also containing elements or functional groups covered by B01J31/0201 - B01J31/0228 (perfluorinated sulfonyl compounds or moieties B01J31/0224; perfluorosulfonic acids B01J31/0227) · CPC title

• B01J2231/324

  Cyclisations via conversion of C-C multiple to single or less multiple bonds, e.g. cycloadditions · CPC title

• C07D295/125

  with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings · CPC title

• B01J31/0271

  also containing elements or functional groups covered by B01J31/0201 - B01J31/0231 · CPC title

• B01J31/0202

  Alcohols or phenols · CPC title