Continuous flow process for the synthesis of organic azides

Abstract

The present disclosure generally relates to the field of synthetic organic chemistry. More specifically, the present disclosure relates to a continuous flow process for the synthesis of azides from alcohols and peroxides, which process involves azidation using trimethylsilyl azide and the catalyst Amberlyst-15. This is a non-hazardous, mild and controlled reaction that exhibits good yields of azides. Azides can further be used in the synthesis of pharmaceutically and industrially useful chemicals.

Description

Technical Field

[0001] The present disclosure generally relates to the field of synthetic organic chemistry. More specifically, the present disclosure relates to a continuous flow process for the synthesis of azides from alcohols and peroxides, which process involves azidation using trimethylsilyl azide and the catalyst Amberlyst-15.

Background Art

[0002] The background description includes information that may be useful in understanding the present invention. None of the information provided herein is admitted to be prior art, or related to the presently claimed invention, or that any of the publications specifically or implicitly referenced are prior art.

[0003] Nitrogen-containing heterocyclic compounds have shown wide utility in pharmaceutical applications. An azide is a compound having the formula N3, which is used, for example, in rocket propellants. In addition to the utility of azides, many 1,2,3- or 1,2-nitrogen-enriched heterocycles have been synthesized from organic azides or hydrazides by click reactions or condensation chemistry. For example, triazole has become a very important heterocycle in many antifungal applications and other diseases. Other heterocycles such as 2H-1,4-benzoxazin-3(4H)-one and quinoxalin-2(1H)-one have also demonstrated utility in pharmaceutical chemistry. Many organic intermediates exhibit attractive reactions for generating each product with higher molecular complexity.

[0004] In the 19th century, azide, an essential tool for performing various chemical operations, experienced an impressive library of powerful named reactions (The Chemistry of the Azido Group (Ed.: S. Patai), Wiley, New York, 1971; The Chemistry of Halides, Pseudo-halides and Azides, Supplement D, (Eds.: S. Patai, Z. Rappoport), Wiley, Chichester, 1983; Chemistry of Halides, Pseudo-Halides and Azides, Part 1 (Ed.: S. Patai), Wiley, Chichester, 1995; Chemistry of Halides, Pseudo-Halides and Azides, Part 2 (Ed.: S. Patai), Wiley, Chichester, 1995; Monograph: Azides and Nitrenes Reactivity and Utility (Ed.: E.F.V. Scriven), Academic Press, New York, 1984). These energy-rich intermediates are components of protein bioconjugation (Jang, S.; Sachin, K.; Lee, H.; Wook Kim, D.; Soo Lee, H. Development of a Simple Method for Protein Conjugation by Copper-Free Click Reaction and Its Application to Antibody-Free Western Blot Analysis. Bioconjugate Chem. 2012, 23, 2256-2261.).These are easily converted into N-heterocycles and are also known as effective ammonia surrogates (Brase, S.; Gil, C.; Knepper, K.; Zimmermann, V. Organic Azides: An Exploding Diversity of a Unique Class of Compounds. Angew. Chem., Int. Ed. 2005, 44, 5188 - 5240; Padwa, A. Aziridines and Azirines: Monocyclic. In Comprehensive Heterocyclic Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier Science: Oxford, 2008; Vol. 1, Chapter 1.01.6.2, pp50 - 64), and are also known as effective ammonia surrogates (Gololobov, Y. G.; Kasukhin, L. F. Recent Advances in the Staudinger Reaction. Tetrahedron 1992, 48, 1353 - 1406).Furthermore, organic azides are also used in (3+2) cycloaddition with alkynes and nitriles to generate triazole and tetrazole moieties for access to important bioactive molecules such as anti-cancer agents, antibacterial drugs, and aldose reductase inhibitors (Li, Y.L.; Combs, A.P. Bicyclic Heteroaryl amino alkyl Phenyl Derivatives as PI3K Inhibitors. Int. Patent Appl. WO2015191677A1, Dec 17, 2015; Kim, M.S.; Yoo, M.H.; Rhee, J.K.; Kim, Y.J.; Park, S.J.; Choi, J.H.; Sung, S.Y.; Lim, H.G.; Cha, D.W. Synthetic Intermediates, Process for Preparing Pyrrolylheptanoic Acid Derivatives Therefrom. Int. Patent Appl. WO2009084827A2, July 9, 2009; Bathula, S.N.V.P.; Vadla, R. Bioactivity of 1,4-disubstituted 1,2,3-triazoles as Cytotoxic Agents Against the Various Human Cell Lines. Asian J. Pharm. Clin. Res. 2011, 4, 66-67; Aganda, K.C.; Hong, B.; Lee, A. Visible-Light-Promoted Switchable Synthesis of C-3-Functionalized Quinoxalin-2(1H)-ones. Adv. Synth. Catal. 2021, 363, 1443-1448). Even with its exponential application in chemical transformations for biological uses, it has serious safety concerns due to its explosiveness in large-scale manufacturing processes. Furthermore, azides with C / N ≥ 3 are generally stable to handle (Brase, S.; Banert, K., Eds. Organic Azides: Syntheses and Applications; John Wiley & Sons, Ltd.: Chichester, U.K., 2010.).Therefore, process technology is required to enhance safety concerns in azide synthesis and related chemical transformations.

