Methods for the removal of n-tosyl protecting group

Abstract

A mild and general method for tosyl protecting group removal from a protected organic nitrogen compound that is additionally suitable for use at commercial scale. A method for the removal of a tosyl protecting group from a protected organic nitrogen compound to form an unprotected nitrogen compound, including azabicyclo[3.1.0]hexane-6-carboxamide derivatives.

Description

METHODS FOR THE REMOVAL OF N-TOSYL PROTECTING GROUPFIELD OF THE INVENTION

[0001] The present invention is directed to novel methods for the removal of protecting groups from organic compounds, such as organic nitrogen compounds including amine functional group(s) and / or heterocycle(s). The present invention is also directed to novel methods for sulfonamide deprotection. The present invention is also directed to novel methods for removal of tosyl protecting groups from certain protected SSTR4 agonist compounds, such as 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives.BACKGROUND OF THE INVENTION

[0002] While organic nitrogen compounds are among the most important class of pharmaceutical compounds, the protection of nitrogen atoms within organic nitrogen compounds can be required for during multi-step synthetic routes for complex organic compounds. One known approach for the protection of nitrogen atoms is the use of a tosyl protecting group, such as p-toluenesulfonyl. The use of the tosyl protecting group appears to be an attractive approach due to its robust stability and often good crystallinity. However, the deprotection reaction to remove the tosyl protecting group can require harsh conditions that can lead to degradation of the synthesized organic nitrogen compound. For example, known deprotection methods can include: (1) hydrolysis with strong acids, such as HBr or HCIO4, which can require high reaction concentrations and higher temperatures; (2) reductive conditions with alkali metals, which can be incompatible with many functional groups leading to compound decomposition ; and (3) n-Bu3SnH / 2,2'- azobis(2-methylpropionitrile) (AIBN) or TiCh / Li / THF system, which have limited use to incompatibility with certain type of compounds. Thus, there is a need for a mild and general method for tosyl group removal from protected organic nitrogen compounds.

[0003] Visible light photoredox catalysis have been widely studied for a variety of organic transformations due to its mild reaction conditions and sustainability. Several photoredox based tosyl deprotection strategies have been reported, including the use of Ir based photoredox catalysts, CdS nano photoredox catalysts and acridine based organic photoredox catalysts. However, these previous studies include reaction conditions that arenot suitable for commercial scale due to the expensive cost of photocatalysts, toxicity of certain reactants, and stability issues associated with the catalyst. Accordingly, there is a need for a mild and general method for tosyl group removal from protected organic nitrogen compounds that is additionally suitable for use at commercial scale.SUMMARY OF THE INVENTION

[0004] Disclosed herein is a mild and general method for tosyl protecting group removal from a protected organic nitrogen compound that is additionally suitable for use at commercial scale. Also disclosed herein is a method for the removal of a tosyl protecting group from a protected organic nitrogen compound to form an unprotected nitrogen functional group.

[0005] Also disclosed herein is a method for the removal of a tosyl protecting group using a mild photoredox conditions, including a photocatalyst, such as 10- Phenylphenothiazine, a hydrogen atom transfer (HAT) catalyst, such as sodium 2- mercaptoethanesulfonate (Mesna), and a reducing agent, such as a formate salt. The mild photoredox conditions can also include UV / Vis radiation.

[0006] Also disclosed herein is a method of removing a tosyl protecting group from a protected organic nitrogen compound, the method comprising: (a) combining the protected organic nitrogen compound, a photocatalyst, a hydrogen atom transfer (HAT) catalyst, and a reducing agent in a solvent; and (b) applying UV / Vis radiation.

[0007] Also disclosed herein is a method of removing a tosyl protecting group from a protected organic nitrogen compound, the method comprising: (a) combining the protected organic nitrogen compound, a photocatalyst comprising PTH, a hydrogen atom transfer (HAT) catalyst comprising Mensa, and a reducing agent comprising potassium formate in a solvent comprising DMSO; and (b) applying UV / Vis radiation, the UV / Vis radiation having a wavelength of about 390 nm.

[0008] Also disclosed herein are compounds, such as 3-azabicyclo[3.1.0]hexane-6- carboxamide derivatives, that are made with the disclosed methods.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The above mentioned and other features of this disclosure, and the manner of attaining them, will become more apparent and the disclosure itself will be better understood by reference to the following description of aspects of the disclosure taken in conjunction with the accompanying drawings, wherein:

[0010] FIG. 1 shows the particle size of a protected organic nitrogen compound prior to grinding; and

[0011] FIG. 2 shows the particle size of a protected organic nitrogen compound after grinding.

