Asymmetric Bisamidation of Malonic Ester Derivatives

Abstract

The present invention relates to processes, process steps and intermediates useful in the asymmetric bisamidation of malonic ester derivatives wherein the new processes, process steps and intermediates are, for example, useful in the preparation of asymmetric malonic acid bisanilides such as cabozantinib.

Claims

1. A process for preparing an asymmetric malonic acid diamide of formula (IV) ##STR00165## or a pharmaceutically acceptable salt thereof, the process comprising (i) reacting a compound of formula (I) ##STR00166## with an M.sub.a salt of a compound H.sub.2NX.sub.1, obtaining a reaction mixture comprising an M.sub.a salt of formula (II) ##STR00167## or an M.sub.a salt of formula (II) ##STR00168## or a mixture of the M.sub.a salt of formula (II) and the M.sub.a salt of formula (II); (ii) converting the M.sub.a salt of formula (II) and/or of formula (II) to the compound of formula (IV) comprising forming an amide bond between the carbon atom of the ester moiety comprised in the compound of formula (II) and/or formula (II) and the nitrogen atom comprised in a compound H.sub.2NX.sub.2; wherein R.sub.1 and R.sub.1 are alkyl or aryl, and R.sub.1 and R.sub.1 are the same or different; R.sub.2 and R.sub.3 are alkyl, alkoxy, aryl or heteroaryl and R.sub.2 and R.sub.3 are the same or different, or R.sub.2 and R.sub.3, together with the C atom at which R.sub.2 and R.sub.3 are attached, form a cycle; X.sub.1 is a substituted aromatic or heteroaromatic residue; X.sub.2 is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aromatic or heteroaromatic residue wherein X.sub.1 is different from X.sub.2; M.sub.a is an alkali or alkaline earth metal.

2. The process of claim 1, wherein R.sub.1 and R.sub.1 are the same, the process comprising (i) reacting a compound of formula (I) ##STR00169## with an M.sub.a salt of a compound H.sub.2NX.sub.1 obtaining an M.sub.a salt of formula (II) ##STR00170## (ii) converting the M.sub.a salt of formula (II) to the compound of formula (IV).

3. The process of claim 1, wherein the compound of formula (I) is ##STR00171##

4. The process of claim 1, wherein M.sub.a is Mg, Na or K.

5. The process of claim 1, wherein the compound of formula (I) is ##STR00172## the compound H.sub.2NX.sub.1 is 4-fluoroaniline and the M.sub.a salt of formula (II) is ##STR00173##

6. The process of claim 5, wherein the M.sub.a salt of formula (II) is ##STR00174##

7. The process of claim 1, wherein converting the M.sub.a salt of formula (II) and/or of formula (II) to the compound of formula (IV) according to (ii) comprises (ii.a.1) converting the M.sub.a salt of formula (II) to a compound of formula (III) ##STR00175## or the M.sub.a salt of formula (II) to a compound of formula ##STR00176## or the mixture of the M.sub.a salt of formula (II) and the M.sub.a salt of formula (II) to a mixture of the compounds of formula (III) and formula (III).

8. The process of claim 7, wherein the amide bond is formed by (ii.a.2) reacting the compound of formula (III) and/or of formula (III) with an M.sub.b salt of the compound H.sub.2NX.sub.2; wherein M.sub.b is an alkali or alkaline earth metal.

9. The process of claim 1, wherein the amide bond is formed by (ii.b.1) reacting the compound of formula (II) and/or of formula (II) with an M.sub.b salt of a compound H.sub.2NX.sub.2; wherein M.sub.b is an alkali or alkaline earth metal.

10. A process for preparing an asymmetric malonic acid diamide of formula (IV) ##STR00177## or a pharmaceutically acceptable salt thereof, the process comprising (i) reacting a compound of formula (III) ##STR00178## or a compound of formula (III) ##STR00179## or a mixture of the compound of formula (III) and the compound of formula (III) with an M.sub.b salt of a compound H.sub.2NX.sub.2, obtaining a reaction mixture comprising an M.sub.b salt of the compound of formula (IV); (ii) converting the M.sub.b salt of the compound of formula (IV) to the compound of formula (IV); wherein R.sub.1 and R.sub.1 are alkyl or aryl, and R.sub.1 and R.sub.1 are the same or different; R.sub.2 and R.sub.3 are alkyl, alkoxy, aryl or heteroaryl and R.sub.2 and R.sub.3 are the same or different, or R.sub.2 and R.sub.3, together with the C atom at which R.sub.2 and R.sub.3 are attached, form a cycle; X.sub.1 is a substituted aromatic or heteroaromatic residue; X.sub.2 is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aromatic or heteroaromatic residue wherein X.sub.1 is different from X.sub.2; M.sub.b is an alkali or alkaline earth metal.