[0005] Regarding the synthesis of alkyl azides, the conventional batch method involves the activation of the -OH group, which requires two steps: i) conversion to a good leaving group, and ii) substitution reaction with NaN3. After activation of the -OH group, the -OH group can be converted to a genotoxic alkyl halide (Li, J.; Cao, J.; Wei, J.; Shi, X.; Zhang, L.; Feng, J.; Chen, Z. Ionic Liquid Brush as a Highly Efficient and Reusable Catalyst for On-Water Nucleophilic Substitutions. Eur. J. Org. Chem. 2011, 2011, 229-233), sulfonate (Denk, C.; Wilkovitsch, M.; Skrinjar, P.; Svatunek, D.; Mairinger, S.; Kuntner, C.; Filip, T.; Frohlich, J.; Wanek, T.; Mikula, H. [18F]Fluoroalkyl Azides for Rapid Radiolabeling and (Re)investigation of their Potential Towards in vivo Click Chemistry. Org. Biomol. Chem. 2017, 15, 5976-5982) or acetate (Kurosawa, W.; Kan, T.; Fukuyama, T. Stereocontrolled Total Synthesis of (-)-Ephedradine A (Orantine). J. Am. Chem. Soc. 2003, 125, 8112-8113), and reacted with NaN3 to obtain the azide. Additionally, other precursors such as amines and hydrazines can also be used for access. However, the redundant workup and safety concerns in the scale-up of the reaction are substantial issues. Therefore, developing a direct azidation approach is the best way to avoid waste generation and minimize synthetic steps. With this conviction, the Mitsunobu reaction shows the direct substitution of the hydroxyl group to obtain the azide using hydroazoic acid (Besset, C.; Chambert, S.; Fenet, B.; Queneau, Y.Direct Azidation of Unprotected Carbohydrates under Mitsunobu Conditions using Hydrazoic Acid. Tetrahedron Lett. 2009, 50, 7043 - 7047). However, considering the potential safety concerns associated with the genotoxic sodium azide and hydrazoic acid, new methods need to be investigated for safe and practical azide sources. Separately, azides are also generated using various Lewis acid catalysts such as BF3·OEt2, NaAuCl4, Cu(OTf)2, AgOTf, FeCl3, MoCl5, InBr3, and Bi(OTf)3, which promote substitution by activation of the hydroxyl group (Terrasson, V.; Marque, S.; Georgy, M.; Campagne, J.M.; Prim, D. Lewis Acid-Catalyzed Direct Amination of Benzhydryl Alcohols. Adv. Synth. Catal. 2006, 348, 2063 - 2067; Khedar, P.; Pericherla, K.; Kumar, A. Copper Triflate: An Efficient Catalyst for Direct Conversion of Secondary Alcohols into Azides. Synlett 2014, 25, 515 - 518; Rueping, M.; Vila, C.; Uria, U. Direct Catalytic Azidation of Allylic Alcohols. Org. Lett. 2012, 14, 768 - 771; Sawama, Y.; Nagata, S.; Yabe, Y.; Morita, K.; Monguchi, Y.; Sajiki, H. Iron-Catalyzed Chemoselective Azidation of Benzylic Silyl Ethers. Chem. Eur. J. 2012, 18, 16608 - 16611; Reddy, C.R.; Madhavi, P.P.; Reddy, A.S.Molybdenum(V) Chloride-Catalyzed Amidation of Secondary Benzyl Alcohols with Sulfonamides and Carbamates. Tetrahedron Lett. 2007, 48, 7169-7172; Kumar, A.; Sharma, R.K.; Singh, T.V.; Venugopalan, P. Indium(III) Bromide Catalyzed Direct Azidation of α-hydroxyketones using TMSN3. Tetrahedron 2013, 69, 10724-10732; Tummatorn, J.; Thongsornkleeb, C.; Ruchirawata, S.; Thongarama, P.; Kaewmee, B. Convenient and Direct Azidation of Sec-Benzyl Alcohols by Trimethylsilyl Azide with Bismuth(III) Triflate Catalyst. Synthesis 2015, 47, 323-329). However, in contrast to the Lewis acid-mediated azidation reaction, there are few approaches to achieve this conversion using Brønsted acid catalysts. For this conversion using alcohol and sodium azide, Hajipour used the acidic ionic liquid [H-NMP]HSO4, (Hajipour, A.R.; Rajaei, A.; Ruoho, A.E. A Mild and Efficient Method for Preparation of Azides from Alcohols using Acidic Ionic Liquid [H-NMP]HSO4. Tetrahedron Lett. 2009, 50, 708-711) while Onaka demonstrated the combination of TMSCl and TMSN3 with montmorillonite clay to obtain azide. (Tandiary, M.A.; Masui, Y.; Onaka, M.A Combination of Trimethylsilyl Chloride and Hydrous Natural Montmorillonite Clay: An Efficient Solid Acid Catalyst for the Azidation of Benzylic and Allylic Alcohols with Trimethylsilyl Azide. RSC Adv. 2015, 5, 15736 - 15739). Similarly, Rode achieved it using a hybrid of solid povidone and phosphotungstic acid as a catalyst for the heterogeneous azidation of alcohols (Kamble, S.; More, S.; Rode, C. Highly Selective Direct Azidation of Alcohols Over a Heterogeneous Povidone - Phosphotungstic Solid Acid Catalyst. New J. Chem. 2016, 40, 10240 - 10245). More recently, Zhou and Regier demonstrated it using aqueous perchloric acid (Yin, X. P.; Zhu, L.; Zhou, J. Metal - Free Azidation of α - Hydroxy Esters and α - Hydroxy Ketones Using Azidotrimethylsilane. Adv. Synth. Catal. 2018, 360, 1116 - 1122) and HBF4·OEt2 (Regier, J.; Maillet, R.; Bolshan, Y. A Direct Bronsted Acid Catalyzed Azidation of Benzhydrols and Carbohydrates. Eur. J. Org. Chem. 2019, 2390 - 2396), respectively. Although numerous azidation methods exist, a more convenient method for safer azide generation is highly desirable.

[0006] Under batch conditions, the continuous flow method may be considered to minimize the safety risks associated with the scale-up of the reactions of these explosive and high-energy molecules that decompose upon heat, light, or shock. The potential of continuous flow for azidation has been investigated by using imidazole-1-sulfonyl azide hydrochloride (Delvillea, M.; Nieuwland, P.; Janssena, P.; Koch, K.; Van Hest, J.; Rutjes, F. Continuous Flow Azide Formation: Optimization and Scale-up. Chem. Eng. J. 2011, 167, 556 - 559) as a diazotransfer reagent for the transfer reaction from benzylamine to azide and aqueous sodium azide solution (Sagandira, C.; Watts, P. Safe and Highly Efficient Adaptation of Potentially Explosive Azide Chemistry Involved in the Synthesis of Tamiflu Using Continuous-Flow Technology. Beilstein J. Org. Chem. 2019, 15, 2577 - 2589) for the C-3 azidation of shikimic acid mesylate. Furthermore, azidation using an azide exchange resin was an extremely important step in the total synthesis of oxomaritidine (Baxendale, I.; Deeley, J.; Griffiths-Jones, C.; Ley, S.; Saaby, S.; Tranmer, G. A Flow Process for the Multi-Step Synthesis of the Alkaloid Natural Product Oxomaritidine: A New Paradigm for Molecular Assembly. Chem. Commun. 2006, 2566 - 2568).Furthermore, a telescoped flow process for obtaining propargylamine using DPPA has also been established (Donnelly, A.; Zhang, H.; Baumann, M. Development of a Telescoped Flow Process for the Safe and Effective Generation of Propargylic Molecules 2019, 24, 3658). However, these methods used NaN3 or harsh heating conditions.

[0007] Therefore, there is a need in the art to develop a mild, safe, and efficient process for the synthesis of azides from a wide range of substrates that is suitable for large-scale synthesis and does not use toxic reagents.

[0008] Objectives of the Invention An object of the present disclosure is to provide a continuous flow process for the synthesis of azides that is a direct azidation process.

[0009] Another object of the present disclosure is to provide a continuous flow process for the synthesis of azides that can be easily scaled up and does not use toxic reagents.

[0010] Another object of the present disclosure is to provide a process for the high-yield synthesis of azides from alcohols and peroxides.

Summary of the Invention

[0011] This summary is provided to introduce, in simplified form, a selection of concepts that are further described below in the section on the mode for carrying out the invention. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.

[0012] Aspects of the present disclosure provide a process for synthesizing azides from different alcohols and peroxides by a continuous flow method that is safe and mild.

[0013] In one aspect, the present disclosure provides a process for synthesizing an organic azide of formula (I) by direct azidation of an alcohol of formula (II).

[0014] In one embodiment, the present disclosure provides a continuous flow process for synthesizing an organic azide of formula (I), a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, the continuous flow process comprising reacting a compound of formula (II) with trimethylsilyl azide and the catalyst Amberlyst-15, [Chemical formula] wherein R 1 is selected from substituted or unsubstituted (C 6-16 ) aryl, or substituted or unsubstituted (C 5-10 ) heterocycle, R 2 and R 3 are independently selected from H, substituted or unsubstituted (C 6-16 ) aryl, substituted or unsubstituted (C 1-6 ) alkyl, or substituted or unsubstituted -CH2-(C 6-16 ) aryl, The substituents may be selected from one or more of halogen, (C 1-6 ) alkyl, cyano, nitro, -NH2, (C 1-6 ) alkoxy, -COOH, or combinations thereof.

