Apparatus and process for the automated chemical synthesis of compounds

Abstract

Provided is an process for the automated synthesis of at least one chemical compound including providing at least one substrate in at least one solvent in the at least one reaction container; automatically passing the at least one substrate through at least one first compartment of the at least one cartridge once or several times and collecting a formed substrate-reagent intermediate product in the at least one reaction container prior to passing the substrate-reagent intermediate product into a subsequent compartment; automatically passing the substrate-reagent intermediate product through at least one second compartment once or several times and collecting a formed reaction product prior to passing the reaction product into a subsequent compartment; automatically passing the reaction product through at least one third compartment for purifying the product once or several times and collecting a purified product in the at least one reaction container.

Claims

1. A process for the automated synthesis of chemical compounds, comprising: providing an apparatus comprising: (a) at least one solvent container for storing solvent system(s) used for at least one compartment of at least one cartridge, the at least one solvent container comprising at least one solvent reservoir, the at least one solvent reservoir having an inlet and an outlet, (b) at least one reaction container for providing compound(s) to be fed into at least one of the compartments of the at least one cartridge and/or collecting reaction product(s) from at least one of the compartments of the at least one cartridge, the at least one reaction container having an inlet and an outlet; (c) at least one first valve for selecting a liquid source from the at least one solvent reservoir or the at least one reaction container, the at least one first valve having an inlet connected to the outlet of the at least one solvent reservoir and the outlet of the at least one reaction container, and an outlet connected to a pump inlet; (d) at least one pump comprising a first pump comprising the pump inlet for receiving liquid from the outlet of the first valve and a pump outlet connected to an inlet of at least one second valve for directing the liquid received from the at least one first valve to the at least one second valve either directly or through optional pump(s) of the at least one pump; (e) the at least one second valve for directing the liquid received from the at least one pump to an inlet of at least one compartment of the at least one cartridge or the inlet of the at least one reaction container, the at least one second valve having the inlet for receiving the liquid from the at least one pump, and an outlet connected to the inlet of the at least one compartment of the at least one cartridge and the inlet of the at least one reaction container; (f) at least one cartridge comprising: (i) at least one first compartment for providing at least one first reagent for the chemical synthesis of the at least one compound, the at least one first compartment having the inlet connected to the outlet of the at least one second valve, and an outlet connected to the at least one reaction container for passing a formed substrate-reagent intermediate product into the at least one reaction container; (ii) at least one second compartment for providing at least one second reagent for the chemical synthesis of the at least one compound, the at least one second compartment having an inlet for receiving the substrate-reagent intermediate product from the outlet of the at least one reaction container, and an outlet connected to the inlet of the at least one reaction container for passing a formed reaction product into the at least one reaction container, and (iii) at least one third compartment for purifying the at least one synthesized compound, the at least one third compartment having an inlet connected to the outlet of the reaction container for receiving the formed reaction product from the outlet of the first reaction container, and an outlet connected to the inlet of the at least one reaction container for passing the purified product into the at least one reaction container, at least one heating unit for heating at least one of the first compartment or the second compartment, at least one stirring unit for stirring the at least one reaction container, and a controller programmed to operate and control the at least one first valve, the at least one second valve, the pump, the at least one heating unit, and the at least one stirring unit; providing at least one substrate in at least one solvent in the at least one reaction container; controlling the at least one first valve, the at least one second valve and the pump with the controller to automatically pass the at least one substrate through the at least one first compartment comprising the first reagent as at least one immobilized reagent once or several times, controlling the temperature of the at least one substrate with the controller to form a substrate-reagent intermediate product, and controlling the at least one first valve, the at least one second valve and the pump with the controller to collect the formed substrate-reagent intermediate product prior to passing the substrate-reagent intermediate product into a subsequent compartment; controlling the at least one first valve, the at least one second valve and the pump with the controller to automatically pass the substrate-reagent intermediate product through at least one second compartment comprising at least one catalyst as the second reagent once or several times, controlling the temperature of the substrate-reagent intermediate product with the controller to form a reaction product, and controlling the at least one first valve, the at least one second valve and the pump with the controller to collect the formed reaction product prior to passing the reaction product into a subsequent compartment; and controlling the at least one first valve, the at least one second valve and the pump with the controller to automatically pass the reaction product through at least one third compartment comprising at least one ion exchange support for purifying the reaction product once or several times and collect the purified product.

