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CAS No. : | 321-38-0 | MDL No. : | MFCD00003873 |
Formula : | C10H7F | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CWLKTJOTWITYSI-UHFFFAOYSA-N |
M.W : | 146.16 | Pubchem ID : | 9450 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 10 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 43.91 |
TPSA : | 0.0 Ų |
GI absorption : | Low |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.04 cm/s |
Log Po/w (iLOGP) : | 2.12 |
Log Po/w (XLOGP3) : | 3.03 |
Log Po/w (WLOGP) : | 3.4 |
Log Po/w (MLOGP) : | 3.76 |
Log Po/w (SILICOS-IT) : | 3.44 |
Consensus Log Po/w : | 3.15 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.33 |
Solubility : | 0.0687 mg/ml ; 0.00047 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.7 |
Solubility : | 0.295 mg/ml ; 0.00202 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.33 |
Solubility : | 0.00684 mg/ml ; 0.0000468 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.5% | for 2 h; Reflux | 1-Fluoronaphthalene (20.0 g, 0.137 mol) and carbon tetrachloride (120.0 mL) were added to a 500 mL one-necked flask, and bromine (10.9 g, 0.068 mol) was added dropwise and refluxed for 2 h. After completion of the reaction, the concentrated solution was concentrated under reduced pressure, and the concentrated solution was poured into methanol (80.0 mL). The solid was precipitated at room temperature overnight, and 28.2 g of 1-bromo-4-fluoronaphthalene. The yield was 91.5percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.6% | Stage #1: With sodium hydride In N,N-dimethyl acetamide at 70℃; for 0.333333 h; Stage #2: at 110℃; for 1 h; |
DX-A 03 (2.0 g, 0.011 mol)Was dissolved in dimethylacetamide (100 mL)A solution of 60percent sodium hydride (463 mg, 0.012 mol)Dropwise.The resulting mixture was heated at 70 ° C. for 20 minutes.1-Fluoronaphthalene (1.27 mL, 0.012 mol)Was added dropwise to this mixed solution,And heated at 110 ° C. for 60 minutes.The reaction mixture was diluted with water,And extracted twice with diethyl ether.The extracts are combined,Wash with water,Then washed with saturated sodium chloride solution,It was dried over anhydrous sodium sulfate,After concentration under reduced pressure,To obtain an oily compound (DX-A 04, 3.28 g, 75.6percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80 % | With oxalic acid In ISOPROPYLAMIDE; water; (S)-3-dimethylamino-1-(2-thienyl)propan-1-ol; ethyl acetate; mineral oil | Example 4 Synthesis of (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine oxalate In 50 ml of dimethylacetamide 0.5 g of sodium hydride (suspension in mineral oil) is suspended. Suspension is stirred and in few portions 2 g of (s)-3-(dimethylamino)-1-(thienyl)-propan-1-ol is added. After the addition is completed the suspension is warmed up to 70°C. 1.27 ml of 1-fluoronaphthalene is added and the reaction mixture is heated to 110°C. At this temperature the solution is stirred for another three hours. Then the reaction solution is dissolved with 300 ml of water and extracted twice with 100 ml ether. Combined ether phases are rinsed with water, dried with sodium sulphate end evaporated to dryness. Obtained oil is dissolved in 50 ml ethyl acetate and 0.9 g of oxalic acid is added. The suspension is further stirred for one hour, filtered off the product and washed with ethyl acetate. The product is dried to obtain 3.5 g (80 percent) of (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine oxalate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: With tin(IV) chloride In dichloromethane at 0℃; for 0.75 h; Stage #2: at 20℃; |
A solution OF A, A-DICHLOROMETHYL methyl ether (5.9 mL, 65 mmol) in CH2C12 (30 mL) was cooled in an ice bath and then treated dropwise over 15 min with SNCL4 (7.6 mL, 65 mmol). After stirring for 45 min, a solution of 1-FLUORONAPHTHALENE (5.5 mL, 50 mmol) in CH2C12 (30 mL) was added. The mixture was allowed to slowly warm to room temperature while stirring overnight. The mixture was poured in ice water (100 mL) and diluted with CH2C12 (50 mL). The layers were separated. The organic layer was diluted with CH2C12 (100 mL), washed with H20 (3 x 50 mL), dried over NA2S04, filtered, and the solvent was removed in vacuo to give the title compound (7.62 g, 87percent) as a pale yellow solid: MS (ESI) mle 175 (M + H) +. |
55% | Stage #1: With tin(IV) chloride In dichloromethane at -5 - 0℃; for 0.5 h; Stage #2: at 20℃; for 18 h; |
To a 250 mL flask was added dichloromethane (30 mL) and dichloromethyl methyl ether (0.81 mL, 8.89 mmol, 1.3equivalent).The clear solution was cooled to -5 & lt; 0 & gt;Tin (IV) chloride (1.04 ml, 8.89 mmol, 1.3 eq.) Was then slowly addedGt; C), keeping the temperature below 0 & lt; 0 & gt; C. The solution was stirred at 0 & lt; 0 & gt; C for 30 minutes and then 1-fluoronaphthalene in dichloromethane (10 ml) was added(1.0 g, 6.84 mmol). The reaction mixture was allowed to equilibrate to room temperature. After about 18 hours, the dark green was mixedThe mixture was poured into ice water (40 mL) and transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with dichloromethane(3 x 20 mL). The combined organic layers were washed with water (150 mL) and saturated sodium chloride (150 mL). WillThe organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a beige solid. By Biotage color(Gradient elution: 5percent to 50percent dichloromethane / hexane) to give 0.60 g (55percent) of 8 asAn off-white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.5% | With tetrachloromethane; bromine; for 2h;Reflux; | 1-Fluoronaphthalene (20.0 g, 0.137 mol) and carbon tetrachloride (120.0 mL) were added to a 500 mL one-necked flask, and bromine (10.9 g, 0.068 mol) was added dropwise and refluxed for 2 h. After completion of the reaction, the concentrated solution was concentrated under reduced pressure, and the concentrated solution was poured into methanol (80.0 mL). The solid was precipitated at room temperature overnight, and 28.2 g of 1-bromo-4-fluoronaphthalene. The yield was 91.5%. |
With N2; bromine; In methanol; tetrachloromethane; | A. 4-Bromo-1-fluoronaphthalene To a 50 mL round-bottomed flask equipped with condenser and N2 inlet were added 3.75 mL (5.0 g, 34.25 mmol) 1-fluoronaphthalene and 10 mL carbon tetrachloride, followed by dropwise addition of 1.7 mL (5.5 g., 34.375 mmol) bromine over 3 min. The reaction was heated to 50-60 C. as HBr was evolved for 2 hours, then cooled and concentrated. The residue was dissolved in methanol and kept overnight at 0 C. After filtration with cold methanol, the product, with mp close to room temperature, was 4.62 g (60%) of a yellow oil. 1H-NMR (δ, CDCl3): 7.02 (t, J=8, 1H), 7.6-7.7 (m, 3H), 8.10 (d, J=8.5, 1H), 8.20 (d, J=8.5, 1H). | |
With N2; bromine; In methanol; tetrachloromethane; | A. 4-Bromo-1-fluoronaphthalene To a 50 mL round-bottomed flask equipped with condenser and N2 inlet were added 3.75 mL (5.0 g, 34.25 mmol) 1-fluoronaphthalene and 10 mL carbon tetrachloride, followed by dropwise addition of 1.7 mL (5.5 g., 34.375 mmol) bromine over 3 min. The reaction was heated to 50-60 C. as HBr was evolved for 2 hour, then cooled and concentrated. The residue was dissolved in methanol and kept overnight at 0 C. After filtration with cold methanol, the product, with melting point close to room temperature, was 4.62 g (60%) of a yellow oil. 1H-NMR (δ, CDCl3): 7.02 (t, J=8, 1H), 7.6-7.7 (m, 3H), 8.10 (d, J=8.5, 1H), 8.20 (d, J=8.5, 1H); GCMS (%): 224/226 (parent, Br79/Br81 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With chlorosulfonic acid at 25℃; for 0.5h; | |
82% | With chlorosulfonic acid at 20℃; for 0.5h; | 11 4-Fluoro-naphthalene-1-sulfonyl chloride (27) 1-Fluoronaphthalene (20.0 g, 0.14 mol) was added in small portions to a stirred solution of chlrosulfonic acid (79 g, 45 mL, 0.68 mol) at room temperature. The reaction was stirred for 30 minutes until gas evolution ceased. The reaction mixture was poured carefully over a mixture of ice (300 g) and dichloromethane (300 mL) and charged to a separatory funnel. The organic layer was separated, washed twice with water and brine and dried over MgS04. Filtration and concentration in vacuo afforded 27 as a tan solid. Wt.: 27.6 g (82%). LH NMR (300 MHz, CDCL3) 8 8.79 (dd, 1H), 8.38 (dd, 1H), 8.28 (d, 1H), 7.88 (m, 1H), 7.77 (m, 1H), 7.26 (dd, 1H). |
82% | With chlorosulfonic acid at 20℃; for 0.5h; | 4-FLUORO-NAPHTHALENE-1-SULFONYL chloride (27) 1-Fluoronaphthalene (20.0 g, 0.14 mol) was added in small portions to a stirred solution of chlrosulfonic acid (79 g, 45 mL, 0.68 mol) at room temperature. The reaction was stirred for 30 minutes until gas evolution ceased. The reaction mixture was poured carefully over a mixture of ice (300 g) and dichloromethane (300 mL) and charged to a separatory funnel. The organic layer was separated, washed twice with water and brine and dried over MGS04. Filtration and CONCENTRATION IN VACUO afforded 27 as a tan solid. Wt.: 27.6 g (82%).'H NMR (300 MHz, CDCl3) 8 8.79 (dd, 1H), 8.38 (dd, 1H), 8.28 (d, 1H), 7.88 (m, 1H), 7.77 (m, 1H), 7.26 (dd, 1H). |
With chlorosulphuric acid | ||
With chlorosulfonic acid In chloroform | Preparation of 4-Fluoro-1-naphthalenesulfonyl chloride: Preparation of 4-Fluoro-1-naphthalenesulfonyl chloride: To a mixture of 1-fluoronaphthalene (1.47 g, 10.1 mmol) in chloroform (25 mL) at 0° C. was added chlorosulfonic acid (1.40 mL, 21.1 mmol) dropwise over 5-10 min. The mixture was allowed to slowly warm to room temperature while stirring overnight. The mixture was then poured onto a mixture of ice and water. The layers were separated and the aqueous layer was washed with hexane. The organic layers were combined and dried over magnesium sulfate and then concentrated to dryness under vacuum to give 2.11 g of 4-fluoro-1-naphthalenesulfonyl chloride as a white solid. 1H NMR (CDCl3) δ7.27, 7.77, 7.88, 8.29, 8.39, 8.80. | |
With chlorosulfonic acid at 0 - 20℃; for 3.83333h; | 77 1-Fluoronaphthalene (1.262ml) was added dropwise over a period of 20 min to an ice- cooled, stirred solution of chlorosulphonic acid (2.3mi). The mixture was stirred for an additional 30min at5 C and 3h at room temperature. The mixture was then poured onto ice and extracted twice with ethyl acetate. The organic solution was washed with water, brine, dried(MgS04) and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 10 to 30% ethyl acetate in hexane. The title compound was obtained as a pale yellow solid (0.86g),SH(dg-CDCI3) 7.27 (1 H, dd, J 8.6, 9.1 Hz), ), 7.77 (1H, ddd,J 0. 8,7. 2,8. 2Hz), 7.89 (1H, ddd,J 1. 3,7. 1,8. 6Hz), 8. 29 (1H, d,J 8. 4Hz), 8.39 (1H, dd,J 8. 4,5.1 Hz), 8.80,(1H, ddd,J 0. 9,0. 9,8. 7Hz). | |
Stage #1: 1-Fluoronaphthalene With trifluoroacetic acid at 0℃; for 0.166667h; Inert atmosphere; Stage #2: With chlorosulfonic acid at 0 - 20℃; for 2.5h; | 55.a a) 4-fluoronaphthalene- 1-sulfonyl chloride To a stirred solution of 1-fluoronaphthalene (500 mg, 0.342 mmol) was added TFA (2.43 mL) drop wise at 0 °C under an inert atmosphere. The solution was stirred for 10 min. after which HSO3CI (0.5 ml) was added drop wise to the reaction mixture. The reaction was stirred at 0 °C for 0.5 h and subsequently warmed to room temperature 2h. The reaction mixture was quenched with ice cold water and the resulting material was isolated by filtration. The hygroscopic solid was dried in a vacuum desiccator containing P205 to provide intermediate 4- fluoronaphthalene-l-sulfonyl chloride. LCMS purity: 90.7 % | |
With chlorosulfonic acid In chloroform at 0℃; for 4h; Cooling with ice; | General procedure for the synthesis of intermediates 15a-15d General procedure: Substituted naphthalene (5.0 mmol) was dissolved in 15 mL of chloroform, chlorosulfonic acid (658 mL, 10.0 mmol) was added under ice bath and stirred for about 4 h at 0 °C. The mixture was poured slowly into 50 mL of ice water and extrated with ethyl acetate for three times. The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum to give 15a-15d, which were used directly for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.8% | Stage #1: 1-amino-naphthalene With hydrogenchloride; sodium nitrite In water at 5 - 75℃; Stage #2: With tetrafluoroboric acid In water for 0.25h; Stage #3: at 85 - 90℃; | 1.1-1.4; 2.1-2.4; 3.1-3.4; 4.1-4.4; 5.1-5.4 Example 2 Preparation method of naphthalene-based fluorine-containing intermediate 1-fluoronaphthalene of the invention:1) Diazotization reaction: 1500 g of hydrochloric acid (mass concentration: 25%) and 300 g of naphthylamine were added to a 3000 mL three-necked flask, stirred and heated to 75 ° C to dissolve, and the temperature was lowered to below 5 ° C, and 148 g was slowly added at this temperature. Sodium nitrite, stirred at low temperature for 0.3 hours after the addition, to obtain a diazonium salt solution;2) Substitution reaction: 360 g of fluoroboric acid solution (concentration: 45%) was added to the resulting solution obtained in the step 1), stirred for 0.25 h, filtered, and the filter cake was dried at a temperature of 50 ° C for 0.2 h to obtain Dry naphthylamine diazonium salt fluoroborate double salt;3) Hot air decomposition: the dried diazonium salt fluoroborate double salt is slowly added to the reactor through which hot air (hot air temperature is 85-90 ° C), and the dried powdered naphthylamine diazonium salt fluoroborate double salt is The hot air blows up the dispersion and absorbs the heat for thermal decomposition to obtain a 1-fluoronaphthalene solution containing a small amount of solid impurities;4) Purification treatment: the 1-fluoronaphthalene solution obtained in the step 3) is first washed with pure water for 3 to 6 times, then neutralized with a soda ash to a pH of 6.8 to 7.2, and finally the oil layer is separated by filtration, and the filtrate is taken. The distillation treatment gave 210 g of a naphthalene-based fluorine-containing intermediate 1-fluoronaphthalene in an amount of 99.8%. |
With potassium nitrite; hydrogen fluoride | ||
With tert.-butylnitrite; silicon tetrafluoride 1.) CH2Cl2, room temp., 1 h, 2.) 130-140 deg C, 1 h; Yield given. Multistep reaction; |
Multi-step reaction with 2 steps 1.1: hydrogenchloride; sodium nitrite / water / 0.75 h / 0 - 5 °C 1.2: 1 h 2.1: boron trifluoride diethyl etherate / tetrachloromethane / 0.08 h / 20 °C / Inert atmosphere 2.2: 1 h / Reflux | ||
Multi-step reaction with 2 steps 1: ethanol / 1 h / 0 - 20 °C / Inert atmosphere 2: boron trifluoride diethyl etherate; 1-fluoro-3,3-dimethyl-1,3-dihydro-1λ3-benzo[d][1,2]iodaoxole / 36 h / 50 °C / Glovebox; Sealed tube; Inert atmosphere | ||
64.5 g | Stage #1: 1-amino-naphthalene With hydrogenchloride; sodium nitrite In water at 80℃; Stage #2: With hexafluorophosphoric acid at 8℃; for 0.5h; Stage #3: With sodium fluoride In acetic acid butyl ester at 100℃; for 1h; | 1-6 Example 3 (1) Add 600mL of 10% hydrochloric acid solution and 120g of 1-naphthylamine to a 2000mL three-necked flask, dissolve at 80°C and stirring, and slowly add 15% sodium nitrite solution dropwise at 3°C to carry out the diazotization reaction , Take a sample during the dripping process and use a 1% potassium iodide starch solution indicator for detection. When the indicator begins to change color, no more sodium nitrite solution is added dropwise, the diazotization reaction is over, and the diazonium salt solution is obtained;(2) Add 126g to the diazonium salt solution obtained in step (1) at 8°CFluorophosphoric acid, conduct salt precipitation for 0.5h,Obtain the slurry fluorophosphoric acid diazonium salt crystal liquid, and then perform suction filtration. After the suction filtration is completed, rinse with 400mL of anhydrous methanol, and finally dry in a vacuum oven at 40°C for 4 hours to obtain a light brown powder solid with a moisture content of less than 0.5% Diazonium salt; wherein the ratio of the amount of fluorophosphoric acid to the amount of diazonium salt in the diazonium salt solution is 1.1:1;(3) Suspend 36 g of sodium fluoride in 500 mL of butyl acetate, add the diazonium salt obtained in step (2) in batches with stirring, and cleave at 100°C for 1 hour to obtain a crude solution of 1-fluoronaphthalene; in which sodium fluoride The ratio of the amount of the substance to the diazonium salt is 1.8:1;(4) Filter out the sodium hexafluorophosphate suspended in the crude 1-fluoronaphthalene solution, which can be reused in the salt precipitation step; then add 200 mL of water to the filtrate to wash for 15 minutes, stand still to separate the organic layer; Water sodium sulfate was dried overnight to remove anhydrous sodium sulfate; rectification was carried out, first collecting butyl acetate under normal pressure, and collecting the fraction at 140150 under 6.0KPa to obtain 64.5g HPLC purity of 99.5%, single impurity less than 0.3% The 1-fluoronaphthalene boutique. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With aluminum (III) chloride; In dichloromethane; at 0℃; for 0.5h; | A mixture of l-fluoronaphthalene (5.00 g, 34.21 mmol, 4.42 mL, 1.00 eq) and aluminum chloride (6.84 g, 51.31 mmol, 2.80 mL, 1.50 eq) in dichloromethane (50 mL) was added acetyl chloride (3.22 g, 41.05 mmol, 2.93 mL, 1.20 eq) in dichloromethane (10 mL) at 0 C. The mixture was stirred at 0 C for 0.5 hour. Then the mixture was stirred at 20 C for 4 hours. The mixture was pouring into water (60 mL), It was extracted with dichloromethane (50 mL x 2). The combined organic layer was washed with water (80 mL x 2) and brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/Ethyl acetate=l/0 to 20/1) to give compound l-(4-fluoro-l -naphthyl) ethanone (5.40 g, 28.69 mmol, 84 % yield) as a colorless oil. 1 H-NMR (400MHz, CDCL) d 8.94 - 8.86 (m, 1H), 8.17 (d, 7=8.3 Hz, 1H), 7.98 (dd, 7=5.4, 8.1 Hz, 1H), 7.71 - 7.65 (m, 1H), 7.64 - 7.58 (m, 1H), 7.16 (dd, 7=8.1, 9.7 Hz, 1H), 2.84 - 2.67 (m, 3H). |
