Flow chemical process for preparing azabicyclic heteroaryl

Abstract

The present disclosure relates to a continuous flow process for the synthesis of heterocyclic ketone compounds, and in particular 3 '-substituted 3-hydroxy-(8-aza-bicyclo [3.2. 1] oct-8-yl)-[5-(1h-pyrazol-4-yl)-thiophen-3-yl]-ketone compounds and aza-bicyclo intermediates thereof. In particular, the present disclosure also relates to a continuous flow process that can be used in the synthesis of Xanamem.

Description

Technical Field

[0001] This disclosure generally relates to a continuous flow process for synthesizing heterocyclic ketone compounds, and more specifically to 3'-substituted 3-hydroxy-(8-aza-bicyclo[3.2.1]oct-8-yl)-[5-(1h-pyrazol-4-yl)-thiophen-3-yl]-ketone compounds and their aza-bicyclo intermediates. Background Technology

[0002] Synthetic organic chemists have devised numerous methods for preparing organic compounds. However, despite the wide range and variety of known reactions, most have been developed under batch reaction conditions and are still largely in practice.

[0003] Specifically, the synthesis of aziridine-bicyclic heteroaryl moieties, such as nortropinone moieties, is typically carried out under batch conditions. These aziridine-bicyclic heteroaryl moieties are common intermediates in the synthesis of many pharmaceutical compounds, including Xanamem.

[0004] Xanamem, also known as UE2343, is a potent inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Due to its inhibitory effect and associated reduction in cortisol levels, Xanamem has been proposed for the treatment of Alzheimer's disease and depression.

[0005]

[0006] To date, reported processes for the preparation of Xanamem and related analogues involve coupling the pyrimidine moiety with an azabicyclic heteroaryl moiety, particularly the nortropinone moiety. A significant drawback of this step is that known methods require the use of highly reactive species, such as organolithium reagents. Furthermore, the addition of organolithium reagents to the reaction mixture induces an exothermic reaction, thereby increasing the temperature of the reaction mixture upon its addition. Therefore, the reaction is typically carried out cautiously at low temperatures (e.g., -80°C or lower) and requires slow addition of reagents. While such processing methods may be suitable for small-scale synthesis, this reaction is not well-suited for scaling up. The required slow addition of reagents leads to scale-dependent reaction behavior due to the formation of local hot spots, stoichiometric imbalances, and the accumulation of reactive and potentially unstable intermediates. Additionally, maintaining the necessary reaction conditions (e.g., low reaction temperatures) is costly and difficult when preparing large quantities of Xanamem, and increases safety risks due to thermal runaway.

[0007] Therefore, there remains a need for safe, efficient, and scalable synthesis of Xanamem and related analogues, in which the generation of any undesirable byproducts is significantly reduced or avoided, thereby achieving high yields and purity. Summary of the Invention

[0008] It has been surprisingly discovered that nitrogen-based bicyclic heteroaryl compounds can be prepared using a continuous flow process.

[0009] On the one hand, a continuous flow process is provided for preparing a nitrogen-containing bicyclic compound of formula 1 or its salts:

[0010]

[0011] The continuous flow process includes the nortropinone compound of formula 2:

[0012]

[0013] With the halogenated compounds of Formula 3:

[0014] XR 1

[0015] Formula 3;

[0016] Organolithium reactions in the presence of organolithium reagents; where R 1 It is a monocyclic or bicyclic heteroaryl group, either unsubstituted or substituted by one or more substituents selected from the group consisting of: halogens, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -OC 1-6 Halogenated alkyl; R 2 It is an amine protecting group; and X is a halogen.

[0017] Those skilled in the art will understand that numerous variations and / or modifications can be made to the above embodiments without departing from the broad general scope of this disclosure. Therefore, the embodiments of the present invention should be considered illustrative rather than restrictive in all respects. Attached Figure Description

[0018] Figure 1 Calibration curves were plotted to show the linear response (and gradient) between the mass ratio of N-boc-nortropinone to biphenyl (internal standard) and the HPLC area ratio.

[0019] Figure 2 The calibration was depicted to show the linear response (and gradient) between the mass ratio of 2-iodopyrimidine to biphenyl (internal standard) and the HPLC area ratio.

[0020] Figure 3 A calibration curve was plotted showing the linear response (and gradient) between the mass ratio of product EU1G relative to biphenyl (internal standard) and the HPLC area ratio.

[0021] Figure 4 Example calibration chromatograms showing all three reaction components and biphenyl (internal standard) are depicted.

[0022] Figure 5 Experimental setup A is described.

[0023] Figure 6 Experimental setup B is described.

[0024] Figure 7 Experimental setup C is described.

[0025] Figure 8 Chromatograms of the reaction mixture after flow reaction using MeLi·LiBr were depicted. All known substances were labeled. The peak at 3.95 min is likely a product of the reaction between MeLi and N-boc-nortropinone. The small byproduct peak at 3.44 min cannot be assigned to any particular structure.

[0026] Figure 9 Chromatograms of the reaction mixture after the flow reaction with HexLi were depicted. No peak was observed at 3.95 min in the reaction with HexLi, but a peak was observed at 9.76 min, which likely corresponds to the addition of HexLi to N-boc-nortropinone.

[0027] Figure 10 The flowchart setup D is depicted, which shows all the flows and equivalents used in Example 7: a stability argument during a longer run.

[0028] Figure 11 The EU1H2·2pTSA from the first flow separation experiment (Example 9) was depicted. 1 ¹H-NMR spectra (DMSO-d6). 1,3,5-trimethoxybenzene was used as an internal standard, and the purity was evaluated in triplicate (95% NMR purity).

[0029] Figure 12 The HPLC trace of EU1H2·2pTSA separated from the first flow separation experiment was plotted at 233 nm (Example 9; 95% NMR purity). Due to the high polarity of the analyte, HPLC method A was used.

[0030] Figure 13 The EU1H2·2pTSA from the second flow separation experiment (Example 9) was depicted. 1 ¹H-NMR spectra (DMSO-d6). 1,3,5-trimethoxybenzene was used as an internal standard, and the purity was evaluated in triplicate (91% NMR purity).

[0031] Figure 14The HPLC trace of EU1H2·2pTSA separated from the second flow separation experiment was plotted at 233 nm (Example 9; 91% NMR purity). Due to the high polarity of the analyte, HPLC method A was used. Detailed Implementation

[0032] General definition

[0033] Unless otherwise specifically defined, all technical and scientific terms used herein should be regarded as having the same meaning as commonly understood by one of ordinary skill in the art (e.g., chemistry, biochemistry, medicinal chemistry, microbiology, etc.).

[0034] Unless otherwise specified or required by the context, references to a single step, composition of matter, group of steps, or group of composition of matter should be considered to cover one or more (i.e., one or more) of those steps, compositions of matter, groups of steps, or groups of composition of matter. Therefore, as used herein, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” include the plural aspect. For example, reference to “a” includes one and two or more; reference to “an” includes one and two or more; reference to “the” includes one and two or more, and so on.

[0035] Those skilled in the art will understand that changes and modifications can be made to the disclosure herein, in addition to those specifically described. It should be understood that this disclosure includes all such changes and modifications. This disclosure also includes all steps, features, compositions, and compounds individually or collectively mentioned or indicated in this specification, and any and all combinations of any two or more of said steps or features.

[0036] Unless otherwise specified, each example of this disclosure described herein, with necessary modifications, will be applicable to every other example. This disclosure is not limited to the specific examples described herein, which are intended for illustrative purposes only. Functionally equivalent products, compositions, and methods as described herein are clearly within the scope of this disclosure.

[0037] As used herein, the term “and / or” (e.g., “X and / or Y”) should be understood to mean “X and Y” or “X or Y”, and should be regarded as providing explicit support for both meanings or for either meaning (e.g., A and / or B includes options i) A, ii) B, or iii) A and B).

[0038] As used herein, unless otherwise stated, the term approximately means + / - 20% of the specified value, typically + / - 10%, typically + / - 5%.

[0039] The compounds disclosed herein may contain a chiral (asymmetric) center, or the molecule as a whole may be chiral. Individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are within the scope of this invention.

[0040] As used in this article, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0041] As used herein, the term "alkyl" encompasses both straight-chain (i.e., linear) and branched-chain hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, pentyl, and hexyl. In one instance, an alkyl group has one to six carbon atoms (i.e., C64-C ... 1-6 alkyl).

[0042] As used herein, the term "carbocyclic group" refers to an aromatic or non-aromatic cyclic group containing a carbon atom. Carbocyclic groups can be, for example, monocyclic or polycyclic (i.e., bicyclic, tricyclic). Polycyclic carbocyclic groups can contain fused rings. In one instance, a carbocyclic group has three to ten carbon atoms (i.e., C364, C464, C56, C66, C66, C7 ...76, C66, C76, C76, C76, C76, C 3-10 (Carbocyclic group). Examples of monocyclic non-aromatic carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Aromatic carbocyclic groups include phenyl and naphthylvinyl groups.

[0043] As used herein, the term "heterocyclic group" refers to an aromatic or non-aromatic cyclic group similar to a carbocyclic group, but in which one to three carbon atoms are replaced by one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur. Heterocyclic groups can be, for example, monocyclic or polycyclic (e.g., bicyclic). Polycyclic heterocyclic groups can, for example, contain fused rings. In bicyclic heterocyclic groups, one or more heteroatoms may be present on each ring or only on one of the rings. The heteroatoms can be N, O, or S. Heterocyclic groups containing a suitable nitrogen atom include corresponding N-oxides. In one example, the heterocyclic group has three to ten atoms (i.e., 3- to 10-membered heterocyclic groups). Examples of monocyclic non-aromatic heterocyclic groups include aziridinyl, azircyclic butyl, pyrrolyl, imidazoyl, pyrazolyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, and azircyclic heptyl. Examples of bicyclic heterocyclic groups in which one ring is non-aromatic include dihydrobenzofuranyl, indanyl, indololinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and benzozaheptanyl. Examples of monocyclic aromatic heterocyclic groups (also known as monocyclic heteroaryl groups) include furanyl, thiopheneyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiazolyl, pyridinyl, triazolyl, triazinyl, pyridazinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidine. Examples of bicyclic aromatic heterocyclic groups (also known as bicyclic heteroaryl groups) include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiopheneyl, benzoimidazolyl, naphridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridinyl, pyridopyrimidinyl, isoquinolinyl, and benzohydrooxazolyl.

[0044] As used herein, the term "anion" refers to an ion carrying a negative charge. Similarly, as used herein, the term "cation" refers to an ion carrying a positive charge.

[0045] This disclosure relates to a continuous flow process for preparing a nitrogen-containing bicyclic compound of Formula 1 and its salts. Salts can be formed in the case of compounds of Formula 1 containing suitable acidic or basic groups. Suitable salts of compounds of Formula 1 include salts formed from organic or inorganic acids or bases. As used herein, the phrase "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt. Exemplary acid addition salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannins, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucuronates, sucrose salts, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl)ates (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthyl)ates). Exemplary base addition salts include, but are not limited to, ammonium salts; alkali metal salts, such as potassium and sodium salts; alkaline earth metal salts, such as calcium and magnesium salts; and salts containing organic bases, such as dicyclohexylamine, N-methyl-D-glucosamine, morpholine, thiomorpholine, piperidine, and pyrrolidine; mono-, di-, or tri-lower alkylamines, such as ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl-, or dimethyl-propylamine; or mono-, di-, or trihydroxy lower alkylamines, such as mono-, di-, or triethanolamine. Pharmaceutically acceptable salts may involve another molecule including, for example, acetate ions, succinate ions, or other counterions. Counterions can be any organic or inorganic part that stabilizes the charge on the parent compound. Furthermore, pharmaceutically acceptable salts may have more than one charged atom in their structure. Examples of pharmaceutically acceptable salts having multiple charged atoms as part of multiple counterions may have multiple counterions. Therefore, pharmaceutically acceptable salts may have one or more charged atoms and / or one or more counterions. It will also be understood that non-pharmaceutically acceptable salts also fall within the scope of this disclosure, as these salts may be used as intermediates in the preparation of pharmaceutically acceptable salts, or may be useful during storage or transport.

[0046] Those skilled in the art of organic chemistry and / or medicinal chemistry will understand that many organic compounds can form complexes with solvents in which they react or precipitate or crystallize. These complexes are referred to as “solvents.” For example, a complex with water is referred to as a “hydrate.” As used herein, the phrase “pharmaceutically acceptable solvate” or “solvent” refers to the association of one or more solvent molecules with a compound of this disclosure. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. It should be understood that this disclosure covers solvated forms of compounds of Formula 1 and their salts, including hydrates.

[0047] Those skilled in the art of organic chemistry and / or medicinal chemistry will understand that compounds of Formula 1 and their salts can exist in amorphous or crystalline forms. It should be understood that this disclosure covers all forms and polymorphs of compounds of Formula 1 and their salts.

[0048] It should be understood that, for clarity, certain features described herein in the context of individual embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, the various features described in the context of a single embodiment may also be provided individually or in any sub-combination.

[0049] Throughout this specification, various aspects and components of the invention may be presented in a scope format. This scope format is included for convenience and should not be construed as an inflexible limitation of the scope of the invention. Therefore, unless otherwise stated, descriptions of scopes should be considered as explicitly disclosing all possible sub-scopes and individual numerical values ​​within those scopes. For example, unless integers or contextually implied integers are required, descriptions of scopes such as 1 to 5 should be considered as having specifically disclosed sub-scopes, such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 5, 3 to 5, etc.; and individual and partial numbers within the stated scopes, such as 1, 2, 3, 4, 5, 5.5, and 6. This applies regardless of the breadth of the disclosed scope. Specific values ​​will be indicated in the specification when required.

[0050] Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising” shall be understood to imply inclusion of the stated elements, integers or steps, or groups of elements, groups of integers or groups of steps, but not to exclude any other elements, integers or steps, or groups of elements, groups of integers or groups of steps.

[0051] It will be clearly understood that although this document references several prior art disclosures, such references do not constitute an admission that any of these documents form part of the general common knowledge in the art in Australia or any other country.

[0052] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. While similar or equivalent methods and materials to those described and used herein may be used in the practice or testing of this invention, suitable methods and materials are described below. In case of conflict, this specification (including definitions) shall prevail. Furthermore, the materials, methods, and examples described are illustrative only and are not intended to be limiting.

[0053] Continuous flow process

[0054] The subject matter of this disclosure is partly based on the surprising discovery of an efficient and scalable method for preparing nitrogen-containing bicyclic compounds of Formula 1 via a continuous flow process.