11. (canceled)

12. The process of claim 10, wherein R.sub.2 and R.sub.3, together with the C atom at which R.sub.2 and R.sub.3 are attached, form a cycle having 3 carbon atoms.

13. The process of claim 10, wherein the compound of formula (IV) is ##STR00180## wherein X.sub.2 is a substituted aromatic or heteroaromatic residue different from para-C.sub.6H.sub.4F.

14. The process of claim 10, wherein the compound of formula (IV) is the compound ##STR00181##

15. An M.sub.a salt of formula (II) ##STR00182## wherein M.sub.a is an alkali metal.

Description

EXAMPLES

Example 1: Preparation of methyl 1-((4-fluorophenyl)carbamoyl)cyclopropane carboxylate

[0579] 4-Fluoraniline (1.11 g, 10 mmol) was dissolved in toluene (12 mL), sodium methoxide (0.54 g, 10 mmol) were added. Then the mixture was stirred 30 minutes under inert atmosphere wherein the bath temperature was raised from 80 to 100 C. and about 2 mL of azeotropic methanol/toluene mixture was evaporated. Next, dimethyl cyclopropane-1,1-dicarboxylate (1.58 g, 10 mmol) in toluene (5 mL) was added and azetropic distillation under stirring and inert gas flow was continued for another 30 minutes. Upon cooling to room temperature water (10 mL) and 1N hydrochloric acid (10 mL 1M) were added, the mixture was stirred for 10 minutes and extracted with dichloromethane (10 mL). The organic layer was dried over magnesium sulfate and the solvent was evaporated. The residue (2.07 g) was extracted with iso-pentane (1210 mL) Evaporation of the solvent provided 1.32 g (56%) of the crystalline title compound (m.p.: 76 C.).

Example 2: Preparation of N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluoro-phenyl)cyclo-propane-1,1-dicarboxamide (cabozantinib)

[0580] Experiment 1:

[0581] 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (90 mg, 0.30 mmol) and sodium methoxide (36 mg, 0.67 mmol) in toluene (5 mL) were stirred at 100 C. under inert gas flow whereby the majority of the solvent evaporated. Next, toluene (5 mL) and a solution of methyl 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylate (76 mg, 0.32 mmol) in toluene (5 mL) was added and azeotropic distillation, the bath temperature raised to 120 C. and stirring under inert gas flow was continued for another 50 minutes. Within this period additional solvent (10 mL) was added in order to compensate evaporation. Upon cooling to room temperature the residue was dissolved in ethyl acetate and washed with saturated aqueous ammonium chloride solution. The organic layer was dried over sodium sulfate und the solvent was evaporated. The residue (140 mg) was extracted with MTBE (31 mL) providing 100 mg of the title compound as a yellow solid. Purity of the material determined by .sup.1H-NMR was found to be 30%.

[0582] Experiment 2:

[0583] 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (240 mg, 0.81 mmol) and sodium methoxide (115 mg, 2.1 mmol) in toluene (15 mL) were stirred at 100 C. for 1 hour under inert gas flow whereby the majority of the solvent evaporated. Next, a solution of methyl 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylate (230 mg, 0.97 mmol) in toluene (15 mL) was added and toluene/methanol azeotrope distilled off. The bath temperature was raised to 110 C. and stirring under inert gas flow was continued for another 4 hours. Within this period additional portions of toluene (320 mL) were added in order to compensate evaporation. Upon cooling to room temperature the residue was dissolved in ethyl acetate (30 mL) and washed sequentially with saturated aqueous ammonium chloride (30 mL) and bicarbonate (10 mL) solutions. The organic layer was dried over magnesium sulfate und the solvent was evaporated. The residue was extracted with MTBE (33 mL) providing after drying in vacuo 230 mg of pure title compound as a slightly brownish powder in 62% yield. The respectively obtained material was subjected to .sup.1H-NMR analysis; the .sup.1H-NMR is shown in FIG. 1.

BRIEF DESCRIPTION OF THE FIGURES

[0584] FIG. 1 shows the .sup.1H-NMR spectrum of the material obtained from Example 2, Experiment 2.

CITED LITERATURE

[0585] WO 2005/030140 [0586] WO 2010/083414 [0587] F. D. Chattaway et al., J. Chem. Soc. 97, 339 pp. 1910 [0588] U.S. Pat. No. 5,334,747 [0589] Sechi et al., Molecules 2008, 13, pp. 2442-2461