[0012] Corresponding reference characters indicate corresponding parts throughout the several views. Although the drawings represent aspects of the present disclosure, the drawings are not necessarily to scale and certain features may be exaggerated in order to better illustrate and explain the present disclosure. The exemplification set out herein illustrates many aspects of the disclosure, in one form, and such exemplifications are not to be construed as limiting the scope of the disclosure in any manner.DETAILED DESCRIPTION OF THE INVENTION

[0013] Disclosed herein are methods of removing a tosyl protecting group from a protected organic nitrogen compound to form an unprotected organic nitrogen compound. The disclosed method can be used on protected organic nitrogen compounds, such as monoalkyl substituted sulfonamide compounds, dialkyl substituted sulfonamide compounds, aryl substituted sulfonamide compounds, and / or aza-heteroaromatic sulfonamide compounds. The disclosed method includes mild reaction conditions that allow for the removal of the tosyl protecting group effectively without impacting other portions of the organic nitrogen compound.

[0014] Organic Nitrogen Compounds - Protected and Unprotected

[0015] Disclosed herein is a method for the removal of tosyl protecting group using mild reaction conditions. Also disclosed herein is a method for the removal of a tosyl protecting group from a protected organic nitrogen compound to form an unprotected organic nitrogen compound using mild photoredox conditions, including a photocatalyst, a hydrogen atom transfer (HAT) catalyst, and a reducing agent. The mild photoredoxconditions can also include UV / Vis radiation in the visible wavelength spectrum and / or the ultraviolet wavelength spectrum.

[0016] The disclosed methods for removing tosyl protecting groups can be represented by Formula I. In Formula I, M is any suitable metal counter ion, such as, for example, sodium, lithium, potassium, cesium, magnesium, or calcium, Ts is a tosyl protecting group, and Ri and R2 can independently be, for example, H, Ci to C20 alkyl, Ci to C20 alkenyl, Ci to C20 alkynyl, carbonyl, C3 to C12 cycloalkyl, C5 to C12 aryl, three-member to twelve-member heterocycloalkyl with from 1 to 5 heteroatoms selected from N, O, or S excluding the nitrogen atom attached to the tosyl group, five-member to twelve-member heteroaryl with from 1 to 5 heteroatoms selected from N, O, or S excluding the nitrogen atom attached to the tosyl group, or combinations thereof. The amine of Formula I can also be a secondary amine, a tertiary amine, orRi and R2 can also be connected into a single moiety combining one or more of the functional groups described in the preceding sentence, such as a heterocycloalkyl as shown in Formula II, or Formula III, wherein M is any suitable metal counter ion, such as, for example, sodium, lithium, potassium, cesium, magnesium, or calcium, Ts is a tosyl protecting group.Formula I. Deprotection SchemeFormula II. Deprotection SchemeFormula III. Deprotection Scheme

[0017] Tosyl Protecting Group

[0018] The tosyl protecting group can be represented by the compound of Formula IV, wherein W is the connection point to a nitrogen atom in the protected organic nitrogen compound, or M, any suitable metal counter ion, such as, for example, sodium, lithium, potassium, cesium, magnesium, or calcium, and wherein Z is a H or Ci to Cio alkyl.Formula IV. Tosyl Protecting Group

[0019] In a specific embodiment, the tosyl protecting group is represented by the compound of Formula V, wherein W is the connection point to a nitrogen atom in the protected organic nitrogen compound .Formula V. Tosyl Protecting Group

[0020] Photocatalyst

[0021] The disclosed methods for removing a tosyl protecting group from a protected organic nitrogen compound can include combining the protected organic nitrogen group with a photocatalyst.

[0022] Suitable photocatalysts include any compound capable of catalyzing a photoreaction. Other suitable photocatalysts include phenylphenothiazine, 2, 4,5,6- T etra(9H-carbazol-9-yl)isophthalonitrile, and / or 9-mesityl- 10-methylacridinium tetrafluoroborate. In one embodiment, the photocatalyst is phenylphenothiazine.

[0023] The photocatalyst can be added at a molar ratio relative to the protected organic nitrogen compound of from about 0.01 mol % to about 5 mol %, from about 0.1 mol% to about 2.5 mol %, or from about 0.5 mol % to about 1.5 mol %.

[0024] Hydrogen Atom Transfer (HAT) Catalyst

[0025] The disclosed methods for removing a tosyl protecting group from a protected organic nitrogen compound can include combination of the protected organic nitrogen group with a hydrogen atom transfer (HAT) catalyst.