[0055] Therefore, a continuous flow process for preparing a nitrogen-containing bicyclic compound of formula 1 or its salt is provided:

[0056]

[0057] The continuous flow process includes the nortropinone compound of formula 2:

[0058]

[0059] With the halogenated compounds of Formula 3:

[0060] XR 1

[0061] Formula 3;

[0062] Organolithium reactions in the presence of organolithium reagents; where R 1 It is a monocyclic or bicyclic heteroaryl group, either unsubstituted or substituted by one or more substituents selected from the group consisting of: halogens, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -OC 1-6 Halogenated alkyl; R 2 It is an amine protecting group; and X is a halogen.

[0063] Continuous flow reactor

[0064] The synthesis of small molecules using continuous flow reactors (often simply called flow reactors) offers an alternative to traditional batch chemical reactions. However, despite the increasing use of continuous flow reactors in chemical and bioprocesses, their application in pharmaceutical manufacturing is rare.

[0065] A continuous flow reactor allows materials (e.g., chemicals) to be introduced and carried through the system as a fluid in one or more conduits within the reactor. As used herein, "conduit" can refer to any pipe, tube, channel, channeled plate, or any other container of a shape suitable for conveying fluids in a continuous flow process. A pumping system propels the flow through the reactor, ultimately combining one or more flow streams together, where the fluids come into contact and chemically react to produce the desired chemical (e.g., small molecules). Ultimately, the reactor can be configured to produce an output containing a single flow stream of the desired chemical.

[0066] Chemical synthesis in a continuous flow reactor can offer one or more advantages over conventional batch or semi-batch synthesis. Specifically, using a flow reactor allows for close monitoring of reaction variables, such as concentration, flow rate, residence time, temperature, etc., and adjustments as needed to optimize the conversion of starting materials and reagents to the desired product. In one example, the continuous flow reaction described herein allows for the adjustment of one or more reaction variables selected from the group consisting of: molar ratio of reagents, reagent concentration, flow rate, residence time, temperature, solvent, and output rate.

[0067] As used herein, the term "feed concentration" refers to the concentration of the reagent before it is introduced into the conduit within the continuous flow reactor. Feed concentration is measured in mol / L.

[0068] As used herein, the term "flow rate" refers to volumetric flow rate, which is defined as a measure of the volume of liquid passing through per unit time. That is, it refers to the velocity at which a flow moves through a conduit within a reactor. Flow rate is measured in mL / min.

[0069] As used herein, the term "residence time" refers to the period of time during which a fluid parcel (and therefore the reagent contained therein) of a flowing stream resides in a specific section of a continuous flow reactor. As used herein, a "fluid parcel" refers to a very small amount of fluid that can be identified throughout its dynamic history as it moves with the flowing stream. Therefore, residence time is a function of reactor volume and flow rate. In fact, residence time can be calculated as the ratio of the volume of a section to the flow rate through that section. It should be understood that specific sections and conduits of the reactor may produce different residence times due to, for example, the volume of the section and / or the flow rate within that section or conduit. It should be understood that one way to achieve a longer residence time is to reduce the flow rate. Similarly, it should be understood that one way to achieve a shorter residence time is to increase the flow rate. Residence time is typically measured in seconds.

[0070] While such continuous flow reactors were previously best suited for small-scale chemical reactions, the continuous output of a single flow containing the desired chemical makes it possible to apply them on a larger scale in a scale-independent manner. Therefore, the use of continuous flow reactors in the synthesis of chemicals, especially small molecules, is an emerging area of ​​interest for both research and industrial / commercial laboratories.

[0071] Compound of Formula 1

[0072] The azabicyclic compound of Formula 1 or its salt is prepared by a continuous flow process in the presence of an organolithium reagent, by reacting the nortropinone compound of Formula 2 with the organolithium of the halogenated compound of Formula 3.

[0073] The continuous flow process described herein is used to prepare nitrogen-containing bicyclic compounds of Formula 1 or their salts:

[0074]

[0075] In the azabicyclic compound of Formula 1 or a salt thereof, R 1 It is a monocyclic or bicyclic heteroaryl group, either unsubstituted or substituted by one or more substituents selected from the group consisting of: halogens, -C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Haloalkyl. In one example, R 1 It is a monocyclic heteroaryl group. In one example, R 1 It is a bicyclic heteroaryl group. Cyclic or bicyclic heteroaryl groups can be unsubstituted or substituted. In one example, R... 1 It is an unsubstituted cyclic heteroaryl group. In one example, R 1 It is an unsubstituted bicyclic heteroaryl group. In one example, R 1It is a substituted monocyclic heteroaryl group. In one example, R 1 It is a substituted bicyclic heteroaryl group.

[0076] If substituted, the monocyclic or bicyclic heteroaryl group can be replaced by one or more substituents selected from the group consisting of: halogens, -C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Haloalkyl. In some embodiments, R 1 It is a monocyclic heteroaryl group substituted by one or more substituents selected from the group consisting of: halogens, -C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Haloalkyl. In some embodiments, R 1 It is a bicyclic heteroaryl group substituted by one or more substituents selected from the group consisting of: halogens, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -OC 1-6 Haloalkyl. In one example, R 1 It is a halogen-substituted monocyclic heteroaryl group. In one example, R 1 It was -C 1-6 -alkyl-substituted monocyclic heteroaryl groups. In one example, R 1 Is -OC 1-6 Alkyl-substituted monocyclic heteroaryl groups. In one example, R 1 It was C 1-6 Haloalkyl-substituted monocyclic heteroaryl groups. In one example, R 1 Is -OC 1-6 Haloalkyl-substituted monocyclic heteroaryl groups. In one example, R 1 It is a halogen-substituted bicyclic heteroaryl group. In one example, R 1 It was -C 1-6 -alkyl-substituted bicyclic heteroaryl groups. In one example, R 1 Is -OC 1-6 Alkyl-substituted bicyclic heteroaryl groups. In one example, R 1 It was C 1-6 Haloalkyl-substituted bicyclic heteroaryl groups. In one example, R 1 Is -OC 1-6 Haloalkyl-substituted bicyclic heteroaryl groups. In one example, R 1 It is an unsubstituted pyrimidine group.

[0077] In the azabicyclic compound of Formula 1 or a salt thereof, R 2 It is an amine protecting group. The term "amine protecting group" specifically refers to a protecting group that chemically modifies the amine functional group in a subsequent chemical reaction to obtain chemoselectivity. Examples of amine protecting groups include, but are not limited to, urethane protecting groups, amide protecting groups, benzyl protecting groups, benzenemethylene protecting groups, toluenesulfonyl protecting groups, and triphenylmethyl protecting groups. In some embodiments, R 2 The protecting group is an amino group selected from the group consisting of: urethane protecting groups, amide protecting groups, benzyl protecting groups, benzenemethylene protecting groups, toluenesulfonyl protecting groups, and triphenylmethyl protecting groups. Examples of urethane protecting groups include, but are not limited to, methyl and ethyl, 9-fluorenylmethyl, 9-fluorenylmethoxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), benzyl carbamate (Cbz), and p-methoxybenzylcarbonyl (MeOZ). In some embodiments, R 2 It is a tert-butoxycarbonyl (Boc) protecting group. Examples of amide protecting groups include, but are not limited to, acetyl (Ac), benzamide, trifluoroacetamide, trichloroacetamide, phenylacetamide, pyridinecarboxamide, and phthalimide. Other examples of amino protecting groups include, but are not limited to, benzoyl, benzyl, benzyl p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), toluenesulfonyl (Ts), trichloroethyl chloroformate (Troc), toluene sulphonyl, triphenylmethyl, and triphenylmethyl. Therefore, in some embodiments, R 2 The amine protecting group is selected from the group consisting of: methyl and ethyl, 9-fluorenylmethyl, 9-fluorenylmethoxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), benzyl carbamate (Cbz), and p-methoxybenzylcarbonyl (MeOZ). In some embodiments, R 2 It is a tert-butoxycarbonyl (Boc) protecting group. Examples of amide protecting groups include, but are not limited to, acetyl (Ac), benzamide, trifluoroacetamide, trichloroacetamide, phenylacetamide, pyridinecarboxamide, and phthalimide. Other examples of amino protecting groups include, but are not limited to, benzoyl, benzyl, benzyl p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), toluenesulfonyl (Ts), trichloroethyl chloroformate (Troc), toluene sulphonyl, triphenylmethyl, and triphenylmethyl. In one example, R 2It is the amine protecting group for the tert-butyloxycarbonyl (boc). In one example, R 2 It is the amine protecting group for 9-fluorenyl methyl carbamate FMOC. In one example, R 2 It is the amine protecting group of benzyl carbamate (CBZ). In one example, R 2 It is the amine protecting group of acetamide. In one example, R 2 It is the amine protecting group for trifluoroacetamide. In one example, R 2 It is the amine protecting group for phthalimide. In one example, R 2 It is the amine protecting group of the benzyl group. In one example, R 2 It is the amine protecting group of the benzenemethylene group. In one example, R 2 It is an amine protecting group for tosyl (e.g., toluenesulphonyl). In one example, R 2 It is an amine protecting group for triphenylmethyl (e.g., triphenylmethyl).

[0078] Compound of Formula 2

[0079] The continuous flow process described herein is used to prepare azabicyclic compounds of Formula 1 or their salts, and nortropinone compounds of Formula 2.

[0080]

[0081] The organolithium reaction with the halogenated compound of Formula 3 is carried out in the presence of an organolithium reagent.

[0082] In the nortropinone compound of Formula 2, R 2 It is an amine protecting group as described herein. Therefore, in one example, R 2 It is the amine protecting group for the tert-butyloxycarbonyl (boc). In one example, R 2 It is the amine protecting group for 9-fluorenyl methyl carbamate (FMOC). In one example, R 2 It is the amine protecting group of benzyl carbamate (CBZ). In one example, R 2 It is the amine protecting group of acetamide. In one example, R 2 It is the amine protecting group for trifluoroacetamide. In one example, R 2 It is the amine protecting group for phthalimide. In one example, R 2 It is the amine protecting group of the benzyl group. In one example, R 2It is the amine protecting group of the benzenemethylene group. In one example, R 2 It is the amine protecting group of tosyl (e.g., toluene sulphonyl). In one example, R 2 It is an amine protecting group for triphenylmethyl (e.g., triphenylmethyl).

[0083] As those skilled in the art will understand, R present in the nortropinone compound of formula 2 2 The functional group remains unchanged during the reaction with the organolithium halogenated compound, which will act as the R group of the azabicyclic compound of Formula 1. 2 Groups are incorporated. For example, when R in formula 2... 2 When the protecting group is tert-butoxycarbonyl (boc)amine, the R of the prepared azabicyclic compound of formula 1 2 It is also a tert-butoxycarbonyl (boc)amine protecting group.

[0084] The compound of Formula 2 is provided in any amount suitable for carrying out the continuous flow reaction described herein. In some embodiments, the amount of the compound of Formula 2 is provided in a molar ratio of at least about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.15, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 relative to the amount of the compound of Formula 3. In some embodiments, the amount of compound 2 relative to the amount of compound 3 is provided in a molar ratio less than about 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.25, 1.2, 1.15, 1.1, or 1.0. In some embodiments, the amount of compound 2 relative to the amount of compound 3 is within a molar ratio range provided by any two of the higher and / or lower amounts described above, for example, where the molar ratio range is about 1.0 to 2.0, 1.1 to 1.7, 1.1 to 1.5, 1.15 to 1.25, or 1.2 to 1.3. In one example, the amount of compound 2 relative to the amount of compound 3 is in a molar ratio range of 1.5 to 1.6. In one example, the amount of compound 2 relative to the amount of compound 3 is in the molar ratio range of 1.2 to 1.3. In one example, the amount of compound 2 relative to the amount of compound 3 is in the molar ratio range of 1.15 to 1.25. In one example, the molar ratio of compound 2 relative to the amount of compound 3 is about 1.15. In one example, the molar ratio of compound 2 relative to the amount of compound 3 is about 1.25.

[0085] The concentration of the compound of Formula 2 can be configured to any concentration suitable for carrying out the continuous flow reaction described herein. In some embodiments, the compound of Formula 2 is provided at a concentration of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 mol / L. In some embodiments, the compound of Formula 2 is provided at a concentration of less than about 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 mol / L. In some embodiments, the compound of Formula 2 is provided in a concentration range (in mol / L) provided by any of the higher and / or lower amounts previously described, for example, at a concentration (in mol / L) of about 0.1 to 1.5, 0.2 to 1.2, 0.2 to 0.7, or 0.3 to 0.5 mol / L.

[0086] The continuous flow of the compound comprising Formula 2 can be configured to any flow rate suitable for carrying out the continuous flow reaction described herein. In some embodiments, the flow rate (mL / min) of the continuous flow of the compound comprising Formula 2 is at least about 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mL / min. In some embodiments, the flow rate (mL / min) of the continuous flow of the compound comprising Formula 2 is less than about 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, or 0.5 mL / min. In some embodiments, the flow rate of the continuous flow of the compound comprising Formula 2 is within the range provided by any of the higher and / or lower amounts previously described, for example, the flow rate (mL / min) is about 0.1 to 5, 0.5 to 4.5, 1.0 to 4.0, 1.5 to 3.5, or 2.0 to 3.0 mL / min.

[0087] Compound of Formula 3

[0088] The continuous flow process described in this article involves the nortropinone compound of Formula 2 and the halogenated compound of Formula 3:

[0089] XR 1

[0090] Formula 3;

[0091] Organolithium-based compounds of formula 1 or their salts are prepared by organolithium-based reactions in the presence of an organolithium reagent.

[0092] In the halogenated compounds of Formula 3, R 1It is a monocyclic or bicyclic heteroaryl group, either unsubstituted or substituted by one or more substituents selected from the group consisting of: halogen, -OH, -C. 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Halogenated alkyl groups, as described herein.

[0093] If substituted, the monocyclic or bicyclic heteroaryl group can be replaced by one or more substituents selected from the group consisting of: halogen, -OH, -C. 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Haloalkyl. In some embodiments, R 1 It is a monocyclic heteroaryl group substituted with one or more substituents selected from the group consisting of: halogen, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 Haloalkyl. In some embodiments, R 1 It is a bicyclic heteroaryl group substituted with one or more substituents selected from the group consisting of: halogen, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -OC 1-6 Haloalkyl. In one example, R 1 It is a halogen-substituted monocyclic heteroaryl group. In one example, R 1 It is a monocyclic heteroaryl group substituted with -OH. In one example, R 1 It was -C 1-6 -alkyl-substituted monocyclic heteroaryl groups. In one example, R 1 Is -OC 1-6 Alkyl-substituted monocyclic heteroaryl groups. In one example, R 1 It was C 1-6 Haloalkyl-substituted monocyclic heteroaryl groups. In one example, R 1 Is -OC 1-6 Haloalkyl-substituted monocyclic heteroaryl groups. In one example, R 1 It is a halogen-substituted bicyclic heteroaryl group. In one example, R 1 It is a bicyclic heteroaryl group substituted with -OH. In one example, R 1 It was -C 1-6 -alkyl-substituted bicyclic heteroaryl groups. In one example, R 1 Is -OC 1-6Alkyl-substituted bicyclic heteroaryl groups. In one example, R 1 It was C 1-6 Haloalkyl-substituted bicyclic heteroaryl groups. In one example, R 1 Is -OC 1-6 Haloalkyl-substituted bicyclic heteroaryl groups. In one example, R 1 It is an unsubstituted pyrimidine group.