With aluminum (III) chloride; In dichloromethane; at 0 - 20℃; for 4.25h; | Reference Example 74 To a mixture of 1-fluoronaphthalene (2.50 g), aluminum chloride (2.74 g), and dichloromethane (13 mL) was added mixture of acetyl chloride (1.22 mL) and dichloromethane (2.0 mL) at 0C for 15 minutes. The temperature was elevated to room temperature and the mixture was stirred for 4 hours. The reactant was poured into water and extracted with hexane. The extracts were washed with a sodium carbonate solution and brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 1-(4-fluoro-1-naphthyl)ethanone (1.20 g). 1H-NMR (300 MHz, CDCl3) delta: 2.73 (3H, s), 7.15 (1H, dd, J=9.9 and 8.1 Hz), 7.56-7.69 (2H, m), 7.96 (1H, dd, J=8.1 and 5.4 Hz), 8.13-8.16 (1H, m), 8.86-8.90 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With palladium 10% on activated carbon In isopropyl alcohol at 100℃; for 12h; Inert atmosphere; | 4 37.0 mg (0.25 mmol) of 4-fluorobiphenyl, 10 wt% Pt / C (platinum-supporting carbon catalyst, specific surface area of carbon particles by the BET method of 1050 m 2 / g, the median diameter : 24 μm, amount of platinum supported per 1 g of carbon particles: 0.57 mmol in terms of platinum element, 14.6 mg (trade name: 10% Pt - C (W) K type manufactured by NEC Chemcat Corporation) 7.5 μmol as platinum element) and 2.0 ml of isopropanol were charged into a test tube, and the atmosphere was replaced with argon. The temperature was increased to 100 ° C., and the reaction was carried out by stirring for 12 hours. Thereafter, the obtained reaction solution was filtered using a membrane filter (manufactured by Millipore, Millex-LH, pore diameter 0.45 μm), and the membrane filter was washed with 15 ml of ether. The obtained filtrate was concentrated, and the obtained concentrate was subjected to 1 H-NMR. From the obtained spectrum, the recovery rate of 4-fluorobiphenyl as a raw material and the yield of biphenyl and cyclohexylbenzene obtained as a product were calculated. In the present specification, the recovery rate of the raw material refers to the molar ratio of the raw material remaining unreacted after the reaction to the raw material used in the reaction, and the yield of the product is the raw material used in the reaction Of the product. Reaction / post-treatment was carried out in the same manner as in Experiment 1-1 except that 36.5 mg (0.25 mmol) of 1-fluoronaphthalene was used instead of 4-fluorobiphenyl in Experiment 1-1, and 1 H-NMR Spectrum was obtained. From the obtained spectrum, when the recovery rate of 1-fluoronaphthalene as a raw material and the yield of naphthalene obtained as a product were calculated, all the raw materials were converted, and the yield of naphthalene was 99% . |
96% | With C32H46N2Ru; sodium carbonate; isopropyl alcohol at 70℃; for 96h; Inert atmosphere; Schlenk technique; Glovebox; | |
88% | With s-butylmagnesium chloride In tetrahydrofuran at 50℃; for 12h; |
88% | With 10 % platinum on carbon; sodium carbonate In water; isopropyl alcohol at 100℃; for 3h; Inert atmosphere; | |
85% | With s-butylmagnesium chloride In tetrahydrofuran at 50℃; for 24h; | |
84% | With isopropylmagnesium bromide In tetrahydrofuran at 50℃; for 24h; | |
80% | With s-butylmagnesium chloride In tetrahydrofuran at 50℃; for 48h; | |
76% | With zirconocene dichloride; [{((2,6-dimethylphenyl)NC(methyl))2CH}AlH2] In (2)H8-toluene at 110℃; for 96h; Inert atmosphere; | |
75% | With s-butylmagnesium chloride In tetrahydrofuran at 50℃; for 24h; | |
74% | With s-butylmagnesium chloride In tetrahydrofuran at 50℃; for 24h; | |
67% | With vinyl magnesium bromide In tetrahydrofuran at 50℃; for 48h; | |
57% | With s-butylmagnesium chloride In tetrahydrofuran at 50℃; for 24h; | |
57% | With s-butylmagnesium chloride In tetrahydrofuran at 50℃; for 48h; | |
56% | With potassium <i>tert</i>-butylate; N,N-dimethyl-formamide In dimethyl sulfoxide at 35℃; for 48h; Schlenk technique; Inert atmosphere; Irradiation; | |
46% | With tert-butylmagnesium chloride In tetrahydrofuran at 50℃; for 24h; | |
40% | With ethylmagnesium bromide In tetrahydrofuran at 50℃; for 24h; | |
37% | With 1,4-dioxane; 1,10-Phenanthroline; sodium hydride In mineral oil at 160℃; for 22h; Schlenk technique; Inert atmosphere; | |
28% | With s-butylmagnesium chloride In tetrahydrofuran at 50℃; for 24h; | |
6% | With s-butylmagnesium chloride In tetrahydrofuran at 50℃; for 24h; | |
3% | With s-butylmagnesium chloride In tetrahydrofuran at 50℃; for 48h; | |
With lithium aluminium tetrahydride; cerium(III) chloride In 1,2-dimethoxyethane for 3h; Heating; reduction withont CeCl3, with LiAlD4; | ||
92 % Spectr. | With 2-pentanol; sodium hydride In 1,4-dioxane at 100℃; for 3h; | |
With methylmagnesium bromide In tetrahydrofuran at 50℃; for 24h; | ||
With phenylmagnesium bromide In tetrahydrofuran at 50℃; for 24h; | ||
With benzylmagnesium chloride In tetrahydrofuran at 50℃; for 24h; | ||
78 %Spectr. | With 1-propylmagnesium chloride In tetrahydrofuran at -78 - 50℃; for 24h; | |
76.9 %Chromat. | With sodium tetrahydroborate In ISOPROPYLAMIDE at 70℃; for 25h; | |
With platinum-loaded on titanium(IV) oxide In water; isopropyl alcohol at 19.84℃; for 3h; Sealed tube; Inert atmosphere; UV-irradiation; High pressure; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium tert-butylate; In dimethyl sulfoxide; at 60℃; for 8h; | Example 4Synthesis of (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine (Duloxetine) (S)-(-)-3-methylamino-1-(2-thienyl)-propan-1-ol (20.0 g) and 1-fluoronaphthalene (68.3 g) were charged into a 4-neck round bottomed flask. Potassium tert-butoxide (13.1 g) and DMSO (36.0 g) were then added, and the resulting mixture was heated to 60 C. for 8 hours. After completion of the reaction, the reaction mixture was cooled down and washed with water. Layers were separated, and the organic layer was further extracted with 32% HCl(aq) (14.7 g) to separate Duloxetine from 1-floronaphthalene. The acidic aqueous layer was adjusted to pH 12-13 with 45% NaOH(aq) (17.6 g) to obtain Duloxetine in a free base form as an oily liquid (31.3 g, 90%). Optical purity of the resulting Duloxetine measured by chiral HPLC was 95% e.e.1H NMR (400 MHz, CDCl3) delta (ppm)=2.2 (m, 1H), 2.4 (m, 1H), 2.4 (s, 3H), 2.8 (m, 2H), 5.8 (m, 1H), 6.8 (d, 1H), 6.9 (m, 1H), 7.1 (d, 1H), 7.2 (d, 1H), 7.3 (d, 1H), 7.4 (m, 1H), 7.5 (m, 2H), 7.8 (m, 1H), 8.3 (m, 1H). |
90% | With potassium tert-butylate; In dimethyl sulfoxide; at 60℃; for 8h; | Example 4 Synthesis of (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine (Duloxetine) (S)-(-)-3-methylamino-1-(2-thienyl)-propan-1-ol (20.0 g) and 1-fluoronaphthalene (68.3 g) were charged into a 4-neck round bottomed flask. Potassium tert-butoxide (13.1 g) and DMSO (36.0 g) were then added, and the resulting mixture was heated to 60C for 8 hours. After completion of the reaction, the reaction mixture was cooled down and washed with water. Layers were separated, and the organic layer was further extracted with 32% HCI(aq) (14.7 g) to separate Duloxetine from 1-floronaphthalene. The acidic aqueous layer was adjusted to pH 12-13 with 45% NaOH(aq) (17.6g) to obtain Duloxetine in a free base form as an oily liquid (31.3 g, 90%). Optical purity of the resulting Duloxetine measured by chiral HPLC was 95% e.e. 1H NMR (400 MHz, CDCI3) delta (ppm) = 2.2 (m, 1H), 2.4 (m, 1H), 2.4 (s, 3H), 2.8 (m, 2H), 5.8 (m, 1H), 6.8 (d, 1H), 6.9 (m, 1H), 7.1 (d, 1H), 7.2 (d, 1H), 7.3 (d, 1H), 7.4 (m, 1H), 7.5 (m, 2H), 7.8 (m, 1H), 8.3 (m, 1H). |
78% | With sodium hydride; In dimethyl sulfoxide; mineral oil; for 8h; | To a solution of (S)-5(171 mg, 1 mmol) in DMSO (5 mL), were added NaH (36mg 1.5 mmol) and 1-fluoronaphthalene (190 mg, 1.3 mmol).After stirring for 8 h, the reaction mixture was partitionedwith ethyl acetate and water. After an extractive workup, thecombined organic layers were dried over sodium sulfate andthen concentrated in vacuo. The residue was purified byflash chromatography (CH2Cl2/MeOH/NH4OH = 40:10:1)to yield 1 (232 mg, 78%) as a colorless oil. = +110.5(c 1.1, MeOH); 1H NMR (300 MHz, CDCl3) delta 8.37-8.33 (m,1H), 7.79-7.74 (m, 1H), 7.50-7.44 (m, 2H), 7.39-7.37 (m,1H), 7.28-7.18 (m, 2H), 7.05-7.04 (m, 1H), 6.93-6.90 (m,1H), 6.86-6.84 (m, 1H), 5.78 (dd, 1H, J = 7.6, 5.3 Hz ), 2.86-2.78 (m, 2H), 2.50-2.39 (m, 4H), 2.27-2.16 (m, 1H); 13CNMR (75 MHz, CDCl3) delta 153.3, 145.2, 134.5, 127.4, 126.5,126.2, 126.1, 125.7, 125.2, 124.6, 124.5, 122.1, 120.5, 106.9,74.7, 48.3, 39.0, 36.5; MS (EI) m/z (%) 297 (M+, 4), 187(80), 153 (69), 144 (100); HPLC analysis: (Chiralcel OD-H,hexane/IPA = 85/15, 0.5 mL/min; t1 = 18 min (S), t2 = 25min (R); ee = 96%. |
78% | (S) -3-methylamino-1- (2-thienyl) -1-propanol obtained in Example 5(600 mg, 3.5 mmol) were placed in a round bottom flask and 15 mL of dimethylsulfoxide (DMSO) was added to dissolve.Sodium hydride (806 mg, 21 mmol) was added to the solution and stirred for 30 minutes. 1-Fluoronaphthalene (0.9 mL, 7.01 mmol) was added and reacted. The reaction was allowed to proceed for about 24 hours until the (S) -3-methylamino-1- (2-thienyl) -1-propanol spot disappears while confirming by TLC.Distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed with distilled water and brine.The resulting organic layer was dried over Na2SO4, filtered, and the solvent was evaporated to remove (S) -duloxetine (yield 78%) by flash silica column chromatography (dichloromethane: methanol: ammonium hydroxide = 100: | |
69% | To (S)-3-methylamino-1-(2-thienyl)propan-1-ol (compound 4) (171 mg, 1.0 mmole, ee>99%) in dry DMSO (2 ml) was added at room temperature and under stirring NaH (60% suspension in a mineral oil, 44 mg, 1.1 mmole) in two portions. After 30 min, 1- fluoronaphthalene (195 mul, 1.5 mmole) was added, and the mixture heated to 5O0C and stirred at this temperature for 8 h. The cooled reaction mixture was poured onto ice-cold H2O (80 ml), the pH of the solution was adjusted to 3 and the aqueous phase was washed with hexane (2x10 ml). The pH of the aqueous solution was adjusted to pH 11 with IM NaOH and the product was extracted with diethylether (3x20 ml). The combined ether phases were washed with water (4x10 ml) and with a saturated aqueous NaCl (10 ml), and dried (Na2SO4). After concentration, duloxetine as a light yellow oil (205 mg, 69%) was obtained. | |
65% | The 8 · 56g (S) -N-methyl-3-hydroxy-3- (2-thienyl) propanamine was dissolved in 2p 50mLN, N-dimethyl acetamide, was slowly added under ice-cooling 2. 40g sodium hydride,addition was complete, the reaction was heated 50 C for 2 hours. Followed byaddition of 14. 60g of 1-fluoro-naphthalene, and reacted at 80 C for 4 hours,cooled after heating is completed. Toluene was added to dilute the reactionsolution, water was extracted with toluene, the combined organic phase wasdried and concentrated to give an oily liquid. Column chromatography to obtainthe oily liquid 9. 65g, Duloxetine product yield of 65%. | |
With potassium hydroxide; In dimethyl sulfoxide; toluene; at 60 - 85℃; for 8 - 12h;Product distribution / selectivity; | Procedure A; Charge Radleys Carousel Reaction Station tubes with 0.342 g (2 mmol) of Compound Ia, 0.264 mL (2.4 mmol, 1.2 equiv) 1-fluoronaphthalene and 0.48 g (8 mmol, 4 equiv, corrected for ca. 90% potency) powdered KOH. The solvent composition is adjusted by a) adding toluene (3 mL) in several tubes followed by variable amounts of DMSO, ranging from 0.2 mL (toluene/DMSO=15:1 v/v) to 1 mL (toluene/DMSO=3:1 v/v) and b) in one tube, adding DMSO alone (3 mL). Fit the tubes in the Carousel Reaction Station under nitrogen and heat to 60 C. (internal T) with magnetic stirring for 8 h. Monitor Compound Ia conversion by TLC and the % R enantiomer by chiral HPLC under the following conditions: column: Daicel, Chiralcel OD-H, 5 microns, 4.6×250 mm internal diameter, 40 C.; solvent: 83% hexane+0.1% diethylamine (DEA)-17% isopropanol+0.1% DEA, 1 mL/min; detection UV 220 nm. EXAMPLE 2 Arylation of (S)-3-Methylamino-1-(2-thienyl)-1-propanol Combine Compound Ia (10.0 g, 58.5 mmol), potassium hydroxide (14.7 g, 235 mmol), and 1-fluoronaphthalene (10.8 g, 74.0 mmol) in toluene (100 ml) and DMSO (10 ml). Heat to about 85 C. with agitation. After 12 hours, cool the resulting mixture to ambient temperature and carefully add water (100 ml). Separate the layers and wash the organic extract with additional water (50 ml). Separate the layers again and concentrate the remaining organic extract to provide a residue (19.0 g) of crude duloxetine free amine. % DeltaR: 1.0. Monitor the % R enantiomer by chiral HPLC under the following conditions: Column; Diacel Chiralcel OD-H, 5 micron silica, 4.6×250 mm internal diameter, 40 C.; Solvent: 83% hexane+0.1% DEA-17% isopropanol+0.1% DEA, 1 mL/min; detection UV 230 nm. EXAMPLE 3; Arylation of (S)-3-Methylamino-1-(2-thienyl)-1-propanol Charge a 250 ml reactor with Compound Ia (8.56 g, 0.05 mol), potassium hydroxide (12.5 g, 0.06 mol), toluene (100 m) 1,1-fluoronaphthalene (8.77 g, 0.06 mol) and DMSO (10 ml). Heat the resulting suspension to 85 C. over 30 minutes. After 8 h, cool the suspension is cooled to ambient temperature and add water (100 ml). Separate the layers and extract the aqueous layer is extracted with toluene (50 ml). Wash the combined organic layers with 15% aq. NaCl (50 ml) and concentrate. % DeltaR: 2.2. Monitor the % R enantiomer by chiral HPLC under the following conditions: Column; Diacel Chiralcel OD-H, 5 micron silica, 4.6×250 mm internal diameter, 40 C.; Solvent: 83% hexane+0.1% DEA-17% isopropanol+0.1% DEA, 1 mL/min; detection UV 220 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | A solution OF A, A-DICHLOROMETHYL methyl ether (5.9 mL, 65 mmol) in CH2C12 (30 mL) was cooled in an ice bath and then treated dropwise over 15 min with SNCL4 (7.6 mL, 65 mmol). After stirring for 45 min, a solution of 1-FLUORONAPHTHALENE (5.5 mL, 50 mmol) in CH2C12 (30 mL) was added. The mixture was allowed to slowly warm to room temperature while stirring overnight. The mixture was poured in ice water (100 mL) and diluted with CH2C12 (50 mL). The layers were separated. The organic layer was diluted with CH2C12 (100 mL), washed with H20 (3 x 50 mL), dried over NA2S04, filtered, and the solvent was removed in vacuo to give the title compound (7.62 g, 87%) as a pale yellow solid: MS (ESI) mle 175 (M + H) +. | |
55% | To a 250 mL flask was added dichloromethane (30 mL) and dichloromethyl methyl ether (0.81 mL, 8.89 mmol, 1.3equivalent).The clear solution was cooled to -5 & lt; 0 & gt;Tin (IV) chloride (1.04 ml, 8.89 mmol, 1.3 eq.) Was then slowly addedGt; C), keeping the temperature below 0 & lt; 0 & gt; C. The solution was stirred at 0 & lt; 0 & gt; C for 30 minutes and then 1-fluoronaphthalene in dichloromethane (10 ml) was added(1.0 g, 6.84 mmol). The reaction mixture was allowed to equilibrate to room temperature. After about 18 hours, the dark green was mixedThe mixture was poured into ice water (40 mL) and transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with dichloromethane(3 x 20 mL). The combined organic layers were washed with water (150 mL) and saturated sodium chloride (150 mL). WillThe organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a beige solid. By Biotage color(Gradient elution: 5% to 50% dichloromethane / hexane) to give 0.60 g (55%) of 8 asAn off-white solid | |
With tin(ll) chloride; In dichloromethane; at 5 - 20℃; for 5h; | a) 4-Fluoro-naphthalene-1 -carbaldehyde19.9 g Dichloromethyl methyl ether and 45.7 g tin chloride were dissolved in 70 ml dichloromethane. The solution was cooled to +5 0C and 20.0 g fluoronapthalene in dichloromethane (49 ml) was added over a 60 min period, while keeping the temperature at 5 0C. The reaction was brought to room temperature after the addition. After 4 h the reaction was quenched by slowly pouring it into an ice/water mixture. This mixture was stirred for 15 min and left standing overnight. The dichloromethane layer was washed with water, dried (sodium sulphate), filtered through celite and concentrated in vacuo to obtain 24.0 g of 4-fluoro-naphthalene-1 -carbaldehyde as an off white solid. |
With tin(ll) chloride; In dichloromethane; at 5 - 20℃; for 5h; | 4-Fluoro-1 -hydroxynaphthalene-2-carboxylic acida) 4-Fluoro-naphthalene-1-carbaldehyde19.9 g Dichloromethyl methyl ether and 45.7 g tin chloride were dissolved in 70 ml dichloromethane. The solution was cooled to +5 0C and 20.0 g fluoronapthalene in dichloromethane (49 ml) was added over a 60 min period, while keeping the temperature at 5 0C. The reaction was brought to room temperature after the addition. After 4 h the reaction was quenched by slowly pouring it into an ice/water mixture. This mixture was stirred for 15 min and left standing overnight. The dichloromethane layer was washed with water, dried (sodium sulfate), filtered through celite and concentrated in vacuo to obtain 24.0 g of 4-fluoro-naphthalene-1-carbaldehyde as an off white solid. | |
Step B; (13 mi, 1M solution In dichiorcmethane) is added to a solution of djchtormethyi-?iethyiethbetar in dichioromethane (6 m.) at O0C. After 1 hour at 00C, a solution of 1-fiuoro-naphtatene (1.46 g) in dtohioromethane (4 ml) is added over 10 minutes. The reaction is stirred overnight at room temperature and then quenched with c°ict water (30 ml). The organic phase is separated an the aqueous phase is extracted 3 times with dichior°mbetathane. The combined organic phases are dried over Na3SO4 an concentrated in vacuo to yield 44luoro-naphihatene~1-carbaidehyde (1.73 Q1 dark brown crystals). The crude product obtained is used without further purification. MS (HPLC/MS): no ionisatio?. Retention time: 3.88 min. |
Yield | Reaction Conditions | Operation in experiment |