[0026] The HAT catalyst can include any compound that can give a proton to another compound. The HAT catalyst can include a thiol catalyst. Suitable thiol catalysts can include a Ci to Cio alkyl thiol.

[0027] The HAT catalyst can also include l,4-diazabicyclo[2.2.2]octane, 1- dodecanethiol, p-thiobenzoic acid, sodium 2-mercaptoethanesulfonate, and / or cyclohexanethiol. In one embodiment, the HAT catalyst is sodium 2- mercaptoethanesulfonate.

[0028] The HAT catalyst can be added at a molar ratio relative to the protected organic nitrogen compound of from about 1 mol % to about 25 mol %, from about 2.5 mol % to about 10 mol %, or about 5 mol %.

[0029] Reducing Agent

[0030] The disclosed methods for removing a tosyl protecting group from a protected organic nitrogen compound can include combination of the protected organic nitrogen group with a reducing agent.

[0031] The reducing agent can comprise any compound capable of giving electrons to another compound. Other suitable reducing agents include formate salts, such as lithium formate, sodium formate, potassium formate, cesium formate, and / or ammonium formate. In an embodiment, the reducing agent is potassium formate.

[0032] The reducing agent can be added at a ratio of from about 0.5 to about 2 or from about 1 to about 1.5 equivalents of the protected organic compound.

[0033] Reaction Conditions

[0034] The disclosed methods for removing a tosyl protecting group from a protected organic nitrogen compound can also include a solvent. The solvent can be a polar aprotic solvent. Suitable polar aprotic solvents can include dimethylsulfoxide, l,3-Dimethyl-2- imidazolidinone, and / or dimethylformamide.

[0035] The method can be conducted at a temperature of from about 25 °C to about 100 °C, from about 50 °C to about 80 °C, from about 40 °C to about 65 °C, from about 50 °C to about 65 °C, or about 65 °C.

[0036] UV / Vis radiation can be applied to the combination of the protected organic nitrogen compound, the photocatalyst, the HAT catalyst, the reducing agent, and optionally the solvent.

[0037] UV / Vis radiation can be provided using any suitable source which would be well known to a person of ordinary skill in the art, such as a lamp, a bulb, the sun, etc.Suitable UV / Vis radiation that can lead to the photoredox reaction proceeding to the removal of the tosyl protecting group can include ultraviolet radiation, visible radiation, or combinations thereof. The UV / Vis radiation can be applied with electromagnetic waves having a wavelength from about 200 inn to about 600 urn, from about 350 nm to about 450 nm, from about 385 nm to about 425 nm, from about 385 nm to about 390 nm, from about 420 nm to about 425 nm, about 390 nm, or about 425 nm.

[0038] Definitions

[0039] As used herein, “organic nitrogen compound” means a compound with one or more non-aromatic nitrogen atoms. Organic nitrogen compounds include compoundswith amine functional groups and / or heterocyclic nitrogen atoms capable of forming a sulfonamide functional group upon combination with a tosyl protecting group, including tosyl chloride.

[0040] As used herein, “protected organic nitrogen compound,” is an organic nitrogen compound including a tosyl protecting group attached to the nitrogen atom in the amine functional group forming a sulfonamide functional group.

[0041] As used herein, “unprotected organic nitrogen compound” is an organic nitrogen compound where a tosyl protecting group has been removed from the sulfonamide functional group to result in an amine functional group.

[0042] As used herein, the term “alkyl” means saturated linear or branched-chain monovalent hydrocarbon radical, containing the indicated number of carbon atoms. For example, “C1-C20 alkyl” means a radical having 1-20 carbon atoms in a linear or branched arrangement.

[0043] As used herein, the term “alkenyl” means saturated linear or branched-chain monovalent hydrocarbon radical, containing the indicated number of carbon atoms and at least one alkene functional groups. For example, “C1-C20 alkenyl” means a radical having 1-20 carbon atoms in a linear or branched arrangement including at least one alkene functional groups.

[0044] As used herein, the term “alkynyl” means saturated linear or branched-chain monovalent hydrocarbon radical, containing the indicated number of carbon atoms and at least one alkene functional groups. For example, “C1-C20 alkynyl” means a radical having 1-20 carbon atoms in a linear or branched arrangement including at least one alkyne functional groups.

