Continuous flow processes for making bicyclic compounds

Patent metadata

Field	Value
Publication number	US-11339103-B2
Application number	US-201816644640-A
Country	US
Kind code	B2
Filing date	Sep 6, 2018
Priority date	Sep 11, 2017
Publication date	May 24, 2022
Grant date	May 24, 2022

Abstract

Processes for making bicyclic compounds and precursors thereof, and particularly for making [1.1.1]propellane and bicyclo[1.1.1]pentane and derivatives thereof, utilize continuous flow reaction methods and conditions. A continuous process for making [1.1.1]propellane can be conducted under reaction conditions that advantageously minimize clogging of a continuous flow reactor. A continuous flow process can be used to make precursors of [1.1.1]propellane.

First claim

What is claimed is:

1. A continuous flow process for making a bicyclic compound, comprising mixing 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with an organometallic reagent in a continuous flow reactor to thereby form a reagent mixture; and mixing the reagent mixture with a static mixer in the continuous flow reactor under first reaction conditions selected to react the 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane with the organometallic reagent to produce [1.1.1]propellane and a salt; wherein the static mixer provides a mixing rate that is effective to minimize clogging of the continuous flow reactor by the salt.

2. The process of claim 1 , wherein the organometallic reagent is selected from the group consisting of n-butyllithium, methyllithium, methyllithium lithium bromide complex, and phenyllithium.

3. The process of claim 1 , wherein the salt comprises LiCl, LiBr, or both.

4. The process of claim 1 , wherein the first reaction conditions comprise mixing a solvent with the 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane and the organometallic reagent in the continuous flow reactor, wherein the solvent is selected from the group consisting of diethylether, diethoxymethane, dibutylether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and mixtures thereof.

5. The process of claim 1 , wherein the continuous flow reactor comprises a first stage and a second stage.

6. The process of claim 5 , wherein the reaction conditions further comprise a first reaction temperature in the range of about −50° C. to about 0° C. during the first stage.

7. The process of claim 6 , wherein the reaction conditions further comprise a second reaction temperature in the range of about −10° C. to about 25° C. during the second stage.

8. The process of claim 5 , wherein the continuous flow reactor further comprises a third stage.

9. The process of claim 8 , wherein the third stage comprises mixing an aqueous composition with the produced [1.1.1]propellane and the salt in the continuous flow reactor to form a salt-containing aqueous phase.

10. The process of claim 9 , wherein the aqueous composition comprises a buffer.

11. The process of claim 9 , further comprising separating the salt-containing aqueous phase from the produced [1.1.1]propellane to thereby produce a [1.1.1]propellane composition.

12. The process of claim 8 , wherein the third stage comprises distilling the produced [1.1.1]propellane to thereby produce a [1.1.1]propellane composition.

13. The process of claim 11 , further comprising mixing the [1.1.1]propellane composition with 2,3-butanedione in the continuous flow reactor under second reaction conditions selected to react the produced [1.1.1]propellane with the 2,3-butanedione to produce 1,3-diacetylbicyclo[1.1.1]pentane, wherein the second reaction conditions comprise exposing the produced [1.1.1]propellane and the 2,3-butanedione to a light source.

14. The process of claim 13 , wherein the light source is a source of radiation in the range of about 350 nm to about 380 nm.

15. The process of claim 13 , wherein the light source comprises a light emitting diode.

16. The process of claim 1 , further comprising mixing the produced [1.1.1]propellane with a magnesium amide reagent in the continuous flow reactor under second reaction conditions selected to react the produced [1.1.1]propellane with the magnesium amide reagent to produce a compound of Formula (I):

wherein R 1 and R 2 are each individually selected from the group consisting of hydrogen, an optionally substituted C 1-10 alkyl, an optionally substituted C 3-10 monocyclic cycloalkyl, an optionally substituted C 6-10 aryl, an optionally substituted (C 6-10 aryl)alkyl, an optionally substituted C 5-10 heteroaryl, an optionally substituted (C 5-10 heteroaryl)alkyl, phenyl and benzyl; or R 1 , R 2 and the nitrogen to which they are attached together form an optionally substituted heterocyclyl.