[0094] The feed concentration of the compound of Formula 3 can be configured to any concentration suitable for carrying out the continuous flow reaction described herein. In some embodiments, the compound of Formula 3 is provided at a concentration of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 mol / L. In some embodiments, the compound of Formula 3 is provided at a concentration of less than about 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 mol / L. In some embodiments, the compound of Formula 3 is provided in a concentration range (in mol / L) provided by any of the higher and / or lower amounts previously described, for example, a concentration (in mol / L) of about 0.1 to 1.5, 0.2 to 1.2, 0.2 to 0.7, or 0.3 to 0.5 mol / L.

[0095] The continuous flow of the compound comprising Formula 3 can be configured to any flow rate suitable for carrying out the continuous flow reaction described herein. In some embodiments, the flow rate (mL / min) of the continuous flow of the compound comprising Formula 3 is at least about 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mL / min. In some embodiments, the flow rate (mL / min) of the continuous flow of the compound comprising Formula 3 is less than about 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, or 0.5 mL / min. In some embodiments, the flow rate of the continuous flow of the compound comprising Formula 3 is within the range provided by any of the higher and / or lower amounts previously described, for example, the flow rate (mL / min) is about 0.1 to 5, 0.5 to 4.5, 1.0 to 4.0, 1.5 to 3.5, or 2.0 to 3.0 mL / min.

[0096] In one instance, the halogenated compound of formula 3 is selected from the group consisting of:

[0097] as well as

[0098] As those skilled in the art will understand, R present in the halogenated compounds of Formula 3 1 The functional group remains unchanged during the organolithium reaction, and the halogenated compound will serve as the R group of the azabicyclic compound of Formula 1. 1 Groups are incorporated. For example, when R in formula 3... 1 When the pyrimidine group is unsubstituted, the R of the prepared azabicyclic compound of formula 1 1 It is also an unsubstituted pyrimidine group.

[0099] Therefore, in one instance, the halogenated compound of formula 3 is the compound of formula 3a:

[0100]

[0101] Furthermore, the azabicyclic compound of formula 1 is a compound of formula 1a:

[0102]

[0103] In the halogenated compounds of Formula 3, X is a halogen. In some embodiments, X is selected from the group consisting of chlorine, bromine, and iodine. In one example, X is chlorine. In one example, X is bromine. In one example, X is iodine.

[0104] In one example, a continuous flow process is provided for preparing a nitrogen-containing bicyclic compound of formula 1a or a salt thereof:

[0105]

[0106] The continuous flow process includes the nortropinone compound of formula 2:

[0107]

[0108] With the halogenated compounds of formula 3a:

[0109]

[0110] Organolithium reactions in the presence of organolithium reagents; where R 2 It is an amine protecting group as described in this article.

[0111] In one example, a continuous flow process is provided for preparing a nitrogen-containing bicyclic compound of formula 1a or a salt thereof:

[0112]

[0113] The continuous flow process includes the nortropinone compound of formula 2:

[0114]

[0115] With the halogenated compounds of formula 3a:

[0116]

[0117] Organolithium reactions in the presence of organolithium reagents; where R 2 It is a tert-butoxycarbonyl (boc)amine protecting group.

[0118] organolithium reagents

[0119] As those skilled in the art will understand, the organolithium reagent used in a continuous flow process can be any organolithium reagent suitable for such organolithium reactions. For example, the organolithium reagent can be any compound containing a carbon-lithium bond. In one instance, the organolithium reagent is a compound containing a carbon-lithium bond.

[0120] Examples of suitable organolithium reagents include, but are not limited to, alkyllithium, alkenyllithium, alkynyllithium, aralkyllithium, aryllithium, heteroaryllithium, alkyllithium-magnesium complexes, and any lithium halide complexes thereof. Therefore, in some embodiments, the organolithium reagent is selected from the group consisting of: alkyllithium, alkenyllithium, alkynyllithium, aralkyllithium, aryllithium, heteroaryllithium, alkyllithium-magnesium complexes, and any lithium halide complexes thereof.

[0121] More specifically, in some embodiments, the organolithium reagent may be selected from the group consisting of: methyllithium, ethyllithium, propyllithium, butyllithium, pentyllithium, hexyllithium, methoxymethyllithium, ethoxymethyllithium, vinyllithium, allyllithium, propenyllithium, butenyllithium, ethynyllithium, butynyllithium, pentyynyllithium, hexynyllithium, benzyllithium, phenylethyllithium, phenyllithium, naphthyllithium, 2-thiophenyllithium, 4-pyridyllithium, 2-quinolinyllithium, tris(n-butyl)magnesiumlithium and trimethylmagnesiumlithium, (trimethylsilyl)methyllithium, (trimethylsilyl)ethynyllithium, ethynyllithium, phenylethynyllithium, cyclopentadienyllithium, pentamethylcyclopentadienyllithium, lithium methyllithium, and any lithium halide complex thereof. In some embodiments, the organolithium reagent is selected from the group consisting of lithium methyllithium or any lithium halide complex thereof. In one example, the organolithium reagent is a lithium methyllithium bromide complex.

[0122] As those skilled in the art will understand, organolithium reagents are generally provided in suitable solvents. In one example, the organolithium reagent is provided in an organic solvent. In one example, the organolithium reagent is provided in an organic solvent selected from the group consisting of: 2-methyltetrahydrofuran, diethoxymethane, diethyl ether, tetrahydrofuran, and any combination thereof. In one example, the organolithium reagent is provided in a 2-methyltetrahydrofuran solvent. In one example, the organolithium reagent is provided in a diethoxymethane solvent. In one example, the organolithium reagent is provided in a diethyl ether / tetrahydrofuran solvent. In one example, the organolithium reagent is a methyllithium lithium bromide complex and is provided in a 2-methyltetrahydrofuran solvent. In one example, the organolithium reagent is a methyllithium lithium bromide complex and is provided in a diethoxymethane solvent. In one example, the organolithium reagent is a methyllithium lithium bromide complex and is provided in a diethyl ether / tetrahydrofuran solvent.

[0123] The organolithium reagent can be provided in a defined amount (mol / L) in a suitable solvent. In some embodiments, the organolithium reagent is provided in an organic solvent in an amount (mol / L) of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. In some embodiments, the organolithium reagent is provided in an organic solvent in an amount (mol / L) of less than about 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1. In some embodiments, the organolithium reagent is provided in an organic solvent in an amount (mol / L) provided by any of the higher and / or lower amounts previously described, for example, said amount (mol / L) is about 0.2 to 1.8 and 0.5 to 1.5. In one example, the organolithium reagent is provided in an organic solvent in an amount (mol / L) of about 1.5. In one example, the organolithium reagent is provided in an organic solvent in an amount (mol / L) of about 0.5. In one example, the organolithium reagent is a methyllithium lithium bromide complex and is provided in an ether / tetrahydrofuran solvent in an amount (mol / L) of about 0.5. In one example, the organolithium reagent is a methyllithium lithium bromide complex and is provided in a 2-methyltetrahydrofuran solvent in an amount (mol / L) of about 1.5.

[0124] The organolithium reagent is provided in any amount suitable for carrying out the continuous flow reaction described herein. In some embodiments, the amount of the organolithium reagent is provided in a molar ratio of at least about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 relative to the amount of the compound of Formula 3. In some embodiments, the amount of the organolithium reagent is provided in a molar ratio of less than about 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, or 1.1 relative to the amount of the compound of Formula 3. In some embodiments, the amount of the organolithium reagent relative to the compound of Formula 3 is provided within a molar ratio range provided by any of the higher and / or lower amounts previously described, for example, where the molar ratio range is about 1.0 to 3.0, 1.1 to 1.8, 1.2 to 1.6, or 1.3 to 1.4. In one example, the amount of the organolithium reagent relative to the compound of Formula 3 is provided within a molar ratio range of 1 to 3.

[0125] The feed concentration of the organolithium reagent can be configured to any concentration suitable for carrying out the continuous flow reaction described herein. In some embodiments, the organolithium reagent is provided at a concentration (mol / L) of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 mol / L. In some embodiments, the organolithium reagent is provided at a concentration (mol / L) of less than about 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 mol / L. In some embodiments, the organolithium reagent is provided in a concentration range provided by any of the higher and / or lower amounts previously described, for example, about 0.1 to 1.5, 0.2 to 1.2, or 0.3 to 0.9 mol / L.

[0126] The continuous flow containing the organolithium reagent can be configured to any flow rate suitable for carrying out the continuous flow reaction described herein. In some embodiments, the flow rate (mL / min) of the continuous flow containing the organolithium reagent is at least about 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mL / min. In some embodiments, the flow rate (mL / min) of the continuous flow containing the organolithium reagent is less than about 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, or 0.5 mL / min. In some embodiments, the flow rate of the continuous flow containing the organolithium reagent is within the range provided by any of the higher and / or lower amounts previously described, for example, the flow rate (mL / min) is about 0.1 to 5, 0.5 to 4.5, 1.0 to 4.0, or 2.0 to 3.0 mL / min.

[0127] In some embodiments, two or more organolithium reagents are used in the organolithium reaction. The two or more organolithium reagents may be provided in a single continuous flow stream, or otherwise provided in two or more separate continuous flow streams. In one example, one organolithium reagent is used in a single continuous flow stream. In one example, two organolithium reagents are used in a single continuous flow stream (i.e., two organolithium reagents are combined in a single continuous flow stream). In one example, two organolithium reagents are used in two continuous flow streams, wherein each organolithium reagent is provided in a separate continuous flow stream. In one example, a lithium methyl bromide complex is provided in two or more separate streams. In one example, a lithium methyl bromide-containing diethyl ether / tetrahydrofuran is provided in a first stream, and a lithium methyl bromide-containing 2-methyltetrahydrofuran is provided in a second stream.

[0128] Quenching

[0129] It should be understood that, following the organolithium reaction, the resulting solution comprising the azabicyclic compound of Formula 1 or a salt thereof may require quenching. As used herein, the term "quenching" refers to the deactivation of any unreacted reagent in the reaction mixture. Therefore, in some embodiments, the continuous flow process further comprises combining the azabicyclic compound of Formula 1 or a salt thereof with a quenching solution. That is, in one example, the resulting solution comprising the azabicyclic compound of Formula 1 or a salt thereof is quenched.

[0130] The quenching solution can be any suitable solution as understood by those skilled in the art. In some embodiments, the quenching solution is selected from the group consisting of: polar protic solvents, nonpolar protic solvents, aqueous solvents, alcohols and acids, or combinations thereof. In one example, the quenching solution is a protic solvent. In one example, the quenching solution contains a polar protic solvent. In one example, the quenching solution contains a nonpolar protic solvent. In one example, the quenching solution contains an aqueous solvent. In one example, the quenching solution contains ethanol. In one example, the quenching solution contains isopropanol. In one example, the quenching solution contains methanol. In one example, the quenching solution contains benzyl alcohol. In one example, the quenching solution contains cyclohexanol. In one example, the quenching solution contains acetone. In one example, the quenching solution contains an acid. In one example, the quenching solution contains citric acid. In one example, the quenching solution contains about 0.25 M citric acid. In one example, the quenching solution contains phosphoric acid. In one example, the quenching solution contains sulfuric acid. In one example, the quenching solution contains ammonium chloride. In one example, the quenching solution contains benzoic acid. In one example, the quenching solution contains p-toluenesulfonic acid (pTSA). In one example, the quenching solution contains acetic acid. In one example, the quenching solution contains trifluoroacetic acid.

[0131] The quenching of a solution containing a nitrogen-containing bicyclic compound of Formula 1 or a salt thereof can be carried out outside the continuous flow reactor. That is, the output flow stream of the solution containing a nitrogen-containing bicyclic compound of Formula 1 or a salt thereof can be collected from the continuous flow reactor and then combined separately with the quenching solution (i.e., "quenching"). In other words, in one example, the quenching of the solution containing a nitrogen-containing bicyclic compound of Formula 1 is carried out outside the continuous flow reactor.

[0132] Alternatively, the quenching of a solution containing a aziridine compound of formula 1 can be carried out in a continuous flow reactor. Therefore, in some embodiments, the process comprises combining a continuous flow of a aziridine compound of formula 1 or a salt thereof with a continuous flow of a quenching solution to obtain a continuous flow of a aziridine compound of formula 1.

[0133] As those skilled in the art will understand, the quenching solution can be provided at any concentration to effectively quench the reaction. In some embodiments, the concentration (mol / L) of the quenching solution can be at least about 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 3, 4, 5, 6, 7, 8, 9, or 10 mol / L. In some embodiments, the concentration (mol / L) of the quenching solution can be less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 1.8, 1.6, 1.4, 1.2, 1.09, 0.8, 0.7, 0.6, or 0.5 mol / L. In some embodiments, the concentration (mol / L) of the quenching solution may be within the range provided by any of the higher and / or lower amounts previously described, for example, about 0.1 to 10, 0.5 to 8, or 2 to 7 mol / L.

[0134] In some embodiments, the quenching solution may be anhydrous. For example, the amount of water in the solution may be less than about (in ppm) 500, 400, 300, 200, 100, 75, 50, 25, 10, 5 or 1 ppm.

[0135] In some embodiments, when the quenching solution is introduced as a continuous flow, the flow rate (mL / min) of the continuous flow is at least about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 1000, 2000, 3000, 4000, 5000, or 10000 mL / min. In some embodiments, when the quenching solution is introduced as a continuous flow, its flow rate (mL / min) is less than about 10000, 5000, 4000, 3000, 2000, 1000, 500, 400, 300, 200, 100, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, or 0.1 mL / min. In some embodiments, the quenching solution is introduced as a continuous flow with a flow rate (mL / min) within the range provided by any of the higher and / or lower amounts previously described, for example, about 0.1 to 10, 0.5 to 8, or 2 to 7 mL / min.