[0015] In a preferred embodiment, the compound of formula (I) may be selected from the following: (Azidomethylene)dibenzene, 1-(Azido(phenyl)methyl)-4-chlorobenzene, 4,4'-(Azidomethylene)bis(methoxybenzene), (1-Azidoethyl)benzene, 2-(1-Azidoethyl)naphthalene, (1-Azidoethane-1,1-diyl)dibenzene, (Azidomethanetriyl)tribenzene, 5-(Azidomethyl)benzod][1,3]dioxole, 5-(Azidomethyl)-6-chlorobenzod][1,3]dioxole, 4-(Azidomethyl)pyrene, Stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof.

[0016] In one aspect, the present disclosure provides a process for synthesizing organic azides by direct azidation of 3-hydroxy-2-oxoindole compounds.

[0017] In one embodiment, the present disclosure provides a continuous flow process for synthesizing an organic azide of formula (III), a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, the continuous flow process comprising reacting a compound of formula (IV) with trimethylsilyl azide and the catalyst Amberlyst-15,

Chemical formula

[0018] In a preferred embodiment, the compound of formula (III) may be selected from: 3-Azido-3-methylindolin-2-one, 3-Azido-3-phenylindolin-2-one, 3-Azido-3-(p-tolyl)indolin-2-one, 3-Azido-3-(4-methoxyphenyl)indolin-2-one, 3-Azido-3-benzylindolin-2-one, 3-Azido-3-(3,4-dimethoxybenzyl)indolin-2-one, 3-Azido-3-(4-bromobenzyl)indolin-2-one, 3-Azido-3-benzyl-6-chloroindolin-2-one, 3-Azido-1,3-dibenzylindolin-2-one, 3-Azido-1,3-dimethylindolin-2-one, Stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof.

[0019] In one aspect, the present disclosure provides a process for synthesizing an organic 2-azido-2H-benzo[b][1,4]oxazin-3(4H)-one derivative from a peroxyoxindole.

[0020] In one embodiment, the present disclosure provides a continuous flow process for synthesizing an organic azide of formula (V), stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, the continuous flow process comprising reacting a compound of formula (VI) with trimethylsilyl azide and a catalyst Amberlyst-15, [Chemical formula] wherein R 7 is selected from H, (C 1-6 )alkyl, substituted or unsubstituted (C 6-16 )aryl, or substituted or unsubstituted -CH2-(C 6-16 )aryl, R 8 and R 9 are independently selected from H, halogen, (C 1-6 )alkyl, cyano, nitro, (C 1-6 )alkoxy, substituted or unsubstituted -CH2-(C6-16 ) It may be selected from one or more of aryl, substituted or unsubstituted (C 6-16 ) aryl or combinations thereof, The substituents are halogen, (C 1-6 ) alkyl, cyano, nitro, (C 1-6 ) alkoxy, -COOH, -NH2 or combinations thereof, Pr is a protecting group.

[0021] In a preferred embodiment, the compound of formula (V) may be selected from: 2-Azido-2-benzyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-Azido-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-Azido-2-(4-methoxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-Azido-2-(2-fluorobenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-Azido-2-(4-bromobenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-Azido-2-benzyl-6-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-Azido-2-(4-bromobenzyl)-6-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-Azido-6-chloro-2-(4-methylbenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-Azido-2,4-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-Azido-4-benzyl-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, Stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof.

[0022] In one aspect, the present disclosure provides a process for synthesizing organic azides by direct azidation of 9-alkyl / aryl-9H-fluoren-9-ols.

[0023] In one embodiment, the present disclosure provides a continuous flow process for synthesizing an organic azide of formula (I’), stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, the continuous flow process comprising reacting a compound of formula (II’) with trimethylsilyl azide and the catalyst Amberlyst-15.

Chemical formula

[0024] In a preferred embodiment, the compound of formula (I’) may be selected from: 9-azido-9-phenyl-9H-fluorene, 9-azido-9-(p-tolyl)-9H-fluorene, 9-azido-9-(4-methoxyphenyl)-9H-fluorene, 9-([1,1’-biphenyl]-4-yl)-9-azido-9H-fluorene, 9-azido-9-hexyl-9H-fluorene, 9-azido-2,7-dibromo-9-(4-methoxyphenyl)-9H-fluorene, 9-azido-9-benzyl-9H-fluorene, 9-azido-9-(3-phenoxybenzyl)-9H-fluorene, 9-([1,1'-Biphenyl]-4-ylmethyl)-9-azido-9H-fluorene, 9-azido-9-(4-methoxybenzyl)-9H-fluorene, 9,9'-diazido-9H,9'H-9,9'-bifluorene, 9-azido-2-bromo-9-phenyl-9H-fluorene, 9-azido-2,7-dibromo-9-phenyl-9H-fluorene, 9-azido-2,7-dibromo-9-(p-tolyl)-9H-fluorene, or a stereoisomer, tautomer, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

[0025] Other aspects of the invention are set forth in the following description, some of which are derived from the description or can be learned by the practice of this specification. Detailed Description of the Invention

[0026] The following is a detailed description of embodiments of the present disclosure. The embodiments are detailed enough to clearly convey the present disclosure. However, the amount of detailed information provided is not intended to limit the variations of the expected embodiments, but rather to cover all modifications, equivalents, and alternatives within the spirit and scope of the present disclosure as defined by the appended claims.

[0027] All publications are incorporated herein by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. If the definition or use of a term in an incorporated reference conflicts with or is contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

[0028] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0029] In some embodiments, the numbers are used to quantify quantities, percentages, ratios, etc. for the purpose of describing and claiming particular embodiments of the invention and are to be understood as being optionally modified by the term "about." Thus, in some embodiments, the numerical parameters set forth in the written description and the claims are approximations that may vary depending upon the desired characteristics sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the reported number of significant digits and by applying ordinary rounding techniques. Although the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0030] Various terms used herein are defined below. Unless a term used in a claim is defined below, the broadest definition given to that term as reflected in printed publications and issued patents as would be understood by one of ordinary skill in the relevant art at the time of filing shall apply.

[0031] As used in the description of this specification and throughout the following claims, unless the context clearly dictates otherwise, the meanings of "a", "an", and "the" include plural referents. Also, as used in the description of this specification, the meaning of "in" includes "in" and "on" unless the context clearly dictates otherwise.

[0032] Unless the context requires otherwise, throughout the following specification, the word "comprise", and variations such as "comprises" and "comprising", are to be construed in an inclusive sense as "including, but not limited to".

[0033] The recitation of a range of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated herein as if it were individually recited herein.

[0034] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein with respect to particular embodiments is merely intended to better illuminate the invention and does not limit the scope of the invention as otherwise claimed. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0035] The grouping of alternative elements or embodiments of the invention disclosed herein should not be construed as a limitation. Members of each group can be referred to and claimed individually, or in any combination with other members of that group or other elements described herein. One or more members of a group may be included in or removed from the group for reasons of convenience and / or patentability. If either such inclusion or removal occurs, the specification is deemed herein to contain the modified group.