[0045] As used herein, the term “cycloalkyl” means a radical derived from a nonaromatic monocyclic or polycyclic ring comprising carbon and hydrogen atoms. The cycloalkyl can have one or more carbon-carbon double bonds in the ring as long as the ring is not rendered aromatic by their presence. The cycloalkyl group can be unsubstituted or substituted with from one to three suitable substituents, which are well known to a person of ordinary skill in the art. The cycloalkyl group can be referred to by the number of total carbon atoms in the monocyclic or polycyclic ring. For example, a C3to C12 cycloalkyl includes cycloalkyl radical group with 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms.

[0046] As used herein, the term "heterocycloalkyl" means a radical derived from a nonaromatic monocyclic or polycyclic ring comprising one or more carbon atoms and one or more heteroatoms, such as nitrogen, oxygen, and sulfur. A heterocycloalkyl group can have one or more carbon-carbon double bonds or carbon-heteroatoms double bonds in the ring as long as the ring is not rendered aromatic by their presence. Examples of heterocycloalkyl groups include aziridinyl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, and pyranyl. A heterocycloalkyl group can be unsubstituted or substituted with one or two suitable substituents. The heterocycloakyl group can be referred to by the number of total atoms in the monocyclic or polycyclic ring. For example, a four-member to seven-member heterocycloalkyl includes four, five, six, or seven members (including carbon atoms and heteroatoms).

[0047] As used, herein, the term “aryl” means a radical derived from an aromatic monocyclic or polycyclic ring including only carbon atoms in the monocyclic or polycyclic ring. The aryl group can be unsubstituted or the aryl group can be substituted with from 1 to 5 suitable substituents, which are well known to a person of ordinary skill in the art. The aryl group can be referred to by the number of total carbon atoms in the monocyclic or polycyclic ring. For example, a C5 to C7 aryl includes an aryl radical group with 5, 6, or 7 carbon atoms.

[0048] As used herein, the term “heteroaryl” means a radical derived from an aromatic monocyclic or polycyclic ring including one or more carbon atoms and one or more heteroatoms in the monocyclic or polycyclic ring. The heteroaryl group can be unsubstituted or the heteroaryl group can be substituted with from 1 to 5 suitable substituents, which are well known to person of ordinary skill in the art. The heteroaryl group can be referred to by the number of total atoms in the monocyclic or polycyclic ring. For example, a four member to seven-member heteroaryl includes four, five, six, or seven members (including carbon atoms and heteroatoms).

[0049] Certain abbreviations are as follows: “CySH” refers to Cyclohexanethiol; “4Cz- IPN” refers to 2,4,5,6-Tetra(9H-carbazol-9-yl)isophthalonitrile; “DABCO” refers to 1,4- diazabicyclo[2.2.2]octane; “DCM” refers to dichloromethane; “DMAP” refers to 4- dimethylaminopyridine; “DMF” refers to dimethylformamide; “DMI” refers to 1,3- dimethyl-2-imidazolidinone; “DMSO” refers to dimethyl sulfoxide; “EtOH” refers to ethanol; “equiv” refers to equivalent; “GC / MS” refers to Gas Chromatography / Mass Spectrometry; “HPLC” refers to High-performance liquid chromatography; “LC / MS” refers to Liquid chromatography / mass spectrometry; “LED” refers to light-emitting diode; “Mesna” refers to sodium 2-mercaptoethanesulfonate; “Mes-Acr-Ph+BF4-“ refers to 9-mesityl-10-methylacridinium tetrafluoroborate; “Min” refers to minute / minutes;“PC” refers to photocatalyst; “PTH” refers to phenylphenothiazine; “rt” refers to retention time; “TEA” refers to triethylamine; “THF” refers to tetrahydrofuran; “Ts” refers to tosyl; and “UPLC-MS” refers to Ultra-performance liquid chromatography-mass spectrometry.Preparation of Tosylated AminesPreparation 1