17. The process of claim 16 , wherein the magnesium amide reagent comprises at least one selected from R 1 R 2 NMgCl, R 1 R 2 NMgBr, R 1 R 2 NMgCl.LiCl and R 1 R 2 NMgBr.LiBr.

18. The process of claim 1 , further comprising mixing the produced [1.1.1]propellane with a reagent of the formula R 3 -MX 1 and a compound of the formula R 4 —X 22 in the continuous flow reactor under second reaction conditions selected to react the produced [1.1.1]propellane with the reagent of the formula R 3 -MX 1 and the compound of the formula R 4 —X 2 to produce a compound of Formula (II):

wherein R 3 is selected from the group consisting of an optionally substituted C 1-10 alkyl, an optionally substituted C 2-10 alkenyl, an optionally substituted C 3-10 cycloalkyl, an optionally substituted C 5-10 cycloalkenyl, an optionally substituted C 6-10 aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl;
wherein R 4 is selected from the group consisting of an optionally substituted C 1-10 alkyl, an optionally substituted C 2-10 alkenyl, an optionally substituted C 3-10 cycloalkyl, an optionally substituted C 5-10 cycloalkenyl, an optionally substituted C 6-10 aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl
wherein X 1 and X 2 are each independently selected from the group consisting of a halide and a pseudohalide;
wherein M is magnesium or lithium; and
wherein the second reaction conditions comprise the presence of a transition metal catalyst that is selected from the group consisting of a Pd catalyst and a Ni catalyst.

19. The process of claim 18 , wherein the second reaction conditions comprise mixing a zinc salt with the produced [1.1.1]propellane, the reagent of the formula R 3 -MX 1 and the compound of the formula R 4 —X 2 in the continuous flow reactor prior to mixing with the transition metal catalyst.

20. The process of claim 1 , further comprising mixing the produced [1.1.1]propellane with a compound of the formula R 5 —X 3 and carbon dioxide in the continuous flow reactor under second reaction conditions selected to react the produced [1.1.1]propellane with the compound of the formula R 5 X 3 and the carbon dioxide to produce a compound of Formula (III):

wherein R 5 is selected from the group consisting of an optionally substituted C 1-10 alkyl, an optionally substituted C 2-10 alkenyl, an optionally substituted C 3-10 cycloalkyl, an optionally substituted C 5-10 cycloalkenyl, an optionally substituted C 6-10 aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl; and
wherein X 3 is selected from the group consisting of a lithium halide, a lithium pseudohalide, a zinc halide, a zinc pseudohalide, a magnesium halide, and a magnesium pseudohalide.

21. The process of claim 1 , further comprising mixing the produced [1.1.1]propellane with a compound of the formula R 5 —X 3 and a compound of the formula X 4 —CO 2 R 6 in the continuous flow reactor under second reaction conditions selected to react the produced [1.1.1]propellane with the compound of the formula R 5 X 3 and the compound of the formula X 4 —CO 2 R 6 to produce a compound of Formula (IV):

Assignees

• Recurium Ip Holdings Llc

Inventors

• Pinchman Joseph Robert
• Bunker Kevin Duane
• Bio Matthew M
• Breen Christopher
• Clausen Andrew M
• Fang Yuanqing
• Li Hui
• Sheeran Jillian W

Classifications

• C07C13/605

  with a bridged ring system · CPC title

• C07C209/02

  by substitution of hydrogen atoms by amino groups · CPC title

• C07C2602/38

  the bicyclo ring system containing five carbon atoms · CPC title

• C07D209/08 Primary

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring · CPC title

• C07C2603/62

  containing three- or four-membered rings · CPC title