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76% | Stage #1: 1-Fluoronaphthalene With sec.-butyllithium In tetrahydrofuran; cyclohexane at -78℃; for 2h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; cyclohexane at -78℃; for 0.0833333h; | 1-fluoro-2-naphthaldehyde (17) To a solution of 1-fluoronaphthalene (580 mg, 4 mmol, 1 equiv) in dry THF (8 mL) at -78 °C wasadded a solution of sec-butyllithium (4 mmol, 1 equiv) in cyclohexane. The reaction mixture wasstirred at -78 °C for 2 hr after which dry DMF (580 mg, 8 mmol, 2 equiv) was added to the reaction mixture at -78 °C. After stirring for another 5 min at -78 °C, the reaction was diluted with diethylether and quenched with water. The mixture was partitioned, and the aqueous phase was extracted with diethyl ether. The combined organic phase was dried over anhyd. Na2SO4 and filtered. Removal of the solvent in vacuo gave the crude product which was purified by silica gel columnchromatography (petroleum ether/ethyl acetate 19:1) to afford 17 as a yellow solid (530 mg, 76%): Spectral data is consistent with reported values.6 1H NMR (400 MHz, CDCl3): δ = 10.58 (d, J = 0.8 Hz,1H), 8.23 (dd, J = 8.3, 0.6 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.83 (dd, J = 8.6, 6.7 Hz, 1H), 7.70 - 7.60 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): δ = 187.2 (d, J = 8.7 Hz), 163.2 (d, J = 267.7 Hz), 138.1 (d, J =6.1 Hz), 130.2, 128.0 (d, J = 2.9 Hz), 127.4 (d, J = 2.0 Hz), 124.4 (d, J = 4.2 Hz), 123.3 (d, J = 15.4 Hz),122.1 (d, J = 6.4 Hz), 122.0 (d, J = 2.3 Hz), 119.0 ppm (d, J = 5.8 Hz). |
75% | Stage #1: 1-Fluoronaphthalene With n-butyllithium In tetrahydrofuran at -78℃; for 2h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -78℃; for 0.0833333h; | |
66% | Stage #1: 1-Fluoronaphthalene With sec.-butyllithium In tetrahydrofuran; hexane at -75℃; for 2h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane |
47% | Stage #1: 1-Fluoronaphthalene With sec.-butyllithium In tetrahydrofuran; cyclohexane at -70 - -50℃; for 2.33333h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; cyclohexane at -70 - 0℃; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With palladium diacetate; DavePhos In 1,2-dimethoxyethane at 80℃; for 12h; | |
94% | Stage #1: 1-Fluoronaphthalene With 1,3-bis(2,6-diisopropylphenyl)-1,3,2-diazaphospholidine-2-oxide; nickel(II) acetylacetonate In tetrahydrofuran at 20℃; for 0.0833333h; Stage #2: 4-methoxyphenyl magnesium bromide In tetrahydrofuran at 20℃; for 15h; | |
88% | With nickel(II) chloride hexahydrate; C32H39N2OP In tetrahydrofuran at 25℃; for 20h; Inert atmosphere; |
88% | Stage #1: 1-Fluoronaphthalene With Ni(PPh<SUB>3</SUB>)(1,3-di-tert-butylimidazol-2-ylidene)Br<SUB>2</SUB> In tetrahydrofuran at 0℃; for 0.0333333h; Inert atmosphere; Schlenk technique; Stage #2: 4-methoxyphenyl magnesium bromide In tetrahydrofuran at 0 - 25℃; for 10h; Inert atmosphere; Schlenk technique; | |
12% | With C35H31BrN4NiP In tetrahydrofuran at 25℃; for 4h; Schlenk technique; Inert atmosphere; | |
Stage #1: 4-methoxyphenyl magnesium bromide With titanium(IV) tetraethanolate In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: 1-Fluoronaphthalene With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; cobalt(II) chloride In tetrahydrofuran at 50℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodium bicarbonate | R.11 Reference Example 11 Reference Example 11 To a mixture of 1-fluoronaphthalene (20.0 g) and adipic acid monoethyl ester chloride (27.5 g) was added gradually aluminum chloride (38.5 g) with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water (500 ml) and extracted with diethyl ether (200 ml*2). The organic layer was washed with a 10% aqueous solution of sodium hydrogen carbonate (200 ml), dried over anhydrous magnesium sulfate, and concentrated to give ethyl 6-(4-fluoro-1-naphthyl)-6-oxohexanoate as an oil (27.7 g, 67%). NMR(CDCl3) δ: 1.25(3H, t, J=7 Hz), 1.6-2.0 (4H, m), 2.37 (2H, t, J=7 Hz), 3.07 (2H, t, J=7 Hz), 4.13 (2H, q, J=7 Hz), 7.15 (1H, dd, J=8/10 Hz), 7.55-7.65 (2H, m), 7.89 (1H, dd, J=5/8 Hz), 8.1-8.2 (2H, m), 8.5-8.6 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphoric acid; In hexane; water; dimethyl sulfoxide; mineral oil; | EXAMPLE 1 (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, phosphoric acid salt A 13.5 g portion of (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine was dissolved in 80 ml of dimethylsulfoxide at 25° C. To the solution was slowly added 3 g of sodium hydride as a 60percent dispersion in mineral oil, with vigorous stirring. After 15 minutes of stirring, 1.17 g of potassium benzoate was added and stirring was continued at approximately constant temperature for another 15 minutes. Then, 12.8 g of 1-fluoronaphthalene was slowly added to the reaction mixture, and after the addition was complete, the mixture was heated and was stirred for 2.5 hours at 60°-65° C. The mixture was then poured slowly into 190 ml of cold water and the DH was adjusted to 4.8 by addition of acetic acid. The temperature of the mixture was brought to 25° C., and 75 ml of hexane was added and stirring was continued for 10 minutes. The layers were then separated and the aqueous phase was stirred again with 75 ml of hexane and the phases separated. The pH of the aqueous phase was adjusted to 10.2 by addition of aqueous sodium hydroxide, and 75 ml of ethyl acetate was added. That mixture was stirred for 15 minutes at 25° C., and the 2-phase mixture was vacuum filtered through a pad of filter aid. The phases of the filtrate were allowed to separate, and the aqueous phase was extracted with 75 ml of ethyl acetate. The extract was combined with the previous ethyl acetate layer, and that mixture was washed with 100 ml of water. The organic layer was stirred at 25° C., and to it was added, dropwise, 7 g of 85percent phosphoric acid. After the addition was complete, the mixture was stirred for 20 minutes more and was then cooled to 0° C. and stirred for 1 hour at that temperature. The slurry was then filtered and the solids washed three times with 20 ml portions of cold ethyl acetate. The solid was dried at 60° C. to afford 24.19 g of the title compound as a white solid, 98.1percent potency, adjusted yield 79.6percent, 91percent EE. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 3-(N,N-dimethylamino)-1-(thien-2-yl)propan-1-ol; 1-Fluoronaphthalene With potassium hydroxide In dimethyl sulfoxide at 100℃; for 2h; Stage #2: D-tartaric acid In water Heating / reflux; | 1 Example 1 : (jR5)-N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine-D-tartrate.; A mixture of N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine (370 g), potassium hydroxide (336 g) and 1-fluoronaphthalene (284 ml) in dimethylsulfoxide (2 1) is stirred at 100 0C for 2 hours. The mixture is then cooled down to lab temperature, diluted with water (4 1) and toluene (2 1). The organic phase is separated, shaken with water and evaporated. A hot solution of D-tartaric acid (252 g) in water (3 1) is added to the evaporation residue under stirring. After cooling down, the precipitated product is sucked off, washed with water and dried. The yield is 687 g (75 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In 1,2-dimethoxyethane; at 60℃; for 8h;Product distribution / selectivity; | Procedure A; Charge Radleys Carousel Reaction Station.(TM). tubes with 0.342 g (2 mmol) of Compound Ia, 0.264 mL (2.4 mmol, 1.2 equiv) 1-fluoronaphthalene and 0.48 g (8 mmol, 4 equiv, corrected for ca. 90percent potency) powdered KOH. The solvent composition is adjusted by a) adding toluene (3 mL) in several tubes followed by variable amounts of DMSO, ranging from 0.2 mL (toluene/DMSO=15:1 v/v) to 1 mL (toluene/DMSO=3:1 v/v) and b) in one tube, adding DMSO alone (3 mL). Fit the tubes in the Carousel Reaction Station.(TM). under nitrogen and heat to 60° C. (internal T°) with magnetic stirring for 8 h. Monitor Compound Ia conversion by TLC and the percent R enantiomer by chiral HPLC under the following conditions: column: Daicel, Chiralcel.(R). OD-H, 5 microns, 4.6.x.250 mm internal diameter, 40° C.; solvent: 83percent hexane+0.1percent diethylamine (DEA)-17percent isopropanol+0.1percent DEA, 1 mL/min; detection UV 220 nm. | |
With potassium hydroxide; In Tetraethylene glycol dimethyl ether; at 60℃; for 8h;Product distribution / selectivity; | Procedure A; Charge Radleys Carousel Reaction Station.(TM). tubes with 0.342 g (2 mmol) of Compound Ia, 0.264 mL (2.4 mmol, 1.2 equiv) 1-fluoronaphthalene and 0.48 g (8 mmol, 4 equiv, corrected for ca. 90percent potency) powdered KOH. The solvent composition is adjusted by a) adding toluene (3 mL) in several tubes followed by variable amounts of DMSO, ranging from 0.2 mL (toluene/DMSO=15:1 v/v) to 1 mL (toluene/DMSO=3:1 v/v) and b) in one tube, adding DMSO alone (3 mL). Fit the tubes in the Carousel Reaction Station.(TM). under nitrogen and heat to 60° C. (internal T°) with magnetic stirring for 8 h. Monitor Compound Ia conversion by TLC and the percent R enantiomer by chiral HPLC under the following conditions: column: Daicel, Chiralcel.(R). OD-H, 5 microns, 4.6.x.250 mm internal diameter, 40° C.; solvent: 83percent hexane+0.1percent diethylamine (DEA)-17percent isopropanol+0.1percent DEA, 1 mL/min; detection UV 220 nm. | |
With potassium hydroxide; In diethylene glycol dimethyl ether; at 60℃; for 8h;Product distribution / selectivity; | Procedure A; Charge Radleys Carousel Reaction Station.(TM). tubes with 0.342 g (2 mmol) of Compound Ia, 0.264 mL (2.4 mmol, 1.2 equiv) 1-fluoronaphthalene and 0.48 g (8 mmol, 4 equiv, corrected for ca. 90percent potency) powdered KOH. The solvent composition is adjusted by a) adding toluene (3 mL) in several tubes followed by variable amounts of DMSO, ranging from 0.2 mL (toluene/DMSO=15:1 v/v) to 1 mL (toluene/DMSO=3:1 v/v) and b) in one tube, adding DMSO alone (3 mL). Fit the tubes in the Carousel Reaction Station.(TM). under nitrogen and heat to 60° C. (internal T°) with magnetic stirring for 8 h. Monitor Compound Ia conversion by TLC and the percent R enantiomer by chiral HPLC under the following conditions: column: Daicel, Chiralcel.(R). OD-H, 5 microns, 4.6.x.250 mm internal diameter, 40° C.; solvent: 83percent hexane+0.1percent diethylamine (DEA)-17percent isopropanol+0.1percent DEA, 1 mL/min; detection UV 220 nm. |
With potassium hydroxide; In Triethylene glycol dimethyl ether; at 60℃; for 8h;Product distribution / selectivity; | Procedure A; Charge Radleys Carousel Reaction Station.(TM). tubes with 0.342 g (2 mmol) of Compound Ia, 0.264 mL (2.4 mmol, 1.2 equiv) 1-fluoronaphthalene and 0.48 g (8 mmol, 4 equiv, corrected for ca. 90percent potency) powdered KOH. The solvent composition is adjusted by a) adding toluene (3 mL) in several tubes followed by variable amounts of DMSO, ranging from 0.2 mL (toluene/DMSO=15:1 v/v) to 1 mL (toluene/DMSO=3:1 v/v) and b) in one tube, adding DMSO alone (3 mL). Fit the tubes in the Carousel Reaction Station.(TM). under nitrogen and heat to 60° C. (internal T°) with magnetic stirring for 8 h. Monitor Compound Ia conversion by TLC and the percent R enantiomer by chiral HPLC under the following conditions: column: Daicel, Chiralcel.(R). OD-H, 5 microns, 4.6.x.250 mm internal diameter, 40° C.; solvent: 83percent hexane+0.1percent diethylamine (DEA)-17percent isopropanol+0.1percent DEA, 1 mL/min; detection UV 220 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In dimethyl sulfoxide; at 60℃; for 8h;Product distribution / selectivity; | Procedure A; Charge Radleys Carousel Reaction Station.(TM). tubes with 0.342 g (2 mmol) of Compound Ia, 0.264 mL (2.4 mmol, 1.2 equiv) 1-fluoronaphthalene and 0.48 g (8 mmol, 4 equiv, corrected for ca. 90percent potency) powdered KOH. The solvent composition is adjusted by a) adding toluene (3 mL) in several tubes followed by variable amounts of DMSO, ranging from 0.2 mL (toluene/DMSO=15:1 v/v) to 1 mL (toluene/DMSO=3:1 v/v) and b) in one tube, adding DMSO alone (3 mL). Fit the tubes in the Carousel Reaction Station.(TM). under nitrogen and heat to 60° C. (internal T°) with magnetic stirring for 8 h. Monitor Compound Ia conversion by TLC and the percent R enantiomer by chiral HPLC under the following conditions: column: Daicel, Chiralcel.(R). OD-H, 5 microns, 4.6.x.250 mm internal diameter, 40° C.; solvent: 83percent hexane+0.1percent diethylamine (DEA)-17percent isopropanol+0.1percent DEA, 1 mL/min; detection UV 220 nm. |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 1; Arylation of (S)-(-)-N,N-dimethyl-3(2-thienyl)-3-hydroxypropanamine To a 25 mL 3-neck round bottom flask equipped with a condenser, N2 inlet, thermocouple, and overhead stirrer charge Compound Ib (0.55 g, 3 mMol), powdered KOH (0.9 g, 14.2 mMol), diglyme (6 mL) and 1-fluoronaphthalene (0.5 mL). Heat the mixture with good agitation to 120° C. for 3 to 6 hrs. Cool to ambient temp. and dilute with water (6 mL) and EtOAc (6 mL). Separate layers, back extract aqueous with EtOAc (6 mL). Separate layers and combine organic layers. Place organic layers in a 25 mL 3-neck round bottom flask with overhead agitation. Slowly add 85percent H3PO4 (0.25 mL). Seed after 10 drops have been added. Stir 5-15 minutes, complete acid addition and stir 1 hr. Filter and wash cake with EtOAc (10 mLs). Dry under reduced pressure to yield 1.0 g of the title compound. percent DeltaR:0.2. Monitor the percent R enantiomer by chiral HPLC under the following conditions: Column; Diacel Chiralcel.(R). OD-H, 5micron silica, 4.6.x.250 mm internal diameter, 40° C.; Solvent: 95percent hexane, 5percent isopropanol+0.2percent DEA, 1 mL/min; detection UV 280 nm. | ||
100 gm of (S) - (+)-N, N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine is dissolved in DMSO (500 ml) at room temperature. Sodium hydride (23 gm) is added over a period of 1 hour in three equal lots at room temperature and stirred for 1 hour. 10 gm of potassium 4-methyl benzoate as added and stirred for 15 minutes. The reaction mixture was heated to about 55 °C and then 4-fluoronapthalene (100 gm) was added slowly for 45 minutes. The reaction mixture was maintained for 4 hours at about 65 0C. After completion of the reaction, the reaction mass is quenched into ice cold water (600 ml) and pH was adjusted to about 4 with 140 ml of acetic acid. Reaction mixture was washed with pet ether (3 X 100 ml). Aqueous layer was separated and pH adjusted about 8.5 with caustic soda and extracted with ethyl acetate (2 X 200 ml; 1 X 150 ml). The organic layer was washed with saturated aqueous sodium chloride solution (3x200) and further dried with sodium chloride. The organic layer pH was adjusted to about 2 with phosphoric acid and maintain for 30 minutes. The precipitated phosphate salt was filtered and washed with ethyl acetate to obtain 230 gm of the title compound as wet solid. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium hydroxide; In dimethyl sulfoxide; at 60℃; for 8h;Product distribution / selectivity; | Procedure A; Charge Radleys Carousel Reaction Station tubes with 0.342 g (2 mmol) of Compound Ia, 0.264 mL (2.4 mmol, 1.2 equiv) 1-fluoronaphthalene and 0.48 g (8 mmol, 4 equiv, corrected for ca. 90% potency) powdered KOH. The solvent composition is adjusted by a) adding toluene (3 mL) in several tubes followed by variable amounts of DMSO, ranging from 0.2 mL (toluene/DMSO=15:1 v/v) to 1 mL (toluene/DMSO=3:1 v/v) and b) in one tube, adding DMSO alone (3 mL). Fit the tubes in the Carousel Reaction Station under nitrogen and heat to 60 C. (internal T) with magnetic stirring for 8 h. Monitor Compound Ia conversion by TLC and the % R enantiomer by chiral HPLC under the following conditions: column: Daicel, Chiralcel OD-H, 5 microns, 4.6×250 mm internal diameter, 40 C.; solvent: 83% hexane+0.1% diethylamine (DEA)-17% isopropanol+0.1% DEA, 1 mL/min; detection UV 220 nm. |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 11 Preparation of (S)-Duloxetine Oxalate from (S-7) 2.24 g of the compound (S-7) was dissolved in 28 mL of DMSO and 4 mL of THF under nitrogene atmosphere. 1.0 g of potassium hexanoate was dissolved in the mixture followed by addition of 1.8 g of 60% sodium hydride. Reaction mixture was stirred at ambient temperature for 1 h and 2.9 g of 1-fluoronaphthalene was added. The reaction mixture was heated at 60 C. for 6 hours. Then the reaction mixture was cooled, diluted with 100 mL of water, and five times extracted with 50 mL of toluene. Toluene extracts were combined and washed with 30 mL of brine. Toluene was removed in vacuo, residue dissolved in 40 mL of isopropanol and 2.52 g of oxalic acid was added. Precipitated solid was filtered off, washed with isopropanol and air dried to give 3.5 g of raw product. This product was dissolved in hot mixture of 50 mL of methanol and 1.7 mL of water. Crystals precipitated on cooling and were filtered off, washed with methanol and air dried to give 3.1 g of duloxetine oxalate with ee=91% (measured by HPLC). Structure of the product was confirmed by NMR. | ||