[0136] Sufficient time is necessary before quenching a solution containing an azabicyclic compound of formula 1 or a salt thereof. That is, sufficient time is required for the organolithium reaction to occur (and preferably occur at optimal conversion). Therefore, after adding the organolithium reagent, it may be necessary to allow the resulting solution to remain in the reactor for a certain period of time to allow the organolithium reaction to occur (and preferably occur at optimal conversion), said period of time being referred to as the "residence time". Thus, in some embodiments, the residence time (in seconds) of the solution containing the azabicyclic compound of formula 1 or a salt thereof before quenching is at least about 0.01, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 seconds. In some embodiments, the residence time (in seconds) of the solution comprising the azabicyclic compound of Formula 1 or a salt thereof prior to quenching the solution is less than about 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0.01 seconds. In some embodiments, the residence time (in seconds) of the solution comprising the azabicyclic compound of Formula 1 or a salt thereof prior to quenching the solution is within the range provided by any one of the higher and / or lower amounts previously described, for example, about 0.01 to 30, 1 to 29, 2 to 28, 3 to 27, 4 to 26, 5 to 25, 6 to 24, 7 to 23, 8 to 22, 9 to 21, 10 to 20, 11 to 19, 12 to 18, 13 to 17, or 14 to 16 seconds. In some embodiments, the residence time (in seconds) of the solution containing the azabicyclic compound of Formula 1 or a salt thereof prior to quenching the solution is within a range provided by either the higher or lower amounts previously described, for example, about 1 to 10, 2 to 8, 3 to 6, or 4 to 5 seconds. In one example, the residence time (in seconds) of the solution containing the azabicyclic compound of Formula 1 or a salt thereof prior to quenching the solution is about 2.5 seconds or less. In one example, the residence time (in seconds) of the solution containing the azabicyclic compound of Formula 1 or a salt thereof prior to quenching the solution is about 5 seconds. In one example, the residence time (in seconds) of the solution containing the azabicyclic compound of Formula 1 or a salt thereof prior to quenching the solution is about 4 seconds.

[0137] It may be necessary to configure the temperature of the continuous flow reactor throughout the quenching process of the solution containing the azabicyclic compound of Formula 1 or its salt, especially for example, to control any exothermic reactions. In some embodiments, the quenching of the solution containing the azabicyclic compound of Formula 1 or its salt is carried out at temperatures below about 20°C, about 10°C, about 0°C, about -10°C, about -20°C, about -30°C, about -40°C, about -50°C, about -60°C, about -70°C, or about -80°C. In some embodiments, the quenching of the solution containing the azabicyclic compound of Formula 1 is carried out at temperatures at least about -80°C, about -70°C, about -60°C, about -50°C, about -40°C, about -30°C, about -20°C, about -10°C, about 0°C, about 10°C, or about 20°C. In some embodiments, the quenching of the solution containing the azabicyclic compound of Formula 1 is carried out at a temperature within a range provided by either the higher or lower amounts previously described, for example, about -80°C to 20°C, about -70°C to 10°C, about -60°C to 0°C, about -50°C to -10°C, or about -30°C to -10°C. In some embodiments, the quenching of the solution containing the azabicyclic compound of Formula 1 is carried out at a temperature of about 0°C. Those skilled in the art will understand that the temperature at which the solution containing the azabicyclic compound of Formula 1 or a salt thereof is quenched may differ from the temperature at which the organolithium reaction or any other stage of the continuous flow process is carried out. For example, the organolithium reaction may be carried out at a temperature in the range of about -50°C to about -70°C, and the temperature at which the solution containing the azabicyclic compound of Formula 1 or a salt thereof is quenched may be about 0°C. Similarly, the temperature at which the solution containing the azabicyclic compound of Formula 1 or a salt thereof is quenched may differ from the temperature at which any other section of the continuous flow reactor is maintained.

[0138] Continuous flow reactor configuration

[0139] The continuous flow reactor can be configured in any suitable way to optimize the organolithium reaction for the preparation of nitrogen-containing bicyclic compounds of Formula 1 as described herein.

[0140] Therefore, in some embodiments, the continuous flow process includes providing a reaction component, which is a nortropinone compound of formula 2, a halogenated compound of formula 3, and an organolithium reagent, in one or more continuous flow streams in a continuous flow reactor configured at a temperature conducive to the efficient synthesis of a aziridine compound of formula 1 or a salt thereof.

[0141] In other words, in one example, the nortropinone compound of Formula 2, the halogenated compound of Formula 3, and the organolithium reagent are sequentially introduced as streams into a continuous flow reactor. In such cases, separate, pre-prepared premixes of the nortropinone compound of Formula 2, the halogenated compound of Formula 3, and the organolithium reagent are provided in a suitable solvent before being sequentially introduced into the continuous flow reactor. Continuous flow reactors allow for control of reaction variables, such as the order of addition, concentration, flow rate, pressure, and temperature, thereby enabling efficient synthesis of the azabicyclic compound of Formula 1 or its salts.

[0142] Alternatively, more than one reaction component may be provided in each flow stream. Therefore, it should be understood that in such cases, it is necessary to provide a pre-prepared premixture of two or more of the nortropinone compound of Formula 2, the halogenated compound of Formula 3, or the organolithium reagent.

[0143] Therefore, in some embodiments, the nortropinone compound of Formula 2 and the halogenated compound of Formula 3 are initially combined. This combination of the nortropinone compound of Formula 2 and the halogenated compound of Formula 3 can be carried out in any suitable manner as understood by those skilled in the art. For example, the nortropinone compound of Formula 2 and the halogenated compound of Formula 3 can be initially mixed in a suitable solvent before being introduced into a continuous flow reactor (e.g., in an external container and in the same flow stream as the continuous flow reactor). In another example, the nortropinone compound of Formula 2 and the halogenated compound of Formula 3 can be combined after being introduced into the continuous flow reactor (e.g., in a separate flow stream). In such cases, the continuous flow reactor can be configured such that a flow stream containing the nortropinone compound of Formula 2 is mixed with a separate flow stream containing the halogenated compound of Formula 3, thereby producing a flow stream in the continuous flow reactor containing a combination of the nortropinone compound of Formula 2 and the halogenated compound of Formula 3.

[0144] Regardless of the method of combining the nortropinone compound of Formula 2 and the halogenated compound of Formula 3, as discussed above, in some embodiments, the combination of the nortropinone compound of Formula 2 and the halogenated compound of Formula 3 is subsequently combined with an organolithium reagent. That is, the nortropinone compound of Formula 2 and the halogenated compound of Formula 3 are introduced into a reactor to provide a single flow containing the combination of the nortropinone compound of Formula 2 and the halogenated compound of Formula 3, and this single flow is then mixed with an organolithium reagent in the reactor. In one example, the organolithium reagent is introduced into a continuous flow reactor in a separate flow. This separate flow containing the organolithium reagent can then be provided to react with a single flow containing the combination of the nortropinone compound of Formula 2 and the halogenated compound of Formula 3. Therefore, in some embodiments, the process comprises combining a continuous flow containing the compound of Formula 2 and the compound of Formula 3 with a continuous flow containing an organolithium reagent to obtain a continuous flow containing an azabicyclic compound of Formula 1 or a salt thereof.

[0145] In some embodiments, the process includes combining a continuous flow of a compound comprising Formula 2 with a continuous flow of a compound comprising Formula 3 to obtain a continuous flow of a compound comprising Formula 2 and Formula 3; and combining a continuous flow of a compound comprising Formula 2 and Formula 3 with a continuous flow of an organolithium reagent to obtain a continuous flow of a aziridine compound comprising Formula 1 or a salt thereof.

[0146] In some embodiments, the process includes combining a continuous flow stream containing a compound of formula 3 with a continuous flow stream containing an organolithium reagent to obtain a continuous flow stream containing an organolithium reaction intermediate; and combining the continuous flow stream containing the organolithium reaction intermediate with a continuous flow stream containing a compound of formula 2 to obtain a continuous flow stream containing an azabicyclic compound of formula 1 or a salt thereof.

[0147] It should be understood that a continuous flow reactor can be configured in any suitable manner, and in particular, to provide a flowing stream to allow the nortropinone compound of Formula 2 to react with the halogenated compound of Formula 3 in the presence of an organolithium reagent. This includes any premixing steps to provide a suitable combination of reactants / reagents. The final product of a continuous flow reaction produced by a single flowing stream is a solution containing the azabicyclic compound of Formula 1 or a salt thereof.

[0148] In some embodiments, the flow rate of the combined flow stream containing the compound of formula 2 and the compound of formula 3 is configured to allow for optimal reaction conditions. Specifically, in some cases, it may be advantageous for the individual flow streams to have different flow rates, such that a higher overall flow rate is achieved when the individual flow streams are combined. Thus, in some embodiments, the flow rate (mL / min) of the continuous flow stream containing the compound of formula 2 and the compound of formula 3 is at least about 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mL / min. In some embodiments, the flow rate (mL / min) of the continuous flow stream containing the compound of formula 2 and the compound of formula 3 is less than about 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, or 0.5 mL / min. In some embodiments, the flow rate of the continuous flow comprising the compound of formula 2 and the compound of formula 3 is within the range provided by any two of the higher and / or lower amounts previously described, for example, the flow rate (mL / min) is about 0.1 to 5, 0.5 to 4.5, 1.0 to 4.0, 1.5 to 3.5 or 2.0 to 3.0 mL / min.

[0149] Similarly, the temperature of a continuous flow reactor can be configured at any specific point to obtain optimal reaction conditions. Temperature configuration can be related to, for example, increasing reagent solubility, controlling exothermic reactions, and / or increasing the yield of the azabicyclic compound of Formula 1. The temperature configuration of the continuous flow reactor can be such that a specific section of the reactor is configured at a temperature different from at least one other section of the reactor. Furthermore, the temperature configuration can be such that a specific stage of the continuous flow process is configured at a temperature different from at least one other stage of the continuous flow process. For example, organolithium reactions and quenching reactions can be carried out at different temperatures. Thus, in one example, a section of the continuous flow reactor is configured at a temperature different from at least one other section of the reactor. Similarly, in one example, a stage of the continuous flow process is configured at a temperature different from at least one other stage of the continuous flow process. Therefore, in some embodiments, at any stage during the continuous flow reaction as described herein, the continuous flow reactor is configured to operate at temperatures less than about 20°C, about 10°C, about 0°C, about -10°C, about -20°C, about -30°C, about -40°C, about -50°C, about -60°C, about -70°C, or about -80°C. In some embodiments, at any stage during the continuous flow reaction as described herein, the continuous flow reactor is configured to operate at temperatures at least about -80°C, about -70°C, about -60°C, about -50°C, about -40°C, about -30°C, about -20°C, about -10°C, about 0°C, about 10°C, or about 20°C. In some embodiments, at any stage during a continuous flow reaction as described herein, the continuous flow reactor is configured to operate at temperatures within a range provided by either the higher or lower amounts previously described, for example, about -80°C to 20°C, about -70°C to 10°C, about -60°C to 0°C, about -50°C to -10°C, or about -30°C to -10°C.

[0150] In some embodiments, at any stage during a continuous flow process as described herein, sections of the continuous flow reactor are independently configured to operate at temperatures less than about 20°C, about 10°C, about 0°C, about -10°C, about -20°C, about -30°C, about -40°C, about -50°C, about -60°C, about -70°C, or about -80°C. In some embodiments, at any stage during a continuous flow process as described herein, sections of the continuous flow reactor are independently configured to operate at temperatures at least about -80°C, about -70°C, about -60°C, about -50°C, about -40°C, about -30°C, about -20°C, about -10°C, about 0°C, about 10°C, or about 20°C. In some embodiments, at any stage during a continuous flow process as described herein, sections of the continuous flow reactor are independently configured to operate at temperatures within a range provided by either the higher or lower amounts previously described, for example, about -80°C to 20°C, about -70°C to 10°C, about -60°C to 0°C, about -50°C to -10°C, or about -30°C to -10°C.

[0151] In one example, the continuous flow process is carried out at a temperature less than about 20°C, about 10°C, about 0°C, about -10°C, about -20°C, about -30°C, about -40°C, about -50°C, about -60°C, about -70°C, or about -80°C. In one example, the continuous flow process is carried out at a temperature of at least about -80°C, about -70°C, about -60°C, about -50°C, about -40°C, about -30°C, about -20°C, about -10°C, about 0°C, about 10°C, or about 20°C. In one example, the continuous flow process is carried out at a temperature within a range provided by any of the higher and / or lower amounts described above, for example, about -80°C to 20°C, about -70°C to 10°C, about -60°C to 0°C, about -50°C to -10°C, or about -30°C to -10°C.

[0152] In one example, the stages of the continuous flow process are independently carried out at temperatures less than about 20°C, about 10°C, about 0°C, about -10°C, about -20°C, about -30°C, about -40°C, about -50°C, about -60°C, about -70°C, or about -80°C. In one example, the stages of the continuous flow process are independently carried out at temperatures at least about -80°C, about -70°C, about -60°C, about -50°C, about -40°C, about -30°C, about -20°C, about -10°C, about 0°C, about 10°C, or about 20°C. In one example, the stages of the continuous flow process are independently carried out at temperatures within a range provided by any of the higher and / or lower amounts described above, for example, about -80°C to 20°C, about -70°C to 10°C, about -60°C to 0°C, about -50°C to -10°C, or about -30°C to -10°C.

[0153] In one example, the organolithium reaction is carried out at a temperature less than about 20°C, about 10°C, about 0°C, about -10°C, about -20°C, about -30°C, about -40°C, about -50°C, about -60°C, about -70°C, or about -80°C. In one example, the organolithium reaction is carried out at a temperature at least about -80°C, about -70°C, about -60°C, about -50°C, about -40°C, about -30°C, about -20°C, about -10°C, about 0°C, about 10°C, or about 20°C. In one example, the organolithium reaction is carried out at a temperature within a range provided by any of the higher and / or lower amounts previously described, for example, about -80°C to 20°C, about -70°C to 10°C, about -60°C to 0°C, about -50°C to -10°C, or about -30°C to -10°C.