[0036] The following description, and the embodiments described herein, are provided as an illustration of one or more examples of specific embodiments of the principles and aspects of the present disclosure. These examples are provided for purposes of illustration and not for purposes of limitation of those principles and the present disclosure.

[0037] It should also be understood that the present disclosure can be implemented in many ways as a system, method, or device. In this specification, these embodiments, or any other form the invention may take, may be referred to as a process. Generally, the order of steps of the disclosed processes may be changed within the scope of the present invention.

[0038] The titles and abstracts of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.

[0039] The following description provides many exemplary embodiments of the subject matter of the present invention. Each embodiment represents a single combination of elements of the invention, but the subject matter of the present invention is considered to include all possible combinations of the disclosed elements. Thus, if one embodiment includes elements A, B, and C and a second embodiment includes elements B and D, the subject matter of the present invention is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.

[0040] As used herein, the term "or" is generally used in the sense of "and / or" unless the context clearly dictates otherwise.

[0041] As used herein, the term “(C 1-6 )alkyl” refers to a saturated aliphatic group containing a straight-chain or branched-chain alkyl group having 6 or fewer carbon atoms in its backbone. For example, in the case of a straight chain, it is C 1-6 , and in the case of a branched chain, it is C3-C6. As used herein, (C 1-6 )alkyl refers to an alkyl group having 1 to 6 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, and 3-methylbutyl.

[0042] Furthermore, unless otherwise specified, the alkyl group may be unsubstituted or may be substituted with 1 or more substituents, for example, 1 to 4 substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, and amino. Examples of substituted alkyl include, but are not limited to, hydroxymethyl, 2-chlorobutyl, trifluoromethyl, and aminoethyl.

[0043] The term “(C 1-6 )alkoxy” refers to (C 1-6 )alkyl having a bonded oxygen. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. Furthermore, unless otherwise specified, the alkoxy group may be unsubstituted or may be substituted with 1 or more groups. Substituted alkoxy refers to (C 1-6 )alkoxy substituted with 1 to 4 groups independently selected from the groups shown above as substituents for the alkyl group.

[0044] As used herein, “(C 6-16) The term "aryl" or "Aryl" refers to a monocyclic, bicyclic, tricyclic, or tetracyclic hydrocarbon group having 6 to 16 ring carbon atoms, and at least one carbocyclic ring has a π - electron system. (C6 - C 16 ) Examples of aryl ring systems include, but are not limited to, phenyl, pyrenyl, or naphthyl. Unless otherwise indicated, the aryl group may be unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, (C 1-6 ) alkyl, hydroxy, cyano, nitro, - COOH, amino, and (C 1-6 ) alkoxy.

[0045] As used herein, (C 5-10) The term "heterocyclic ring" refers to a 5- to 10-membered saturated, partially unsaturated or unsaturated monocyclic or bicyclic ring system containing 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. A saturated heterocyclic ring system contains no double bonds at all, a partially unsaturated heterocyclic ring system contains at least one double bond, and an unsaturated heterocyclic ring system forms an aromatic system containing heteroatom(s). Oxidized forms of ring nitrogen and sulfur atoms contained in the heterocyclic ring to provide the corresponding N-oxide, S-oxide or S,S-dioxide are also included within the scope of the present invention. Representative examples of heterocyclic rings include, but are not limited to, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, dihydropyran, tetrahydropyran, thio-dihydropyran, thio-tetrahydropyran, piperidine, piperazine, morpholine, 1,3-oxazinane, 1,3-thiazinane, 4,5,6-tetrahydropyrimidine, 2,3-dihydrofuran, dihydrothiene, dihydropyridine, tetrahydropyridine, isoxazolidine, pyrazolidine, furan, pyrrole, thiophene, imidazole, oxazole, thiazole, triazole, tetrazole, benzofuran, indole, benzoxazole, benzodioxole, benzothiazole, isoxazole, triazine, purine, pyridine, pyrazine, quinoline, isoquinoline, phenazine, oxadiazole, pteridine, pyridazine, quinazoline, pyrimidine, isothiazole, benzopyrazine and tetrazole. Unless otherwise specified, (C 5-10 ) The heterocyclic ring may be unsubstituted or substituted with one or more substituents, for example, substituents independently selected from the group consisting of oxo, halogen, hydroxy, cyano, nitro, amine, (C 1-6 ) alkyl and COOH.

[0046] As used herein, the term "halogen" refers to a chlorine atom, a fluorine atom, a bromine atom or an iodine atom.

[0047] Aspects of the present disclosure provide a continuous flow synthesis of organic azides that rationalizes the assembly and delivery of reactants and products by reducing safety concerns.

[0048] In one embodiment, the present disclosure provides a process for the synthesis of organic azides from alcohols including primary, secondary and tertiary alcohols, and substrates such as peroxides, using trimethylsilyl azide (TMSN3) as an azide transfer agent, the process being a continuous flow process.

[0049] In one embodiment, the present disclosure provides a process for the synthesis of organic azides by direct azidation using environmentally benign and industrially useful Amberlyst-15 as a catalyst.

[0050] In one embodiment, the present disclosure provides a process for synthesizing an organic azide of formula (I) by direct azidation of an alcohol of formula (II).

[0051] In one embodiment, the present disclosure provides a continuous flow process for synthesizing an organic azide of formula (I), stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, the continuous flow process comprising reacting a compound of formula (II) with trimethylsilyl azide and catalyst Amberlyst-15 in a suitable solvent. [Chemical formula] Wherein R 1 is selected from substituted or unsubstituted (C 6-16 ) aryl, or substituted or unsubstituted (C 5-10 ) heterocycle, R 2 and R 3 are independently selected from H, substituted or unsubstituted (C 6-16 ) aryl, substituted or unsubstituted (C 1-6 ) alkyl, or substituted or unsubstituted -CH2-(C 6-16 ) aryl, The substituent is halogen, (C 1-6)Alkyl, cyano, nitro, -NH2, (C 1-6 )It may be selected from one or more of alkoxy, -COOH, or combinations thereof.

[0052] In one embodiment, R 1 is a substituted or unsubstituted (C 6-16 )aryl selected from phenyl, naphthyl, or pyrenyl, or a substituted or unsubstituted (C 5-10 )heterocycle selected from 1,3 - benzodioxole, and the substituent may be one or more of -OCH3 or halogen.

[0053] In one embodiment, R 2 and R 3 are independently selected from H, substituted or unsubstituted phenyl, or -CH3, and the substituent may be selected from one or more of halogen or -OCH3.

[0054] In one embodiment, the ratio of TMSN3 to formula (II) is in the range of about 1:10 to about 10:1, and may preferably be about 1:3.

[0055] In one embodiment, the present disclosure provides a compound of formula (I), stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates obtained by the process described above.

[0056] In a preferred embodiment, the compound of formula (I) may be selected from: (Azidomethylene)dibenzene, 1-(Azido(phenyl)methyl)-4-chlorobenzene, 4,4’-(Azidomethylene)bis(methoxybenzene), (1 - Azidoethyl)benzene, 2-(1 - Azidoethyl)naphthalene, (1 - Azidoethane - 1,1 - diyl)dibenzene, (Azidomethanetriyl)tribenzene, 5-(Azidomethyl)benzod[d][1,3]dioxole, 5-(Azidomethyl)-6-chlorobenzene[d][1,3]dioxole, 4-(Azidomethyl)pyrene, Stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof.