Example-5 Preparation of S-(+)-Duloxetine hydrochloride A mixture of sodium hydride (2.08 g, 60 %, 0.0578 mol) and DMA (27 ml) was stirred at 60 C. (1S)-(-)-3-(methylamino)-1-thien-2-ylpropan-1-ol (9.0 g in 9.0 ml DMA, 0.052 mol) was added and stirred for 30 mins. 1-Fluoro naphthalene (7.59 g of in 9.0 ml DMA, 0.052 mol) was added and the reaction mass was stirred at 75-80 C for 8-10 hrs. The reaction mixture was cooled to room temperature and poured into water (250 ml). The mixture was extracted with ethyl acetate (150 ml x 2) and extract was washed with water. The ethyl acetate layer was evaporated to dryness and the residue was dissolved in ethyl acetate (20 ml) and oxalic acid dihydrate (4.77 gm in 75 ml ethyl acetate) was added and the mixture was stirred at room temperature for 30 mins. The resulting suspension was filtered and washed with ethyl acetate to give duloxetine oxalate. Wt. of dry material: 12.5 g. The solid was converted to free base with sodium hydroxide solution and extracted with ethyl acetate. The extracts were washed with water and then evaporated to give Duloxetine base. Wt. of oil 6.0 g. The duloxetine base (6.0 g) was dissolved in ethyl acetate (48 ml). Ethyl acetate HCl/IPA:HCl solution (2-7 %) was added and stirred for 30 mins. The solid was filtered and washed with ethyl acetate (25 ml). The material was dried under vacuum to give Duloxetine HCl. Yield: - 6 g Chiral purity: >99.90 % |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 12 Preparation of (R)-Duloxetine Oxalate from (R-7) Under conditions of the Example 11, 1.1 g of (R)-Duloxetine oxalate was received from 1.4 g of (R-7) with ee=96% EXAMPLE 11; Preparation of (S)-Duloxetine Oxalate from (S-7); 2.24 g of the compound (S-7) was dissolved in 28 mL of DMSO and 4 mL of THF under nitrogene atmosphere. 1.0 g of potassium hexanoate was dissolved in the mixture followed by addition of 1.8 g of 60% sodium hydride. Reaction mixture was stirred at ambient temperature for 1 h and 2.9 g of 1-fluoronaphthalene was added. The reaction mixture was heated at 60 C. for 6 hours. Then the reaction mixture was cooled, diluted with 100 mL of water, and five times extracted with 50 mL of toluene. Toluene extracts were combined and washed with 30 mL of brine. Toluene was removed in vacuo, residue dissolved in 40 mL of isopropanol and 2.52 g of oxalic acid was added. Precipitated solid was filtered off, washed with isopropanol and air dried to give 3.5 g of raw product. This product was dissolved in hot mixture of 50 mL of methanol and 1.7 mL of water. Crystals precipitated on cooling and were filtered off, washed with methanol and air dried to give 3.1 g of duloxetine oxalate with ee=91% (measured by HPLC). Structure of the product was confirmed by NMR. |
Yield | Reaction Conditions | Operation in experiment |
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93.9% | In a 500 mL four-necked flask, 18.5 g of (1S)-3-(dimethylamino)-1-(thiophen-2-yl)propan-1-ol was added.(0.1 mol) and 100 mL of DMSO. After stirring and dissolution, 8 g of sodium hydride (60percent content) was added. After stirring for 10 minutes, it was heated to 60.°C, stirring for 1 hour; adding 17.5 g of 1-fluoronaphthalene (0.12 mol) at 60 °C, and keeping this temperature for 24 hours, reaction knotAfter the bundle is added 200mL of water and extracted twice with 100mL x 2 toluene, the toluene layer is combined and washed with 200mL x 2 water twicedimethyl[(3S)-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propyl]amine in toluene (purity 95.4percent, isomer content4.7percent, external standard content 29.2 g, yield 93.9percent). | |
92% | To a solution of (S)-3a (55.5 g, 300 mmol) dissolved in dry DMSO (120 mL) was carefully added sodium hydride (60percent in mineral oil, 14.4 g, 360 mmol) at ambient temperature in portions with stirring for 30 min. Potassium benzoate (9.6 g, 60 mmol) was combined with an additional stirring for 30 min. Then, 1-fluoronaphthalene (52.5 g, 360 mmol) was added dropwise and the reaction mixture was heated at 65 °C for 8 h. After complete reaction, the residual was slowly poured into the ice water (300 mL) followed by adding acetic acid to pH 4.8. The mixture was extracted with petroleum ether (3 * 300 mL). The residual aqueous phase was treated with 50percent sodium hydroxide to pH 11-12, and extracted by toluene (3 * 300 mL). The combined toluene phase was washed with 1percent sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated to afford product 4. Yield: 85.8 g, 92percent, amber oil. 1H NMR (500 MHz, DMSO-d6): delta = 8.26 (m, 1H), 7.84 (dt, J = 6.7, 2.9 Hz, 1H), 7.52 (m, 2H), 7.43 (dd, J = 8.4, 4.6 Hz, 2H), 7.34 (m, 1H), 7.22 (m, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.97 (td, J = 4.7, 2.9 Hz, 1H), 5.92 (d, J = 5.9 Hz, 1H), 2.38 (m, 2H), 2.33 (m, 1H), 2.13 (s, 6H), 2.09 (m, 1H). 13C NMR (126 MHz, DMSO-d6): delta = 152.74, 144.84, 134.11, 128.84, 128.13, 127.39, 126.57, 126.30, 125.91, 125.49, 125.27, 121.57, 120.18, 107.24, 73.68, 55.13, 45.19, 36.28. MS (ESI): m/z 312.2 [M+H]+. [alpha]25D = + 136.8° (c = 10 mg/mL, methanol). | |
90% | 0g (0.16mol) (S) -N , N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine at room temperature, dissolved in 150ml of dimethylsulfoxide was slowly added 60percent NaH (7.6g, 0.19 mol), the reaction was stirred for 0.5h, warmed to 40-50 deg.] C, was added dropwise 27.8 g of(0.19 mol) fluoro-l- naphthyl, dropwise, 45 ~ 50 reaction 8h, TLC the reaction was complete, the reaction was stopped, the reaction solution was Slowly poured into300 ml of ice water, adjusted to pH 4.5 with acetic acid. The aqueous phase was extracted three times with 100 ml of ethyl acetate. The organic phaseswerecombined and the organic phasewas washed twice with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. To give 45.4 g of a reddish brown oil in a yield of 90percent. |
65% | Example 7; (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanaminc (6) :lambda solution of (S)-(-)-3-(dimethylamino)-l-(2-thienyl)-l-propanol (175 g, 0.945 mole) in dimethyl sulphoxide (750 ml) was added lot wise to a mixture of 60percent sodium hydride (47.3 g, 1.18 mole) in dimethyl sulphoxide (475 ml) at 30-350C. This mixture was stirred for 30 min and the temperature was raised to 60-65° C followed by dropwise addition of 1 -fluoronaphthalene (152 g, 1.04 mole). Reaction mixture was stirred for 6-8 hrs. After cooling, methanol was added to quench the excess sodium hydride followed by addition of water (4.9 L) to the reaction mass and extraction with ethyl acetate. The combined organic extracts were washed with water and dried over sodium sulphate. The organic layer was concentrated under reduced pressure to get oil (298 g). 8 percent aqueous solution of acetic acid (1.49 L) was added to this oil and stirred for 30 min. Aqueous mixture was washed with methyl tert butyl ether (3x1.49 L). Aqueous layer was then basified with 5 percent aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulphate and concentrated under reduced pressure to get (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine as oil. Yield: 192 g (65percent).Example 8(S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanaminc (6) :To the solution of (S)-(-)-3-(dimethylamino)-l-(2-thienyl)-l-propanol (175 g, 0.945 mole) in dimethyl sulphoxide (1225 ml), 60percent sodium hydride (47.3 g, 1.18 mole) was added lot wise at 30-350C. This mixture was stirred for 30 minutes. The temperature was raised to 60-65° C and 1 -fluoronaphthalene (152 g, 1.04 mole) was added drop wise. Reaction mixture was stirred for 6-8 h. After cooling methanol was added to quench the excess <n="16"/>sodium hydride followed by addition of ethyl acetate (250 ml) and water (4.9 L) . Layers were separated and lower aqueous layer was extracted with ethyl acetate (2x250 ml). The combined organic extracts were washed with water. 8 percent aqueous solution of acetic acid (1.49 L) was added to this layer and stirred for 30 min. Aqueous layer was basified with 5 percent aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulphate and concentrated under reduced pressure to get (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine as oil. Yield: 19O g (65percent). Example 9(S)-(+)-N, N-dimethyI-3-(l-naphthalenyloxy)-3-(2-thienyl) propanaminc (7): To the solution of (S)-(-)-3-(dimethylamino)-l-(2-thienyl)-l-propanol (175 g, 0.945 mole) in dimethyl sulphoxide (1225 ml), 60percent sodium hydride (47.3 g, 1.18 mole) was added lot wise at 30-350C. This mixture was stirred for 30 minutes. Then raised temperature to 60-65° C and 1 -fluoronaphthalene (152 g, 1.04 mole) was added drop wise. Reaction mixture was stirred for 6-8 hrs. After cooling methanol is added to quench the excess sodium hydride then ethyl acetate (250 ml) followed by water (4.9 L) was added to the reaction mass. Layers were separated and lower aq. layer was extracted with ethyl acetate (2X250 ml). The combined organic extracts were washed with water. 8 percent aqueous solution of acetic acid (1.49 L) was added to this organic layer and stirred the mixture for 30 minutes. Separated aqueous layer was basified with 5 percent aqueous sodium hydroxide solution and extracted with toluene (3X175 ml). The organic layer was washed with water, dried over sodium sulphate. | |
To a 1 lt/4 neck round bottom flask fitted with a mechanical stirrer, reflux condenser and calcium chloride drying tube under an atmosphere of nitrogen gas were charged dimethyl sulphoxide (DMSO) (225 ml) and (S)-(-)-3-methylamino-l-(thio[phene-2-yl) propan-1-ol and the colorless solution cooled to 10-15omicronC. The solution when cooled sodium hydride (12.5 gm, 60percent dispersion) was added lot wise over a period of 60 minutes keeping the temperature at 10-20°C and the contents were stirred for 30 minutes at the same temperature. Slowly heat the reaction mixture to 60-65°C and charge drop wise 1-Fluoronaphthalene (50 gm). The solution was stirred at 60omicronC to 65omicronC and the progress of the reaction was monitored by TLC. After complete conversion, cooled the reaction mass followed by the reaction mixture was poured into mixture of 10 ml acetic acid in 1000 ml water. Allow the temperature raise to ambient temperature. 10omicronC to 20omicronC and stirred for 15 to 20 minutes. Adjust the pH of the reaction mixture to 12 using 30percent caustic solution. Extract the reaction mixture with toluene (3 X 150 ml). Combined organic layer washed with water (1 X 50 ml). Dry over anhydrous sodium sulphate. Use the organic layer as such for the next step. | ||
25 gm of (S) - (+)-N, N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine is dissolved in DMSO (125 ml) at room temperature. Sodium hydride (5.75 gm) is added over a period of 1 hour in three equal lots at room temperature and stirred for 1 hour. 2.5 gm of potassium 4-methyl benzoate was added and stirred for 15 minutes. The reaction mixture was heated to about 55 0C and then 1-fiuoronapthalene (25 gm) was added slowly for 45 minutes. The reaction mixture was maintained for 4 hours at about 65 0C. After completion of the reaction, the reaction mass is quenched into ice cold water (150 ml) and pH was adjusted to about 4 with 25 ml of acetic acid. Reaction mixture was washed with pet ether (3 X -25 ml). Aqueous layer was separated and pH adjusted about 8.5 with caustic soda and extracted with ethyl acetate (2 X 50 ml). The organic layer was washed with saturated aqueous sodium chloride solution (3X50 ml) and further dried with sodium chloride. The organic layer was distilled completely under vacuum to give 29 gm of title compound as residue. | ||
Example 1Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl) Propylamine Oxalic Acid Salt(S-3-Dimethylamino-1-(2-thienyl)-1-propanol (50 g, 0.270 moles) and sodium hydroxide (21.6 g, 0.540 moles, 2 eq.) were heated in DMSO (500 mL) at 60-80° C. for 1 hour. The temperature was controlled at 60° C.+/-4° C. before 1-fluoronaphthalene (43.6 g, 38.5 mL, 0.299 moles) was added. The mixture heated at this temperature for 64 hours. Water (500 mL) was added, and the mixture extracted with toluene (2.x.500 mL). The organic layers were then combined and washed with water (500 mL). HPLC analysis of an evaporated aliquot showed the molar ratio of Compound IV to Compound S-II to be 90:10 and Compound IV to be 88percent ee. Pyridine sulfur trioxide (6.4 g, 0.040 moles) was added to the mixture, the mixture was stirred for 30 minutes, and was then washed with water (500 mL). The organic layers were then concentrated by distillation until 600 mL of solvent was removed, and ethyl acetate (500 mL) was added. Oxalic acid dihydrate (27.2 g, 0.216 moles) was then added. The resulting suspension was stirred for 16 hours and filtered to yield the product as a white solid. The resulting product was slurried in additional ethyl acetate (200 mL), filtered and dried under vacuum to yield 63.3 g of the product as a white solid (0.158 moles, Yield: 59percent). The resulting product had a molar ratio of Product:(S)-3-dimethylamino-1-(2-thienyl)-1-propanol: 1-fluoronaphthalene of 99.53:0.46:0.02 and 88percent ee. | ||
Example 14Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-3dimethylamino-1-(2-thienyl)-1-propanol (50 g, 269.8 mmoles), sodium hydroxide (21.58 g, 539.7 mmoles), potassium carbonate (83.91 g, 607.2 mmoles) and 1-methyl-2-pyrrolidinone (500 mL) were charged in a reactor. The suspension was heated to 80° C. and 10 mL of solvent distilled under vacuum in 4 hours. The mixture then was allowed to cool to 40° C. under argon and 1-fluoronaphthalene (38 mL, 296.8 mmoles) was added. The mixture was stirred at 40° C. for 40 hours, and then at 60° C. for 24 hours. The mixture was allowed to cool to ambient temperature. Water (350 mL) and isopropyl acetate (150 mL) were added; the mixture was stirred and the layers were separated. The aqueous layer was extracted with isopropyl acetate (130 mL). The organic layers were combined and washed with water (250 mL). To this solution pyridine sulfur trioxide complex (4.3 g, 27.0 mmoles) was added and the mixture stirred at room temperature for 1 hour. The mixture was washed with water (300 mL). The aqueous pH was 6. To the organic layer was added oxalic acid dihydrate (27.2 g, 215.8 moles). The mixture was stirred for 20 hours at ambient temperature and then filtered. The filter cake was washed with isopropyl acetate (2.x.40 mL) and dried under vacuum at 50° C. to yield 57.39 g of the product as a-white solid (Yield: 53percent; HPLC (peak area at 220 nm) oxalic acid 2.69percent, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol 0.21percent, 1-naphthol 0.43percent, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 95.42percent; XRD analysis as shown in FIG. 6, Form B; IR as shown in FIG. 7, Form B; Titration 93.14percent). | ||
Example 6; Preparation of (S)-N-methyl-(3-(1-naphthyloxy)-3-thien-2-yl) Propylamine Hydrochloride (Duloxetine Hydrochloride)Sodium hydroxide (0.324 kg, 8.1 moles, 2 eq), potassium carbonate (126 kg, 9.1 moles, 2.25 eq.) and (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (750 g, 4.05 moles), were heated in DMSO (7.5 L) at 80° C. for 3 hours and cooled to 40° C. 1-fluoronaphthalene (770'gi.5.3 mol, 1.3 eq) was then added over 5 minutes. Next, the mixture was heated at 40° C. for 17 hour and then at 50-60° C. for 40 hours. The molar ratio of product (Compound IV) to staring alcohol (Compound S-II) was 85.3:14.7, and Compound IV was 92percent ee as determined by HPLC of an aliquot. The mixture was then cooled to 20° C. and quenched with water (5 L). The mixture was divided in two and each portion was extracted twice with isopropyl acetate (2.x.2 L). The four organic phases were combined, washed with water (5 L), and pyridine sulphur trioxide complex (110 g, 0.69 moles, 0.17 eq.) was added. The mixture was then stirred at 20° C. for 30 minutes, and washed with water (5 L). Oxalic acid dihydrate (0.38 kg, 3.0 moles, 0.75 eq.) was then added, and the mixture stirred at 15-20° C. for 16 hours. The mixture was then filtered and slurried in acetone (2.5 L) and isopropyl acetate (5 L) for one hour, and then filtered to yield 2.1 kg (wet product) of (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt as an off-white solid (Yield: 75percent; equivalent to 1.21 kg, (dry product)). The molar ratio of product (Compound IV) to starting alcohol (Compound S-II) was 98.7:1.3 as determined by HPLC. Compound IV oxalate salt was 92percent ee as determined by chiral HPLC.; Example 7Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine Oxalic Acid SaltSodium hydroxide (8.635 g, 216 mmol, 2 eq), potassium carbonate (33.565 g, 243 mmol, 2.25 eq.) and (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (20 g, 108 mmol), were heated in DMSO (200 mL) at 80° C. (temperature inside flask) under vacuum such that approximately 100 mL of DMSO were distilled in 1 hour. An additional 100 mL of DMSO were then added, and the mixture heated at 80° C. for a further 2 hours. Thereafter, the mixture was cooled to 40° C. and stirred under an atmosphere of nitrogen. 1-Fluoronaphthalene (17.35 g, 119 mmol, 1.1 eq) was then added, and the mixture maintained with stirring at 40° C. Samples were taken periodically and analysed by NMR. Once an approximately 92percent conversion had been achieved (24 hours), as determined by the ratio of Compounds IV and S-II in the 1H-NMR spectrum, the mixture was cooled to 25° C., quenched with water (150 mL) and extracted twice with isopropyl acetate (2.x.100 mL). The two organic phases were combined, washed with water (75 mL), and pyridine sulphur trioxide complex (1.72 g, 10.8 mmol, 0.1 eq.) was added. The mixture was then stirred at 20° C. for 60 minutes and washed with water (150 mL). The aqueous layer was analysed to be pH 6.8. Oxalic acid dihydrate (10.9 g, 86 mmol, 0.8 eq.) was then added, and the mixture stirred at 15-20° C. for 16 hours. The mixture was then filtered and homogenized to yield 41.83 g of (S)-N,N-dimethyl(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt as an off-white solid (Loss on drying: 6.94percent, Titration: 98.1percent, Karl Fischer: 0.06percent).Example 8Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine Oxalic Acid SaltSodium hydroxide (34.2 kg), potassium carbonate (133 kg) and (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (80 kg), were heated in DMSO (1328 kg) at 70-80° C. for one hour and then distilled under vacuum at this temperature such that approximately 445 kg of DMSO were distilled within 4 hours. After this time the mixture was cooled to 40-45° C. and stirred under an atmosphere of nitrogen. 1-Fluoronaphthalene (69 kg) was then added, and the mixture maintained with stirring at 40° C. Samples were taken periodically and analyzed by HPLC. Once approximately 92percent conversion had been achieved (24 hours), the mixture was cooled to 25° C., quenched with water (533 kg) and extracted twice with isopropyl acetate (2.x.460 kg). The two organic phases were combined, washed with water (400 kg), and added to pyridine sulphur trioxide complex (6.8 kg.). The mixture was then stirred at 20-25° C. for 30 minutes and then a solution made from ammonium chloride (32 kg) in water (533 kg) was added and the mixture stirred for 30 minutes. The aqueous layer was adjusted to pH 6.5-pH 7.0, the mixture stirred for an additional 30 minutes before the aqueous phases were separated. Oxalic acid dihydrate (44 kg) was dissolved in methanol (173 kg), and this solution was added over a period of 2 hours to the organic mixture above maintained at 40-45° C. The mixture was placed under vacuum at this temperature and 500 kg of solvent removed by distillation. Iso-propyl acetate (1000 kg) was added and a further 500 kg removed by distil... | ||
