Granted Patent B2

US 8,497,384 · App. 13/129,213 · Granted Jul 30, 2013

Abstract

Claims (32)

1. A process for the preparation of a cyclopropane derivative of Formula (I),

by reacting an olefin of Formula (II),

with a carbene of the formula:CR 1 R 2 , in a reaction vessel, optionally in the presence of a solvent, wherein,

R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocyclyl, —C(O)R 7 or —NR 8 2 ;

R 3 , R 4 , R 5 and R 6 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, aryl, aryloxy, heteroaryl, heterocyclyl, carbocyclyl, heterocyclyl, —C(O)R 9 , —NR 10 2 , —SR 11 , —S(O)R 11 , or —SO 2 R 11 , or

R 3 and R 6 are as defined above and R 4 and R 5 together form a ring, which ring is carbocyclyl, heterocyclyl, aromatic or heteroaromatic;

R 7 is hydrogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, aryloxy, heteroaryl or —NR 10 2 ;

R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, aryl, heteroaryl, carbocyclyl or heterocyclyl;

R 9 is hydrogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, aryloxy or heteroaryl;

R 10 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, aryl, heteroaryl, carbocyclyl, heterocyclyl or C(O)R 12 ;

R 11 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, aryl, heteroaryl, carbocyclyl or heterocyclyl; and

R 12 is hydrogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, or aryloxy,

in the presence of copper metal or copper oxide, wherein the process is a continuous process.

2. A process according to claim 1 , wherein a portion of an inner surface of the reaction vessel is copper metal.

3. A process according to claim 1 wherein the reaction vessel is a microreactor.

4. A process according to claim 1 , wherein a solvent is present and said solvent is recycled.

5. A process according to claim 1 , wherein no solvent is present.

6. A process according to claim 1 , wherein unreacted olefin of Formula (II) is recycled.

7. A process according to claim 1 , comprising generating the carbene in situ from a diazo compound of the formula N 2 CR 1 R 2 , wherein R 1 and R 2 are as defined in claim 1 .

8. A process according to claim 7 , further comprising the step of producing the diazo compound of the formula N 2 CR 1 R 2 , in a continuous process, and continuously with the preparation of the cyclopropane derivative of Formula (I).

9. A process according to claim 8 , wherein the diazo compound of the formula N 2 CR 1 R 2 is produced in a process utilizing at least one microreactor.

10. A process according to claim 1 , wherein the cyclopropane derivative of Formula (I) is a cyclopropane derivative of Formula (I′),

wherein R 1 , R 3 and R 6 are as defined in claim 1 .

11. A process according to claim 1 , wherein the cyclopropane derivative of Formula (I) is a cyclopropane derivative of Formula (Ia),

the olefin of Formula (II) is thiophene, the carbene of formula:CR 1 R 2 is ethoxycarbonyl carbene (:CHCO 2 Et) and the diazo compound of formula N 2 CR 1 R 2 is ethyldiazoacetate (N 2 CHCO 2 Et).

12. A process according to claim 1 , further comprising the step of isolating a cyclopropane derivative of (Ib),

from the cyclopropane derivative of Formula (Ia).

13. A process for the preparation of a cyclopropane derivative of Formula (Ia),

by reaction of thiophene with:CHCO 2 Et, generated in situ from ethyldiazoacetate (N 2 CHCO 2 Et), in a copper metal microreactor, wherein the thiophene is recycled; the ethyldiazoacetate is produced in a continuous process, utilizing at least one microreactor, and continuously with the preparation of the cyclopropane derivative of Formula (Ia).

14. A process according to claim 13 , further comprising the step of isolating a cyclopropane derivative of (Ib),

from the cyclopropane derivative of Formula (Ia).

15. A process according to claim 12 , further comprising reacting the cyclopropane derivative of formula (Ib) with a hydroxide donor to produce a compound of formula (III),

Assignments (7)