2. The process according to claim 1, wherein the process further comprises controlling the at least one first valve, the at least one second valve and the pump with the controller to automatically pass the reaction product formed in the at least one second compartment through at least one compartment C comprising at least one scavenging matrix for removing the at least one catalyst from the reaction product and collect a second reaction product prior to passing the second reaction product into the at least one third compartment.

3. The process according to claim 1 for the automated synthesis of a chemical compound comprising at least one N-heterocyclic structure, wherein the substrate comprises at least one aldehyde of the general formulae (IIa) R.sup.8CHO or at least one ketone of the general formulae (IIb) R.sup.8R.sup.9CO, wherein R.sup.8 and R.sup.9 are selected from a group comprising alkyl, alkenyl, cycloalkyl, cycloalkenyl, COOR.sup.12 (R.sup.12 being alkyl), aryl, heteroaryl, which are in each case non-substituted or substituted; or where R.sup.8 and R.sup.9 are joined to form an alkyl ring system, which can be interrupted by one or multiple oxygen atoms, sulphur atoms, substituted and/or unsubstituted nitrogen atoms and/or by one or multiple groups of the type C(O)O, OC(O), C(O), NHC(O)O, OC(O)NH and/or OC(O)O, wherein the at least one first compartment comprises at least one immobilized Sn-containing reagent of general formulae (Ia) or general formulae (Ib), wherein general formulae (Ia) is R.sup.1R.sup.2R.sup.3SnCH.sub.2X(CR.sup.4R.sup.5).sub.n(CR.sup.6R.sup.7).sub.mNY-carrier and general formulae (Ib) is R.sup.1R.sup.2R.sup.3SnCHXR.sup.10(CR.sup.4R.sup.5).sub.n(CR.sup.6R.sup.7).sub.mNY-carrier, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.10 are selected from a group comprising alkyl, wherein R.sup.1, R.sup.2, R.sup.3 can be the same or different; X is selected from a group comprising O, protected N, S; R.sup.4, R.sup.5, R.sup.6, R.sup.7 are selected from a group comprising H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7 can be the same or different; and/or at least one of R.sup.4, R.sup.5 and at least one of R.sup.6, R.sup.7 together form an alkyl or (hetero-) aryl ring system, or at least two of R.sup.4 and R.sup.5 or at least two of R.sup.6, R.sup.7 together form a alkyl or aryl spirocyclic ring system, which can be interrupted by one or multiple oxygen atoms, sulphur atoms, substituted and/or unsubstituted nitrogen atoms and/or by one or multiple groups of the type C(O)O, OC(O), C(O), NHC(O)O, OC(O)NH and/or OC(O)O, n, m=1-6, YP(R.sup.11).sub.2, wherein R.sup.11 can be at least one alkyl or aryl, carrier is a polymer or a silica compound wherein the at least one second compartment comprises at least one cyclization catalyst and the formed reaction product comprises at least one N-heterocyclic compound of the general formulae (IIIa); (IIIb) or (IIIc), wherein the at least one third compartment comprises at least one cyclization catalyst scavenging matrix and the purified product comprises a cyclized catalyst free N-heterocyclic compound of the general formulae (IIIa), (IIIb) or (IIIc), wherein general formulae (IIIa) is R.sup.8CHCH.sub.2X(CR.sup.4R.sup.5).sub.n(CR.sup.6R.sup.7).sub.mNH, general formulae (IIIb) is R.sup.8R.sup.9CCH.sub.2X(CR.sup.4R.sup.5).sub.n(CR.sup.6R.sup.7).sub.mNH, and general formulae (IIIc) is R.sup.8R.sup.9CCXR.sup.10CR.sup.4R.sup.5).sub.n(CR.sup.6R.sup.7).sub.mNH.

4. The process according to claim 1, wherein the reaction product is eluted from the at least one third compartment after the cartridge is removed by the user from the apparatus.