[0154] solvent

[0155] Those skilled in the art will understand that various suitable solvents can be used in continuous flow processes. In some embodiments, the continuous flow process is carried out in a polar solvent, such as a polar aprotic solvent. In some embodiments, the continuous flow process is carried out in a nonpolar solvent, such as a nonpolar aprotic solvent. Examples of polar aprotic solvents include, but are not limited to, halogenated hydrocarbons, nitriles, esters, carbonates, ethers, sulfoxides, sulfones, amides, nitroalkanes, and pyrrolidines. Examples of ketones include, but are not limited to, acetone, methyl ethyl ketone (MEK), methyl butyl ketone (MBK), methyl isobutyl ketone (MIBK), and methyl isopropyl ketone. Examples of nitriles include, but are not limited to, acetonitrile (MeCN). Examples of esters include, but are not limited to, ethyl formate, methyl acetate (MeOAc), ethyl acetate (EtOAc), propyl acetate, isopropyl acetate (iPAC), n-butyl acetate, and isobutyl acetate. Examples of carbonates include, but are not limited to, dimethyl carbonate (DMC) and propylene carbonate (PC). Examples of polar and nonpolar ethers include, but are not limited to, methyl tert-butyl ether (MTBE), diethyl ether, 1,4-dioxane, 2-methoxyethanol, 2-ethoxyethanol, dimethoxyethane (DME or ethylene glycol dimethyl ether), 1,1-dimethoxymethane, 2,2-dimethoxypropane, 1,1-diethoxypropane, isopropyl ether, petroleum ether, cyclopentylmethyl ether (CPME), anisole (methoxybenzene), methyltetrahydrofuran (MeTHF), and tetrahydrofuran (THF). Examples of sulfoxides include, but are not limited to, dimethyl sulfoxide (DMSO). Examples of sulfones include, but are not limited to, sulfolane. Examples of amides include, but are not limited to, formamide, N,N-dimethylacetamide, and N,N-dimethylformamide (DMF). Examples of nitroalkanes include, but are not limited to, nitromethane. Examples of pyrrolidines include, but are not limited to, N-methylpyrrolidone (NMP). Examples of nonpolar aprotic solvents include benzene, chloroform, cyclohexane, diethyl ether, hexane, pentane, and toluene. In one example, the nonpolar aprotic solvent is toluene. Examples of polar and nonpolar halogenated hydrocarbons (such as chlorinated hydrocarbons) include, but are not limited to, 1,1,1-trichloroethane, 1,1-dichloroethylene, and 1,2-dichloroethylene. In some embodiments, the solvent comprises or is composed of one or more polar aprotic ether solvents (such as MeTHF and THF). In one example, the continuous flow process is carried out in an ether (such as MeTHF or THF). In one example, the continuous flow process is carried out in MeTHF. In one example, the continuous flow process is carried out in THF. The solvent may be present in the continuous flow process in any suitable amount to affect the organolithium reaction. In some examples, the solvent may be anhydrous. For example, the amount of water in the solvent may be less than about (in ppm) 500, 400, 300, 200, 100, 75, 50, 25, 10, 5, or 1 ppm.

[0156] Dilution stream

[0157] At any stage during a continuous flow reaction, it may be necessary to dilute one or more flow streams. It should be understood that diluting the flow streams will subsequently reduce the concentration of any reactants / reagents in that flow stream. This may be necessary as a way to optimize the reaction. Therefore, in some embodiments, the continuous flow process further includes combining a continuous flow stream containing a solvent with a continuous flow stream containing an organolithium reagent to controllably dilute the concentration of one or more reagents. In one example, the continuous flow process further includes combining a continuous flow stream containing a solvent with a continuous flow stream containing an organolithium reagent to controllably dilute the concentration of the organolithium reagent.

[0158] Furthermore, dilution streams can be used to modify the solvent composition at the reaction point to optimize the reaction. For example, introducing a second solvent via a dilution stream can increase or decrease miscibility, thereby increasing or decreasing reagent solubility, and thus potentially increasing or decreasing the reaction rate and the conversion of starting materials and reagents to reaction products. As used herein, the term "miscibility" refers to the property of two substances (e.g., solvents) to mix in all proportions to form a homogeneous mixture (e.g., a solution). In one example, the continuous flow process further includes combining a continuous flow stream containing a first solvent with a continuous flow stream containing a second solvent, wherein the second solvent is used to increase the resulting miscibility. In one example, the continuous flow process further includes combining a continuous flow stream containing a first solvent with a continuous flow stream containing a second solvent, wherein the second solvent is used to decrease the resulting miscibility.

[0159] Advantageously, the use of a continuous flow reactor allows for the introduction of a dilution stream at any suitable point in the reaction.

[0160] In some embodiments, the dilution stream is provided at a flow rate (mL / min) of at least about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mL / min. In some embodiments, the continuous flow stream containing the solvent is provided at a flow rate (mL / min) of less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, or 0.1 mL / min. In some embodiments, the continuous flow stream containing the solvent is provided within a range provided by any of the higher and / or lower amounts previously described, for example, the flow rate (mL / min) is about 0.1 to 10, 1 to 9, or 5 to 7 mL / min.

[0161] Yield

[0162] As used herein, the term "yield" will be considered to mean the amount of crude or purified compound (e.g., an azabicyclic compound of Formula 1) obtained from the reaction, measured as a percentage of the theoretical yield of the compound in the reaction, as will be understood by those skilled in the art. Thus, in some embodiments, the yield of the azabicyclic compound of Formula 1 provided by the continuous flow process is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, as determined by using a compound of Formula 2 or Formula 3 as a starting material. Similarly, in some embodiments, the yield of the azabicyclic compound of Formula 1 provided by the continuous flow process is about 20% to 90%, about 30% to 80%, about 50% to 80%, or about 50% to 70%, or about 60% to 80%, or about 70% to 80%, as determined by using a compound of Formula 2 or Formula 3 as a starting material.

[0163] Continuous flow processes can be monitored using any conventional method known to those skilled in the art, such as TLC (thin-layer chromatography) or HPLC (high-performance liquid chromatography). Advantageously, the ability to monitor continuous flow processes provides an indication of the consumption (conversion) of starting materials (i.e., compounds of Formula 2 and / or Formula 3). Thus, in some embodiments, the continuous flow process provides consumption of at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the compound of Formula 3 or the compound of Formula 2, as determined by HPLC. In some embodiments, the continuous flow process provides consumption of about 20% to 90%, about 30% to 80%, about 50% to 80%, or about 60% to 80% of the compound of Formula 3 or the compound of Formula 2, as determined by HPLC. It should be understood that the consumption of starting materials (i.e., compounds of Formula 2 and / or Formula 3) can be measured at any point during the reaction. Typically, aliquots of the reaction mixture are subjected to HPLC, in which relevant component peaks are identified and integrated relative to each other.

[0164] productivity

[0165] As used herein, the term "productivity" refers to the rate of product output from a continuous flow reactor, measured in grams per hour. Therefore, in some embodiments, the continuous flow process provides a productivity or product output rate (in grams per hour) of at least about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 500, 1000, 2000, or 5000 g / h. In some embodiments, the productivity or product output rate (in g / h) of the continuous flow process is within the range provided by any of the previously described quantities, for example, product output (in g / h) is about 0.1 to 100, 1 to 50, 5 to 40, 10 to 30, or 15 to 25 g / h.

[0166] Air-hour production rate

[0167] As used herein, the term “space-time yield” refers to the amount of product obtained per liter of reactor volume per hour (in kg / L / h). Therefore, in some embodiments, the space-time yield (in kg / L / h) of a continuous flow process is at least about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 400, 600, 800, 1000, 1500, 2000, 2500, 3000, 4000, 5000, or 10000 kg / L / h. In some embodiments, the space-time yield (in kg / L / h) of the continuous flow process is within the range provided by any two of the quantities previously described, for example, the space-time yield (in kg / L / h) is about 1 to 10,000, 5 to 200, 10 to 100, 20 to 90, 30 to 80, or 40 to 60 kg / L / h.

[0168] reactor section

[0169] A continuous flow reactor can be defined by the various “sections” through which the flow passes. In fact, a continuous flow process as described herein can be considered as taking place within one or more sections of a continuous flow process. A section can comprise a combination of one or more conduits or portions thereof, wherein portions of all conduits or combinations thereof are commonly adjacent. Such sections help define specific configurations within the reactor, such as concentration, solvent, and temperature. Therefore, the total volume of each section can be defined independently and is referred to as the “section volume” (in mL). Thus, in one example, the total section volume (mL) of the continuous flow process is at least about 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 500, or 1000 mL. In some embodiments, the total segment volume (mL) of the continuous flow process is within the range provided by any two of the previously described quantities, for example, the total segment volume (mL) is about 1 to 1000, 5 to 1000, 100 to 1000, or 500 to 1000 mL.

[0170] purity

[0171] As used herein, the term "purity" refers to the amount of the desired substance relative to the total amount of all substances found in the sample, such as impurities (or undesirable substances) and optionally any solvents that may be present in the sample. Purity can be expressed qualitatively (e.g., high purity) or quantitatively (e.g., as a percentage). Purity can be assessed based on the weight, volume, or molar ratio of one substance to other substances. Therefore, it should be understood that a high-purity sample of the desired substance (e.g., an azabicyclic compound of Formula 1) is optimal. Thus, in some embodiments, the process described herein provides an azabicyclic compound of Formula 1 with high purity. As those skilled in the art will understand, purity is a measure independent of yield. That is, a sample may have high purity even with a low yield. As used herein, the term "high purity" means that at least 70% of the final obtained sample is the desired compound (e.g., an azabicyclic compound of Formula 1), which can be measured, for example, by HPLC or NMR methods. The purity of a sample can be measured based on the crude reaction mixture, a sample separated from the reaction mixture (i.e., after post-reaction processing), or a purified sample (i.e., after chromatography, recrystallization, etc.).

[0172] In some embodiments, the continuous flow process provides a nitrogen-containing bicyclic compound of Formula 1 with a purity of at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, or 95%.

[0173] Continuous flow reactor system

[0174] It should be understood that both research and industrial / commercial continuous flow reactor systems have many variations. As described herein, specific variations can be more practical when conducting continuous flow processes. Flow reactors must provide sufficient heat and mass transfer to maintain the selectivity levels required to produce the compounds of Formula 1. These parameters depend on the flow rate of the input stream but can be enhanced through optimized reactor design. For example, using static mixing elements in a slug reactor will improve mass transfer. Examples of continuous flow reactor systems include, but are not limited to, slug reactors, tubular reactors, fixed-bed reactors, fluidized-bed reactors, continuous stirred-tank reactors (CSTRs), rotating disk reactors, rotating tube reactors, multi-pool flow reactors, oscillating flow reactors, microreactors, hex reactors, and sucker reactors. In one example, the continuous flow process described herein is carried out in a continuous flow reactor system selected from the group consisting of: slug reactors, tubular reactors, fixed-bed reactors, fluidized-bed reactors, continuous stirred-tank reactors (CSTRs), rotating disk reactors, rotating tube reactors, multi-pool flow reactors, oscillating flow reactors, microreactors, hex reactors, and sucker reactors. In one example, the continuous flow process described herein is carried out using a slug reactor. In one example, the continuous flow process described herein is carried out using a tubular reactor. In one example, the continuous flow process described herein is carried out using a fixed-bed reactor. In one example, the continuous flow process described herein is carried out using a fluidized-bed reactor. In one example, the continuous flow process described herein is carried out using a continuous stirred tank reactor (CSTR). In one example, the continuous flow process described herein is carried out using a rotating disk reactor. In one example, the continuous flow process described herein is carried out using a rotating tube reactor. In one example, the continuous flow process described herein is carried out using a multi-tank flow reactor. In one example, the continuous flow process described herein is carried out using an oscillating flow reactor. In one example, the continuous flow process described herein is carried out using a microreactor. In one example, the continuous flow process described herein is carried out using a hex reactor. In one example, the continuous flow process described herein is carried out using a suction reactor.

[0175] A plug flow reactor (PFR), sometimes also called a continuous tubular reactor (CTR) or plug flow reactor, is a type of reactor used to conduct and characterize chemical reactions in a continuous flow system. PFR reactor models are used to predict the behavior of chemical reactors of this design, allowing estimation of key reactor variables such as reactor dimensions. The fluid flowing through a PFR can be modeled as a series of infinitely thin, coherent “plugs” flowing through the reactor, each plug having a uniform composition, traveling in the axial direction of the reactor, where the composition of each plug differs from that of the plugs preceding and following it. A key assumption is that the fluid is completely mixed in the radial direction (i.e., in the transverse direction) as the plug flow passes through the PFR, but not mixed in the axial direction (forward or backward).

[0176] In one example, the continuous flow process described herein is carried out using a tubular reactor. In another example, the continuous flow process described herein is carried out in a continuous stirred tank reactor (CSTR). In yet another example, the continuous flow process described herein is carried out in a microreactor.

[0177] Therefore, the terms used herein to define reactor types in the context of this invention, such as “continuous flow reactor,” “plug flow reactor,” “tubular reactor,” “continuous flow reactor system,” “plug flow reactor system,” “tubular reactor system,” “continuous flow system,” “plug flow system,” “tubular system,” and “microreactor,” are synonyms for each other and are interchangeable.

[0178] Reactors or systems can be arranged as a number of conduits, which can be linear, annular, tortuous, circular, coiled, or a combination thereof. For example, if they are coiled, the reactor or system is also referred to as a "coiled reactor" or "coiled system".

[0179] A conduit comprising a large number of tubing tubes can be described based on its maximum inner diameter or internal cross-sectional dimensions (i.e., radial or lateral dimensions, respectively). Such a description defines the lateral dimensions of the reactor or reactor system. In some embodiments, the lateral dimensions of the reactor or reactor system may be less than about 10 cm, less than about 9 cm, less than about 8 cm, less than about 7 cm, less than about 6 cm, less than about 5 cm, less than about 4 cm, less than about 3 cm, less than about 2 cm, less than about 1 cm, less than about 0.9 cm, less than about 0.8 cm, less than about 0.7 cm, less than about 0.6 cm, less than about 0.5 cm, less than about 0.4 cm, less than about 0.3 cm, less than about 0.2 cm, less than about 10 mm, less than about 9.5 mm, less than about 9.0 mm, less than about 8.5 mm, or less than about 8.0 m. m, less than about 7.5 mm, less than about 7.0 mm, less than about 6.5 mm, less than about 6.0 mm, less than about 5.5 mm, less than about 5.0 mm, less than about 4.5 mm, less than about 4.0 mm, less than about 3.5 mm, less than about 3.0 mm, less than about 2.5 mm, less than about 2.0 mm, less than about 1.5 mm, less than about 1.0 mm, less than about 0.9 mm, less than about 0.8 mm, less than about 0.7 mm, less than about 0.6 mm, less than about 0.5 mm, less than about 0.4 mm, less than about 0.3 mm, less than about 0.2 mm, or less than about 0.1 mm. In some embodiments, the lateral dimensions of the reactor or reactor system may be greater than approximately 10 cm, approximately 9 cm, approximately 8 cm, approximately 7 cm, approximately 6 cm, approximately 5 cm, approximately 4 cm, approximately 3 cm, approximately 2 cm, approximately 1 cm, approximately 0.9 cm, approximately 0.8 cm, approximately 0.7 cm, approximately 0.6 cm, approximately 0.5 cm, approximately 0.4 cm, approximately 0.3 cm, approximately 0.2 cm, approximately 10 mm, approximately 9.5 mm, approximately 9.0 mm, approximately 8.5 mm, or approximately 8.0 mm. m, greater than about 7.5 mm, greater than about 7.0 mm, greater than about 6.5 mm, greater than about 6.0 mm, greater than about 5.5 mm, greater than about 5.0 mm, greater than about 4.5 mm, greater than about 4.0 mm, greater than about 3.5 mm, greater than about 3.0 mm, greater than about 2.5 mm, greater than about 2.0 mm, greater than about 1.5 mm, greater than about 1.0 mm, greater than about 0.9 mm, greater than about 0.8 mm, greater than about 0.7 mm, greater than about 0.6 mm, greater than about 0.5 mm, greater than about 0.4 mm, greater than about 0.3 mm, greater than about 0.2 mm, or greater than about 0.1 mm. In some embodiments, the lateral dimension of the reactor or reactor system is within the range provided by any two of the higher and / or lower quantities described above, for example, wherein the lateral dimension is about 0.1 mm to 1 cm, 0.1 mm to 0.5 mm, 1 mm to 1 cm, or 1 cm to 3 cm.

