US-20260125349-A1 - PROCESS FOR THE FLUORINATION AND/OR CYCLIZATION OF AN AMINO ALKENE OR ALKYNE IN A CONTINUOUS STREAM AND FACILITY FOR PERFORMING THE PROCESS

US20260125349A1US 20260125349 A1US20260125349 A1US 20260125349A1US-20260125349-A1

Abstract

The present invention relates to a process for the fluorination and/or cyclization of an amino alkene or alkyne in a continuous-stream microreactor. The invention also relates to a facility for performing such a process.

Inventors

Zahra ABADA
Agnès MARTIN-MINGOT
Yves Bleriot
Sébastien THIBAUDEAU
Ali ABOU-HASSAN

Assignees

UNIVERSITE DE POITIERS
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
SORBONNE UNIVERSITE

Dates

Publication Date: 20260507
Application Date: 20231003
Priority Date: 20221004

Claims (14)

1 - 13 . (canceled)
14 . A process for the fluorination and/or cyclization of an amino alkene or alkyne, involving: a) providing a first phase comprising an amino alkene or alkyne and a second phase comprising a superacid reagent, b) placing the first and second phases in contact in a continuous-flow microreactor, and c) recovering the fluorination and/or cyclization product of said amino alkene or alkyne.
15 . The process according to claim 14 , characterized in that: the residence time of the first phase and the second phase in the continuous-flow microreactor in step (b) is between 2 seconds and 400 seconds, and/or the flow rate of the first phase and the flow rate of the second phase in step (b) are independently between 0.1 mL/min and 3.5 mL/min.
16 . The process according to claim 14 , characterized in that the continuous-flow microreactor comprises a micro-mixer and a tubular pipe, in which the tubular pipe has: a length of between 20 cm and 800 cm, and an inside diameter of between 0.5 mm and 2.5 mm.
17 . The process according to claim 14 , characterized in that it is performed in a facility comprising: a storage unit for a first phase comprising an amino alkene or alkyne, a storage unit for a second phase comprising a superacid reagent, a first phase continuous feed means connected to the first phase storage unit, and to a first phase equilibration tubular pipe, a second phase continuous feed means connected to the second phase storage unit and to a second phase equilibration tubular pipe, a continuous-flow microreactor comprising a micro-mixer comprising two inlets and one outlet, and a tubular pipe comprising one inlet and one outlet, in which the inlet of the tubular pipe is connected to the outlet of the micro-mixer, in which the first phase equilibration tubular pipe is connected to the first inlet of the micro-mixer and the second phase equilibration tubular pipe is connected to the second inlet of the micro-mixer, and a collection unit, connected to the outlet of the tubular pipe of the microreactor.
18 . The process according to claim 14 , characterized in that the superacid reagent is selected from the group consisting of HF/MF 5 and HSO 3 F/MF 5 , where M is Sb, As, P, Ta, or Nb.
19 . The process according to claim 14 , characterized in that said amino alkene or alkyne is an allyl or propargyl amine.
20 . The process according to claim 19 , characterized in that said amino alkene or alkyne is an amino alkene of formula (Ia): in which: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 12 heteroalkyl, C 3 -C 12 cycloalkyl, C 2 -C 12 heterocycloalkyl, aryl, heteroaryl, a group —S(O) 2 —R 8 and a group —C(O)—R 9 , where R 8 and R 9 are chosen independently from C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 12 heteroalkyl, C 3 -C 12 cycloalkyl, C 2 -C 12 heterocycloalkyl, aryl, and heteroaryl, said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups being optionally substituted, or two groups each chosen from R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 may alternatively form, together with the atom(s) to which they are attached, an optionally substituted 3- to 12-membered ring.