[0050] A mixture of amine (10 g, 1 equiv), and DCM (10 V, 100 mL) was placed into an ice bath. 4-Toluenesulfonyl chloride (1 equiv) was then added into the mixture in three portions slowly. To the mixture was then added TEA (1.2 equiv) slowly. Upon finishing addition of TEA, the mixture was removed from the ice bath and the reaction stirred at room temperature for 6 hrs. The reaction mixture was then washed with water (50 mL). The organic phase solution was collected and concentrated to 2-3 V (20-30 mL). n- Heptane (50 mL) was added dropwise to the resulting solution at room temperature forming white crystals in the solution. The mixture was then placed in an ice bath and stirred for extra 2 hrs. The solution was filtered and the white crystals washed with n- heptane (10 mL). The resulting solid was dried under vacuum oven overnight to obtain the tosylated amine, as the starting material.Preparation 2(S)- 1 -(4-Fluoro- 1 -methyl- 1 H-indazol-5 -yl)-3 -(2-(4-fluoro-3 ,5 -dimethylphenyl)-4-methyl- 5-tosyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c] 1 lyridine-3-yl)- 1 ,3-dihydro-2H-imidazol-2- one(S)-l-(4-Fluoro-l-methyl-lH-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4- methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c] 1 lyridine-3-yl)- 1 ,3-dihydro-2H-imidazol-2- one (compound 8A) prepared according to U.S. Patent No. 10,858,356 (Page 212, compound 67b) was tosylated using a similar procedure as described in Preparation 1 to give compound 8T. Observed the mass at 490 [M+H]+extracted by ion chromatogram at rt=3.507 min via the high pH fast LC / MS method.Preparation 3 (lR,5S,6r)-N-(2-Methyl-l-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-tosyl-3- azabicyclo [3.1.0]hexane-6-carboxamide

[0051] (lR,5S,6r)-3-Tosyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (32.33 g, 88.2% purity, 9A) was dissolved in toluene (320 mL) at 15~25 °C. DMF (741.0 mg) and (COC1)2 (19.20 g) was added to the solution and heated to 45-55 °C for 3~4 hrs. The mixture was concentrated in vacuo and exchanged with THF (100 mL x 2). THF (320 mL) was added and the mixture cooled to 0-10 °C. A mixture of 2-Methyl-l-((3- methylpyridin-2-yl)oxy)propan-2-amine (23.60 g), TEA (30.80 g), DMAP (620.0 mg) was added at 0-10 °C then warmed to 15-25 °C for 2~4 hrs. The mixture was concentrated in vacuo and solvent exchanged with EtOH (140 mL x 2). The mixture was again concentrated in vacuo to 140 mL and heated to 50 °C until the solid was dissolved. Water (210 mL) was added dropwise into the solution at 40 °C. The solution was cooled to 10 °C for 14 hrs., then filtered and rinsed with EtOH / FhO (75 mL, 1 : 1.5). The wet cake was dried at 45 °C for 20 hrs., to give the title compound as a solid (41.87 g, 87.4%, 9T).JH NMR (CDCh) <5 7.94 - 7.87 (m, 1 H) 7.60 (d, .7=8.0 Hz, 2 H) 7.37 (d, .7=6.6 Hz, 1 H) 7.26 (d, .7=8.0 Hz, 2 H) 6.78 (dd, .7=6.6, 5.0 Hz, 1 H) 6.48 (s, 1 H) 4.25 (s, 2 H) 3.52 (d, .7=9.4 Hz, 2 H) 2.95 (d, .7=9.4 Hz, 2 H) 2.39 - 2.33 (m, 3 H) 2.17 (s, 3 H) 1.84 (s, 2 H) 1.39 (s, 6 H); HRMS (ESI+) Calcd. For [C23H29N3O4S+H]+: 444.1952, Found: 444.2089 (M+H).Removal of Tosyl Protecting Groups Preparation 4

[0052] To a 20 mL scintillation vial that was equipped with a stir bar was added 0.5 g of the prepared tosylated amine starting material of Preparations 1-3, followed by adding 1mol% 10-phenylphenothiazine as photocatalyst, and 5 mol% Mesna as co-catalyst. The vial was then added 1.2 equiv of potassium formate and followed by 6 V of DMSO and capped with a pressure release cap. The solution was sparged with a positive N2 flow for 10 minutes to remove air from the reaction vial. The vial was then placed on stir plate that equipped with two Kessil lamp PR160L- nm blue LED lamp with 7 cm to the reaction vial from each side. The reaction was stirred at 500 rpm for 12 hrs., under blue LED irradiation and the reaction temperature was 48 °C. Upon completion of the reaction, the lights were turned off and the vial was removed from the stir plate. 50 L of the reaction solution was taken and diluted in a 1 mL HPLC vial with acetonitrile. The samples were subjected to LC-MS for results analysis to evaluate for the presence of compounds 1A-9A in Table 1.Table 1: Removal of Tosyl Protecting Group

[0053] Table 1 shows that the formation of compounds 1 A-9A were observed following the reaction procedure of Preparation 4. This indicated that the disclosed methods could be used to removal tosyl protecting groups from a variety of protected organic nitrogen compounds.