[0057] In one embodiment, the present disclosure provides a process for synthesizing organic azides by direct azidation of 3-hydroxy-2-oxoindole compounds.

[0058] In one embodiment, the present disclosure provides a continuous flow process for synthesizing an organic azide of formula (III), stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, the continuous flow process comprising reacting a compound of formula (IV) with trimethylsilyl azide and catalyst Amberlyst-15 in a solvent.

Chemical formula

[0059] In one embodiment, R 4 is a substituted or unsubstituted (C 6-16 ) aryl selected from -CH3, phenyl, or a substituted or unsubstituted -CH2-(C 6-16) It can be selected from aryl, and the substituent can be selected from one or more of halogen, -CH3, or -OCH3.

[0060] In one embodiment, R 5 and R 6 are selected from H, -CH3, halogen, or a substituted or unsubstituted -CH2-(C 6-16 ) aryl selected from one or more of.

[0061] In one embodiment, the ratio to TMSN3 of formula (IV) is in the range of about 1:10 to about 10:1, and preferably can be about 1:3.

[0062] In one embodiment, the present disclosure provides a compound of formula (III), stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates obtained by the process described above.

[0063] In a preferred embodiment, the compound of formula (III) can be selected from the following: 3 - azido - 3 - methylindolin - 2 - one, 3 - azido - 3 - phenylindolin - 2 - one, 3 - azido - 3 - (p - tolyl) indolin - 2 - one, 3 - azido - 3 - (4 - methoxyphenyl) indolin - 2 - one, 3 - azido - 3 - benzylindolin - 2 - one, 3 - azido - 3 - (3,4 - dimethoxybenzyl) indolin - 2 - one, 3 - azido - 3 - (4 - bromobenzyl) indolin - 2 - one, 3 - azido - 3 - benzyl - 6 - chloroindolin - 2 - one, 3 - azido - 1,3 - dibenzylindolin - 2 - one, 3 - azido - 1,3 - dimethylindolin - 2 - one, Stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates.

[0064] In one embodiment, the present disclosure provides a process for synthesizing an organic 2-azido-2H-benzo[b][1,4]oxazin-3(4H)-one derivative from peroxyindole.

[0065] In one embodiment, the present disclosure provides a continuous flow process for synthesizing an organic azide of formula (V), stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, the continuous flow process comprising the step of reacting a compound of formula (VI) with trimethylsilyl azide and catalyst Amberlyst-15 in a solvent.

Chemical formula

[0066] The process using peroxide proceeds continuously with skeletal rearrangement and azidation reaction. Although not bound by theory, this process is thought to proceed via deprotection of peroxo by a catalyst, followed by generation of N3− by attack of peroxo on TMS. The positively charged species generates an in situ carbocation via ring expansion, which is attacked by N3− to obtain the compound.

[0067] In one embodiment, R 7 is a substituted or unsubstituted (C 6-16 ) aryl selected from -CH3, phenyl, or a substituted or unsubstituted -CH2-(C 6-16 ) aryl selected from -CH2-C6H5, and the substituent may be selected from -OCH3, -CH3, or halogen.

[0068] In one embodiment, R 8 and R 9 may be selected from H, halogen, -CH3, or -CH2-C6H5.

[0069] In one embodiment, the protecting group may be n-butyl, t-butyl, methyl, benzyl, etc.

[0070] In one embodiment, the present disclosure provides a compound of formula (V), stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, obtained by the process described above.

[0071] In a preferred embodiment, the compound of formula (V) may be selected from: 2-azido-2-benzyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-azido-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-azido-2-(4-methoxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-azido-2-(2-fluorobenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-Azido-2-(4-bromobenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-Azido-2-benzyl-6-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-Azido-2-(4-bromobenzyl)-6-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-Azido-6-chloro-2-(4-methylbenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-Azido-2,4-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-Azido-4-benzyl-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, Stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof.

[0072] In one embodiment, the present disclosure provides a process for synthesizing organic azides by direct azidation of 9-alkyl / aryl-9H-fluoren-9-ol derivatives.

[0073] In one embodiment, the present disclosure provides a continuous flow process for synthesizing an organic azide of formula (I’), stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, the continuous flow process comprising reacting a compound of formula (II’) with trimethylsilyl azide and a catalyst Amberlyst-15 in a solvent.

Chemical formula

[0074] In a preferred embodiment, the compound of formula (I’) can be selected from the following: 9-azido-9-phenyl-9H-fluorene, 9-azido-9-(p-tolyl)-9H-fluorene, 9-azido-9-(4-methoxyphenyl)-9H-fluorene, 9-([1,1’-biphenyl]-4-yl)-9-azido-9H-fluorene, 9-azido-9-hexyl-9H-fluorene, 9-azido-2,7-dibromo-9-(4-methoxyphenyl)-9H-fluorene, 9-azido-9-benzyl-9H-fluorene, 9-azido-9-(3-phenoxybenzyl)-9H-fluorene, 9-([1,1’-biphenyl]-4-ylmethyl)-9-azido-9H-fluorene, 9-azido-9-(4-methoxybenzyl)-9H-fluorene, 9,9’-diazido-9H,9’H-9,9’-bifluorene, 9-azido-2-bromo-9-phenyl-9H-fluorene, 9-azido-2,7-dibromo-9-phenyl-9H-fluorene, 9-azido-2,7-dibromo-9-(p-tolyl)-9H-fluorene, or stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof.

[0075] In one embodiment, the ratio of TMSN3 to the compound of formula (VI) is in the range of about 1:10 to about 10:1, preferably about 1:3.

[0076] In one embodiment, the process can be carried out in the presence of a solvent selected from dichloromethane, 1,2-dichloroethane, etc., and preferably, the solvent is dichloromethane. The catalyst may be filled in a column, and the residence time for the reaction may be at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 60 minutes, at least 120 minutes, or at least 180 minutes, and preferably about 21 minutes.

[0077] In one embodiment, the process can be carried out in a temperature range of about 15 °C to about 100 °C, preferably about 25 °C to 80 °C.

[0078] In one embodiment, Amberlyst-15 can be present in a ratio of about 1:1 w / w to about 1:20 w / w, preferably about 1:1 w / w of the reactant compound with respect to the reactant compound. In one embodiment, the flow rate of the reactant in the continuous flow process can be about 0.08 mL / min to about 0.5 mL / min, preferably about 0.1 mL / min. In one embodiment, the process can be carried out under a pressure of about 1 to 3 bar, preferably about 0 to 1 bar.

[0079] This process tolerates both electron-withdrawing groups and electron-donating groups to obtain the respective azides via direct nucleophilic substitution reactions. This process also provides azides of more sterically hindered alcohols.

[0080] This process efficiently synthesizes azides including those having quaternary stereocenters.

[0081] Due to its inherently small volume, the continuous flow reactor provides an ideal tool for the synthesis of potentially volatile organic compounds such as the azides of the present disclosure, resulting in very effective collisions and highly controlled reaction conditions. The emergence of continuous flow as a green tool demonstrates enhanced heat and mass transfer, precise control of residence time, shortened process time, improved safety, reproducibility, better product quality, and easy scalability. This process reduces the waste generated from the two-step processes conventionally used in azide synthesis.