21 . The process according to claim 20 , characterized in that: R 1 and R 2 are selected independently from a hydrogen, a C 2 -C 12 alkenyl, an aryl, optionally substituted with a C 1 -C 6 alkyl, a nitro, or a fluoro group selected from the group consisting of —CF 3 , —OCF 3 , —SCF 3 , —OCF 2 R′, —OCF(R′) 2 , —SCF 2 R′ and —SCF(R′) 2 where each R′ independently represents a hydrogen, a halogen, a C 1 -C 6 alkyl, a C 2 -C 6 alkenyl, a C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, —S(O) 2 —R 8 and —C(O)—R 9 , where R 8 and R 9 are independently aryl optionally substituted with C 1 -C 6 alkyl, nitro or a fluoro group chosen from —CF 3 , —OCF 3 , —SCF 3 , —OCF 2 R′, —OCF(R′) 2 , —SCF 2 R′ and —SCF(R′) 2 where each R′ independently represents hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or a C 3 -C 6 cycloalkyl, or alternatively R 1 and R 2 , together with the atom to which they are attached, form a piperidine or piperazine, optionally substituted with an aryl or an acetyl, R 3 and R 4 are hydrogens, and R 5 , R 6 and R 7 are independently selected from the group consisting of hydrogen and halogen.
22 . The process according to claim 19 , characterized in that said amino alkene or alkyne is an amino alkyne of formula (Ib): in which: R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 12 heteroalkyl, C 3 -C 12 cycloalkyl, C 2 -C 12 heterocycloalkyl, aryl, heteroaryl, a group —S(O) 2 —R 8 and a group —C(O)—R 9 , where R 8 and R 9 are selected independently from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 12 heteroalkyl, C 3 -C 12 cycloalkyl, C 2 -C 12 heterocycloalkyl, aryl, and heteroaryl, said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups being optionally substituted, or two groups each selected from the group consisting of R 1 , R 2 , R 3 , R 4 and R 5 may alternatively form, together with the atom(s) to which they are attached, an optionally substituted 3- to 12-membered ring.
23 . The process according to claim 22 , characterized in that: R 1 and R 2 are selected independently from the group consisting of a hydrogen, a C 2 -C 12 alkenyl, an aryl, optionally substituted with a C 1 -C 6 alkyl, a nitro, or a fluoro group chosen from —CF 3 , —OCF 3 , —SCF 3 , —OCF 2 R′, —OCF(R′) 2 , —SCF 2 R′ and —SCF(R′) 2 where each R′ independently represents a hydrogen, a halogen, a C 1 -C 6 alkyl, a C 2 -C 6 alkenyl, a C 2 -C 6 alkynyl or a C 3 -C 6 cycloalkyl, —S(O) 2 —R 8 and —C(O)—R 9 , where R 8 and R 9 are independently aryl optionally substituted with C 1 -C 6 alkyl, nitro or a fluoro group selected from the group consisting of —CF 3 , —OCF 3 , —SCF 3 , —OCF 2 R′, —OCF(R′) 2 , —SCF 2 R′ and —SCF(R′) 2 where each R′ independently represents hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or a C 3 -C 6 cycloalkyl, or alternatively R 1 and R 2 , together with the atom to which they are attached, form a piperidine or piperazine, optionally substituted with an aryl or an acetyl, and R 3 , R 4 and R 5 are hydrogens.
24 . The process according to claim 19 , characterized in that said amino alkene or alkyne is selected from the group consisting of:
25 . A facility for performing the process according to claim 14 , characterized in that it comprises: a storage unit for a first phase comprising an amino alkene or alkyne, a storage unit for a second phase comprising a superacid reagent, a first phase continuous feed means connected to the first phase storage unit, and to a first phase equilibration tubular pipe, a second phase continuous feed means connected to the second phase storage unit and to a second phase equilibration tubular pipe, a continuous-flow microreactor comprising a micro-mixer comprising two inlets and one outlet, and a tubular pipe comprising one inlet and one outlet, in which the inlet of the tubular pipe is connected to the outlet of the micro-mixer, in which the first phase equilibration tubular pipe is connected to the first inlet of the micro-mixer and the second phase equilibration tubular pipe is connected to the second inlet of the micro-mixer, and a collection unit, connected to the outlet of the tubular pipe of the microreactor, in which the tubular pipe of the continuous-flow microreactor has: a length of between 20 cm and 800 cm, and an inside diameter of between 0.5 and 2.5 mm.
26 . The facility according to claim 25 , characterized in that it also comprises: a 3-way valve providing the connection between the first phase continuous feed means, the first phase storage unit, and the first phase equilibration tubular pipe, and/or a 3-way valve providing the connection between the second phase continuous feed means, the second phase storage unit and the second phase equilibration tubular pipe.