Example 5Preparation of (S)-N-methyl-(3-(1-naphthyloxy)-3-thien-2-yl) Propylamine Hydrochloride (Duloxetine Hydrochloride)Sodium tert-pentoxide (1.06 kg of a 40percent solution in toluene, 3.85 moles, 0.95 eq.) was added over 10 minutes to a suspension of (S)-3-dimethylamino-12-thienyl)-1-propanol (750 g, 4.05 moles) dissolved in DMSO (3 L) at a temperature of 13-15° C. The (S)-3-dimethylamino-1-(2-thienyl)-1-propanol was dissolved completely to form a brown solution. The mixture was then heated to 70° C. for one hour before 1-fluoronaphthalene (710 g, 4.86 moles) was added over 5 minutes. The mixture was then heated at 70° C. for 7 hours. The molar ratio of product (Compound IV) to starting alcohol (Compound S-II) was observed to be 91.6:8.4 as determined by HPLC of an aliquot. The mixture was next cooled to 20° C., quenched with water (5 L), and extracted twice with isopropyl acetate (4+3 L). The organic layers were then combined, washed with water (4 L), and pyridine sulphur trioxide complex (64 g, 0.4 moles, 0.1 eq.) was added. The mixture was stirred at 20° C. for 30 minutes, and washed with water (5 L). Oxalic acid dihydrate (0.41 kg, 3.2 moles, 0.8 eq.) was then added, and the mixture was stirred at 25° C. for 2.5 hours and then at 20° C. for 2 days. The mixture was next filtered and washed with isopropyl acetate (2.5 L) to yield (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt as an off-white solid (2.3 kg (wet product), equivalent to 1.3 kg (dry product) in 80percent yield). The molar ratio of product (Compound IV) to starting alcohol (Compound S-II) was 99.6:0.4 as determined by HPLC. | ||
Example 13Preparation of (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-3-dimethylamino-1-(2-thienyl)-1-propanol (20 g, 108 mmoles), potassium hydroxide (12.11 g, 216 mmoles) and DMSO (300 mL) were charged in a reactor. The suspension was heated to 75-80° C. and 100 mL of solvent distilled under vacuum in 1 hour. The mixture then was allowed to cool to 40° C. under nitrogen and 1-fluoronaphthalene (15.3 mL, 119 mmoles) was added. The mixture was stirred at 40° C. for 46 hours. The mixture was allowed to cool to ambient temperature. Water (300 mL) and isopropyl acetate (200 mL) were added; the mixture was stirred and the layers were separated. The aqueous layer was extracted with isopropyl acetate (100 mL). The organic layers were combined and washed with water (100 mL). To this solution pyridine sulfur trioxide complex (1.7 g, 11 mmoles) was added and the mixture stirred at room temperature for 1 hour. The mixture was washed with water (50 mL). The aqueous pH was 6.5. To the organic layer was added oxalic acid dihydrate (10.9 g, 86 mmoles). The mixture was stirred for 1 hour at ambient temperature and then filtered. The filter cake was washed with isopropyl acetate (25 mL) and dried under vacuum at 50° C. to yield 28.96 g of the product as a white solid (Yield: 67percent; Titration 89.68percent; HPLC (peak area at 220 nm) oxalic acid 2.09percent, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol 0.045percent, 1-naphthol 0.20percent, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 95.19percent; XRD analysis as shown in FIG. 4, Form C; IR as shown in FIG. 5, Form C). | ||
Stage-IV: Preparation of (3S)-N, N-dimethyl-3-(l-naphthyloxy)-3-(2-thienyl) propan-1-ammonium oxalateCharge DMSO (500 ml) to the flask. Charge S-(-)-3-(dimethylamino)-l-(2-thienyl) propan-1-ol (100 g) to the flask. Stir the reaction mass for 10 mins to get clear solution. Cool to 10-150C. Charge Sodium hydride (23.84 g) to the reaction mass at 10-150C. Stir the reaction mixture for 30 min at ambient temperature. Add Potassium Iodide (9.0 g) at 20-250C. Heat the reaction mixture to 65-75°C. Add a solution of 1-Fluoronaphthalene in DMSO (71.6 ml in 100 ml) to the reaction mixture. Stir the reaction mixture for 5 hrs. After the completion of the reaction, cool the reaction mixture to 20-250C. Add methanol (5 ml) at 20-250C under nitrogen. Add D M Water (6000 ml) to the reaction mixture. Add Ethyl acetate (500 ml) to the reaction mixture. Stir the reaction mixture for 15 mins. Separate the org. layer. Re-extract the org. layer with Ethyl acetate (500 ml). Combine both org. layer and wash with D M Water (300 ml). Remove Ethyl acetate (-500 ml) under vacuum at below 500C. Add Ethyl acetate (500 ml) to the residual mass. Add Oxalic acid dihydrate (71.5 g) to the reaction mass. Add Methanol (50 ml) to the reaction mass. Stir the reaction mixture for 1 hr. Cool the reaction mixture to 0-50C. Stir the reaction mixture for 2 hrs. at 0-50C. Filter the content. Wash the wet cake with Ethyl acetate (100 ml). Suck dry the wet cake. Dry the wet material in hot air oven at 50-600C. | ||
Example 2: <n="8"/>A 150 ml reactor three necked flask equipped with mechanical stirrer, thermometer, and condenser was charged with 1O g of AT-OL and 60 ml DMSO at 200C. The mixture was stirred until complete dissolution, and 4.20 g of NaOH were added and stirred for an additional time. After 15 minutes, 8 ml of 1-fluoronaphthalene were added, the solution was heated to 600C, and stirred for 5 days or till full consumption of AT-OL.To the reaction mixture was added water, followed by 5 ml AcOH and 60 ml ethyl acetate. After phase separation, the water phase was extracted with ethyl acetate and the organic extracts were combined, and concentrated to dryness to give 17.34 g of brownish oil containing 8.80 percent enantiomer R. | ||
Example 7:A 100 ml reactor three necked flask equipped with mechanical stirrer, thermometer, and condenser was charged with 1O g of AT-OL and 60 ml DMSO at room temperature under N2. The mixture was stirred until complete dissolution, and 7 g OfNa+MeO" were added and stirred for an additional time. After 15 minutes, 8 ml of 1 -fluoronaphthalene were added, the solution was heated to 6O0C, and stirred for 26 hours.To the reaction mixture was added water, followed by 10 ml HCl (5percent) and 60 ml ethyl acetate. After phase separation, the organic phase was washed with brine, and concentrated to dryness to give 19 g of brownish oil containing 5.87 percent enantiomer R.Example 8:A 100 ml reactor three necked flask equipped with mechanical stirrer, thermometer, and condenser was charged with 1O g of AT-OL and 60 ml DMSO at room temperature under N2. The mixture was stirred until complete dissolution, and 7 g OfNa+MeO" were added and stirred for an additional time. After 15 minutes, 8 ml of 1 -fluoronaphthalene were added, the solution was heated to 1100C, and stirred for 26 hours.To the reaction mixture was added water, followed by 10 ml HCl (5percent) and 60 ml ethyl acetate. After phase separation, the organic phase was washed with brine, dried on <n="10"/>MgSO4, and concentrated to dryness to give 13.37 g of brownish oil containing 9.53 percent enantiomer R. | ||
Example 5:A 250 ml two necked flask equipped with magnetic stirrer, and condenser was charged with 1O g of AT-OL and 60 ml DMF at room temperature under N2- The mixture was stirred until complete dissolution, and 7.11 g of KOH were added and stirred for an <n="9"/>additional time. After 15 minutes, S ml of 1 -fluoronaphthalene were added, the solution was heated to 600C, and stirred for 27 hours.To the reaction mixture was added water, followed by 10 ml HCl (5percent) and 60 ml ethyl acetate. After phase separation, the organic phase was washed with brine, and concentrated to dryness to give 16.16 g of brownish oil containing 1.49 percent enantiomer R. | ||
Example 4:A 250 ml two necked flask equipped with magnetic stirrer, and condenser was charged with 1O g of AT-OL and 60 ml ACN at room temperature under N2. The mixture was stirred until complete dissolution, and 7.11 g of KOH were added and stirred for an additional time. After 15 minutes, 8 ml of 1-fluoronaphthalene were added, the solution was heated to 6O0C, and stirred for 27 hours.To the reaction mixture was added water, followed by 10 ml HCl (5percent) and 60 ml ethyl acetate. After phase separation, the organic phase was washed with brine, and concentrated to dryness to give 22.2 g of brownish oil containing 0.53 percent enantiomer R. | ||
Example 3:A 100 ml reactor three necked flask equipped with mechanical stirrer, thermometer, and condenser was charged with 1O g of AT-OL and 60 ml DMSO at room temperature under N2. The mixture was stirred until complete dissolution, and 7.11 g of KOH were added and stirred for an additional time. After 15 minutes, 8 ml of 1-fluoronaphthalene were added, the solution was heated to 400C, and stirred for 120 hours (or until completion).' To the reaction mixture was added water, followed by 10 ml HCl (5percent) and 60 ml ethyl acetate. After phase separation, the organic phase was washed with brine, and concentrated to dryness to give brownish oil containing 5.80percent enantiomer R. | ||
Example 6:A 250 ml two necked flask equipped with magnetic stirrer, and condenser was charged with 1O g of AT-OL and 60 ml DMA at room temperature under N2. The mixture was stirred until complete dissolution, and 7.11 g of KOH were added and stirred for an additional time. After 15 minutes, 8 ml of 1 -fluoronaphthalene were added, the solution was heated to 6O0C, and stirred for 27 hours.To the reaction mixture was added water, followed by 10 ml HCl (5percent) and 60 ml ethyl acetate. After phase separation, the organic phase was washed with brine, and concentrated to dryness to give 20.37 g of brownish oil containing 1.35 percent enantiomer R.Example 9:A 250 ml reactor equipped with a mechanical stirrer, and condenser was charged with 1O g of AT-OL and 60 ml DMA at room temperature under N2. The mixture was stirred until complete dissolution, and 7.11 g of KOH were added and stirred for an additional time. After 30 minutes, 8 ml of 1-fluoronaphthalene were added, the solution was heated to SO0C, and stirred for 18 hours.To the reaction mixture was added 90 ml of water, followed by 12 ml HCl (5percent) and 60 ml ethyl acetate. After phase separation, the organic phase was concentrated to dryness to give 20 g of brownish oil containing 0.52percent enantiomer R.Example 10:A 250 ml reactor equipped with a mechanical stirrer, and condenser was charged with 1O g of AT-OL and 60 ml DMA at room temperature. The mixture was stirred until complete dissolution, and 7.11 g of KOH were added and stirred for an additional time. After 30 minutes, 8 ml of 1-fluoronaphthalene were added, the solution was heated to 1100C, and stirred for 26 hours.To the reaction mixture was added 90 ml of water, followed by 12 ml HCl (5percent) and 60 ml ethyl acetate. After phase separation, the organic phase was concentrated to dryness to give 21 g of brownish oil containing 0.47 percent enantiomer R. Example 11 :A 250 ml reactor equipped with a mechanical stirrer, and condenser was charged with 1O g of AT-OL and 60 ml DMA at room temperature under N2. The mixture was stirred until complete dissolution, and 6 g of KOH were added and stirred for an additional time. After one hour, 8 ml of 1-fluoronaphthalene were added, the solution was heated to 800C, and stirred at the same temperature. During the following 4 hours, two portions of KOH were added (6 g), and the reaction mixture kept at the same temperature for an additional hour.To the reaction mixture was added water, followed by 12 ml HCl (5percent) and 60 ml ethyl acetate. After phase separation, the organic phase was concentrated to dryness to give 25 g of brownish oil containing 4.85 percent enantiomer R. | ||
Example 5 Preparation of DNT To a solution of 7 g. of AT-OL in 42 ml of DMSO at room temperature were added 5 g of KOH, and stirred for an additional time. After 1 hour, 5 ml of 1-fluoronaphthalene were added, the solution was heated to 60° C., and stirred overnight. To the reaction mixture was added water, followed by 80 ml HCl [5percent], and extracted with 40 ml ethyl acetate (twice). After phase separation, the organic phase was washed with brine, and concentrated to dryness to give 10.5 g of brownish oil containing 0.12percent of DNT-ISO3: 0.12percent. | ||
e) Preparation of (1S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamineSodium hydride (7.27 g) was added to the residue obtained from step (d) in dimethyl sulfoxide (122 mL) at 10-20° C. in portions over a period of 30 minutes. The mixture was stirred at about 25° C. for 30 minutes. Potassium benzoate (237 g, 0.0173 mole) was added to the reaction mixture and stirred at about 25° C. for 30 additional minutes. A solution of 1-fluoronaphthalene (30.3 g) in dimethyl sulfoxide (61 mL) was added to the reaction mixture at about 25° C. The reaction mixture was stirred at 50-55° C. for 3-4 h. After the completion of the reaction, the reaction mixture was cooled to 10° C. and acidified to the pH of 4-4.5 with acetic acid. The reaction mixture was diluted with water (732 mL) and further acidified to the pH of 1.5-2.0 with 6 N hydrochloric acid. The reaction mixture was washed with hexane (2.x.290 mL) at about 25° C. The pH of the aqueous layer was adjusted to about 11 using 30percent aqueous sodium hydroxide solution and subsequently extracted with ethyl acetate (2.x.584 mL). The ethyl acetate layer was washed with water (2.x.584 mL) and concentrated under reduced pressure to obtain the title compound as an oily mass. | ||
Example1Preparation of (S)-(+)-N,N-dimethyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine_10 g of (S)-(-)-3-(dimethylamino)-1-(thiophen-2-yl)propan-1-ol was dissolved in 60 mL of dimethyl sulfoxide at 25° C. To the soln. 2.3g of NaH (1.1 eq neat) was added slowly as 60percent dispersion in mineral oil with vigorous stirring. Reaction mass was stirred for 15 minutes. 0.86g of Potassium benzoate was added and stirred at the 25 to 30° C for 15 minutes. 9.46g of 1-Flouoro Naphthalene was added slowly to the reaction mixture. After complete addition, mixture was stirred at 25 to 30° C for 48h. Reaction mixture was quenched by pouring it into crushed ice. 60mL of Ethyl acetate was added and stirred for 10 minutes. The biphasic mixture was filtered through celite. Separated the layers aqueous phase was stirred again with 30mL Ethyl acetate. Separated the layers aqueous phase was extracted with 30mL Ethyl acetate. Combined extract was washed with water. Organic layer was dried over sodium sulfate concentrated under vacuum at 40-45° C to obtain syrup. | ||
With sodium hydride; In dimethyl sulfoxide; mineral oil; at 20 - 50℃; for 18h; | Into a suspension of DMSO (75 mL) and NaH (60 percent suspension in mineral oil; 2.9 g) (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine was added carefully at 20-25 °C. The reaction mixture was then heated to 40 °C and a solution of F- naphthalene (9 mL) in DMSO (10 mL) was slowly added dropwise. After complete addition the suspension was heated to 50 °C and kept at 50 °C over night. After 18 hours the mixture was cooled to 20 °C and carefully poured into the ice-cold mixture of water (200 mL) and acetic acid ( 12 mL). After quenching the mixture was heated to 20 °C, pl l was measured (5-5.5) and hexane (80 mL) was added. After 10 minutes of stirring the phases were separated. The aqueous phase was alkalized with 10 percent NaOI I and extracted into toluene (100 mL). The toluene phase was rinsed with water ( 1 x 60 mL). The toluene phase of (S)-N.N-dimethyl-3-(naphthalen-l-yloxy)-3-(thiophen-2- yl)propan-l -amine was heated to 55 °C, diisopropylethylamine (0.69 ml.) was added and phenyl chloro formate (10.35 mL) was added slowly dropwise. It was heated for 1.25 hours, 1 percent NaHCOj (215 mL) was added and after 10 minutes at 40-50 °C the phases were separated. The organic phase was rinsed with 0.5 M HC1 (2 X 50 mL) and 1 percent NaHC03 (50 mL). The rinsed toluene phase was concentrated on a rotary evaporator to a constant mass, dissolved in DMSO (150 mL), heated to 45 °C, the aqueous solution (50 mL) of NaOH (8.7 g) was added and heated for 18 hours at 50 °C. After the hydrolysis was completed the cooled mixture was poured into an ice- cold mixture of water (250 mL) and acetic acid (12 mL, pH about 5-5.5). The aqueous phase was rinsed with hexane (40 mL), alkalized with a 10 percent base and a duloxetine base was extracted into isopropyl acetate (2 X 60 mL). The organic phase was rinsed with water (2 x 40 mL), treated in hot with activated carbon and the hot filtrate was cooled. To the cooled filtrate acetic acid (5 mL) was added and the product was precipitated with 2.5 M HCi in isopropyl acetate (23 mL). The suspension was stirred at 10 °C - 15 °C for 5-6 hours. The precipitate was filtered off and rinsed with cold isopropyl acetate. The product was dried in a vacuum drier at 50 °C for 5 hours. 13.5 g (75percent) with 99.71 percent HPLC purity and 99 percent ee were obtained, which was recrystallized from iPrOH. 12.46 g (92percent) of pure product (HPLC purity 99.92 percent and 99.9 percent ee) were obtained. | |