[0180] If the maximum lateral dimension of a reactor or reactor system is less than about 1 mm, the reactor is usually referred to as a "microreactor". Therefore, in the use of microreactors, in one instance, the lateral dimension of the reactor or reactor system can range from about 0.1 mm to at most about 1 mm.

[0181] The reactor or reactor system can be configured such that, during use, the pressure drop across the reactor (in Pa / m) is in the range of about 0.1 to 1,000,000 Pa / m (or 1 MPa / m), inclusive of any value or range thereof. For example, the pressure drop across a continuous flow reactor (in Pa / m) can be less than about 500,000, 250,000, 100,000, 50,000, 10,000, 5,000, 1,000, 750, 500, 250, 100, 75, 50, 25, 20, 15, 10, or 5 Pa / m. Alternatively, the total pressure drop across the reactor can be measured in MPa and is in the range of about 0 to 10 MPa (or 100 bar), inclusive of any value or range thereof. For example, the total pressure drop (in MPa) across a continuous flow reactor can be less than about 10, 5, 4, 3, 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.04, 0.03, 0.02, or 0.01 MPa. Continuous flow reactors can be configured to provide a low pressure drop relative to a specific flow rate. In this respect, as described herein, reactors, systems, and processes can be provided with parameters suitable for industrial applications. The aforementioned pressure drops can be maintained with volumetric flow rates of at least 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 20, 30, 40, and 50 mL / min.

[0182] Scaling up of continuous flow processes

[0183] Those skilled in the art will understand that the use of continuous flow reactors enables continuous input / output of materials, meaning that scalability of the continuous flow process is achievable (e.g., by continuing to operate the continuous flow process for longer periods by using reactors with larger lengths or cross-sectional areas that allow for higher flow rates). In one example, the continuous flow process described herein is carried out in a microreactor. In an alternative embodiment of the invention, it is also optionally desirable to employ continuous flow reactors other than microreactors, particularly where greater throughput (i.e., scaling up) is desired. In such cases, it is desirable to employ a continuous flow reactor with a lateral dimension larger than that of the microreactor indicated above. Thus, in the case of employing a larger continuous flow reactor (i.e., scaling up), the term "continuous flow reactor" refers to an apparatus in which a chemical reaction occurs within a typical lateral dimension greater than about 1 mm, and may be limited to at most about 5 mm, 10 mm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, or even 10 cm. In such embodiments, plug flow reactors and / or tubular flow reactors may be desired as continuous flow reactors. When using a large, continuous flow reactor, the reactor's ability to facilitate sufficient heat and mass transfer must be considered to maintain the desired selectivity level required to produce the compound of Formula 1. Those skilled in the art will understand that it may be desirable for the reactor to allow for rapid mixing of reagents while maintaining a low reaction temperature. As will be further understood, the heat and / or mass transfer facilitated by the reactor can be tuned by incorporating mixing elements such as a static mixer.

[0184] During the scaling up of a continuous flow process as described herein, it may be desirable to use higher flow rates for the continuous flow stream in the continuous flow process. For example, such higher flow rates, compared to the typical flow rates described herein (i.e., the flow rates of a microreactor), are at most about 2 times higher, at most about 5 times higher, at most about 10 times higher, at most about 100 times higher, at most about 500 times higher, at most about 1000 times higher, or at most about 1 to about 1000 times higher, at most about 1 to about 500 times higher, at most about 1 to about 100 times higher, at most about 1 to about 10 times higher, at most about 1 to about 5 times higher, or at most about 1 to about 2 times higher. In such embodiments, it may be desirable to independently adjust the flow rate of the continuous flow stream comprising the compound of Formula 1, the compound of Formula 2, the organolithium reagent, and / or the quenching solution as described herein.

[0185] Furthermore, during scaling up, longer residence times in continuous flow reactors may be desired. For example, such longer residence times, compared to typical residence times indicated herein (i.e., residence times in microreactors), are at most about 2 times longer, at most about 3 times longer, at most about 4 times longer, at most about 5 times longer, at most about 6 times longer, at most about 7 times longer, or any intermediate flow rate at most about 1 to about 7 times longer, at most 1 to about 6 times longer, at most 1 to about 5 times longer, at most 1 to about 4 times longer, at most 1 to about 3 times longer, or at most 1 to about 2 times longer. In some embodiments, shorter residence times in continuous flow reactors may be desired. For example, such shorter residence times, compared to the typical residence times indicated herein (i.e., the residence times of microreactors), are any intermediate flow rates that are at most about 2 times shorter, at most about 3 times shorter, at most about 4 times shorter, at most about 5 times shorter, at most about 6 times shorter, at most about 7 times shorter, or about 1 to about 7 times shorter, about 1 to about 6 times shorter, about 1 to about 5 times shorter, about 1 to about 4 times shorter, about 1 to about 3 times shorter, or about 1 to about 2 times shorter. In such embodiments, it may be desirable to independently adjust the residence time of each section of the continuous flow reactor as described herein.

[0186] Of course, in the production of the compounds described herein, preferably for industrial use, one or more reactors may be used. If more than one reactor is used in the production, preferably for industrial use, these reactors may be used in parallel and / or in subsequent arrangements. For example, two, three, four, or more reactors may be used in parallel and / or in subsequent arrangements. Those skilled in the art will understand that the continuous flow process described herein can utilize multiple continuous flow reactors in parallel and / or in subsequent arrangements. As described herein, such reactor configurations can find particular use in scaling up continuous flow processes. Furthermore, the parallel use of one or more reactors allows for overall continuous production even when one or more particular reactors are shut down for maintenance, cleaning purposes, or due to blockage or malfunction events. Cleaning of the reactors can be performed by flushing the reactors with one or more suitable cleaning solvents ('clean in place'), or alternatively, after reactor shutdown and disassembly. Blockage formation can be monitored using pressure sensors.

[0187] Xanamem Synthesis

[0188] As discussed above, the azabicyclic heteroaryl moiety is a common intermediate in the synthesis of many drug compounds, including Xanamem.

[0189] In the synthesis of Xanamem, any reactions prior to or after the synthesis of the azabicyclic heteroaryl moiety, as described herein, may be carried out in a continuous flow reactor. Alternatively, in the synthesis of Xanamem, any reactions prior to or after the synthesis of the azabicyclic heteroaryl moiety, as described herein, may be carried out under batch or semi-batch reaction conditions.

[0190] Therefore, in some embodiments, the continuous flow process further comprises preparing a salt of the amine bicyclic compound of formula 4:

[0191]

[0192] The process described herein involves using a nitrogen-containing bicyclic compound of formula 1:

[0193]

[0194] The compound is reacted with an acid to remove the amine protecting group, thereby obtaining a salt of the compound of formula 4.

[0195] In some embodiments, the compound of formula 1 is isolated prior to reaction with an acid to remove the amine protecting group to obtain a salt of the compound of formula 4. As will be understood by those skilled in the art, the isolation can be performed by any suitable method. Alternatively, in some embodiments, the compound of formula 1 is not isolated prior to reaction with an acid to remove the amine protecting group to obtain a salt of the compound of formula 4.

[0196] The acid used to remove the amine protecting group can be any suitable acid. In one example, the acid is p-toluenesulfonic acid. In such cases, when the acid is p-toluenesulfonic acid, it should be understood that the compound of formula 4 can be obtained as a p-toluenesulfonate. In one example, R 2 It is tert-butoxycarbonyl (Boc), and the acid used to remove the amine protecting group is p-toluenesulfonic acid.

[0197] In some embodiments, the continuous flow process further comprises preparing a heterocyclic ketone compound of formula 5:

[0198]

[0199] The process described herein involves using a carboxylic acid compound of formula 6 or a salt thereof:

[0200]

[0201] With amine bicyclic compounds of formula 4 or their salts:

[0202]

[0203]

[0204] The reaction is carried out in the presence of at least one coupling agent to obtain the heterocyclic ketone compound of formula 5.

[0205] In some embodiments, the continuous flow process further includes the preparation of Xanamem:

[0206]

[0207] The process described herein involves using a carboxylic acid compound of formula 7 or a salt thereof:

[0208]

[0209] With amine bicyclic compounds of formula 1ai or their salts:

[0210]

[0211] The reaction is carried out in the presence of at least one coupling agent to obtain Xanamem.

[0212] Those skilled in the art will understand that the term "coupling agent" refers to a compound that provides a chemical bond between two chemical moieties. In one example, the coupling agent is an "amide coupling agent," and provides a chemical bond between the carboxylic acid moiety and the amine moiety, thereby forming an amide bond.

[0213] In some embodiments, the coupling agent is an oxime coupling agent. Such coupling agents may also be referred to as "additives". In some embodiments, the oxime coupling agent is selected from the group consisting of: OxymaPure (2-cyano-2-(hydroxyimino)acetic acid), K-Oxyma (potassium 2-cyano-2-(hydroxyimino)acetate), COMU (1-[(1-(cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethyl-aminomorpholinomethylene)]methylammonium hexafluorophosphate), PyOxym-M, PyOxim (O-[(cyano(ethoxycarbonyl)-methylimino)amino]oxytripyrrolidinylphosphine cation hexafluorophosphate), HONM (isonitroso Meldrum's acid), Ocyma-B, Oxyma-T, Amox, HMMU, and Fmoc-Amox. In one example, the oxime coupling agent is OxymaPure (2-cyano-2-(hydroxyimino)acetic acid). In some embodiments, the carbodiimide coupling agent is selected from the group consisting of: DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), EDAC.HCl (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide.HCl), and EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide). In one example, the carbodiimide coupling agent is EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide). In some embodiments, the coupling agent is selected from at least one oxime coupling agent and at least one carbodiimide coupling agent, each of which may be provided according to any of the embodiments or examples thereof as described herein. In one example, the coupling agent comprises OxymaPure (2-cyano-2-(hydroxyimino)acetic acid) and EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide). In one example, the coupling agent is an oxime coupling agent. In one example, the coupling agent is a carbodiimide coupling agent.

[0214] Example

[0215] General Experiment Information

[0216] abbreviations

[0217] DIC N,N'-Diisopropylcarbodiimide

[0218] DIPEA N,N'-Diisopropylethylamine

[0219] DMSO (dimethyl sulfoxide)

[0220] EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0221] HCl hydrochloric acid

[0222] HOPO 2-hydroxypyridine-N-oxide

[0223] HPLC (High Performance Liquid Chromatography)

[0224] IPA isopropanol

[0225] IPC ion-pair chromatography

[0226] 2-MeTHF 2-Methyltetrahydropyran

[0227] NMR (Nuclear Magnetic Resonance)

[0228] pTSA p-toluenesulfonic acid

[0229] TFA (trifluoroacetic acid)

[0230] THF Tetrahydrofuran

[0231] THP Tetrahydropyran

[0232] TMS Tetramethylsilane

[0233] General experimental protocol

[0234] The experiment will focus on the reaction of EU1F (2-iodopyrimidine) with N-boc-nortropinone to produce the azabicyclic compound EU1G of Formula 1. EU1G is a key intermediate in the synthesis of Xanamem.

[0235]

[0236] Scheme 1. Synthesis of EU1G, a nitrogen-containing bicyclic compound of Formula 1.

[0237] EU1F (CAS: 31462-54-1) is from AA BLOCKS (Catalog: AG00C6WU; Lot No.: AGN22-762989-1). N-boc-nortropinone (CAS: 185099-67-6) is from Apollo Scientific (Catalog: OR12337; Lot No.: AS498687). Hexyllithium (HexLi, 2.5M in hexane, CAS: 21369-64-2) is from Thermo Scientific (Catalog: 301651000). Butyllithium (n-BuLi, 2.5M in hexane, CAS: 109-72-8) is from Aldrich (Catalog: 230707). Phenyl lithium (1.9M in dibutyl ether, CAS: 591-51-5) is from Aldrich (catalog: 593230). Methyl lithium (MeLi, 1.6M in Et2O, CAS: 917-54-4) is from Sigma Aldrich (catalog: 197343). Methyl lithium bromide complex (MeLi·LiBr, 1.5M in Et2O, CAS: 332360-06-2) is from Sigma Aldrich (catalog: 186201). p-Toluenesulfonic acid monohydrate (pTSA·H2O, CAS: 6192-52-5) is from Acros (catalog: 13902 1000). Tetrahydrofuran (THF, CAS: 109-99-9) is from Fisher Scientific (catalog: 348450010).

[0238] Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker 300MHz instrument. 1 H and 13 C6 spectra were recorded at 300 MHz and 75 MHz, and chemical shifts relative to TMS were expressed in parts per million (ppm). Samples were prepared in CDCl3 or DMSO-d6. The letters s, d, t, and m were used to indicate singlets, doublets, triplets, and multiplets, respectively.

[0239] HPLC Method A (Polar; 12.5 min): HPLC analysis was performed at 37 °C on a Shimadzu LC20 system using a Macherey-Nagel Nucleodur C18 reversed-phase column (150 mm × 4.6 mm, 5 μm particle size) with mobile phases A (90:10 v / v water / acetonitrile + 0.1% TFA) and B (MeCN + 0.1% TFA) at a combined flow rate of 1.5 mL / min. The following gradient was applied: starting with 3% solvent B, linearly increasing from 3% to 5% B over 3 min, linearly increasing from 5% to 30% B over 4 min, linearly increasing from 30% to 100% B over 3 min, holding at 100% B for 2 min, linearly decreasing from 100% to 3% B over 0.5 min, and holding at 3% B for 2.5 min. The final purity of the boc-deprotected pTSA salt was assessed using HPLC Method A.

