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In general, the 6-fluoro and 6-alkyl isoquinolines used in the following experiments were prepared via a Pomeranz-Fritsch synthesis (Typical procedure: Preparation of optically active 8,8-disubstituted 1, 1-biisoquinoline, K.Hirao, R. Tsuchiya, Y. Yano, H. Tsue, Heterocycles 42(1) 1996,415-422) as outlined below. The products were converted into the 1-chloro derivatives via N-oxide intermediates as described elsewhere. General Synthetic Scheme EMI271.1Reagents and reaction conditions: (a) reflux in benzene, azeotropic removal of water; (b) first step: ethyl chloroformate, trimethyl phosphite in THF, second step: titanium tetrachloride in chloroform; (c) MCPBA inCH2CI2 ; (d) POCl3 in benzene
In general, the 6-fluoro and 6-alkyl isoquinolines used in the following experiments were prepared via a Pomeranz-Fritsch synthesis (Typical procedure: Preparation of optically active 8,8-disubstituted 1, 1-biisoquinoline, K.Hirao, R. Tsuchiya, Y. Yano, H. Tsue, Heterocycles 42(1) 1996,415-422) as outlined below. The products were converted into the 1-chloro derivatives via N-oxide intermediates as described elsewhere. General Synthetic Scheme EMI271.1Reagents and reaction conditions: (a) reflux in benzene, azeotropic removal of water; (b) first step: ethyl chloroformate, trimethyl phosphite in THF, second step: titanium tetrachloride in chloroform; (c) MCPBA inCH2CI2 ; (d) POCl3 in benzene
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 17h;
Example 13 1-chloro-<strong>[1075-11-2]6-fluoro-isoquinoline</strong>; To a solution of <strong>[1075-11-2]6-fluoroisoquinoline</strong> (2.64 g, 17.9 mmol) in CH2Cl2 (70 mL) cooled at 0 C., MCPBA is added (3.4 g, 19.69 mmol). The reaction mixture is stirred at RT for 16 h. After 1 h of stirring, a yellow white precipitate forms. The solvent is evaporated under reduced pressure. To the yellow solid is added CH2Cl2 (5 mL), and the solid is isolated by vacuum filtration. Rinsing the solid with CH2Cl2 yields a white solid, which is dried under vacuum to afford 3 g (100%) of <strong>[1075-11-2]6-fluoro-isoquinoline</strong> N-oxide.
With sodium hydride; In ISOPROPYLAMIDE; at 80℃; for 2h;Product distribution / selectivity;
4-(lsoquinolin-6-yloxy)-pipehdine-1 -carbocyclic acid-tert-butylester (154) EPO <DP n="103"/>7.49 g of 4-Hydroxy-piperidine-i-carboyclic acid-tert-butylester are dissolved in 20 mL of dry dimethyl acetamide. 1.49 g of sodium hydride (60%) are added. Then a solution of 3.65 g 6-Fluoroisoquinoline (23) is added dropwise. The solution is heated at 80 0C for 2 hours, then the solvent is removed and the residue is taken up in dichloromethane. The organic layer is extracted twice with water and then with brine, dried over magnesium sulfate and evaporated to dryness. The crude product is purified by silica gel chromatography to yield 6.22g of 4-(lsoquinolin-6-yloxy)-piperidine-1- carbocyclic acid-tert-butylester. R1 = 1.32 min (Method No.1). Detected mass: 329.1 (M+H+).
With sodium hydride; In ISOPROPYLAMIDE; at 80℃; for 2h;
7.49 g of 4-hydroxy-piperidine-1-carboxylic acid-tert-butylester were dissolved in 20 ml_ of dry dimethyl acetamide. 1.49 g of sodium hydride (60%) were added. Then a solution of 3.65 g of <strong>[1075-11-2]6-fluoroisoquinoline</strong> (3) in dimethyl acetamide was added dropwise. The solution was heated at 80 0C for 2 hours, then the solvent was removed and the residue was taken up in dichloromethane. The organic layer was extracted twice with water and then with brine, dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography to yield 6.22 g of 4-(isoquinolin-6-yloxy)-piperidine-1-carboxylic acid-tert-butylester (7). Rt = 1.32 min (Method B). Detected mass: 329.1 (M+H+).