Description

SUBJECT OF THE INVENTION The present invention relates to a process for the fluorination and/or cyclization of an amino alkene or alkyne in a continuous-stream microreactor. The invention also relates to a facility for performing such a process. BACKGROUND OF THE INVENTION In a superacid medium, H0 acidity values are lower than −12, and as such all molecules, even simple alkanes, react as bases. Superacid systems are therefore of great interest because they give access to a particular type of reactivity involving polyprotonated molecules. Numerous processes have been developed in a superacid medium in recent years, and may be envisaged for both laboratory-scale and industrial-scale synthesis. For example, Michelet et al. describes processes for fluorinating amino alkenes or alkynes using the superacid HF/SbF5 (J. Fluorine Chem. 2018, 214, 68-79). This transformation is most particularly interesting because it allows access to fluoro amine units, which are sought after in medicinal chemistry. Moreover, WO 95/03312 shows that vinorelbine can be converted into the anticancer agent Javlor® via a gem-difluorination reaction in the presence of the superacid HF/SbF5. However, these systems have a number of drawbacks that limit their use. In particular, the reagents that generate a superacid medium, such as HF, are toxic, corrosive and hazardous to handle. In addition, many solvents and nucleophiles are not compatible with these media. Finally, the high reactivity of these systems does not make it possible to control the outcome of the reactions: cascade reactions and polyfluorination may be observed. There is thus a real need to develop a process that facilitates the handling of superacids and allows better control of their reactivity, most particularly when they are placed in contact with an amino alkyne or alkene. In this context, the Applicant has shown that the use of microfluidics, and more specifically of a continuous-flow microreactor, allows these limitations to be overcome. More specifically, it has been shown, surprisingly, that the use of a continuous-flow microreactor allows the preparation of fluorinated or cyclized compounds, which are difficult to access or even inaccessible via an equivalent reaction under static (or “batch”) conditions. It has also been shown that the productivity of these reactions under flow conditions was much higher than that obtained under static conditions. SUMMARY OF THE INVENTION The invention thus relates to a process for the fluorination and/or cyclization of an amino alkene or alkyne, involving: a) providing a first phase comprising an amino alkene or alkyne and a second phase comprising a superacid reagent,b) placing the first and second phases in contact in a continuous-flow microreactor, andc) recovering the fluorination and/or cyclization product of said amino alkene or alkyne. In a particular embodiment, the residence time of the first phase and the second phase in the continuous-flow microreactor in step (b) is between 2 seconds and 400 seconds. In a particular embodiment, the flow rate of the first phase and the flow rate of the second phase in step (b) are independently between 0.1 mL/min and 3.5 mL/min, for example between 0.25 m/min and 3.0 mL/min. In a particular embodiment, the continuous-flow microreactor comprises a micro-mixer and a tubular pipe, in which the tubular pipe preferably has: a length of between 20 cm and 800 cm, andan inside diameter of between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and better still between 0.7 mm and 1.2 mm. In a particular embodiment, the placing in contact in the continuous-flow microreactor is performed at a temperature of between −70° C. and 25° C. In a particular embodiment, the process according to the invention is performed in a facility comprising: a storage unit (1) for a first phase comprising an amino alkene or alkyne,a storage unit (1′) for a second phase comprising a superacid reagent,a first phase continuous feed means (3) connected to the first phase storage unit (1), and to a first phase equilibration tubular pipe (4),a second phase continuous feed means (3′) connected to the second phase storage unit (1′) and to a second phase equilibration tubular pipe (4′),a continuous-flow microreactor (2) comprising a micro-mixer (21) comprising two inlets and one outlet, and a tubular pipe (22) comprising one inlet and one outlet, in which the inlet of the tubular pipe (22) is connected to the outlet of the micro-mixer (21), in which the first phase equilibration tubular pipe (4) is connected to the first inlet of the micro-mixer (21) and the second phase equilibration tubular pipe (4′) is connected to the second inlet of the micro-mixer (21), and a collection unit (5), connected to the outlet of the tubular pipe (22) of the microreactor (2). In a particular embodiment, the superacid reagent is chosen from HF/MF5 and HSO3F/MF5, where M is Sb, As, P, Ta, or Nb; preferably the superacid reagent is HF/Sb