Example 1 Preparation of (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine III; In a 5 liters four necked round bottom flask equipped with mechanical stirrer, reflux condenser and thermometer sulfolane (300 mL) and sodium hydride 60percent in mineral oil (25 g) are loaded. To the resulting suspension a solution of II [(S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine] (100 g, in 450 ml of sulfolane) is quickly added. The suspension is heated to 70°C for 1 hour, 1-fluoronaphthalene (77 mL) is added and the mixture is further heated at 110°C for 3 hours. The mixture is then cooled at 10°C and quenched adding 3500 mL of water. Cyclohexane is then added (1L) and the phases are separated. The aqueous phase is further extracted with cyclohexane, the combined organic layer is washed with water and evaporated to dryness. The distilled cyclohexane can be reused in the same step, wile the resulting oil is dissolved in a 20percent aqueous solution of acetic acid at pH 4.5 and extracted with hexane twice. The hexane phase can be evaporated to residue to obtain distilled hexane which can be reused and a residue of 1-fluoronaphthalene which is recovered. The aqueous phase is made neutral with ammonium hydroxide and extracted with toluene (1L). About 100 mL of toluene are distilled in order to eliminate water as a water/toluene azeotrope and the resulting toluene solution containing III is used in the following step. | ||
With sodium hydride; | The duloxetine alkyl carbamate represented by the formula (Ib) was synthesized by a known method (steps 1 to 4 of the above scheme).Specifically, 2-acetylthiophene (63.1 g; 0.5 mol), dimethylamine hydrochloride (53.0 g; 0.65 mol), paraformaldehyde (19.8 g; 0.22 mol) and ethanol (80 ml) (1 ml) to give 3-dimethylamino-1- (2-thienyl) -1-propanone hydrochloride,Reduction with sodium borohydride, resolution with optically active mandelic acid yielded optically active (S) N, N-dimethyl-3- (2-thienyl) -3-hydroxypropylamine.Next, by reaction of 1-fluoronaphthalene with sodium hydride, N, N-dimethyl-duloxetine was obtained.Subsequently, the reaction with the corresponding alkyl chloroformate (4.6 ml; 48.5 mmol) gave the duloxetine alkyl carbamate represented by the above formula (Ib). The ethanol solution (10 mL) of the potassium hydrate (87percent of purity, 2.16g;33.5mmol) was added to the toluene solution (10 mL) of the obtained duloxetine ethyl carbamate (Ib) and (2.5g;6.7mmol) at the room temperature. It heated until it flowed back at 85 to 90 degree C about mixed liquor, and the solvent was distilled off until the internal temperature became 100 degrees C from there. Repeating distilling off of a solvent furthermore, in the range of 95 to 100 degree C, temperature was maintained and it stirred for 2 hours. It cooled to the room temperature and washed the organic layer obtained by adding water (10 mL) and ethyl acetate (10 mL) with water (20 mL). With sodium sulfate, it dried, concentration drying was filtered and carried out, and the compound of the title was obtained at 1.96 g (yield: 98.4percent, optical isomer:0.16percent).[0054]1H-NMR(400-MHz, DMSO-d6):8.23-8.20 (m, 1H), 7.86-7.82 (m, 1H), 7.53-7.49 (m, 2H), 7.44-7.41 (m, 2H), 7.33 (t, 1H), 7.21 (dd, 1H), 7.05(d,1H),6.97(dd,1H),5.99(t,1H),2.62(2H,t)2.26(3H,s),2.36-2.29(m,1H),2.12-2.03(m,1H) |
Yield | Reaction Conditions | Operation in experiment |
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Example (T):Preparation of (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine oxalate:1 -Fluoronaphthalene (118.3g) and (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3- hydroxypropanamine (10Og) was taken in a 500 mL round bottom flask and stirred for 10 minutes. Powdered potassium tertiary butoxide was added to the reaction mass, heated to 90-1000C and maintained for 20-22 hrs for the completion of the reaction. After completion of the reaction; the reaction mass was cooled and to it was added toluene and stirred. The layers were separated and the aqueous layer was extracted with toluene. The combined toluene layer was washed with water followed by 5percent HCl solution. The acidic aqueous layer was extracted with dichloromethane and combined organic layer was washed with 5percent sodium hydroxide then with water. The organic layer <n="9"/>was distilled atmospherically and finally under vacuum to get the thick mass. Ethyl acetate was added to the thick mass and distilled out dichloromethane completely under vacuum and stirred the reaction mass followed by the addition of ethyl acetate under stirring at 25-300C. A solution of methanol and oxalic acid were added to the reaction mass at 25-300C and stirred for 60-90 minutes at 0-50C. The solid was filtered washed with cold ethyl acetate twice and dried to yield the titled compound. Yield 154.g |
Yield | Reaction Conditions | Operation in experiment |
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Example 1:A 150 ml reactor three necked flask equipped with mechanical stirrer, thermometer, and condenser was charged with 10 g of AT-OL and 60 ml DMSO at room temperature. The mixture was stirred until complete dissolution, and 7.11 g of KOH were added and stirred for an additional time. After 15 minutes, 8 ml of 1-fluoronaphthalene were added, and the solution was heated to 600C, and stirred for 20 hours.To the reaction mixture was added water, followed by 10 ml HCl (5%) and 60 ml ethyl acetate. After phase separation, the organic phase was washed with brine, and concentrated to dryness to give 18.14 g of brownish oil containing 10.57 % enantiomer R. |
Yield | Reaction Conditions | Operation in experiment |
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3.5 g (80%) | With oxalic acid; In ISOPROPYLAMIDE; water; (S)-3-dimethylamino-1-(2-thienyl)propan-1-ol; ethyl acetate; mineral oil; | Example 4 Synthesis of (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine oxalate In 50 ml of dimethylacetamide 0.5 g of sodium hydride (suspension in mineral oil) is suspended. Suspension is stirred and in few portions 2 g of (s)-3-(dimethylamino)-1-(thienyl)-propan-1-ol is added. After the addition is completed the suspension is warmed up to 70C. 1.27 ml of 1-fluoronaphthalene is added and the reaction mixture is heated to 110C. At this temperature the solution is stirred for another three hours. Then the reaction solution is dissolved with 300 ml of water and extracted twice with 100 ml ether. Combined ether phases are rinsed with water, dried with sodium sulphate end evaporated to dryness. Obtained oil is dissolved in 50 ml ethyl acetate and 0.9 g of oxalic acid is added. The suspension is further stirred for one hour, filtered off the product and washed with ethyl acetate. The product is dried to obtain 3.5 g (80 %) of (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine oxalate. |
Yield | Reaction Conditions | Operation in experiment |
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88% | (S)-2-(1-N,N-dimethyl-3-hydroxy)propyl amino)-thiophene (12.5gms) wasdissolved in DMSO (60ml). Potassium hydroxide (20.5 gms) and 18-Crown-6 were added (0.12gms). The reaction mixture was stirred at 60° C for 1 hour and 4-fluoro naphthalene (11.9gms) was added slowly over 2 hours. After the reaction was complete, it was quenched in ice-water and extracted into toluene. The toluene layer was dried and concentrated under vacuum. The residue was dissolved in 100ml of ethyl acetate and oxalic acid (7.5 gms) was added. The reaction mixture was stirred for 1 hour and filtered to give the title compound in 88percent yield. |
Yield | Reaction Conditions | Operation in experiment |
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10%; 30% | With Al2CuF8; at 450℃;Gas phase; Inert atmosphere; | Fluorination of 1-chloronaphthalene; Catalyst: CuAl2F8, wt: 2.5 g, reactant: 0.5 ml at 450 C. |
Yield | Reaction Conditions | Operation in experiment |
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76% | With bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; di-tert-butyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1':3',1''-terphenyl]-2-yl)phosphane; cesium fluoride; In toluene; at 100℃; for 18h;Sealed tube; Inert atmosphere; | To an oven-dried flask equipped with a magnetic stir bar was added 3.9 mg (0.0075 mmol) of [Pd(cinnamy)Cl]2, 8.4 mg (0.015 mmol) of 25OMe-TIP-tBu*Phine, 151.9 mg (1.0 mmol) of CsF, 138.1 mg (0.5 mmol) of 1-naphthyl-triflate and 2.5 mL of anhydrous toluene. The flask was crimp sealed with a Teflon-lined cap under argon, heated to 100 C. in an oil bath and vigorously stirred for 18 h. Upon reaction completion, the mixture was cooled to room temperature, diluted with EtOAc and filtered through a pad of Celite. Several portions of EtOAc were used to rinse the Celite and the filtrate was consolidated then concentrated to dryness. The crude residue was purified by column-chromatography on silica gel using petroleum ether as the eluent to give the pure product as a colorless liquid (56 mg, 76%). 1H NMR (600 MHz, Chloroform-d) δ 8.18-8.11 (m, 1H), 7.91-7.85 (m, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.59-7.53 (m, 2H), 7.41 (td, J=8.0, 5.4 Hz, 1H), 7.17 (ddd, J=10.7, 7.6, 1.0 Hz, 1H). 13C NMR (151 MHz, Chloroform-d) δ 159.59, 134.87, 127.51, 127.48, 126.79, 126.15, 126.14, 125.60, 125.54, 123.63, 123.60, 120.53, 120.49, 109.45, 109.32. 19F NMR (280 MHz, Chloroform-d) δ-124.6. |
52% | With cesium fluoride;5-(di-tert-butylphosphino)-1′, 3′, 5′-triphenyl-1′H-[1,4′]bipyrazole; bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; In toluene; at 150℃; for 18h;Sealed tube;Product distribution / selectivity; | Example 2 Synthesis of Fluoroarenes from Trifluoromethanesulfonates 1-Fluoronaphthalene. To an oven-dried screw-cap test tube equipped with a magnetic stir bar was added <strong>[99747-74-7]1-naphthyl trifluoromethanesulfonate</strong> (25 μL, 0.127 mmol, 1.0 eq), cesium fluoride (29.3 mg, 0.191 mmol, 1.5 eq), [Pd(cinnamyl)Cl]2 (3.3 mg, 7 μmol, 5 mol %) and L1 (6.6 mg, 13 μmol, 10 mol %) inside a glovebox. See . The test tube was then sealed off with a screw-cap and taken out of the glovebox. Toluene (2 mL) was promptly added via syringe in such a manner that any reagent on the side of the test tube was washed down to the bottom of the tube. The test tube was then placed in a pre-heated oil bath at the indicated temperature and it was stirred for 18 h. After cooling to room temperature, dodecane (28.9 μL) was added, the reaction was diluted with EtOAc (~1 mL) and the resulting mixture was filtered through a plug of Celite and it was analyzed by GC. |
Yield | Reaction Conditions | Operation in experiment |
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50% | With manganese(II) chloride dihydrate; lithium In tetrahydrofuran at 25℃; for 1h; Inert atmosphere; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
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82.8% | With sodium hydride In N,N-dimethyl-formamide at 20 - 70℃; for 8h; | 3 Example 3 Synthesis of N-methyl-N-methoxyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine 10.0 g of (S)-3-methoxymethylamino-1-(2-thienyl)propan-1-ol from example 2 was dissolved in 30 mL of N,N-dimethylformamide at ambient temperature, to which was added sodium hydride (3.9 g, 60%) with vigorous stirring. Then, 9.4 g of 1-fluoronaphthalene was added and the mixture was stirred at 70° C. for 8 hours. Upon completion of naphthalenation, the reaction mixture was quenched with water (90 mL). After extraction with toluene (30 mL×3), the organic layer was combined and concentrated. Subsequently, the crude product was purified by silica gel column chromatography to give objective compound as an amber oil (13.5 g, 82.8%). 1H NMR (400 MHz, CDCl3) δ (ppm)=2.3 (m, 1H), 2.5 (m, 1H), 2.6 (s, 3H), 2.9 (t, 2H), 3.5 (s, 3H), 5.8 (m, 1H), 6.8 (m, 1H), 6.9 (d, 1H), 7.0 (s, 1H), 7.2 (d, 1H), 7.3 (m, 1H), 7.4 (d, 1H) 7.5 (m, 2H), 7.8 (d, 1H), 8.3 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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Example (1); Preparation of (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine oxalate; 1-Fluoronaphthalene (118.3 g) and (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine (100 g) was taken in a 500 mL round bottom flask and stirred for 10 minutes. Powdered potassium tertiary butoxide was added to the reaction mass, heated to 90-100° C. and maintained for 20-22 hrs for the completion of the reaction. After completion of the reaction; the reaction mass was cooled and to it was added toluene and stirred. The layers were separated and the aqueous layer was extracted with toluene. The combined toluene layer was washed with water followed by 5percent HCl solution. The acidic aqueous layer was extracted with dichloromethane and combined organic layer was washed with 5percent sodium hydroxide then with water. The organic layer was distilled atmospherically and finally under vacuum to get the thick mass. Ethyl acetate was added to the thick mass and distilled out dichloromethane completely under vacuum and stirred the reaction mass followed by the addition of ethyl acetate under stirring at 25-30° C. A solution of methanol and oxalic acid were added to the reaction mass at 25-30° C. and stirred for 60-90 minutes at 0-5° C. The solid was filtered washed with cold ethyl acetate twice and dried to yield the titled compound. Yield 154.g |
Yield | Reaction Conditions | Operation in experiment |
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200 g of N,N-Dimethyl-3-hydroxy-3-(2-thienyl) propanamine mandelate was mixed with 250 ml water and 500ml dichloromethane. The pH of the reaction mixture was adjusted between 1 1 - 12 using 30% sodium hydroxide solutions. The reaction mixture was stirred at 20-25C for 30 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane ( 100 ml). The organic layers were combined and washed with water, The organic layer was concentrated under vacuum. The resulting mass was taken in 450ml dimethylsulphoxide and was stirred at room temperature. To this, 28.4 g sodium hydride was added and the mixture was stirred. To the resulting mass, 103.6 g of 1 - fluoronaphthalene was added and the reaction mass was stirred at 48-50C for 14-16 hours. After completion of the reaction, the reaction mass was cooled to room temperature. The resulting mass was transfer to another flask containing water at temperature 5- 10C. The pH of the resulting mixture was adjusted to 5-6 using acetic acid and cyclohexane was added under stirring at 10- 1 5C. The layers were separated and to the aqueous layer, toluene was added, pH was adjusted between 10- 1 1 .0 using 30% sodium hydroxide solution. The resulting mass was stirred at room temperature for few minutes. The organic layer was separated and aqueous layer was extracted with toluene. The organic layers were combined and distilled out. The resulting reaction mass was taken in 1400ml ethyl acetate at room temperature and 71 .0 g oxalic acid was added. The reaction mass was stirred for 5hr at room temperature. The resulting solid was filtered and washed with ethyl acetate and dried under vacuum at 50-55C for 4hr to obtain title compound.Yield : 90-92% |
Yield | Reaction Conditions | Operation in experiment |
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75% | With 2,6-dimethylpyridine; Selectfluor; silver(l) oxide In acetone at 23 - 90℃; for 2h; regioselective reaction; | 4.3.2. General procedure B (for non-volatile compounds) General procedure: To aryl silane (0.100 mmol, 1.00 equiv) in acetone (2.0 mL) at 23 °C were added silver oxide (46.4 mg, 0.200 mmol, 2.00 equiv), barium oxide (17.2 mg, 0.110 mmol, 1.10 equiv) or 2,6-lutidine (12.8 μL, 0.110 mmol, 1.10 equiv) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1) (70.8 mg, 0.200 mmol, 2.00 equiv). The reaction mixture was stirred for 2 h at 90 °C in a sealed vial. The reaction mixture was cooled to 23 °C and concentrated under reduced pressure. To the residue was added CH2Cl2 and the mixture was filtered through a pad of Celite eluting with CH2Cl2. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel or preparative TLC. |
Yield | Reaction Conditions | Operation in experiment |
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93% | NaH (60 % in paraffin oil, 2.92 g) was suspended in DMSO (75 mL). After mixing of hydride (about 10 minutes) (S)-3-methyl-amino- 1 -(2-thienyl)- 1 -propanol (l Og) at 20 C was added carefully. Stirring was started slowly and the reaction mixture was heated to 30-40 C. A solution of F-naphthalene (9 mL) in DMSO (10 mL) was then added dropwise in about 30 minutes. Red-brownish suspension was heated to 40-50 C for 9 to 18 hours. Heating was stopped, the mixture was cooled to 23 C and quenched with a slow dropwise addition into ice-cold solution of water (200 mL) and acetic acid (12 mL). It was heated to 20 C (pH ~ 5-5.5) and hexane (80 mL) was added. After extraction the phases were separated and the aqueous phase was alkalized with 50 % NaOH (12 mL). After complete addition of hydroxide iPrOAc (lOOmL) was added to the aqueous phase and during vigorous stirring the two-phase system was heated to 20 C. The phases were separated and the aqueous phase was extracted one more time with iPrOAc (100 mL). The combined organic phases were rinsed 2X with water (2 X 80 mL) and treated for 30 minutes in hot with activated carbon. It was hot filtered and the filtrate was cooled. Into the cooled extract acetic acid (5 mL, 15+/-5C) was added and the product was precipitated slowly with 2.5M HC1 (23 mL) in iPrOAc under vigorous stirring. The white suspension was stirred for 5 hours, cooled to 0-5 C. It was filtered off and the filtrate was rinsed with iPrOAc. The product was dried in a vacuum drier for 5 hours. Obtained were 16.33 g (84 %) of crude duloxetine chloride (HPLC purity 99.87 %; 99.0 % ee), which was recrystallized from iPrOH. 15.18 g (93 %) of pure product (HPLC purity 99.94 % and 99.9 % ee) were obtained | |