[0082] Amberlyst-15 can function as an excellent acid source and can be recovered and reused several times.

[0083] The processes of the present disclosure increase the embodiments of azide synthesis not only in the academic community but also in the field of fine chemical manufacturing. Thus, this process helps to scale up the synthesis that reduces the safety concerns of explosives and high-energy molecules that decompose by heat, light, or shock under batch conditions. The yields produced by the continuous flow method are also higher than those under batch conditions.

[0084] The processes of the present disclosure can provide high yields of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%.

[0085] The azides obtained from the above processes can be further used to synthesize industrially available important compounds.

[0086] The application of azides can be demonstrated towards Staudinger reduction to generate amines.

[0087] In one embodiment, the present disclosure provides a process for synthesizing amine derivatives by reducing azides synthesized in the presence of PPh3.

[0088] In one embodiment, a compound of formula (I) is subjected to reduction with triphenylphosphine in tetrahydrofuran and water to obtain a compound of formula (VII).

Chemical formula

[0089] In one embodiment, the compound of formula (III) is subjected to reduction with triphenylphosphine in tetrahydrofuran and water to obtain the compound of formula (VIII).

Chemical formula

[0090] In one embodiment, the compound of formula (V) is subjected to reduction with triphenylphosphine in tetrahydrofuran and water to obtain the compound of formula (IX).

Chemical formula

[0091] The application of azide can be demonstrated for click reactions with alkynes to generate quaternary stereocenters containing triazole moieties.

[0092] In one embodiment, the present disclosure provides a continuous flow process for synthesizing triazole-functionalized derivatives from azides using a Cu catalyst.

[0093] In one embodiment, the compound of formula (I) is reacted with the alkyne of formula (X) in a suitable solvent and a Cu catalyst to obtain the compound of formula (XI), R 10 is C 1-6 alkyl or C 6-10 aryl.

Chemical formula

[0094] In one embodiment, the compound of formula (III) is reacted with the alkyne of formula (X) in a suitable solvent and a Cu catalyst to obtain the compound of formula (XII), R 10 is C 1-6 alkyl or C 6-10 aryl.

Chemical formula

[0095] In one embodiment, a compound of formula (V) is reacted with an alkyne of formula (X) in a suitable solvent and a Cu catalyst to obtain a compound of formula (XIII). R 10 is C 1-6 alkyl or C 6-10 aryl.

Chemical formula

[0096] The above process may be carried out in batch mode.

[0097] In one embodiment, the compound of formula X is ethynylbenzene. A suitable solvent can be a mixture of tert-butyl alcohol and water.

[0098] The application of azide can be demonstrated for the rearrangement of azide to produce quinoxalinone derivatives.

[0099] In one embodiment, the present disclosure provides a continuous flow process for synthesizing quinoxalin-2(1H)-one derivatives from azide under reagent-free conditions.

[0100] In one embodiment, the compound of formula (III) can be heated at about 100 °C to about 200 °C, preferably about 180 °C, to obtain a compound of formula (XIV), and the process is a continuous flow process.

Chemical formula

[0101] In one embodiment, the pressure may be in the range of about 1 to 3 bar.

[0102] Although various embodiments of the present disclosure have been described above, other and further embodiments of the present disclosure may be devised without departing from the basic scope thereof. The scope of the present invention is determined by the following claims. The present invention is not limited to the described embodiments, versions, or examples. These are included so that those skilled in the art can make and use the present invention when combined with the information and knowledge available to those skilled in the art.

Example

[0103] The present invention will be further described in the form of the following examples. However, it should be understood that the following examples are merely illustrative and should not be construed as a limitation on the scope of the present invention.

[0104] Materials and Methods All chemicals were purchased from Sigma - Aldrich and SD Fine Chemicals and used without further modification. All solvents were purchased from Rankem and Finar Chemicals. Deuterated solvents were used as received. Column chromatography separation was performed on 100 - 200 silica gel. Visualization was achieved with UV light. Flow chemistry experiments were carried out on the Vapourtec R series equipped with a glass column (Omni compatible, 6.6×150 mm) and the Vapourtec R series equipped with an SS coil reactor (10 ml). 1 H and 13 C{ 1 H} NMR spectra were recorded at 400 and 100 MHz respectively, using a Bruker or JEOL spectrometer. HRMS spectra were acquired on a Waters - synapt G2 using electrospray ionization (ESI - TOF). Infrared (ATIR) spectra were obtained on a Bruker Alpha - E infrared spectrometer. Single - crystal diffraction analysis data were collected at 100 K using graphite monochromated Mo Kα radiation and Cu - Kα radiation, with a BRUKER KAPPA APEX III CCD Duo diffractometer (operating at an output of 1500 W: 50 kV, 30 mA).

[0105] Abbreviations used in the NMR follow-up experiments: b, broad; s, singlet; d, doublet; t, triplet; q, quartet; td, triplet of doublets and dd of doublet of doublets; m, multiplet, tt, triplet of triplets and ddd, doublet of doublets of doublets.

[0106] Example 1: Continuous flow synthesis of compounds of formula (I) and (III) The reaction was carried out under continuous flow for compound 1a according to Scheme I. In a general procedure, a 0.1 M solution of diphenylmethanol (1a) in dichloromethane and 3 equivalents of 0.3 M azidotrimethylsilane (2a) were pre-mixed and passed through an Omnifit® (6.6 × 150 mm) packed bed column (Vaportec R series) filled with Amberlyst-15 to a height of 5 cm (1.0 g, swelling to 6 cm after passing the solvent) at a flow rate of 0.1 mL / min and a residence time of 21 min at room temperature and a pressure of 0 - 1 bar. After completion of the reaction, the catalyst bed was washed with dichloromethane. The volatile components were evaporated using vacuum. The residue was purified directly by silica gel chromatography (EtOAc:hexane = 1:99 - 5:95). The Amberlyst-15 bed was recycled by washing with DCM and reused for other substrates.

Chemical formula

[0107] The compounds in Table 1 were synthesized using the same procedure as described above, except that compound 3l gave a 93% yield when heated at 80 °C in DCE solvent.

Table 1

[0108] Several other compounds that can be synthesized by the continuous flow method are shown in Table 2 below.

Table 2

[0109] Example 2 Continuous flow synthesis of the compound of formula (V) To synthesize 2-azido-2-benzyl-2H-benzo[b][1,4]oxazin-3(4H)-one (5a) from peroxide 4a, Scheme 2 was used. A 0.1 M dichloromethane solution of the peroxide compound of 4a and 3 equivalents of azidotrimethylsilane (2a, 0.3 M) were pre-mixed and passed through an Omnifit® (6.6×150 mm) packed bed column filled with Amberlyst-15 to a height of 5 cm (1.0 g, swelling to 6 cm after passing the solvent) at a flow rate of 0.1 mL / min and a residence time of 21 minutes at room temperature and a pressure of 0-1 bar. After completion of the reaction, the catalyst bed was washed with dichloromethane. The volatile components were evaporated using vacuum. The residue was purified directly by silica gel chromatography (EtOAc:hexane = 10:90).

Chemical formula

[0110] The compounds in Table 3 were prepared using the same scheme as shown above.