5-Chloro-6-fluoro-isoquino.ine-trifluoro acetate (151) EPO <DP n="102"/>7.0 g (38.1 mmol) of 6-Fluoroisoquinoline (23) are dissolved in 60 ml_ of concentrated sulfuric acid. At 00C 10.18 g of N-Chlorosuccinimide are added. After 1 h another 5.2g of N-Chlorosucciminide are added and the solution is warmed to 5O0C. Two more portions of 5.2 g N-Chlorosuccinimide are added successively and stirring is continued at 50 C until the reaction is complete. The reaction mixture is cooled to room temperature, is poured on ice and adOPJusted to pH 10 by addition of sodium hydroxide. The precipitate is filtered off, taken up in dichloromethane and washed with aqueous sodium hydroxide. The organic layer is dried over magnesium sulfate, evaporated and the crude product is purified by preparative HPLC to yield 4.04 g of 5- Chlor-6-fluor-isoquinoline (151) as trifluoroacetate. Rt = 0.97 min (Method No.2). Detected mass: 182.0/184.0 (M+H+).
6-Fluoro-5-nitro-isoquinoline (152)Under cooling 2.0 mL of concentrated nitric acid are added to 2.8 ml_ of sulphuric acid. Subsequently 350 mg of <strong>[1075-11-2]6-fluoroisoquinoline</strong> (23) are added, the reaction is warmed up to room temperature and allowed to stir overnight. The reaction mixture is poured on ice, extracted with dichloromethane and adOPJusted to alkaline pH by addition of sodium hydroxide. The aqueous layer is extracted again with dichloromethane. The dichloromethane layer is dried over magnesium sulfate and evaporated to give 90 mg of 6-Fluoro-5-nitro-isoquinoline, which can be used without further purification. Rt = 1.03 min (Method No.1). Detected mass: 193.0 (M+H+).
With sulfuryl dichloride; at 60℃; for 8h;Microwave irradiation;
4-Chloro-<strong>[1075-11-2]6-fluoro-isoquinoline</strong> (24) EPO <DP n="45"/>A solution of 1.5 g <strong>[1075-11-2]6-fluoro-isoquinoline</strong> (23) in 4.5 ml sulfuryl chloride was heated to 60 0C in a microwave reactor (CEM Discovery) for 8 h. After cooling to room temperature the mixture was poured on ice and extracted three times with CHCI3. After drying over Na2SO4 the solvent was distilled off and the crude product was purified by flash chromatography to yield 930 mg of compound 24. LCMS Method No. 1 , retention time 1.37 min, detected mass 182.01 [M+H]+
With sulfuryl dichloride; at 60℃; for 8h;Microwave irradiation;
4-Chloro-<strong>[1075-11-2]6-fluoro-isoquinoline</strong> (9); A solution of 1.5 g <strong>[1075-11-2]6-fluoro-isoquinoline</strong> (5) in 4.5 ml sulfuryl chloride was heated to 60 C in a microwave reactor (CEM Discovery) for 8 h. After cooling to room temperature the mixture was poured on ice and extracted three times with CHCI3. After drying over Na2SO4 the solvent was distilled off and the crude product was purified by flash chromatography to yield 930 mg of 9. Rt = 1.37 min (Method No.1). Detected mass: 182.0 (M+H+).
6-Fluoro-isoquinoline (23)41.6 g of AlCI3 were suspended in 400 ml_ of dichloromethane. At room temperature, a solution of 22.95 g of N-(2,2-Dimethoxy-ethyl)-N-(4-fluoro-benzyl)-4-methyl- benzenesulfonamide (22) in 150 ml of dichloromethane was added. Stirring was continued at room temperature overnight, the solution was poured on ice, the organic layer was separated, the aqueous phase was extracted twice with dichloromethane and the combined organic layers are then extracted twice with sodium bicarbonate. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product (8.75g) is purified by silica gel chromatography to yield 2.74 g of compound 23. Rt = 0.30 min (Method No. 4). Detected mass: 148.1 (M+H+).