100.0 g of (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol are dissolved in 400 mL dimethyl sulfoxide and 25.7 g sodium hydride are added portion wise under stirring at 20-35C. The reaction mixture is further stirred for 60-90 minutes and 93.9 g 1-fluoronaphthalene in 100 mL dimethyl sulfoxide is added dropwise in 10-20 minutes. The reaction mixture is heated at 45- 50C for 30 hrs, cooled at 20-30C and then is treated with 1 L D.M.water, 0.5 L toluene and the pH is adjusted at 4.0-5.0 with 180 mL 6N hydrochloric acid.The separated aqueous layer is extracted with 0.5 L toluene and the collected organic layers are discarded. To the aqueous layer is added 1 L toluene and the reaction mass is basified with 80 mL 50% aq. sodium hydroxide solution (pH at 9.0-9.5) and is filtered through Buchner funnel and washed with 100 mL toluene. The separated aqueous layer is extracted with 1 L toluene and the combined organic layers are washed with 800 mL 20% w/v sodium chloride solution and the solvents are removed by distillation under reduced pressure until dry. The residual mass is dissolved in 2 L ethyl acetate, filtered through 10 g celite bed, washed with 100 mL ethyl acetate and 40-45 mL concentrated hydrochloric acid 37% are added under stirring (pH at 5.5-6.5). The reaction mass is distilled off under atmospheric pressure until 1.2 L of solvents are distilled out, cooled and stirred for 120-180 minutes at 0-5C. The precipitated product is filtered, washed with 200 mL ethyl acetate and dried in vacuum oven to afford 160-170 g Duloxetine hydrochloride crude in 82-87% yield (160-170 %w/w). |
Yield | Reaction Conditions | Operation in experiment |
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64.7% | Example -21: Preparation of Dapoxetine (la); Mixture of S(+)-3-N,N-dimethyl amino-3-phenyl propanol (50 g), 1 -fluoronaphthalene (50g), sodium hydroxide (50 g.) in dimethyl sulfoxide (DMSO)(250ml) were taken in a RB Flask and stirred. The reaction mixture was heated to about 100C and stirred for about 4 hours. After completion of the reaction, reaction mixture was cooled to about 30C. The reaction mixture was poured into 1200ml water and extracted with toluene. The combined organic layer was washed with water and added dilute hydrochloric acid solution to the organic layer. The pH of aqueous layer was adjusted to about 9 with ammonia solution.The separated solid was filtered and washed with water and dried to afford the title compound. Dry wt: 55gr. (%Yield: 64.7%); M.P: 75.1-76.2C; SOR:' (+) 1 16.15 (C-1% in CH3OH); Purity by HPLC: 99.9%. | |
With potassium tert-butylate; In N,N-dimethyl-formamide; at 70℃; for 5h; | In a 2 L three-mouth bottle by adding 500 ml tetrahydrofuran, lowering the temperature to 0 C, adding 23.0 g (0.606 muM) NaBH4, Added under mixing 50 g (S)-3 - amino -3 - phenyl propionic acid dap - 1 (303 muM). The 77 g iodine (0.303 muM) dissolved in 250 ml of tetrahydrofuran, is added to the reaction solution under stirring in the drop. Then completing, heating reflux for 20 hours, stopping the reaction, cooling, dropping 50 ml methanol quenching reaction. The organic solvent and steaming and remove, dropping 20% NaOH solution, to PH is 8 - 10, the stirring 2 h. Ethyl acetate is divided into 3 time extraction, the combined organic phase. The addition of about 10% formic acid solution stirring, liquid. In the aqueous phase by adding 70 ml 85% formic acid and 140 ml 37% formaldehyde, 90 C lower reaction 8 hours. The cooling, for 20% NaOH to adjust the PH to 8 - 10, ethyl acetate extraction three times, the combined organic phase, turns on lathe does (S)-3 - dimethyl amino -3 - phenyl propanol dap - 3 crude product. The dap - 3 crude and 37.0g1 - [...] adding 2 L three-opening in the bottle, at room temperature by adding 380 mLN, N - dimethyl formamide and 47.3 g tert-butanolate, the temperature is raised to 70 C stirring 5 h. The reaction liquid to room temperature, hexane and water added, stirring 15 minutes, standing liquid. The upper layer is cetane collected, washed with water once. Hexane phase and steaming and to remove the solvent, adding tetrahydrofuran is dissolved. Stirring next adds by drops 26.2 ml concentrated hydrochloric acid. Reaction 2 hours, steaming and remove the tetrahydrofuran and water, to the solvent-free steam, adding isopropanol, steaming and to the solvent-free steam. In the resultant product added to isopropanol, heating under stirring to make it dissolve completely. Stop heating, dropping ethyl acetate, during the dropping out of the crystal. After dropping cooling to room temperature, continuing to stir overnight, filtered, the filter cake is washed with ethyl acetate, and a ground line, N2 dry, product west reaches anchors the sandbank hydrochloride 41 g, yield 40%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.5% | 1.58 kg (8.8 mol) of (S) -<strong>[82769-75-3]3-dimethylamino-3-phenylpropanol</strong> obtained in the above was dissolved in 10 L of anhydrous N, N-dimethylacetamide under nitrogen, % Of sodium hydride 1.05 g (26.4 mol), heated to 65 C for 1.5 h, 1.54 kg (10.3 mol) of 1-fluoronaphthalene was added and the temperature of the reaction was raised to 100 C for 7 h. After the reaction was complete, Bath to join the 50L ice water, keep heating for 4h, filter, get the intermediate 3 crude.Recrystallization from 8.5 L of 50% ethanol gave 2.48 kg of intermediate 3, the free base as a white powder solid with a yield of 92.21%, a purity of 99.11% and a chiral purity of 99.79%. N, N-dimethylacetamide recovery cycle. Weigh 2.4 g of the free base prepared as described above was dissolved with 24 L of ethyl acetate and 616.88 g of acetyl chloride and 543 g of ethanol were added.Stir crystallization at room temperature for 6 h. Filtration, get dapoxetine hydrochloride.Dried in vacuo to give 2.42 kg of a white powdery solid. Yield: 90.1%, purity (HPLC): 99.92%, chiral purity: 99.81%. Ethyl acetate recovery cycle.[0100] The crude 2.4 mg of crude dapoxetine hydrochloride was weighed, 4.8 L of ethanol was added, and the mixture was heated to reflux. After the solution became clear, 14.5 L of methyl t-butyl ether was added and the mixture was stirred overnight at room temperature. Suction filter, get dapoxetine hydrochloride refined products. Dried in vacuo to give 2.34 kg of a white powdery solid. Yield 97.5%, purity (HPLC): 99.997%, chiral purity: 99.89%. | |
Detailed step in step (3) of the present embodiment is as follows: the reaction flask in three 2000ml 3-dimethylaminopropyl-3-phenyl-propanol (III) 41.23g (0.23mol) was dissolved in 800ml DMF, the ice bath was 5 minutes under stirring added in 118g mass fraction of 25% n-butyllithium solution was stirred for about 30min, was added 40.34g (0.276mol) 1- fluoronaphthalene was slowly heated to 110 deg.] C, and reacted at this temperature for 8h, and then the reaction was cooled to rt, quenched, 200ml × 3 extracted with methylene chloride (15%) the combined organic phases were washed with dilute hydrochloric acid, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, ethyl acetate was added 180ml esters, beating, centrifuged, and dried 50 deg.] C and dried under reduced pressure to give 77.8 g of crude product, a yield of 98.95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With lithium hydroxide monohydrate; silver trifluoromethanesulfonate; Selectfluor In ethyl acetate at 55℃; Sealed tube; | 10 General procedure for the silver-mediated fluorination of potassium aryl and heteroaryl trifluoroborates with Selectfluor (Table 4) General procedure: Trifluoroborate (0.50 mmol, 1.0 equiv), LiOH·H2O (25.2 mg, 0.60 mmol, 1.2 equiv), Selectfluor (212 mg, 0.60 mmol, 1.2 equiv), AgOTf (386 mg, 1.5 mmol, 3.0 equiv) were weighed into a 20 mL microwave vial. EtOAc (5 mL) was added, and sealed with a microwave cap and the mixture was allowed to stir at 55 °C for 5-15 h. The resulting solution was cooled to room temperature. For the compounds reported with isolated yields (2a, 2b, 2c, 2d, 2e, 2g, 2h, 2j, 2k, 2l, 2m, 2o, 2p, 2t, 2u, 2x, 2v, 2y, 2ab, 2ac, and 2ag) the reaction mixture was diluted with MTBE or hexane (5 mL) and H2O (4.0 mL). Then organic phase was separated, the aqueous phase was extracted with MTBE (2*5 mL). The combined organic phases were dried over anhydrous Na2SO4. The filtrate was concentrated in rotavapor and the residue was purified by column chromatography on Combiflash with hexanes/EtOAc to afford the desired compounds. The volatile and low yielding products were not isolated and their yields were determined only by 19F NMR of the reaction mixture. For the compounds reported with 19F NMR yields, 4-fluorobenzonitrile (0.50 mmol) was added as reference to the reaction mixture, stirred for 5 min, and then diluted with MTBE or hexane (5 mL) and H2O (3.0 mL). The layers were separated and an an aliquote of the organic phase was withdrawn for the 19F NMR measurement in CDCl3. |
56% | With tert-butyl isocyanide; 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate; tetrakis(acetonitrile)copper(I) tetrafluoroborate In ethyl acetate at 80℃; for 12h; Inert atmosphere; Glovebox; | |
75 %Spectr. | With iron(III) chloride; potassium fluoride; Selectfluor In ethyl acetate at 55℃; | 1-Fluoronaphthalene (2o) (Table 4, Entry 15) General procedure: FeCl3 (60.8 mg, 0.375 mmol, 1.5 equiv), Selectfluor (177 mg, 0.5mmol, 2.0 equiv), and KF (43.6 mg, 0.75 mmol, 3.0 equiv) wereweighed into a 10-mL microwave vial. EtOAc (2.5 mL) was added, andthe vial was sealed with a septum. The mixture stirred at 25 °C for 5min. Then, potassium aryltrifluoroborate (0.25 mmol, 1.0 equiv) wasadded to the mixture, and the vial was sealed with microwave capand the mixture stirred at 55 °C for 10-15 h. The resulting solutionwas cooled to r.t.The volatile products were not isolated and their yields were determinedonly by 19F NMR of the reaction mixture. For the compoundsreported with 19F NMR yields, 4-fluorobenzonitrile (0.25 mmol) wasadded as reference to the mixture, stirred for 5 min, and then dilutedwith t-BuOMe or hexane (2.5 mL) and H2O (3.0 mL). The layers wereseparated and an organic aliquot was withdrawn for the 19F NMRmeasurement in either in CDCl3 or DMSO-d6. The 19F NMR spectroscopicdata were identical to those reported previously in the literature.The identity of the product was further confirmed by GC-MSanalysis. For the compounds reported as isolated yields, the mixture was dilutedwith t-BuOMe or hexane (2.5 mL) and H2O (4.0 mL). Then organicphase was separated, the aqueous phase was extracted with t-BuOMe(2 × 5 mL). The combined organic phases were dried (anhyd Na2SO4),the solvent was removed at 1.0 bar and the residue was purified bycolumn chromatography (Combiflash, hexanes) to afford the desiredcompounds. The identity of the product was confirmed by 1H NMRand GC-MS analyses. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10%Spectr.; 50%Spectr. | With iron(III) chloride; potassium fluoride; Selectfluor; In ethyl acetate; at 55℃; | General procedure: FeCl3 (60.8 mg, 0.375 mmol, 1.5 equiv), Selectfluor (177 mg, 0.5mmol, 2.0 equiv), and KF (43.6 mg, 0.75 mmol, 3.0 equiv) wereweighed into a 10-mL microwave vial. EtOAc (2.5 mL) was added, andthe vial was sealed with a septum. The mixture stirred at 25 C for 5min. Then, potassium aryltrifluoroborate (0.25 mmol, 1.0 equiv) wasadded to the mixture, and the vial was sealed with microwave capand the mixture stirred at 55 C for 10-15 h. The resulting solutionwas cooled to r.t.The volatile products were not isolated and their yields were determinedonly by 19F NMR of the reaction mixture. For the compoundsreported with 19F NMR yields, 4-fluorobenzonitrile (0.25 mmol) wasadded as reference to the mixture, stirred for 5 min, and then dilutedwith t-BuOMe or hexane (2.5 mL) and H2O (3.0 mL). The layers wereseparated and an organic aliquot was withdrawn for the 19F NMRmeasurement in either in CDCl3 or DMSO-d6. The 19F NMR spectroscopicdata were identical to those reported previously in the literature.The identity of the product was further confirmed by GC-MSanalysis. For the compounds reported as isolated yields, the mixture was dilutedwith t-BuOMe or hexane (2.5 mL) and H2O (4.0 mL). Then organicphase was separated, the aqueous phase was extracted with t-BuOMe(2 × 5 mL). The combined organic phases were dried (anhyd Na2SO4),the solvent was removed at 1.0 bar and the residue was purified bycolumn chromatography (Combiflash, hexanes) to afford the desiredcompounds. The identity of the product was confirmed by 1H NMRand GC-MS analyses. |
Yield | Reaction Conditions | Operation in experiment |
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75% | With sodium hydride; dimethyl sulfoxide In mineral oil at 60 - 65℃; for 4h; Inert atmosphere; | General Procedure for Synthesis of 2a-2o: 4-(naphthalen-1-yloxy)chroman (2a) General procedure: A mineral oil suspension of 60% sodium hydroxide (NaH) (12.0 g, 0.3 mol) was taken in a round-bottomed flask and DMSO (200 mL) was added in 10 min at rt under a nitrogen atmosphere and stirred for 5 min. The temperature was raised to 60-65 °C and maintained for 30 min; after 30 min it was cooled to rt. A solution of 3a (30 g, 0.2 mol in 100 mL DMSO) was added over 25 min and fluoronaphthalene (43.8 g, 0.3 mol) was also added over 10 min at rt. The temperature of the reaction mixture was raised to 60-65 °C, the mixture was stirred for 4h, and after completion of the reaction (monitored by TLC) the reaction mass was cooled to rt. Then 10 ml of methanol was added to the reaction mixture and finally quenched into DM water(550 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layer was washed with brine solution (200 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica-gel chromatography to give pure 2a (27.5 g, 60 %), a white solid. |
Yield | Reaction Conditions | Operation in experiment |
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77% | With sodium hydride; dimethyl sulfoxide In mineral oil at 60 - 65℃; for 4h; Inert atmosphere; | General Procedure for Synthesis of 2a-2o: 4-(naphthalen-1-yloxy)chroman (2a) General procedure: A mineral oil suspension of 60% sodium hydroxide (NaH) (12.0 g, 0.3 mol) was taken in a round-bottomed flask and DMSO (200 mL) was added in 10 min at rt under a nitrogen atmosphere and stirred for 5 min. The temperature was raised to 60-65 °C and maintained for 30 min; after 30 min it was cooled to rt. A solution of 3a (30 g, 0.2 mol in 100 mL DMSO) was added over 25 min and fluoronaphthalene (43.8 g, 0.3 mol) was also added over 10 min at rt. The temperature of the reaction mixture was raised to 60-65 °C, the mixture was stirred for 4h, and after completion of the reaction (monitored by TLC) the reaction mass was cooled to rt. Then 10 ml of methanol was added to the reaction mixture and finally quenched into DM water(550 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layer was washed with brine solution (200 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica-gel chromatography to give pure 2a (27.5 g, 60 %), a white solid. |
Yield | Reaction Conditions | Operation in experiment |
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56% | The S-isomer 3 (1.59 g, 8.59 mmol) was taken up in DMSO (5 mL) at room temperature,And stirred under nitrogen. Then 60percent sodium hydride (0.38 g, 9.45 mmol, 1.1 eq.) Was added in portions and this was addedThe solution was stirred at room temperature. After 30 minutes, addFluoronaphthalene 4 (1.51 g, 10.3 mmol, 1.2 equiv) was added and the reaction was carried outThe mixture turned to amber. The reaction was heated to 60 & lt; 0 & gt; C and stirred under nitrogen. After about 18 hours at 60 & lt; 0 & gt; C,The reaction mixture was cooled to room temperature and poured into ice water (50 mL). The aqueous solution was acidified to pH 4-5 with glacial acetic acid. Of courseAfter addition of hexane (20 ml) and transfer to a separatory funnel. The layers were separated and the aqueous layer was washed with 30percent sodium hydroxide(Aqueous) to pH 12. The solution was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with water(50 mL) and saturated sodium chloride (2 x 20 mL). And dried over sodium sulfate. Filtered and concentrated under reduced pressureTo give an amber oil which was purified by chromatography (gradient 0percent to 5percent methanol / dichloromethane) to give 1.50 g(56percent) of 5, as an orange oil. |
Yield | Reaction Conditions | Operation in experiment |
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86% | Stage #1: 1-Fluoronaphthalene With sec.-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.0833333h; Stage #2: Trimethyl borate In tetrahydrofuran; hexane at -78 - 20℃; for 1.08333h; Stage #3: water With hydrogenchloride In tetrahydrofuran; hexane | 1 Synthesis of 1-fluoronaphtho-2-ylboronic acid (Boronic acid) (11) 1-fluoronaphthalene (14.61 g, 100mmol, Aldrich Chemical) was dissolved in anhydrous THF (50 mL), and cooled to -78 degrees C. Subsequently, sec-butyl lithium solution (1.3M and 100 mL in hexane) was added into this mixture over 5 minutes. This mixture was stirred at -78 degree C for 20 minutes, and trimethyl borate (15 mL, 132mmol, Aldrich Chemical) was added. Stirring was continued at -78 degrees C for 15 minutes , and stirred for 30 minutes at the room temperature. This reaction was quenched by adding 100 mL of 3:1 mixtures of AcOH:H2O, and stirred at room temperature overnight. Next, ethyl acetate and 500 mL of 1:1 mixture of water were added. The organic layer was washed with 10% HCl (200mLx1), water (200mLx2), and brine (100 mL), dried, filtered with sodium sulfate, the solvent was removed, and 18 g of white solids were obtained. The substance was purified by silica gel chromatography (350 g of silica gel, ethyl acetate hexane 1:1 mobile phase) to obtain title compound 16.3g (86%). |