Table 3

[0111] Example 3 Continuous Flow Synthesis of Compounds of Formula (I’) A 0.1 M solution of 1a’ in DCM and a 0.3 M solution of TMSN3 were prepared using Scheme 1’ and passed through a 6.6 mm × 150 mm Omnifit packed bed reactor (1 g of Amberlyst-15, 6 cm bed height) (Vapourtec R series) at a flow rate of 0.1 mL / min at the specified temperature. t R = 21 min. After direct purification by column chromatography on silica gel (EtOAc:hexane = 1:99), Compound 3a’ was synthesized using 9-phenyl-9H-fluorene-9-ol (750.0 mg, 2.9 mmol) to give 9-azido-9-phenyl-9H-fluorene 3a’ (682.0 mg) as a white semi-solid.

Chemical formula

[0112] The compounds in Table 4 were synthesized using the same procedure as described above.

Table 4

[0113] Example 4: Scale-up of Continuous Flow Reaction Using Diphenylmethanol Diphenylmethanol (1a, 0.1 M, 30 mmol, 5.52 g) + 3 equivalents of azidotrimethylsilane (2a, 0.3 M, 90 mmol, 10.35 g) in 300 mL of dichloromethane were pre-mixed and flowed at a flow rate of 0.1 mL / min at room temperature under a pressure of 0 - 2 bar for 50 hours through an Omnifit® (6.6 × 150 mm) packed bed column (1 g of Amberlyst-15, bed height = 5 cm, swollen up to 6 cm) to give 29.38 mmol of the product (3a). The conversion was monitored by TLC and NMR. After 50 hours, the reaction was stopped, the reaction mixture was concentrated under vacuum and then subjected to column chromatography on silica gel (hexane). The product 3a was isolated in 98% yield as 6.144 g, turnover number (TON) = 9.24 and turnover frequency (TOF) = 0.185 h -1 -1. The reaction was stopped after 50 hours, but the catalyst remained active for further reactions. For other chemical transformations, a significant loss of activity of Amberlyst-15 is known, but for the present disclosure, only a slight loss of activity was observed over a longer reaction period.

[0114] Example 5: Synthesis of Amines Using the Staudinger Reaction To carry out the Staudinger reduction step in a flow process (Scheme 3), the flow of a 1.0 M solution of (azidomethylene)dibenzene 3a in 3 mL of THF was combined with the flow of triphenylphosphine (2 M, 2 equiv) in 3 mL of aqueous THF (THF / water, 9:1) using a T-piece, at 0.1 mL / min of 3a and 0.3 mL / min of triphenylphosphine. The resulting mixture was then reacted in a Vapourtec R series SS coil reactor (10 mL, 60 °C, residence time 25 min), then passed through a back-pressure regulator at 5.1 bar and collected in a flask. The volatile components of the crude mixture were evaporated using vacuum and extracted with DCM. The residue compound 6a was purified directly by silica gel chromatography (EtOAc:hexane = 40:60). The yield was 58%.

Chem.

[0115] Example 6: Synthesis of Triazoles Using Click Reaction [3+2] Copper-catalyzed alkyne-azide cycloaddition was carried out on compound 3a with ethynylbenzene using continuous flow to obtain compound 7a (Scheme 4). Azide 3a (0.12 M, 5 mL of t-BuOH:H2O (1:1)) with 1 mol% of CuSO4·5H2O, 10 mol% of sodium ascorbate and ethynylbenzene (0.1 M, 5 mL of t-BuOH:H2O (1:1)) flowed through pumps 1 and 2 at a flow rate of 0.1 mL / min respectively, at a pressure of 0.1 - 0.3 bar at room temperature using PTFE tubes (7 mL) respectively. After 35 minutes, the reaction mixture was continuously collected. The reaction mixture was extracted with EtOAc (10 mL × 3). The solvent was evaporated under vacuum and the residue was subjected to column chromatography purification using EtOAc / n-hexane (20:80) to obtain the corresponding compound 7a in good yield (73%).

Chem.

[0116] Using a similar process, compound 7d was synthesized from starting compound 3d in 62% yield. Compound 7d is an anti-cancer compound.

Chem.

[0117] Example 7: Continuous Flow Synthesis of Quinoxalin-2(1H)-one Derivatives The synthetic utility of the compounds of formula (III) was demonstrated by the synthesis of quinoxalin-2(1H)-one according to General Scheme 5. The azide of 2-oxyindole (formula (III)) (0.1 M, 5 mL of DMSO) was flowed at a flow rate of 0.1 mL / min at 180 °C and a pressure of 1.4 - 2.2 bar using a Vapourtec R series 10 mL SS coil reactor. After 100 minutes, the reaction mixture was continuously collected. To the reaction mixture, 50 mL of water and 2 mL of EtOAc were added and allowed to precipitate overnight. Next, the formed precipitate was filtered, washed several times with water, then dissolved in methanol and passed through a bed of sodium sulfate to obtain the corresponding quinoxalin-2(1H)-one derivative (8) in excellent yield.

Chem.

[0118] The compounds obtained by the above process are provided in Table 5, which were synthesized using compounds 3g, 3o, 3p, 3q and 3r in Table 1. Compound 8r can be further converted to an aldose reductase inhibitor in a single-step reaction.

Table 5

[0119] The foregoing embodiments are merely illustrative and should not be considered as limitations on the scope of the present invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the scope of the present invention.

[0120] Advantages of the Present Invention The present disclosure provides a process for synthesizing azide in a safe, gentle, reproducible, and controlled manner using continuous flow.

[0121] The present disclosure provides a process for synthesizing azide using a non-hazardous, recoverable, and reusable catalyst, Amerlyst-15. References 1. The Chemistry of the Azido Group (Ed.:S.Patai),Wiley,New York,1971. 2. The Chemistry of Halides,Pseudo-halides and Azides,Supplement D,(Eds.: S.Patai,Z.Rappoport),Wiley,Chichester,1983. 3. Chemistry of Halides,Pseudo-Halides and Azides,Part 1(Ed.:S.Patai),Wiley,Chichester,1995. 4. Chemistry of Halides,Pseudo-Halides and Azides,Part 2(Ed.:S.Patai),Wiley,Chichester,1995. 5. Monograph:Azides and Nitrenes Reactivity and Utility(Ed.:E.F.V.Scriven),Academic Press,New York,1984. 6. Jang, S.; Sachin, K.; Lee, H.; Wook Kim, D.; Soo Lee, H. Development of a Simple Method for Protein Conjugation by Copper-Free Click Reaction and Its Application to Antibody-Free Western Blot Analysis. Bioconjugate Chem. 2012, 23, 2256 - 2261. 7. Brase, S.; Gil, C.; Knepper, K.; Zimmermann, V. 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Claims

1. A continuous flow process for synthesizing an organic azide of formula (I), a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof by direct azidation of an alcohol of formula (II), wherein the process comprises: Reacting a compound of formula (II) with trimethylsilyl azide (TMSN3) in a packed bed reactor loaded with an Amberlyst-15 catalyst at room temperature. 【Chemical Formula 1】 Wherein: R １ is selected from substituted or unsubstituted (C ６－１６ ) aryl, or substituted or unsubstituted (C ５－１０ ) heterocycle; R ２ and R ３ are independently selected from H, substituted or unsubstituted (C ６－１６ ) aryl, substituted or unsubstituted (C １－６ ) alkyl, or substituted or unsubstituted -CH ２ -(C ６－１６ ) aryl, and the substituents are selected from one or more of halogen, (C １－６ ) alkyl, cyano, nitro, -NH ２ , (C １－６ ) alkoxy, -COOH, or combinations thereof; The ratio of the trimethylsilyl azide of formula (II) is 1:3 M; The Amberlyst-15 and the reaction compound are present in a ratio of 1:1 w / w; The flow rate of the reaction compound is 0.08 mL / min to 0.5 mL / min; The continuous flow process is carried out under a pressure of 0 to 1 bar.