[0240] HPLC Method B (Standard; 10 min): HPLC analysis was performed at 37 °C on a Shimadzu LC20 system using a Macherey-Nagel Nucleodur C18 reversed-phase analytical column (150 mm × 4.6 mm, 5 μm particle size) with mobile phases A (90:10 v / v water / acetonitrile + 0.1% TFA) and B (MeCN + 0.1% TFA) at a flow rate of 1.5 mL / min. The following gradient was applied: starting with 30% solvent B, increasing (linear gradient) to 100% solvent B over 10 min, then decreasing to 30% solvent B for 3 min to prepare for the next injection. Unless otherwise specified, all experiments were performed using HPLC Method B.

[0241] For all flow settings, standard PFA tubing (0.8 mm or 1.6 mm inner diameter), PTFE or PEEK fittings, and T-joints were used. For pumping reagent solutions, syringe pumps (Syrris Asia) equipped with 0.5 / 0.25 mL (flow rate ≤ 1.25 mL / min), 1.0 / 0.5 mL (flow rate ≤ 2.50 mL / min), or 5.0 / 2.5 mL (flow rate ≤ 10 mL / min) syringes were used. All pumps were used with check valves (Upchurch, CV-3321) and internal pressure sensors. For safety reasons, the pump pressure limit was set to 20 bar (automatic shut-off at pressure > 20 bar). All pumps were tested and found to be accurate to within ±3% of the set value.

[0242] All flow reactions were carried out in a Modular Microreaction System (MMRS) manufactured by Ehrfeld Mikrotechnik (Wendelsheim, Germany). A 1 / 16” input connector (0711-2-00224-F) was used for the reagent inlet. A 1 / 8” input connector (0711-2-0224-F) was used for the quenching solution (methanol containing citric acid) and outlet. A FlowPlate Lab (1701-3-0004-F) equipped with a TG design process board (part number 1701-2643-HC, TG mixer, nominal width 0.2 mm, volume 0.344 mL, flow range 1.5–15 mL / min, channel width (maximum) 0.6 mm × 0.5 mm, Hastelloy C22) was used, and the temperature was controlled by a cryostat (LaudaProline RP-890).

[0243] Prepare a feed solution containing 2-iodopyrimidine and N-boc-nortropinone in a volumetric flask. Weigh 2-iodopyrimidine, N-boc-nortropinone, and approximately 20 mol% biphenyl as internal standards (for reaction development only and will not be included in large-scale processes) into the corresponding flasks, place them under argon atmosphere, and make up the volume with the reaction solvent (dried THF, unless otherwise specified).

[0244] For optimized experiments, all substrate and reagent flows were introduced through the sample loop (PFA, 0.8 mm inner diameter, volume = 1–5 mL, exact volume depending on reagent equivalents). This was achieved using a 2-position 6-port valve (IDEX, V-450) configured to allow reagent loading into the sample loop, after which the reagent was injected into the reactor. This method minimizes the amount of material required for flow experiments because the pump does not need to be prepared separately with reagents. Before each experiment, the entire reactor system was flushed with dry THF at the maximum flow rate of the syringe pump used for at least 10 minutes.

[0245] The solution collected after the reaction (and citric acid quenching) was analyzed using calibrated HPLC to determine the amounts of 2-iodopyrimidine, EU1G, and N-boc-nortropinone. HPLC calibration curves (relative to biphenyl as an internal standard) for N-boc-nortropinone, 2-iodopyrimidine, and EU1G were determined, and are respectively as follows: Figure 1 , 2 As shown in Figure 3. Figure 4Example HPLC calibration chromatograms showing all three reaction components and the internal reference standard (biphenyl) are depicted. For HPLC analysis, 100 μL of the reaction solution was diluted with a mixture of acetonitrile and water (approximately 1 mL). Once a steady state was reached (at least 5 residence times after reagent injection), at least three samples were sequentially collected for each experiment (each sample was collected for approximately 3 residence times). For each experiment, the results from the three samples were averaged to determine the amounts of EU1F, EU1G, and N-boc-nortropinone.

[0246] Example 1 – Flow Setting A

[0247] Optimization experiments were conducted using setting A. Figure 5 ).

[0248] Table 1. Results obtained using setting A.

[0249]

[0250] a. HPLC yield determined using calibration relative to biphenyl as an internal standard, the percentage being related to the initial amount of EU1F added to the reaction. b 2-MeTHF was used instead of THF as the reaction solvent. RT1 = residence time between the confluence of HexLi and N-boc-nortropinone (V1, 152 μL volume); RT2 = residence time between the confluence of N-boc-nortropinone and citric acid (V2, 192 μL volume).

[0251] Table 1 shows the experimental results obtained using setting A. The initial conditions (entry 1) showed low yields of EU1G, high conversions of EU1F, but low conversions of N-boc-nortropinone. These results suggest that EU1F reacts rapidly with HexLi, but the lithiation intermediate is subsequently decomposed during RT1 or consumed in side reactions before the addition of N-boc-nortropinone.

[0252] Increasing the flow rate, thus shortening the residence time in both steps and improving the mass transfer at the mixing point, did not lead to an increase in the yield of EU1G (Item 2).

[0253] To assess the effect of the reaction solvent, the reaction was carried out in 2-MeTHF instead of THF (entry 3). Under these conditions, a slightly higher side yield of EU1G was observed (17%), but the yield was still much lower than that under batch conditions.

[0254] For all conditions (items 1-3), solid formation was observed visually in the mixed structure after the mixing point of EU1F and HexLi. Switching the solvent to 2-MeTHF (item 3) caused even faster solid formation, which led to reactor clogging after 5 minutes of operation.

[0255] Due to the solid formation and low yield observed under the test conditions, it was decided to switch to an alternative setting in which EU1F and N-boc-nortropinone (Setting B) were introduced in a single feed prior to mixing with HexLi.

[0256] Example 2 – Flow Setting B

[0257] Optimization experiment using setting B ( Figure 6 ).

[0258] Table 2. Results obtained using setting B.

[0259]

[0260] a The HPLC yield determined using calibration relative to biphenyl as an internal standard is a percentage related to the initial amount of EU1F added to the reaction. RT = residence time between the confluence with HexLi and the confluence with citric acid.

[0261] Table 2 shows the results of the reactions performed using setting B. For all reactions (entries 1-4), more stable reactions were observed with respect to possible reactor clogging, and no pressure increase or solid formation was observed. Entry 1 shows that the yield of EU1G was 27%, and the conversion of EU1F was incomplete (41% remaining). Increasing the flow rate (and thus reducing the residence time) resulted in a much higher yield of EU1G, 50%, while also improving the conversion of EU1F (entry 2). This behavior shows that the incomplete conversion of EU1F was not due to the residence time being too low, but rather because HexLi was consumed in side reactions caused by inefficient mixing. This also led to increased conversion and yield due to the improved mixing caused by the higher flow rate.

[0262] Items 3 and 4 were carried out at temperatures above -50°C. Compared to item 1, these conditions resulted in lower yields, thus demonstrating a temperature dependence of the reaction. This temperature dependence is because higher temperatures accelerate side reactions, thereby reducing selectivity for the product EU1G.

[0263] Example 3 – Flow Setting C

[0264] Optimization experiments were conducted using setting C. Figure 7 ).

[0265] Table 3. Results obtained using setting C.

[0266]

[0267] a Reaction conditions: 1.5 equivalents of N-boc-nortropinone, 0.25 M EU1F concentration in the feed solution, b. HPLC yield determined using calibration relative to biphenyl as an internal standard, percentage related to the initial amount of EU1F added to the reaction. RT = residence time between the confluence with HexLi and the confluence with citric acid.

[0268] Table 3 shows the results of the initial experiments conducted using setting C. When using conditions similar to the previous best results in Item 1 (Item 2 of Table 2), but diluting HexLi to 1.5 M with THF, the yield increased to 58% EU1G. Only minor differences in yield (58% and 57% EU1G) were observed when the residence time was varied by moving the quench inlet port while keeping the flow rate constant (Items 2 and 3). Item 4 shows that, under the same conditions but at -20 °C, a significant decrease in yield to 16% EU1G was observed. Doubling the flow rate to 5.00 mL / min EU1F (reducing the residence time to 2.5 seconds) was feasible, yielding 60% EU1G (Item 5). When the temperature was increased to -40 °C (Item 6) and -20 °C (Item 7) at the same flow rate, yields decreased to 48% and 44%, respectively. Notably, better results were achieved at higher flow rates than at lower flow rates (Item 4 vs. Item 7).

[0269] Example 4 – Screening of Organolithium Reagents

[0270] Optimization experiments were performed using setting C to screen different organolithium reagents (RLi).

[0271] Table 4. Screening results of different organolithium reagents.

[0272]

[0273] a Reaction conditions: -50℃, 1.3 equivalents of RLi reagent, 1.5 equivalents of N-boc-nortropinone, reactor volume = 344 μL, 0.25 M EU1F concentration in the feed solution, b is the HPLC yield determined using calibration relative to biphenyl as an internal standard, the percentage is related to the initial amount of EU1F added to the reaction. RT = residence time between the confluence with HexLi and the confluence with citric acid.

[0274] Table 4 shows the screening results for different organolithium reagents under other constant conditions. Hexyllithium (entry 1, HexLi) and n-butyllithium (entry 2, n-BuLi) showed similar results (58% and 59% yields, respectively). Phenyllithium (entry 3, PhLi) resulted in only 81% conversion of EU1F and a decrease in yield to 48%. Methyllithium (entry 4, MeLi) and the methyllithium-lithium-bromide complex (entry 5, MeLi·LiBr) showed significantly improved yields (69% and 71% EU1G, respectively). Using MeLi·LiBr, doubling the flow rate to improve mixing showed a slight increase to 72% EU1G, while demonstrating that a residence time of 2.5 seconds was sufficient to complete the reaction.

[0275] Example 5 – Screening of Organolithium Reagent Equivalents

[0276] Optimization experiments were conducted using setting C to screen different equivalents of organolithium reagent (RLi).

[0277] Table 5. Screening results for different organolithium reagent equivalents.

[0278]

[0279]

[0280] a Reaction conditions: -50℃, 1.5 equivalents of N-boc-nortropinone, 344 μL reactor volume, 0.25 M EU1F concentration in feed solution. b The HPLC yield determined using calibration relative to biphenyl as an internal standard is a percentage related to the initial amount of EU1F added to the reaction. RT = residence time between the confluence with HexLi and the confluence with citric acid.

[0281] Table 5 shows the screening results for organolithium reagent equivalents. Both HexLi and MeLi·LiBr were tested at 1.1 and 1.6 equivalents, respectively, and compared with the previously used 1.3 equivalent. For HexLi, no improvement was observed when the equivalent was increased or decreased (entries 1-3). For MeLi·LiBr (entries 4-6), a decrease in yield to 63% was seen at 1.1 equivalent, while an increase in HPLC yield to 75% was observed when using 1.6 equivalent. Figure 8 A representative chromatogram of the reaction mixture with MeLi·LiBr is depicted. Figure 9 Representative chromatograms of the reaction mixture with HexLi are depicted.

[0282] Example 6 – Temperature and Concentration Screening

[0283] Optimization experiments were conducted using setting C to screen EU1F at different temperatures and concentrations.

[0284] Table 6. Screening results for temperature and concentration.

[0285]

[0286] a. Reaction conditions: 1.5 equivalents of N-boc-nortropinone, 1.6 equivalents of MeLi·LiBr, 344 μL reactor volume; b. Concentration of EU1F in the feed solution; c. HPLC calibration yield determined using biphenyl as an internal standard, the percentage being related to the initial amount of EU1F added to the reaction. RT = Residence time between the confluence with HexLi and the confluence with citric acid.

[0287] Table 6 shows the results of further optimization experiments with temperature and concentration. Reducing the concentration of EU1F in the feed to 0.1 M resulted in a yield decrease to 67%. Increasing the concentration to 0.4 M was possible without a decrease in yield.

[0288] At a concentration of 0.25 M, raising the temperature to -40 °C (entry 4) resulted in a slight decrease in yield (72%). Further raising the temperature to -20 °C (entry 5) led to a decrease in yield to 64%. Doubling the flow rate is expected to improve performance at higher temperatures by improving mixing. Results in entries 6 and 7 show no increase in yield at -40 °C or -20 °C, with the final yields of EU1G being slightly lower (68% and 62%, respectively).

[0289] Example 7 – N-boc-nortropinone equivalent screening

[0290] Optimization experiments were conducted using setting C to screen different equivalents of N-boc-nortropinone.

[0291] Table 7. Screening results for N-boc-nortropinone equivalent.

[0292]

[0293] a Reaction conditions: -50℃, reactor volume = 344μL, feed solution contains 0.25M EU1F. b The HPLC yield determined using calibration relative to biphenyl as an internal standard is a percentage related to the initial amount of EU1F added to the reaction. RT = residence time between the confluence with HexLi and the confluence with citric acid.

[0294] Table 7 shows the screening results for N-boc-nortropinone equivalents (0.9–1.8 equivalents). For each level of N-boc-nortropinone equivalent, four different MeLi·LiBr equivalents were screened (16 experiments in total).

[0295] Entries 1-4 show the results for 0.9 equivalents of N-boc-nortropinone. A clear trend is observed in the yield of EU1G as the excess of MeLi·LiBr reagent increases. Generally, lower yields are observed, with a maximum of 61% (entry 1).

[0296] Items 5-8 show the results for 1.2 equivalents of N-boc-nortropinone. A similar trend was observed, showing that 1.1 and 1.3 equivalents of MeLi·LiBr achieved the highest yields (71%). The yields then decreased with increasing excess of the organolithium reagent.

[0297] Entries 9-12 show the results for 1.5 equivalents of N-boc-nortropinone. Here, the previously optimal conditions of 1.6 equivalents of MeLi·LiBr yielded the highest yield (75%). At both higher and lower equivalents, the yield decreased.

[0298] Entries 13-16 show the results for 1.8 equivalents of N-boc-nortropinone. The highest yields (71%) were achieved with 1.3 and 1.6 equivalents of MeLi·LiBr, while higher and lower equivalents showed a slight decrease in yield.

[0299] Following these final optimization experiments, two sets of conditions were selected as preferred conditions for further experiments:

[0300] (1) 1.5 equivalents of N-boc-nortropinone and 1.6 equivalents of MeLi·LiBr (75% yield); and

[0301] (2) 1.2 equivalents of N-boc-nortropinone and 1.3 equivalents of MeLi·LiBr (71% EU1G yield is preferred, but the equivalents are significantly lower).

[0302] Example 8 – Another verification experiment

[0303] To demonstrate that the optimized conditions are suitable for large-scale experiments, several verification experiments focusing on high yield and productivity were conducted.

[0304] Table 8.0.4 shows the verification experiment of the final conditions at the M concentration.