[0054] Conditions for LC / MS or GC / MS Analysis Methods

[0055] Low pH fast UPLC-MS method:

[0056] Using a Phenomenex Gemini NX C18, 2.1 x 50 mm 3.0 um column held at 50 °C, with mobile phase A: 0.1% formic acid in water and mobile phase B: 0.1% formic acid in acetonitrile, at a flow rate of 1.2 mL / min, the mobile phases are gradiated beginning at 5% B, increasing to 95% B in 1.5 minutes, holding for 0.5 minutes, and then returning to 5% B where it is held for 0.25 minutes.

[0057] High pH fast LC / MS method:

[0058] Using a Waters Xbridge C18 2.5uM 3.0 x 75mm column held at 40 °C, with mobile phase A: 5 mM ammonium formate (pH 9) and mobile phase B: acetonitrile, at a flow rate of 1.4 mL / min, the mobile phases are gradiated beginning at 5% B, increasing to 95% B in 6.43 minutes, holding for 1.28 minutes, and then returning to 5% B where it is held for 1.22 minutes.

[0059] GC / MS method:

[0060] 1.0 pL volume of solution is injected onto an inlet at 295 °C and eluted with a 25:1 split ratio; 1.0 pL injection volume onto an Agilent DB-5MS 15 m x 0.25 mm ID, 0.25 pm film column, with helium carrier gas at 1.6 mL / min, and the oven is ramped from 40 °C for 1 min, increasing 20 °C / min. to a final temperature of 330 °C, where it’s held for 1 min.Reaction optimizationFormula VI. Photocatalyst Selection

[0061] Table 2 shows the selection of the photocatalyst for the removal of the tosyl protecting group from the protected organic nitrogen compound of 9T when the HAT catalyst is Mensa, the reducing agent is potassium formate, and 390 nm of UV / Visradiation is used, as shown in Formula VI. In each entry of Table 2, an aliquot of the reaction mixture was analyzed using the low pH fast LC / MS method to determine the mol% of 9T and 9A observed. The reaction conditions were improved where the 9A% was highest. As shown in Table 2, the optimal photocatalyst was observed to be PTH in DMSO, but the reaction did not proceed if the photocatalyst was Mes-Acr-Ph+BF4- or if the solvent was DMF or DMI.

[0062] Table 3 shows the selection of the HAT catalyst for the removal of the tosyl protecting group from the protected organic nitrogen compound of 9T when the photocatalyst was PTH, the solvent was DMSO, the reducing agent was potassium formate, and 390 nm of UV / Vis radiation is used, as shown in Formula VI. . In each entry of Table 3, an aliquot of the reaction mixture was analyzed using the low pH fast LC / MS method to determine the mol% of 9T and 9A observed. The reaction conditions were improved where the 9A% was highest. The reaction proceeded using all of the HAT catalysts tested in Table 3: CySH, 1 -dodecanethiol, p-thiobenzoic acid, and DABCO. However, the de-tosylation reaction proceeded to the greatest level of completion when the HAT catalyst was Mensa (See Table 2, entry 1).

[0063] Table 4 shows the selection of the formate salt as the reducing agent for the removal of the tosyl protecting group from the protected organic nitrogen compound of 9T when the photocatalyst was PTH, the HAT catalyst was Mensa, the solvent was DMSO, and 390 nm of UV / Vis radiation is used, as shown in Formula VI. In each entry of Table 4, an aliquot of the reaction mixture was analyzed using the low pH fast LC / MS method to determine the mol% of 9T and 9A observed. The reaction conditions were improved where the 9A% was highest. The reaction proceeded using all of the formate salts tested in Table 4: HCOOLi, HCOONa, HCOOCs, and HCOONH4. However, the de- tosylation reaction proceeded to the greatest level of completion when the formate salt / reducing agent was HCOOK. (See Table 2, entry 1).

[0064] Table 5 shows the selection of the wavelength of the UV / Vis radiation for the removal of the tosyl protecting group from the protected organic nitrogen compound of 9T when the photocatalyst was PTH, the HAT catalyst was Mensa, the formate salt was HCOOK, and the solvent was DMSO. In each entry of Table 5, an aliquot of the reaction mixture was analyzed using the low pH fast LC / MS method to determine the mol% of 9Tand 9 A observed. The reaction conditions were improved where the 9A% was highest.In Table 5, the reaction proceeded to the greatest level of completion when the wavelength of the UV / Vis radiation was 385-390 nm or 420-425 nm.Formula VII. Selection of mol% of PTH, Mensa, and Reaction Temperature

