Process for preparing quinoline derivatives
A process for preparing a compound of Formula I is disclosed, comprising the steps: wherein: R 1 is halo; R 2 is halo; R 3 is (C 1 -C 6 )alkyl or (C 1 -C 6 )alkyl optionally substituted with heterocycloalkyl; R 4 is (C 1 -C 6 )alkyl; and Q is CH or N; comprising: (a) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in a polar aprotic solvent; (b) adding and a tertiary amine base to the mixture of step (a) to form a compound of Formula A; and (c) coupling a compound of Formula A with an amine of Formula B to form a compound of Formula I.
1. A process for preparing Compound 1:
comprising:
(a) reacting
with POCl 3 to provide
(b) reacting
to provide
(c) converting
using thionyl chloride;
(d) reacting
to form Compound 1;
wherein
is prepared by:
(e) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in a polar aprotic solvent at room temperature; and
(f) adding a mixture comprising 4-fluoroaniline and a triethyl amine in a polar aprotic solvent to the mixture of step (e).
2. The process of claim 1 , wherein
is contaminated with approximately 5 percent or less of the bisamide
3. The process of claim 2 , wherein the polar aprotic solvent in step (e) is selected from the group consisting of dichloromethane, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, dimethyl formamide, acetonitrile, and dimethyl sulfoxide, or combinations thereof.
4. The process of claim 2 , wherein the polar aprotic solvent in step (e) is isopropyl acetate, and wherein approximately 5 to 10 volumes of polar aprotic acid are used relative to volume of 1,1-cyclopropanedicarboxylic acid that is used.
5. The process of claim 2 , wherein approximately 8 volumes of polar aprotic acid are used in step (e) relative to volume of 1,1-cyclopropanedicarboxylic acid that is used.
6. The process of claim 2 , wherein approximately 1.01 to 1.2 molar equivalents of thionyl chloride are used in step (e).
7. The process of claim 2 , wherein approximately 1.05 molar equivalents of thionyl chloride are used in step (e).
8. The process of claim 2 , wherein the mixture of step (e) is stirred at ambient temperature for 2 to 24 hours.
9. The process of claim 2 , wherein the mixture of step (e) is stirred at approximately 24-26° C. for 6 to 16 hours.
10. The process of claim 2 , wherein 4-fluoroaniline and the tertiary amine base is added as a mixture in step (f).
11. The process of claim 10 , wherein the tertiary amine base is triethyl amine.
12. The process of claim 11 , wherein approximately 1.01 to 1.5 molar equivalents of 4-fluoroaniline are used relative to the number of moles of 1,1-cyclopropanedicarboxylic acid that are used and approximately 1.01 to 1.5 molar equivalents of tertiary amine base are used relative to the number of moles of 1,1-cyclopropanedicarboxylic acid that are used.
13. The process of claim 10 , wherein the polar aprotic solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, dimethylformamide, acetonitrile, and dimethylsulfoxide, or combinations thereof.
14. The process of claim 10 , wherein the polar aprotic solvent is isopropyl acetate.
15. The process of claim 10 , wherein approximately 2 volumes of isopropyl acetate are used.
16. The process of claim 10 , wherein the step (f) mixture is allowed to stir for approximately 0.75 to 4 hours at ambient temperature.
17. The process of claim 10 , further comprising quenching the mixture of step (f) with a concentrated aqueous base.
18. The process of claim 17 , wherein the aqueous base is selected from the group consisting of NaOH, KOH, or K 3 PO 4 .
19. The process of claim 1 , further comprising (g) the step of converting Compound 1 to Compound 1, L-malate salt, by reacting Compound 1 with L-malic acid.
20. A process for preparing Compound 1:
comprising:
(a) reacting
with POCl 3 to provide
(b) reacting
to provide
(c) converting
using thionyl chloride;
(d) reacting
to form Compound 1;
wherein
is prepared by:
(e) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in isopropyl acetate at room temperature, followed by adding 4-fluoroaniline and triethyl amine to the mixture, quenching the mixture with concentrated aqueous sodium hydroxide; extracting
into dilute aqueous base, acidifying the mixture with HCl, and isolating
by filtration.
21. A process for preparing Compound 1:
comprising:
(a) reacting
with POCl 3 to provide
(b) reacting
to provide
(c) converting
using thionyl chloride;
(d) reacting
to form Compound 1;
(e) reacting compound 1 with L-malic acid to form Compound 1, L-malate;
and wherein
is prepared by:
(f) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in isopropyl acetate at room temperature; and
(g) adding a mixture comprising 4-fluoroaniline and a triethyl amine in isopropyl acetate to the mixture of step (f).