5. The process according to claim 3, wherein the process further comprises: controlling the at least one first valve, the at least one second valve and the pump with the controller to automatically load at least one fourth compartment comprising at least one ion exchange support with the cyclized catalyst free N-heterocyclic compound of the general formulae (IIIa), (IIIb) or (IIIc), wash a loaded ion exchange support with an appropriate solvent system; elute a N-heterocyclic reaction product from an ion exchange support using an appropriate solvent system and collect the eluted N-heterocyclic reaction product.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The invention is described in more detail by means of the following examples with reference to the Figures. It shows:

(2) FIG. 1 an embodiment of an apparatus according to an embodiment of the present invention;

(3) FIG. 2A a scheme of electrical components of an apparatus for automated synthesis according to an embodiment of the present invention;

(4) FIG. 2B a general flow scheme for liquids in an apparatus according to one embodiment of the present invention;

(5) FIG. 3A an embodiment of a cartridge according to the invention;

(6) FIG. 3B a scheme of components of an apparatus according to an embodiment of the present invention;

(7) FIG. 4 a further flow scheme for liquids in an apparatus and a cartridge according to another embodiment of the present invention;

(8) FIG. 5 an embodiment of a cartridge holder; and

(9) FIG. 6 a flow chart for a process according to the present disclosure.

DESCRIPTION OF THE INVENTION

(10) In FIG. 1 an embodiment of the automatic synthesizer or apparatus is depicted. The apparatus comprises a Touchscreen 1, On/Off Button 2, two Flow path selecting valves 3a,b, a Pump 4, a heating unit 5 preferably made of Aluminum, a single cartridge 6 inserted in the section of a heated cartridge holder 7a, the non-heated section of the cartridge holder 7b.

(11) FIG. 2A shows a general scheme of the different electrical components required in the present apparatus for automated synthesis of N-heterocyclic structures. FIG. 3B shows a general scheme of components of an embodiment of the apparatus.

(12) A common 12V power supply feeds power to the central microcontroller board. It handles the whole program and directs the necessary power to the individual components. The touchscreen offers a simple, intuitive user interface and sends all commands to the microcontroller to be processed. The apparatus could also be controlled by an external interface via RS-232, RS-485 or USB. From the user commands obtained, the microcontroller operates the two flow path selecting valves, pump, heating unit and a stirring unit. The valves are commercial available components consisting of a flow path selecting Teflon valve with attached stepper motors. A commercial available pump is used here, for example a solenoid pump. The heating unit is composed of aluminum with four heating capsules inside. A temperature probe measures the current temperature and the microcontroller adjusts the heating power to the temperature set by the user. The stirring unit consists of four small inductive coils. These are magnetized in a circular fashion to propel a small magnetic stir bar in the reaction container. The machine may also contain further electrical components like a RFID reader for automatic recognition of the inserted cartridge.

(13) The scheme depict in FIG. 2B provides an overview of a general flow scheme for liquids in the automated synthesizer. The automated synthesizer uses two 8-port flow path selecting valves and a pump to handle all liquids during the process. One valve has the task of selecting the source of liquid for the pump (solvent reservoirs/reaction container). The other valve chooses the destination of the liquid or reagent (Waste Container/Reagent Compartments/Reaction Container).

(14) The basic concept of the present invention is explained by means of the embodiment of a cartridge shown in FIG. 3 and the process flow chart in FIG. 6. In the basic concept there is one cartridge which is separated into several, at least three compartments. The cartridge contains at least one compartment for each of the three steps (Reagent compartment, second reagent compartment, Purification compartment).

(15) The substrate can be delivered neat or a substrate concentration range of between 0.1 and 1.0 mmol can be used. The machine is capable of dissolving the substrate given to adjust it to the required concentration. The substrate reacts with the reagent in the reagent compartment and the resulting reagent is released from the solid support. Therefore only the desired amount of reagent is released avoiding any contamination with excess reagent. According to the example in FIG. 3A 0.2 mmol substrate reacts in the reagent compartment containing 1.0 mmol reagent on a polymer support. Only 0.2 mmol is then released as [substrate-reagent]intermediate product. 0.8 mmol reagent remains on polymer support in the reagent compartment.

(16) The substrate-reagent intermediate product is then fed into a second reagent (a catalyst or stoichiometric reagent) compartment and the desired product is formed and collected in a reaction container. The product containing impurities is then fed into the purification compartment containing a commercial purification resin/matrix and the purified product is collected.

(17) The flow scheme of FIG. 4 shows an embodiment of the invention. Here the cartridge comprises four compartments A-D. The inlets of each of the compartments are coupled to one flow path selecting valve (left valve 3b). Said left valve 3b selects the flow of the liquid or substrate into one of the four compartments. Outlet 1 of the left valve 3b is coupled to compartment A, outlet 2 is coupled to the inlet of compartment B, outlet 3 is coupled to the inlet of compartment C and outlet 4 is coupled to the inlet of compartment D. The outlets of each of the compartments A-D are connected to a reaction container which contains a stirring element. The other valve (right valve 3a) selects the source of liquid for the pump (solvent reservoirs/reaction container).