[0065] Table 6 shows the selection of the mol% of the photocatalyst (PTH), the mol% of the HAT catalyst (Mensa), and the reaction temperature when 1.2 equivalents of potassium formate is used as the reducing agent, DMSO is used as the solvent, and 390 nm of UV / Vis radiation is used, as shown in Formula VII. In each entry of Table 6, an aliquot of the reaction mixture was analyzed using the low pH fast LC / MS method to determine the mol% of 9T and 9A observed. The reaction conditions were improved where the 9A% was highest. Table 6 shows that the temperature can be raised from 50 °C to 80 °C to improve the amount of 9A observed (see Table 6, entries 1 and 2). Table 6 also shows that increasing the mol% from 0.1 mol% to 0.25 mol% to 0.5 mol% of the photocatalyst improved the amount of 9A observed, but if the mol% of the photocatalyst was increased beyond 0.5 mol%, there was no additional improvement in the amount of 9A observed. Table 6 also shows that if the amount of the HAT catalyst is increased from 2.5 mol% to 5 mol%, there was an improvement in the amount of 9A observed. However, there was no additional improvement in the amount of 9A observed if the amount of HAT catalyst was increased to 10 mol%.Table 2. Photocatalyst SelectionTable 3. HAT Catalyst SelectionTable 4. Formate Salt SelectionTable 5. Light Wavelength SelectionTable 6. Selection of mol% of PTH, Mensa, and Temperature

[0066] In some aspects, prior to the removal of the tosyl protecting group from the protected organic nitrogen compound, crystals or solids of reagents, such as HCOOK or the protected organic nitrogen compound may be reduced in size, for example bygrinding. FIG.1 shows a photo illustrating the particle size of some reagents prior to grinding and prior to removing the protecting group. As can be seen in FIG. 1 , solids had measured particle sizes of (1) 500.51 pm, (2) 312.59 pm, (3) 226.57, and (4) 147.29 pm (Dv(10): 174pm, Dv(50): 309pm, Dv(90): 495pm). FIG. 2 shows a photo of particle sizes of some reagents after grinding and prior to removing the protecting group. As can be seen in FIG. 2, solids had measured particle sizes of (1) 316.41 pm, (2) 237.78 pm, (3) 91.15, and (4) 13.05 pm (Dv(10): 33.1pm, Dv(50): 163pm, Dv(90): 298pm).

[0067] Table 7 below illustrates the reaction times when the formate salt / reducing agent (in this illustrative aspect being HCOOK) was not ground and when the formate salt / reducing agent (HCOOK in this example) was ground. As can be seen in Table 7, the reaction time was reduced when the formate salt / reducing agent was ground prior to the reduction reaction.Table 7: Reaction Time and Particle Size

[0068] While this disclosure has been described as having various exemplary designs, the present disclosure may be further modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the disclosure using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this disclosure pertains.

[0069] The benefits, advantages, solutions to problems, and any elements that may cause any benefit, advantage, or solution to occur or become more pronounced are not to be construed as critical, required, or essential features or elements. Moreover, where a phrase similar to “at least one of A, B, or C” is used in the claims, it is intended that the phrase be interpreted to mean that A alone may be present in an embodiment, B alone may be present in an embodiment, C alone may be present in an embodiment, or that any combination of the elements A, B or C may be present in a single embodiment; for example, A and B, A and C, B and C, or A and B and C.

[0070] In the detailed description herein, references to “one embodiment,” “an embodiment,” “an aspect,” “an example embodiment,” etc., indicate that the embodiment or aspect described may include a particular feature, structure, or characteristic, but every embodiment or aspect may not necessarily include the particular feature, structure, or characteristic. Moreover, such phrases are not necessarily referring to the same embodiment or aspect. Further, when a particular feature, structure, or characteristic is described in connection with an embodiment or aspect, it is submitted that it is within the knowledge of one skilled in the art with the benefit of the present disclosure to affect such feature, structure, or characteristic in connection with other aspects of this disclosure whether or not explicitly described. After reading the description, it will be apparent to one skilled in the relevant art(s) how to implement the disclosure in alternative aspects of this disclosure.

[0071] Furthermore, no element, component, or method step in the present disclosure is intended to be dedicated to the public regardless of whether the element, component, or method step is explicitly recited in the claims. No claim element herein is to be construed under the provisions of 35 U.S.C. 112(f) unless the element is expressly recited using the phrase “means for.” As used herein, the terms “comprises,” “comprising,” or any othervariation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.