With aluminum (III) chloride; In dichloromethane; at 20℃;
41.6 g of AICI3 were suspended in 400 rmL of dichloromethane. At room temperature, a solution of 22.95 g of N-(2,2-dimethoxy-ethyl)-N-(4-fluoro-benzyl)-4-methyl- benzenesulfonamide (2) in 150 ml_ of dichloromethane was added. Stirring was continued at room temperature overnight, the solution was poured on ice, the organic EPO <DP n="37"/>layer was separated, the aqueous phase was extracted twice with dichloromethane and the combined organic layers were then extracted twice with sodium bicarbonate. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product (8.75 g) is purified by silica gel chromatography to yield 2.74 g of compound (3). R1 = 0.30 min (Method C). Detected mass: 148.1 (M+H+).
With aluminum (III) chloride; In dichloromethane; at 20℃;
6-Fluoro-isoquinoline (3)41.6 g of AICI3 were suspended in 400 ml_ of dichloromethane. At room temperature, a solution of 22.95 g N-(2,2-dimethoxy-ethyl)-N-(4-fluoro-benzyl)-4-methyl- benzenesulfonamide (2) in 150 ml of dichloromethane was added. Stirring was continued at room temperature overnight, the solution was poured on ice, the layers were separated, the aqueous phase was extracted twice with dichloromethane and the combined organic layers were then extracted twice with sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product (8.75 g) was purified by silica gel chromatography to yield 2.74 g of compound 3. R1 = 0.30 min (Method C). Detected mass: 148.1 (M+H+).
6-Fluoro-isoquinoline (5); 41.6 g AICI3 were suspended in 400 ml of dichloroethane. At room temperature, a solution of 22.95 g of N-(2,2-dimethoxy-ethyl)-N-(4-fluoro-benzyl)-4-methyl- benzenesulfonamide (4) in 150 ml of dichloroethane was added. Stirring was continued at room temperature overnight, the solution was poured on ice, the organic layer was separated, the aqueous phase was extracted twice with dichloromethane and the combined organic layers were then extracted twice with sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product (8.75g) was purified by silica gel chromatography to yield 2.74 g of 5. R1 = 0.30 min (Method No.4). Detected mass: 148.1 (M+H+).
With aluminum (III) chloride; In dichloromethane; at 20℃;
6-Fluoro-isoquinoline (3)41.6 g of AICI3 were suspended in 400 ml_ of dichloromethane. At room temperature, a solution of 22.95 g N-(2,2-dimethoxy-ethyl)-N-(4-fluoro-benzyl)-4-methyl- benzenesulfonamide (2) in 150 ml of dichloromethane was added. Stirring was continued at room temperature overnight, the solution was poured on ice, the layers were separated, the aqueous phase was extracted twice with dichloromethane and the combined organic layers were then extracted twice with sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product (8.75 g) was purified by silica gel chromatography to yield 2.74 g of compound 3. R1 = 0.30 min (Method C). Detected mass: 148.1 (M+H+).
With aluminum (III) chloride; In dichloromethane; at 20℃;
41.6 g Of AICI3 were suspended in 400 ml_ of dichloromethane. At room temperature, a solution of 22.95 g of N-(2,2-dimethoxy-ethyl)-N-(4-fluoro-benzyl)-4-methyl- benzenesulfonamide (2) in 150 ml of dichloromethane was added. Stirring was continued at room temperature overnight, the solution was poured on ice, the organic layer was separated, the aqueous phase was extracted twice with dichloromethane and the combined organic layers were then extracted twice with sodium bicarbonate. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product (8.75g) is purified by silica gel chromatography to yield 2.74 g of compound (23). Rt = 0.30 min (Method C). Detected mass: 148.1 (M+H+).
7.0 g (38.1 mmol) of <strong>[1075-11-2]6-fluoroisoquinoline</strong> (3) were dissolved in 60 mL of concentrated sulfuric acid. At 0 0C 10.18 g of N-chloro succinimide were added. After 1 h another 5.2 g of N-chloro succiminide were added and the solution was heated to 50 0C. Two more EPO <DP n="37"/>portions of 5.2 g N-chloro succinimide were added successively and stirring was continued at 50 0C until the reaction was complete. The reaction mixture was cooled to room temperature, was poured on ice and adjusted to pH 10 by addition of sodium hydroxide. The precipitate was filtered off, dissolved in dichloromethane and washed with aqueous sodium hydroxide. The organic layer was dried over magnesium sulfate, evaporated and the crude product was purified by preparative HPLC to yield 4.04 g of 5-chloro-<strong>[1075-11-2]6-fluoro-isoquinoline</strong> (7) as trifluoroacetate. Rt = 0.97 min (Method A). Detected mass: 182.0/184.0 (M+H+).