(18) The cartridge holder shown in FIG. 5 comprises two sections: a heated metal section 7a and a non-heated section 7b made of polypropylene. The cartridge 6 comprising the four compartments A-D is inserted into the holder such that compartments A-C are placed in the heated section 7a and compartment D is placed in the non-heated section 7b.

(19) Example Procedure:

(20) a) Step A: Imine/Ketimine Formation

(21) To start the process a user has to insert a new cartridge into the cartridge holder and provide the aldehyde or ketone (0.1 to 0.5 mmol) in the defined reaction container containing a small magnetic stir bar into the holder in the machine. The synthesizer adds solvent (4 mL DCM or DCE) to the starting material from the solvent reservoir by flowing it through compartment A of the cartridge containing 1.5 mmol of the immobilized SnAP reagent.

(22) ##STR00010##

(23) Afterwards the solution is pumped through compartment A via circular flow for 15 min at 60 C. to form the imine. The residual reagent in compartment A is then washed out with 4 mL DCM or DCE from the solvent reservoir to the reaction container.

(24) b) Step B: Cyclization

(25) To this solution 2 mL HFIP and 2,6-lutidine (0.5 mmol) are added from the solvent reservoirs through compartment B of the cartridge, containing 200 mg Cu(OTf).sub.2, into the reaction container. The mixture is then pumped through compartment B via circular flow for 30 min at 60 C. while stirring the reaction container. The residual reagent in compartment B is then washed out with 4 mL DCM or DCE from the solvent reservoir to the reaction container.

(26) ##STR00011##

(27) Examples of cyclization products include

(28) ##STR00012##
c) Step C: Scavenging

(29) The product containing solution in the reaction container is then pumped through the compartment C containing 500 mg Cu scavenging resin for 10 min at 60 C. via circular flow to remove copper compounds in the mixture. The residual reagent in compartment C is then washed out with 4 mL DCM or DCE from the solvent reservoir to the reaction container.

(30) ##STR00013##
d) Step D: Product Purification

(31) For purification of the product the mixture is pumped through the product catch compartment D, containing 1 g of ion exchange resin, for 10 min at room temperature to catch all product on the resin. The solid support is then washed with 10 mL of MeOH from the solvent reservoir to wash out all impurities.

(32) The waste solution in the reaction container is then pumped into the waste and the container itself is washed with DCM and MeOH from the solvent reservoir which is then pumped into the waste as well.

(33) In the last step the product on the resin is eluted from compartment D using a solution of NH.sub.3 in MeOH (5 mL, 0.1 M) from the solvent reservoirs into the reaction container.

(34) Alternatively the product containing cartridge can be removed by the user and compartment D purged with NH.sub.3 in MeOH to release the product manually.

(35) ##STR00014##

(36) The following table summarizes the process step-by-step. The SnAP process is run in a single flask system using 0.5 mmol aldehyde as a substrate. The numbers for valve A and B refer to the port number that the rotary valve is set to. The pump speed value refers to an arbitrary set value (1-20), which reflects speed values between 0% and 100% of the maximum speed.

(37) The concentration refers to the concentration of the aldehyde or its conversion products. The concentration decreases over time since a small volume of solvent is added in some steps to wash the compartments.

(38) TABLE-US-00001 valve valve pump Add magnetic Conc. B A speed solvent time stirrer heater Remarks (M) 1 1 8 4 mL off 60 C. add 0.125 solvent/dissolve aldehyde 1 2 10 10 min off 60 C. imine or ketimine 0.125 formation 1 1 8 4 mL off 60 C. wash 0.042 compartment A 2 3 8 2 mL on, speed = 13 60 C. add HFIP and 0.036 ligand 2 2 10 30 min on, speed = 13 60 C. cyclization by 0.036 flow through compartment B 2 4 8 4 mL on, speed = 13 60 C. wash 0.023 compartment B 3 2 10 10 min off 60 C. metal removing 0.023 in compartment C 3 4 8 4 mL off 60 C. wash 0.019 compartment C 4 2 10 5 min off rt product catch on 0.019 solid support in compartment D 4 5 8 10 mL off rt washing away N/A impurity of compartment D