2. The continuous flow process according to claim 1, wherein the compound of formula (I) is selected from the group consisting of (azidomethylene)dibenzene, 1-(azido(phenyl)methyl)-4-chlorobenzene, 4,4'-(azidomethylene)bis(methoxybenzene), (1-azidoethyl)benzene, 2-(1-azidoethyl)naphthalene, (1-azidoethane-1,1-diyl)dibenzene, (azidomethanetriyl)tribenzene, 5-(azidomethyl)benzo[d][1,3]dioxole, 5-(azidomethyl)-6-chlorobenzo[d][1,3]dioxole, and 4-(azidomethyl)pyrene or stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof.

3. A continuous flow process for synthesizing an organic azide of formula (III), stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof by direct azidation of an alcohol of formula (IV), wherein the process comprises: reacting a compound of formula (IV) with trimethylsilyl azide in a packed bed reactor loaded with an Amberlyst-15 catalyst at room temperature; 【Chemical formula 2】 wherein R ４ , R ５ and R ６ are independently selected from one or more of H, halogen, -COOH, nitro, -NH ２ , (C １－６ )alkoxy, substituted or unsubstituted (C ６－１６ )aryl, substituted or unsubstituted (C １－６ )alkyl, or substituted or unsubstituted -CH ２ -(C ６－１６ )aryl, and the substituents are selected from one or more of halogen, (C １－６ )alkyl, cyano, nitro, -NH ２ , -COOH, (C １－６ )alkoxy, or combinations thereof; the ratio of the trimethylsilyl azide to the compound of formula (IV) is 1:3M; The Amberlyst-15 and the reaction compound are present in a ratio of 1:1 w / w, the flow rate of the reaction compound is from 0.08 mL / min to 0.5 mL / min, the continuous flow process, wherein the process is carried out under a pressure of 0 to 1 bar.

4. The compound of formula (III) is selected from the group consisting of 3-azido-3-methylindolin-2-one, 3-azido-3-phenylindolin-2-one, 3-azido-3-(p-tolyl)indolin-2-one, 3-azido-3-(4-methoxyphenyl)indolin-2-one, 3-azido-3-benzylindolin-2-one, 3-azido-3-(3,4-dimethoxybenzyl)indolin-2-one, 3-azido-3-(4-bromobenzyl)indolin-2-one, 3-azido-3-benzyl-6-chloroindolin-2-one, 3-azido-1,3-dibenzylindolin-2-one, and 3-azido-1,3-dimethylindolin-2-one, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. The continuous flow process according to claim 3.

5. A continuous flow process for synthesizing an azide of formula (V), a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof by direct azidation of formula (VI), wherein the process comprises: reacting a compound of formula (VI) with trimethylsilyl azide in a packed bed reactor loaded with an Amberlyst-15 catalyst at room temperature; [Chemical Formula 3] wherein R ７ is selected from H, (C １－６ )alkyl, substituted or unsubstituted (C ６－１６ )aryl, and substituted or unsubstituted -CH ２ -(C ６－１６ )aryl; R ８ and R ９ are independently selected from H, halogen, (C １－６), alkyl, cyano, nitro, (C １－６ ), alkoxy, substituted or unsubstituted -CH ２ -(C ６－１６ ), aryl, and substituted or unsubstituted (C ６－１６ ), aryl, selected from one or more of them, and the substituents are halogen, (C １－６ ), alkyl, cyano, nitro, (C １－６ ), alkoxy, -COOH, and -NH ２ ), selected from one or more of them, Pr is a protecting group, The ratio to trimethylsilyl azide of the formula (VI) is 1:3M, The Amberlyst-15 and the reaction compound are present in a ratio of 1:1 w / w, The flow rate of the reaction compound is 0.08 mL / min to 0.5 mL / min, The process is carried out under a pressure of 0 to 1 bar, the continuous flow process.

6. The process according to claim 5, wherein the compound of formula (V) is selected from the group consisting of 2-azido-2-benzyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-azido-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-azido-2-(4-methoxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-azido-2-(2-fluorobenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-azido-2-(4-bromobenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-azido-2-benzyl-6-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-azido-2-(4-bromobenzyl)-6-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-azido-6-chloro-2-(4-methylbenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-azido-2,4-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 2-azido-4-benzyl-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof. **Claim 7** A continuous flow process for synthesizing an organic azide of formula (I'), stereoisomers, tautomers, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof by direct azidation of an alcohol of formula (II'), the process comprising: reacting a compound of formula (II') with trimethylsilyl azide in a packed bed reactor loaded with an Amberlyst-15 catalyst at room temperature; **Chemical Formula 4** wherein Ar / R is a substituted or unsubstituted (C ６－１６ ) aryl, or a substituted or unsubstituted (C ５－１０ ) heterocycle, a substituted or unsubstituted (C ６－１６ ) aryl, a substituted or unsubstituted (C １－６ ) alkyl, or a substituted or unsubstituted -CH2-(C ６－１６), aryl, and halogen, (C １－６ ), alkyl, cyano, nitro, -NH ２ ), (C １－６ ), alkoxy, -COOH, or a combination of one or more thereof, selected from the group consisting of, The ratio to trimethylsilyl azide of the formula (II') is 1:3 M, The Amberlyst-15 and the reaction compound are present in a ratio of 1:1 w / w, The flow rate of the reaction compound is 0.08 mL / min to 0.5 mL / min, The continuous flow process, wherein the process is carried out under a pressure of 0 to 1 bar.

8. The compound of the formula (I') is 9-azido-9-phenyl-9H-fluorene, 9-azido-9-(p-tolyl)-9H-fluorene, 9-azido-9-(4-methoxyphenyl)-9H-fluorene, 9-([1,1'-biphenyl]-4-yl)-9-azido-9H-fluorene, 9-azido-9-hexyl-9H-fluorene, 9-azido-2,7-dibromo-9-(4-methoxyphenyl)-9H-fluorene, 9-azido-9-benzyl-9H-fluorene, 9-azido-9-(3-phenoxybenzyl)-9H-fluorene, 9-([1,1'-biphenyl]-4-ylmethyl)-9-azido-9H-fluorene, 9-azido-9-(4-methoxybenzyl)-9H-fluorene, 9,9'-diazido-9H,9'H-9,9'-bifluorene, 9-azido-2-bromo-9-phenyl-9H-fluorene, 9-azido-2,7-dibromo-9-phenyl-9H-fluorene and 9-azido-2,7-dibromo-9-(p-tolyl)-9H-fluorene, or a stereoisomer, tautomer, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, selected from the group consisting of, the continuous flow process according to claim 7.

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