5-Chloro-<strong>[1075-11-2]6-fluoro-isoquinoline</strong> (8); 7.0 g (38.1 mmol) 6-Fluoroisoquinoline (5) were dissolved in 60 ml concentrated sulfuric acid. At 00C 10.18 g N-chlorosuccinimide were added. After 1 h another 5.2 g of N-chlorosucciminide were added and the solution was warmed to 500C. Two more portions of 5.2 g N-chlorosuccinimide were added successively and stirring was continued at 50 C until the reaction was complete. The reaction mixture was cooled to room temperature, poured on ice and adjusted to pH 10 by addition of sodium hydroxide. The precipitate was filtered off, taken up in dichloromethane and washed with aqueous sodium hydroxide. The organic layer was dried over magnesium sulfate, evaporated and the crude product was purified by preparative HPLC to yield 4.04 g of the desired product as trifluoroacetate. Rt = 0.97 min (Method No.2). Detected mass: 182.0/184.0 (M+H+).
trans-4-hydroxycyclohexylamine hydrochloride[ No CAS ]
C20H26N2O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The examples 16 and 17 were also synthesized using a similar method as described for the synthesis of 12 and 13. The respective starting materials are 6-fluoro isoquinoline (5) and either cis or trans 4-amino-cyclohexanol hydrochloride.
(1s,4s)-4-aminocyclohexanol hydrochloride[ No CAS ]
C20H26N2O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The examples 16 and 17 were also synthesized using a similar method as described for the synthesis of 12 and 13. The respective starting materials are 6-fluoro isoquinoline (5) and either cis or trans 4-amino-cyclohexanol hydrochloride.
To a stirring mixture of <strong>[1075-11-2]6-fluoroisoquinoline</strong> in H2SO4 (5 mL) at 0 0C was added solid NBS (1.5 EQ) slowly over 5 min. The reaction mixture was reacted at 0 0C for 1 h. To this reaction mixture was added NBS (0.5 EQ). The cold bath was then removed. The reaction mixture was reacted until all the starting material was consumed. To this reaction mixture was neutralized with a cold solution of NaOH (5N) until the pH of this mixture >;10. The white solid was filtered off and dissolved in DCM and washed with a solution of NaOH (IN). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified via a column to give 5-bromo-<strong>[1075-11-2]6-fluoroisoquinoline</strong>. Retention time (min) = 2.810, method [3], MS(ESI) 226.0 (M+H).
With N-Bromosuccinimide; acetic acid; at 60℃; for 16h;
To a solution of 30.0 g (197.76 mmol) of <strong>[1075-11-2]6-fluoroisoquinoline</strong> in 200 mL of AcOH was added 53.9 g(296.64 mmol) of N-bromosuccinimide. Then the mixture was heated to 60C for 16 h. The solvent was removed under unreduced pressure and the residue was dissolved in EtOAc, washed with staturedaqueous NaHCO3 solution, water and brine, dried over anhydrous sodium sulfate and concentrated todryness. The residue was purified by silica gel column chromatography (PE: EA = 5:1. Rf= 0.3) to give 15.5 g of 4-bromo-<strong>[1075-11-2]6-fluoro-isoquinoline</strong>as a white solid.MS (ESI+): 226.1, 228.1 [M+H].?H NMR (400 MHz, CDC13) ppm: 9.16 (s, 1H), 8.75 (s, 1H), 8.04 (dd, J 8.8 Hz, 5.6 Hz, 1H), 7.82 (dd, J= 10.0 Hz, 2.4 Hz, 1H), 7.46 (ddd, J= 10.0 Hz, 8.8 Hz, 2.4 Hz, 1H).
