Process of preparing a quinazoline derivative
View Patent ↗A concise, efficient and cost- and time-saving process for the preparation of a quinazoline derivative of formula A given below: which is an intermediate for making gefitinib or gefitinib itself, comprising reacting a compound of Formula B: with 3-chloro-4-fluoroaniline (VI) in the presence of a N,N-dialkyl formamide acetal, a Bronsted acid catalyst, and a solvent in a one-pot reaction.
1. A process of making a compound of formula A:
wherein P is hydrogen, 3-(morpholinyl)propyl, or a hydroxyl-protecting group, comprising reacting a compound of formula B or its salt:
with 3-chloro-4-fluoroaniline (VI) in the presence of a N,N-dialkyl formamide acetal, a Bronsted acid catalyst and a solvent.
2. The process of claim 1 , wherein said N,N-dialkyl formamide acetal is N,N-dimethylformamide dimethylacetal (DMF-DMA).
3. The process of claim 1 , wherein the Bronsted acid catalyst is acetic acid (AcOH) or trifluoroacetic acid (TFA).
4. The process of claim 1 , wherein the solvent is selected from the group consisting of AcOH, toluene (PhMe), methanol (MeOH), acetonitrile (ACN), ethyl acetate (EtOAc), tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), N,N-dimethylformamide (DMF), and combinations thereof.
5. The process of claim 4 , wherein the solvent is the mixture of AcOH and toluene (PhMe).
6. The process of claim 1 , wherein the reacting is performed at a temperature of 20-100° C.
7. The process of claim 1 , wherein the molar equivalents of formula VI and N,N-Dimethylformamide Dimethylacetal (DMF-DMA) are about 1-2 and 1-1.5, respectively, relative to the molar amount of the compound of formula B.
8. The process of claim 1 , wherein the compound of formula A is crystallized from a mixture of dimethyl sulfoxide and water (DMSO/H 2 O) or dimethyl sulfoxide and acetonitrile (DMSO/ACN).
9. A process of making gefitinib or a pharmaceutically acceptable salt thereof comprising:
reacting a compound of Formula V:
or its salt with 3-chloro-4-fluoroaniline (VI) in the presence of a N,N-dialkyl formamide acetal, a Brønsted acid catalyst, and a solvent to prepare a compound of formula VII:
and
converting the compound of formula VII to gefitinib or its pharmaceutically acceptable salt thereof.
10. The process of claim 9 wherein the step of converting comprises reacting the compound of formula VII with 4-(3-chloropropyl)morpholine (VIII) to form gefitinib.
11. The process of claim 9 further comprising:
isolating gefitinib from a reaction mixture obtained in the converting step to obtain crude solid gefitinib;
dissolving crude solid gefitinib in a first solvent selected from the group consisting of N-methyl-2-pyrrolidone (NMP), N,N-dimethyl acetamide (DMAC), N,N-dimethylformamide (DMF), and combinations thereof to obtain a solution;
forming crystals by adding a second solvent selected from the group consisting of a C 1 -C 4 aliphatic alcohol, acetonitrile (ACN), and combination thereof into the solution.
12. The process of claim 11 wherein the first solvent is N-methyl-2-pyrrolidone (NMP), and the second solvent is isopropyl alcohol (IPA), acetonitrile (ACN), or a mixture of isopropyl alcohol (IPA) and acetonitrile (ACN).
13. The process of claim 11 wherein the dissolving is conducted at a temperature of 70-100° C.