Claims

CLAIMSWe claim:

1. A method of removing a tosyl protecting group from a protected organic nitrogen compound, the method comprising:(a) combining the protected organic nitrogen compound, a photocatalyst, a hydrogen atom transfer (HAT) catalyst, and a reducing agent in a solvent; and(b) applying UV / Vis radiation.

2. The method of claim 1, wherein the photocatalyst comprises phenylphenothiazine, 2,4,5 ,6-Tetra(9H-carbazol-9-yl)isophthalonitrile, or 9-mesityl- 10-methylacridinium tetrafluoroborate.

3. The method of claim 1 or 2, wherein the photocatalyst comprises phenylphenothiazine.

4. The method of any one of claims 1 to 3, wherein the photocatalyst is added at a molar ratio relative to the protected organic nitrogen compound of from about 0.01 mol % to about 5 mol %.

5. The method of any one of claims 1 to 4, wherein the photocatalyst is added at a molar ratio relative to the protected organic nitrogen compound of from about 0.1 mol % to about 2.5 mol %.

6. The method of any one of claims 1 to 5, wherein the photocatalyst is added at a molar ratio relative to the protected organic nitrogen compound of from about 0.5 mol % to about 1.5 mol %.

7. The method of any one of claims 1 to 6, wherein the HAT catalyst comprises a thiol catalyst.

8. The method of claim 7, wherein the thiol catalyst comprises an alkyl thiol.

9. The method of any one of claims 1 to 6, wherein the HAT catalyst comprises 1 ,4- diazabicyclo[2.2.2]octane, 1 -dodecanethiol, p-thiobenzoic acid, sodium 2- mercaptoethanesulfonate, and cyclohexanethiol.

10. The method of any one of claims 1 to 9, wherein the HAT catalyst comprises sodium 2-mercaptoethanesulfonate.

11. The method of any one of claims 1 to 10, wherein the HAT catalyst is added at a molar ratio relative to the protected organic nitrogen compound of from about 1 mol % to about 25 mol %.

12. The method of any one of claims 1 to 11, wherein the HAT catalyst is added at a molar ratio relative to the protected organic nitrogen compound of from about 2.5 mol % to about 10 mol %.

13. The method of any one of claims 1 to 12, wherein the HAT catalyst is added at a molar ratio relative to the protected organic nitrogen compound is about 5 mol %.

14. The method of any of claim 1 to 13, wherein the reducing agent comprises a formate salt.

15. The method of claim 14, wherein the formate salt comprises lithium formate, sodium formate, potassium formate, cesium formate, or ammonium formate.

16. The method of any one of claims 1 to 15, wherein the reducing agent is added at a ratio of about 0.5 to about 2 equivalents of the protected organic compound.

17. The method of any one of claims 1 to 16, wherein the reducing agent is added at a ratio of about 1 to about 1.5 equivalents of the protected organic compound.

18. The method of any one of claims 1 to 17, wherein the solvent comprises a polar aprotic solvent.

19. The method of claim 18, wherein the polar aprotic solvent comprises dimethylsulfoxide, l,3-Dimethyl-2-imidazolidinone, or dimethylformamide.

20. The method of any one of claims 1 to 19, wherein the method has a temperature of from about 25° C to about 100 °C.

21. The method of any one of claims 1 to 20, wherein the method has a temperature of from about 50° C to about 80 °C.

22. The method of any one of claims 1 to 21, wherein the UV / Vis radiation is ultraviolet radiation or visible radiation.

23. The method of any one of claims 1 to 22, wherein the UV / Vis radiation has a wavelength of from about 200 nm to about 600 nm.

24. The method of any one of claims 1 to 23, wherein the UV / Vis radiation has a wavelength of from about 350 nm to about 450 nm.

25. The method of any one of clams 1 to 24, wherein the UV / Vis radiation has a wavelength of about 390 nm.

26. The method of any one of claims 1 to 25, wherein the tosyl protecting group comprises a compound of the formula:wherein Z is a Ci to Cio alkyl group and W is the connection point to a nitrogen atom in the protected organic nitrogen compound .

27. The method of any one of claims 1 to 26, wherein the tosyl protecting group comprises a compound of the formula:wherein W is the connection point to a nitrogen atom in the protected organic nitrogen compound.

28. The method of claim 27, wherein the protected organic nitrogen compound is of the formula:the unprotected organic nitrogen compound is of the formula:

29. A compound of the formula:wherein the compound is made by the process of any one of claims 1 to 27.

30. The method of claim 27, wherein the protected organic nitrogen compound is of the formula:the unprotected organic nitrogen compound is of the formula:

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