[0305]

[0306] a Reaction conditions: -50℃, reactor volume = 344μL, feed solution contains 0.4M EU1F. b The HPLC yield determined using calibration relative to biphenyl as an internal standard is a percentage related to the initial amount of EU1F added to the reaction. RT = residence time between the confluence with HexLi and the confluence with citric acid.

[0307] Table 8 shows the results of these initial validation experiments. To improve productivity, a concentration of 0.4 M EU1F was used in all reactions. Item 1 was carried out using 1.2 equivalents of N-boc-nortropinone and MeLi·LiBr. The reaction performed slightly worse than previously observed in the optimization experiments (Item 1, using similar conditions, yield 69% instead of 71%). Increasing MeLi·LiBr to 1.3 equivalents to accurately simulate the conditions in Table 7 did not result in an increase in yield (Item 2, 68%). Items 3 and 4 showed similar yield decreases (70% and 66% yields) compared to the previous experiments (75%).

[0308] To explain the observed yield decrease in Table 8, a search for causes was conducted. Notably, the substrate EU1F exhibited a deeper yellow color compared to its initial color upon delivery. Re-measuring the purity of EU1F using NMR with an internal standard revealed a purity of only 93%. This explains the lower yield shown in Table 8 – the lower purity indicates a lower amount of substrate EU1F present from the outset of the reaction.

[0309] To avoid introducing any water into the reaction, EU1F is always dried before use, but most of the material is stored in air. The degradation of EU1F indicates that this compound needs to be stored under argon at all times.

[0310] Table 9.0.4 shows the verification experiment of the final conditions at the M concentration, which was corrected for the purity of EU1F.

[0311]

[0312] a Reaction conditions: -50℃, reactor volume = 344μL, feed solution contains 0.4M EU1F. b The HPLC yield determined using calibration relative to biphenyl as an internal standard is a percentage related to the initial amount of EU1F added to the reaction, and this percentage has been corrected for the purity of EU1F. RT = residence time between the confluence with HexLi and the confluence with citric acid.

[0313] Table 9 shows the same results as Table 8, but takes into account the decrease in EU1F purity. This results in a slight change in equivalence due to the smaller starting material, and a slight increase in the yield of EU1G.

[0314] Items 1 and 3 show the most promising results from longer stability runs, with yields of 73% and 74%, respectively. The conditions in Item 1 were chosen as the most suitable because the yields were almost identical to those in Item 3, while using significantly lower reagent equivalents. To avoid errors in product yield calculations due to reduced purity of the starting materials, HPLC measurements were performed on the feed solutions for all further experiments to determine the amount of EU1F present in the starting solution for each reaction. Yields calculated from this point were corrected to account for this concentration.

[0315] Example 9 – Stability Demonstration in Long Runs and Separations

[0316] The stability of the flow system over extended durations was demonstrated in three stability experiments. All 6-port valves and sample loops were removed from the setup, and all substrate and reagent flows were directly pumped using a syringe pump.

[0317] The following three solutions (feed 1, feed 2, and quenching solution) are prepared as follows:

[0318] Feed 1: Place 4.148 g EU1F (19.2 mmol, assuming 95.5% purity), 5.437 g N-boc-nortropinone (24.1 mmol, 1.25 equivalents), and 0.633 g biphenyl (4.1 mmol, 0.21 equivalents) in a 50 mL volumetric flask. Place the flask under an argon atmosphere and bring the volume to the required level with dry THF. Feed 2: Under an argon atmosphere, dilute 17.33 mL MeLi·LiBr (1.5 M in Et₂O) with THF in a 50 mL volumetric flask (to a final concentration of 0.52 M). Quenching solution: Dissolve 26.27 g citric acid in 500 mL methanol to achieve a final concentration of 0.25 M.

[0319] Use balloons to keep feeds 1 and 2 under argon at all times. When not in use, store all pumps and tubing under iPrOH (for compatibility reasons). Before starting the experiment, flush the syringe pump, reactor, and all tubing with solvent (dried THF) at the corresponding maximum flow rate for each pump for at least 10 minutes.

[0320] The first stability test was conducted at a 20 mmol scale (corresponding to approximately 20 minutes of operation at a concentration of 0.4 M and a substrate flow rate of 2.5 mL / min). The experiment used 1.25 equivalents of MeLi·LiBr and 1.25 equivalents of N-boc-nortropinone (adjusted for EU1F purity). The first stability run resulted in a 60% yield of EU1G and only 72% conversion of EU1F over the entire 19-minute operation time. This reduction compared to previous experiments can be explained by the modified setup not properly pumping MeLi·LiBr. Directly pumping the solution of MeLi·LiBr into Et2O using a syringe pump caused solvent cavitation due to the high vapor pressure of diethyl ether. This provided an incorrect volumetric flow rate in the experiment. Decomposition of organolithium species within the syringe is also a possible cause of the reduced yield.

[0321] To address the issue of Et2O becoming cavitated during pumping, a solution was developed by adjusting settings. Figure 10 The flow setup (Setup D) used for additional long-term experiments is shown. When switching to Setup D, the dilution stream introduced into Setup C is removed, and a lower final concentration of feed 2 (MeLi·LiBr) is selected instead. Specifically, MeLi·LiBr is pre-diluted to a final concentration of 0.5 M using THF to reduce the vapor pressure of the mixture and avoid cavitation. Since dilution of MeLi·LiBr is no longer required, the additional THF pump is removed from the setup.

[0322] In this first separation experiment, MeLi·LiBr was fed at a rate of 2.4 mL / min, and all other variables remained constant from the start of the first run. After a steady-state collection of 8 minutes (71% HPLC yield), the product as the pTSA salt deprotected by boc was separated. Briefly, methanol was evaporated from the solution using a rotary evaporator, and the solution was diluted with ethyl acetate and washed twice with water / brine. The aqueous phase was subjected to a single reverse extraction with ethyl acetate. The combined organic phases were dried over Na₂SO₄. The solvent was then evaporated and replaced with 2-MeTHF. After heating to 50 °C, 3.5 equivalents of pTSA-containing 2-MeTHF were added. After approximately 15 minutes, a white precipitate formed. After 2.5 hours, the product was separated by filtration and washed with MeTHF, followed by washing with 40–60 g of petroleum ether. 2.6 g (63%) of pTSA salt was separated with an NMR purity of 95%. Based on the flow reaction, this separation yield corresponds to a production rate of 19.5 g / h and a space-time yield of 56.7 kg / L / h. The separated boc-deprotected pTSA product... 1 The 1H NMR spectrum and HPLC traces are as follows: Figure 11 and Figure 12As shown. With all other variables held constant, a second separation experiment was performed using 1.35 equivalents of MeLi·LiBr (flow rate 2.5 mL / min). A steady-state collection over 20 minutes prior to boc deprotection yielded a 72% HPLC yield and 6.0 g (64%) of the separated boc-deprotected pTSA salt, with an NMR purity of 91%. The separated boc-deprotected pTSA product... 1 The 1H NMR spectrum and HPLC traces are as follows: Figure 13 and Figure 14 As shown.

Claims

1. A continuous flow process for preparing a nitrogen-containing bicyclic compound of formula 1 or a salt thereof: The continuous flow process includes the nortropinone compound of formula 2: With the halogenated compounds of Formula 3: X-R 1 Formula 3; Organolithium reactions in the presence of organolithium reagents; in R 1 It is a monocyclic or bicyclic heteroaryl group, either unsubstituted or substituted by one or more substituents selected from the group consisting of: halogens, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and -OC 1-6 Halogenated alkyl groups; R 2 It is an amine protecting group; and X is a halogen.

2. The continuous flow process according to claim 1, wherein the continuous flow process comprises the nortropinone compound of formula 2, the halogenated compound of formula 3, and the organolithium reagent in one or more continuous flow streams in a continuous flow reactor, the continuous flow reactor being configured at a temperature conducive to the efficient synthesis of the azabicyclic compound of formula 1 or a salt thereof.

3. The continuous flow process according to claim 1 or claim 2, wherein the nortropinone compound of formula 2 and the halogenated compound of formula 3 are initially combined.

4. The continuous flow process according to any one of claims 1 to 3, wherein the combination of the nortropinone compound of formula 2 and the halogenated compound of formula 3 is subsequently combined with the organolithium reagent.

5. The continuous flow process according to any one of claims 1 to 4, wherein the process comprises: A continuous flow containing compounds of Formula 2 and Formula 3 is combined with a continuous flow containing the organolithium reagent to obtain a continuous flow containing an azabicyclic compound of Formula 1 or a salt thereof.

6. The continuous flow process according to any one of claims 1 to 5, wherein the process comprises: Combining a continuous flow containing a compound of formula 2 with a continuous flow containing a compound of formula 3 yields a continuous flow containing both the compound of formula 2 and the compound of formula 3; and The continuous flow containing the compound of Formula 2 and the compound of Formula 3 is combined with a continuous flow containing the organolithium reagent to obtain a continuous flow containing the azabicyclic compound of Formula 1 or a salt thereof.

7. The continuous flow process according to claim 1 or claim 2, wherein the process comprises: Combining a continuous flow stream containing a compound of formula 3 with a continuous flow stream containing an organolithium reagent yields a continuous flow stream containing an organolithium reaction intermediate; and The continuous flow containing the organolithium reaction intermediate is combined with a continuous flow containing a compound of formula 2 to obtain a continuous flow containing an azabicyclic compound of formula 1 or a salt thereof.

8. The continuous flow process according to any one of claims 1 to 7, wherein the continuous flow process further comprises: Combine the azabicyclic compound of Formula 1 or its salt with a quenching solution.

9. The continuous flow process according to claim 8, wherein the quenching solution is selected from the group consisting of: polar protic solvents, nonpolar protic solvents, aqueous solvents, alcohols and acids, or combinations thereof.

10. The continuous flow process according to claim 8 or claim 9, wherein the process comprises: A continuous flow containing a nitrogen-containing bicyclic compound of Formula 1 or a salt thereof is combined with a continuous flow containing the quenching solution to obtain a continuous flow containing a nitrogen-containing bicyclic compound of Formula 1.

11. The continuous flow process according to any one of claims 1 to 10, wherein the continuous flow process further comprises: A continuous flow containing a solvent is combined with a continuous flow containing the organolithium reagent to controllably dilute the concentration of the organolithium reagent.

12. The continuous flow process according to any one of claims 1 to 11, wherein the continuous flow process further comprises: Prepare salts of amine bicyclic compounds of formula 4; The process described herein involves reacting the compound of Formula 1 with an acid to remove the amine protecting group in order to obtain a salt of the compound of Formula 4.

13. The continuous flow process according to any one of claims 1 to 12, wherein the continuous flow process further comprises: Preparation of heterocyclic ketone compounds of formula 5: The process described herein involves using a carboxylic acid compound of formula 6 or a salt thereof: The amine bicyclic compound of Formula 4 or its salt is reacted in the presence of at least one coupling agent to obtain the heterocyclic ketone compound of Formula 5.

14. The continuous flow process according to any one of claims 1 to 13, wherein the organolithium reagent is selected from any compound containing a carbon-lithium bond or a carbon-magnesium-lithium bond.

15. The continuous flow process according to any one of claims 1 to 14, wherein the organolithium reagent is selected from the group consisting of: alkyllithium, alkenyllithium, alkynyllithium, aralkyllithium, aryllithium, heteroaryllithium, alkyllithium-magnesium complexes and any lithium halide complexes thereof.

16. The continuous flow process according to any one of claims 1 to 15, wherein the organolithium reagent is selected from the group consisting of: methyllithium, ethyllithium, propyllithium, butyllithium, pentyllithium, hexyllithium, methoxymethyllithium, ethoxymethyllithium, vinyllithium, allyllithium, propenyllithium, butenyllithium, acetylenyllithium, butynyllithium, pentylenyllithium, hexynyllithium, benzyllithium, phenylethyllithium, phenyllithium, naphthyllithium, 2-thiophenyllithium, 4-pyridyllithium, 2-quinolinyllithium, tris(n-butyl)magnesiumlithium and trimethylmagnesiumlithium, (trimethylsilyl)methyllithium, (trimethylsilyl)acetyleniumlithium, acetyleniumlithium, phenylacetyleniumlithium, cyclopentadienyllithium, pentamethylcyclopentadienyllithium, methyllithium and any lithium halide complex thereof.

17. The continuous flow process according to any one of claims 1 to 16, wherein the organolithium reagent is selected from the group consisting of: lithium methyl or any lithium halide complex thereof.

18. The continuous flow process according to any one of claims 1 to 17, wherein the amount of the organolithium reagent is provided in a molar ratio of about 0.1 to about 10 relative to the amount of the halogenated compound of formula 3.

19. The continuous flow process according to any one of claims 1 to 18, wherein the concentration of the organolithium reagent is at least about 0.1 mol / L.

20. The continuous flow process according to any one of claims 1 to 19, wherein the flow rate of each of the one or more continuous flow streams is at least about 0.5 mL / min.

21. The continuous flow process according to any one of claims 1 to 20, wherein the amount of the nortropinone compound of formula 2 is provided in a molar ratio of about 0.1 to about 10 relative to the amount of the halogenated compound of formula 3.

22. The continuous flow process according to any one of claims 1 to 21, wherein the residence time between obtaining the continuous flow containing the organolithium reaction intermediate and obtaining the continuous flow containing the azabicyclic compound of formula 1 or a salt thereof is at least 0.01 seconds.

23. The continuous flow process according to any one of claims 1 to 22, wherein the process is carried out at a temperature less than 20°C, less than 10°C, less than 0°C, less than -10°C, less than -20°C, less than -30°C, less than -40°C, less than -50°C, less than -60°C, less than -70°C, or less than -80°C.

24. The continuous flow process according to any one of claims 1 to 23, wherein two or more continuous flow streams are provided as a solution comprising at least one solvent independently selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, cyclopentylmethyl ether, toluene, and combinations thereof.

25. The continuous flow process according to any one of claims 1 to 24, wherein the yield of the azabicyclic compound of formula 1 provided by the process is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, as determined according to the starting material of the compound of formula 2 or the compound of formula 3.

26. The continuous flow process according to any one of claims 1 to 25, wherein the conversion of the nortropinone compound of formula 2 or the halogenated compound of formula 3 to the azabicyclic compound of formula 1 or a salt thereof provided by the process is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, as determined by HPLC.

27. The continuous flow process according to any one of claims 1 to 26, wherein the purity of the azabicyclic compound of formula 1 provided by the process is at least 70%, at least 80%, at least 90%, or at least 95%, as determined by HPLC.

28. The continuous flow process according to any one of claims 1 to 27, wherein the process is carried out in a reactor of a type selected from the group consisting of: continuous flow reactors; microreactors; continuous tubular reactors; laminar flow reactors; flow reactors; static mixing elements; continuous stirred tank reactors; and semi-batch reactors.

Images