With N-ethyl-N,N-diisopropylamine; In toluene; at 50℃; for 2h;Inert atmosphere;
General procedure: Dimethylsulfamoyl chloride (34; 0.144 mL, 1.34 mmol) was added to a solution of isoquinoline (5; 157 mg, 1.22 mmol) and 1H-indol-7-yl acetate (33; 213 mg, 1.22 mmol) in toluene (4 mL) at r.t. The mixture was concentrated to a thick but stirrable paste (1.5 mL), which was stirred at 50 C for 3 h. TLC and LCMS showed reaction was largely complete by this time. The mixture was diluted with EtOAc (40 mL), washed with H2O (40 mL) and sat. brine (20 mL), dried (Na2SO4), filtered and evaporated to dryness. The residue was purified by flash silica gel chromatography (loading in CH2Cl2) (eluent: gradient 20 to 50% EtOAc in heptane). Fractions containing the desired product were evaporated to afford the title compound 37a (208 mg, 42%) as a white solid
With N-ethyl-N,N-diisopropylamine; In toluene; at 50℃; for 1h;Inert atmosphere;
General procedure: Dimethylsulfamoyl chloride (34; 0.144 mL, 1.34 mmol) was added to a solution of isoquinoline (5; 157 mg, 1.22 mmol) and 1H-indol-7-yl acetate (33; 213 mg, 1.22 mmol) in toluene (4 mL) at r.t. The mixture was concentrated to a thick but stirrable paste (1.5 mL), which was stirred at 50 C for 3 h. TLC and LCMS showed reaction was largely complete by this time. The mixture was diluted with EtOAc (40 mL), washed with H2O (40 mL) and sat. brine (20 mL), dried (Na2SO4), filtered and evaporated to dryness. The residue was purified by flash silica gel chromatography (loading in CH2Cl2) (eluent: gradient 20 to 50% EtOAc in heptane). Fractions containing the desired product were evaporated to afford the title compound 37a (208 mg, 42%) as a white solid
With ammonium hydroxide; In methanol; dichloromethane; at 20℃; for 24h;
General procedure: A solution of 5-methoxy-1H-indene (2.40 g, 16.4 mmol) in MeOH (20mL) and CH2Cl2 (50 mL) was cooled to -78 C under N2. O3 (with O2 carrier gas) was bubbled through the solution for 30 min. An exotherm to -65 C occurred while the reaction was in progress; this subsided at the end of the reaction and a blue colouration of dissolved ozone was seen. Unreacted ozone was removed by flushing the reaction vessel with N2. NaHCO3 (1.75 g, 20.9 mmol) and Me2S (3.28 mL,44.3 mmol) were added. The cooling bath was removed and the mixture was stirred for 16 h at r.t.. Concd (28-30%) aq ammonia (20 mL)was added and the mixture stirred for a further 24 h. The mixture was extracted with CH2Cl2 (3 × 100 mL) and the combined organic phases were extracted with 5% aq HCl (2 × 100 mL). The combined aqueous phases were washed with CH2Cl2 (100 mL) and basified with Na2CO3 to pH 10 with stirring. An oil precipitated from solution; the mixture was extracted with CH2Cl2 (2 × 100 mL). The combined organic extractswere washed with sat. brine (50 mL), dried (MgSO4) and evaporated to afford the title compound 6 (1.27 g, 49%) as a brown oil,which was used without further purification.
ethyl (R)-1-(diazo(dimethoxyphosphoryl)methyl)-6-fluoroisoquinoline-2(1H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With (R)-6,6’-bis(3',4',5'-trifluoro-2,6-dimethyl[1,1'-biphenyl]-4-yl)-1,1'-spirobiindane-7,7'-diyl phosphate In toluene at -30℃; for 94h; Inert atmosphere; Molecular sieve; enantioselective reaction;
ethyl (R)-1-(1-diazo-2-ethoxy-2-oxoethyl)-6-fluoroisoquinoline-2(1H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With (R)-6,6’-bis((4-(tert-butyl)-2-methylphenyl))-1,1'-spirobiindane-7,7'-diyl phosphate In toluene at -20℃; for 64h; Inert atmosphere; Molecular sieve; enantioselective reaction;
Stage #1: para-fluorobenzaldehyde; 2,2-dimethoxyethylamine In chloroform at 90℃; for 36h;
Stage #2: chloroformic acid ethyl ester With triethyl phosphite In chloroform at 0 - 20℃; for 48h;
Stage #3: With titanium(IV) tetrachloride In dichloromethane; chloroform at -5 - 60℃; for 20h;
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