Yield | Reaction Conditions | Operation in experiment |
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The duloxetine alkyl carbamate represented by the formula (Ib) was synthesized by a known method (steps 1 to 4 of the above scheme).Specifically, 2-acetylthiophene (63.1 g; 0.5 mol), dimethylamine hydrochloride (53.0 g; 0.65 mol), paraformaldehyde (19.8 g; 0.22 mol) and ethanol (80 ml) (1 ml) to give 3-dimethylamino-1- (2-thienyl) -1-propanone hydrochloride,Reduction with sodium borohydride, resolution with optically active mandelic acid yielded optically active (S) N, N-dimethyl-3- (2-thienyl) -3-hydroxypropylamine.Next, by reaction of 1-fluoronaphthalene with sodium hydride, N, N-dimethyl-duloxetine was obtained.Subsequently, the reaction with the corresponding alkyl chloroformate (4.6 ml; 48.5 mmol) gave the duloxetine alkyl carbamate represented by the above formula (Ib). The ethanol solution (10 mL) of the potassium hydrate (87percent of purity, 2.16g;33.5mmol) was added to the toluene solution (10 mL) of the obtained duloxetine ethyl carbamate (Ib) and (2.5g;6.7mmol) at the room temperature. It heated until it flowed back at 85 to 90 degree C about mixed liquor, and the solvent was distilled off until the internal temperature became 100 degrees C from there. Repeating distilling off of a solvent furthermore, in the range of 95 to 100 degree C, temperature was maintained and it stirred for 2 hours. It cooled to the room temperature and washed the organic layer obtained by adding water (10 mL) and ethyl acetate (10 mL) with water (20 mL). With sodium sulfate, it dried, concentration drying was filtered and carried out, and the compound of the title was obtained at 1.96 g (yield: 98.4percent, optical isomer:0.16percent).[0054]1H-NMR(400-MHz, DMSO-d6):8.23-8.20 (m, 1H), 7.86-7.82 (m, 1H), 7.53-7.49 (m, 2H), 7.44-7.41 (m, 2H), 7.33 (t, 1H), 7.21 (dd, 1H), 7.05(d,1H),6.97(dd,1H),5.99(t,1H),2.62(2H,t)2.26(3H,s),2.36-2.29(m,1H),2.12-2.03(m,1H) |
Yield | Reaction Conditions | Operation in experiment |
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32% | In 1-methyl-pyrrolidin-2-one | 2.2.3 Synthesis of DPNDI·(1-fluoronaphthalene) (C3) DPNDI (42mg, 0.1mmol) and 1-fluoronaphthalene (44.0mg, 0.3mmol) were dissolved in 5mL of N-methyl pyrrolidone. Block-like yellow crystals of C3 after several days in about 32% yield (based on DPNDI) were obtained and dried in desiccators. Elemental analysis calcd (%) for C34H19FN4O4: C 72.14, N 9.90, H 3.18; found C 72.11, N 9.85, H 3.15. IR (KBr, cm-1): 3074 (w), 1719 (s), 1679 (s), 1617 (s), 1597 (s), 1432 (s), 1345 (s), 1288 (s), 1243 (s), 1017 (m), 981 (m), 878 (m), 837 (m), 766 (s), 709 (s), 632 (s). |
Yield | Reaction Conditions | Operation in experiment |
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87% | Stage #1: (±)-3-(dimethylamino)-1-(thiophen-2-yl)propan-1-ol-d8 With sodium hydride In dimethyl sulfoxide at 60℃; for 1h; Stage #2: 1-Fluoronaphthalene With Potassium benzoate In dimethyl sulfoxide at 60℃; for 12h; | Synthesis of (±)-N,N-dimethyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine-d8 (10) Sodium hydride (60%, 0.13 g) was added to a stirred solution of 9 (0.48 g, 2.5 mmol) in dry DMSO (15 mL) at room temperature, and the resulting mixture was heated at 60 °C for 1 h to form a homogeneous solution. Potassium benzoate (0.40 g, 2.5 mmol) was added to the reaction mixture, which was stirred at 60 °C for another 30 min. Then, to the stirred solution was added dropwise 1-fluoronaphthalene (0.44 g, 3.0 mmol) over 20 min. The resulting mixture was stirred at 60 °C for 12 h and then poured into H2O (30 mL). The aqueous layerwas adjusted to pH 11~12 with 2.5 N NaOH and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed twice with saturated brine and dried over anhydrous MgSO4. The solution was concentrated under reduced pressure and the residue was chromatographed on silica gel using 10% methanol/dichloromethane, affording (±)-N,N-dimethyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine-d8 (10) as a reddish brown oil: 0.69 g (87%); IR (KBr)(νmax/cm-1): 1640, 1550, 1345, 1140; 1H NMR (300 MHz, DMSO-d6): δ 8.32-8.21 (m, H), 7.85-7.80 (m, H), 7.54-6.89 (m, 8H), 6.09-6.03(m, 1H), 2.58-2.30 (m, 2H); 13C NMR (75 MHz, DMSO-d6): δ 155.1,150.3, 135.6, 130.0, 129.2, 129.0, 127.5, 127.3, 125.8, 124.9, 122.7,121.4, 119.9, 106.3, 82.7, 48.3 (t), 43.5 (q), 31.8; HRMS (ESI): Calcd forC19H13D8NOS (M+H)+: 320.1924, found: 320.1903. |
Yield | Reaction Conditions | Operation in experiment |
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85% | With potassium hydroxide In dimethyl sulfoxide at 110℃; for 2h; | 3 Example 3: In a 1000 ml three-necked flask, 128.5 g (0.5 mol) of (RS)-(N-methyl-Nbenzyl)-3-hydroxy-3-(2-thienyl)propylamine obtained in Example 2, 500 ml of DMSO, was added.112 g (1.0 mol) of potassium hydroxide and 73 g (0.5 mol) of 1-fluoronaphthalene were added, and the mixture was heated to 110 ° C for 2 hours, catalyzed by a metal, cooled to 20 ° C, and filtered to obtain a solid of 162.8 g, a yield of 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.6% | DX-A 03 (2.0 g, 0.011 mol)Was dissolved in dimethylacetamide (100 mL)A solution of 60% sodium hydride (463 mg, 0.012 mol)Dropwise.The resulting mixture was heated at 70 C. for 20 minutes.1-Fluoronaphthalene (1.27 mL, 0.012 mol)Was added dropwise to this mixed solution,And heated at 110 C. for 60 minutes.The reaction mixture was diluted with water,And extracted twice with diethyl ether.The extracts are combined,Wash with water,Then washed with saturated sodium chloride solution,It was dried over anhydrous sodium sulfate,After concentration under reduced pressure,To obtain an oily compound (DX-A 04, 3.28 g, 75.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.1% | Stage #1: (S)-3-(N-methyl-N-phenoxycarbonylamino)-1-(2-thienyl)-1-propanol With sodium hydroxide In dimethyl sulfoxide at 20 - 30℃; Inert atmosphere; Stage #2: 1-Fluoronaphthalene at 60 - 65℃; | 6 (S)-N-methyl-N-phenoxycarbonyl-3-(1-naphthyloxy)-3-(2-thienyl)-1-propylamine Under the protection of nitrogen, to the 100 ml [...] is added in embodiment 5 obtained in 8 . 03 g (S)-3-(N-methyl-N-phenoxycarbonylamino)-1-(2-thienyl)-1-propanol (25 mmol) and 40 ml DMSO, temperature control ≤ 30 °C, batch by adding 0.6 g sodium hydride (50 mmol), canada finishes, 20 - 30 °C stirring 2 - 3 hours; the reaction liquid heated to 55 - 60 °C, slowly dropping 4 . 75 g 1-fluoronaphthalene (32.5 mmol). Then completing the reaction liquid is heated to 60 - 65 °C, thermal insulation stirring for 6 - 8 hours, TLC [...] monitoring (developing solvent: dichloromethane/methanol=10:1) to the reaction is complete. Cooling to 20 - 30 °C, slowly adding 100 ml ice water, adding ethyl acetate (150 ml × 2) extraction, the organic phase with saturated salt water wash once, dried with anhydrous sodium sulfate. Filtered and concentrated by decompression, to get the yellow solid 8 . 45 g, yield 81.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With C23H40Br2N2NiO5P; magnesium In tetrahydrofuran at 65℃; for 10h; Inert atmosphere; | 28 Example 28: Reduction cross-coupling reaction of 1-fluoronaphthalene with p-methylchlorobenzyl catalyzed by Ni(NHC)[P(OR)3]X2 (R = CH2CH3, X = Br) Under the protection of argon gas, the catalyst (6.8 mg, 0.010 mmol, 2 mol%), magnesium dust (14.5 mg, 0.6 mmol), and1-fluoronaphthalene (56 μl, 0.5 mmol), p-methylchlorobenzyl (80 μl, 0.6 mmol),Tetrahydrofuran (1.0 ml) was used as a solvent, and the reaction was performed at 65 oC for 10 hours. The reaction was terminated with a saturated ammonium chloride solution. The reaction product was extracted with ethyl acetate and purified by column chromatography (using ethyl acetate / petroleum ether volume ratio of 1: 50% mixed solvent is the developing agent), and the isolated yield is 98%. |
92% | With Ni(IBiox-6)[P(OEt)3]Br2; magnesium In tetrahydrofuran at 50℃; for 12h; Schlenk technique; Glovebox; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With potassium phosphate; In N,N-dimethyl-formamide; at 153℃; for 47h;Inert atmosphere; | Under a nitrogen atmosphere,In a 1000 mL four-necked flask,<strong>[10537-08-3]2-chlorocarbazole</strong> 21.8 g (108 mmol),1-fluoronaphthalene 18.9 g (129 mmol),34.4 g (162 mmol) of tripotassium phosphate,400 mL of N, N-dimethylformamide was added,The mixture was stirred at 153 C for 47 hours.After the reaction,After cooling the reaction solution to room temperature,Pure water (500 mL) was added and the precipitated crystals were collected by filtration.By washing with pure water and methanol,10.9 g of white crystals were obtained(Yield 31%, Purity 99.2%).The white powder obtained by mass spectrometry (FD-MS) is the target compound.(2-chloro-9- (1-naphthyl) carbazole)Was confirmed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium hexamethylsilazane at 120℃; for 7h; Sealed tube; Inert atmosphere; | |
82% | With potassium <i>tert</i>-butylate In toluene at 120℃; for 20h; Inert atmosphere; Sealed tube; | 10 Example 10 This embodiment provides a method for preparing dicyclohexyl (1-naphthyl) phosphine oxide, which is specifically as follows:Under nitrogen atmosphere, add 0.20mmol dicyclohexylphosphine oxide, 0.20mmol 1-fluoronaphthalene, 0.30mmol potassium tert-butoxide, 1.5mL toluene solvent into the reactor, seal the tube and heat to 120, continue to stir for 20h, stop React, cool to room temperature, wash with water to remove excess alkali and salt generated in the reaction, extract the aqueous phase with dichloromethane to obtain the organic phase, dry with anhydrous sodium sulfate, distill under reduced pressure to remove the solvent, the crude product is separated by column chromatography to obtain the target The product has an isolated yield of 82%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.88% | With caesium carbonate In N,N-dimethyl acetamide at 135 - 140℃; Inert atmosphere; | 2 Synthesis of compound 2 Under the protection of nitrogen, add intermediate C67.38g (0.1mol), intermediate E219.0g (0.13mol), cesium carbonate 97.74g (0.3mol), and N,N-dimethylacetamide into a 1000mL three-necked flask. 300mL, after mixing uniformly, stir and increase the temperature, control the temperature of the system at 135-140°C, keep refluxing, and track and sample until the reaction of the raw material intermediate C is complete, and the reaction purity is 74.31%.After the reaction is qualified, the reaction solution is transferred to a 1000mL round bottom flask, the solvent is removed from the rotary evaporator, and 700mL of toluene is added to the system. The temperature is raised to 6070 and stirred until most of the system is dissolved. The insoluble matter is removed by filtration, and the organic phase is removed. Washed with water to pH ≈ 7, the organic phase was dried and passed through an 80.0 g silica gel column, and the solvent was removed by a rotary evaporator to obtain 82.1 g of a light yellow solid, which was recrystallized with toluene 4 times, and the final product was a light yellow solid with a weight of 71.1 g , Product purity: 99.9%, yield 88.88%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With potassium tert-butylate; In toluene; at 120℃; for 20h;Inert atmosphere; Sealed tube; | This embodiment provides a preparation method of bis(4-methoxyphenyl)(1-naphthyl)phosphine oxide, which is specifically as follows:In a nitrogen atmosphere, add 0.20mmol bis(4-methoxyphenyl) phosphine oxide, 0.20mmol 1-fluoronaphthalene, 0.30mmol potassium tert-butoxide, 1.5mL toluene solvent, and heat to 120deg C after sealing the tube, keep stirring for 20h, stop the reaction, cool to room temperature, wash with water to remove excess alkali and salt generated in the reaction, extract the aqueous phase with dichloromethane to obtain the organic phase, dry with anhydrous sodium sulfate, distill under reduced pressure to remove the solvent, crude product The target product can be obtained after separation by column chromatography with a separation yield of 64%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium <i>tert</i>-butylate In toluene at 120℃; for 20h; Inert atmosphere; Sealed tube; | 7 Example 7 This embodiment provides a preparation method of bis(4-methylphenyl)(1-naphthyl)phosphine oxide, which is specifically as follows:Under nitrogen atmosphere, add 0.20mmol bis(4-methylphenyl)phosphine oxide, 0.20mmol 1-fluoronaphthalene, 0.30mmol potassium tert-butoxide, 1.5mL toluene solvent into the reactor, and heat to 120 after sealing the tube , Continue to stir for 20 hours, stop the reaction, cool to room temperature, wash with water to remove excess alkali and salt generated in the reaction, extract the aqueous phase with dichloromethane to obtain the organic phase, dry with anhydrous sodium sulfate, and distill under reduced pressure to remove the solvent. The target product was obtained after column chromatography, and the separation yield was 89%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium <i>tert</i>-butylate In toluene at 120℃; for 20h; Inert atmosphere; Sealed tube; | 1 Example 1 This embodiment provides a method for preparing diphenyl (1-naphthyl) phosphine oxide, which is specifically as follows:Under nitrogen atmosphere, add 0.20mmol diphenylphosphine oxide, 0.20mmol 1-fluoronaphthalene, 0.30mmol potassium tert-butoxide, 1.5mL toluene solvent into the reactor, seal the tube and heat to 120, continue stirring for 20h, stop React, cool to room temperature, wash with water to remove excess alkali and salt generated in the reaction, extract the aqueous phase with dichloromethane to obtain the organic phase, dry with anhydrous sodium sulfate, distill under reduced pressure to remove the solvent, the crude product is separated by column chromatography to obtain the target The product has an isolated yield of 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; (1-[2-(di-tert-butylphosphanyl)phenyl]-4-methoxypiperidine) In tetrahydrofuran; toluene at 110℃; for 10h; Glovebox; Inert atmosphere; | General procedure C: Palladium-catalyzeddiarylmethane derivatives cross-coupling reactionof (hetero)aryl fluorides with functionalizedbenzyltitanium(IV) reagents General procedure: In a glovebox, solid aryl fluorides (0.20 mmol), PdCl2(dppf)2(2 mol%), and L1 (2 mol%) were charged to a dried two-neckround-bottom reaction flask equipped with an addition funnel,and ArCH2Ti(OiPr)3 (0.30 mmol) in 1 cm3toluene:THF(2:1) was added. The mixture was stirred at room temperaturefor 15 min and warmed to 110 °C and was allowed toreact for 10 h and quenched by the addition of 10 cm3water.The solution was extracted with dichloromethane (3 × 30cm3).The combined organic phase was dried over MgSO4and concentrated to dryness under reduced pressures. Theresidue was purified by column chromatography to givethe coupling product. 3aa, 3ba, 3ca, 3da, 3ea, 3fa, 3ga,3 ha, 3ia, 3ja, 3 ka, 3la, 3ma, 3na, 3oa, 3pa, 3qa, 3ra, 3sa,3ta, 3ua, 3va, 3wa, 3xa, 3ya, 3yb, 3yc, 3yd, 3yf, 3yg, 3yh,and 3yj have been reported earlier, and their spectral datamatched with those presented in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; (1-[2-(di-tert-butylphosphanyl)phenyl]-4-methoxypiperidine) In tetrahydrofuran; toluene at 110℃; for 10h; Glovebox; Inert atmosphere; | General procedure B: Palladium-catalyzeddiarylmethane derivatives cross-coupling reactionof (hetero)aryl fluorides with benzyltitanium(IV)reagents General procedure: In a glovebox, solid aryl fluorides (0.20 mmol), PdCl2(dppf)2(2 mol%), and L1 (2 mol%) were charged to a dried two-neckround-bottom reaction flask equipped with an addition funnel,and ArCH2Ti(OiPr)3 (0.30 mmol) in 1 cm3toluene:THF(2:1) was added. The mixture was stirred at room temperaturefor 15 min and warmed to 110 °C and was allowed toreact for 10 h and quenched by the addition of 10 cm3water.The solution was extracted with dichloromethane (3 × 30cm3).The combined organic phase was dried over MgSO4and concentrated to dryness under reduced pressures. Theresidue was purified by column chromatography to givethe coupling product. 3aa, 3ba, 3ca, 3da, 3ea, 3fa, 3ga,3 ha, 3ia, 3ja, 3 ka, 3la, 3ma, 3na, 3oa, 3pa, 3qa, 3ra, 3sa,3ta, 3ua, 3va, 3wa, 3xa, 3ya, 3yb, 3yc, 3yd, 3yf, 3yg, 3yh,and 3yj have been reported earlier, and their spectral datamatched with those presented in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; (1-[2-(di-tert-butylphosphanyl)phenyl]-4-methoxypiperidine) In tetrahydrofuran; toluene at 110℃; for 10h; Glovebox; Inert atmosphere; | General procedure B: Palladium-catalyzeddiarylmethane derivatives cross-coupling reactionof (hetero)aryl fluorides with benzyltitanium(IV)reagents General procedure: In a glovebox, solid aryl fluorides (0.20 mmol), PdCl2(dppf)2(2 mol%), and L1 (2 mol%) were charged to a dried two-neckround-bottom reaction flask equipped with an addition funnel,and ArCH2Ti(OiPr)3 (0.30 mmol) in 1 cm3toluene:THF(2:1) was added. The mixture was stirred at room temperaturefor 15 min and warmed to 110 °C and was allowed toreact for 10 h and quenched by the addition of 10 cm3water.The solution was extracted with dichloromethane (3 × 30cm3).The combined organic phase was dried over MgSO4and concentrated to dryness under reduced pressures. Theresidue was purified by column chromatography to givethe coupling product. 3aa, 3ba, 3ca, 3da, 3ea, 3fa, 3ga,3 ha, 3ia, 3ja, 3 ka, 3la, 3ma, 3na, 3oa, 3pa, 3qa, 3ra, 3sa,3ta, 3ua, 3va, 3wa, 3xa, 3ya, 3yb, 3yc, 3yd, 3yf, 3yg, 3yh,and 3yj have been reported earlier, and their spectral datamatched with those presented in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; (1-[2-(di-tert-butylphosphanyl)phenyl]-4-methoxypiperidine) In tetrahydrofuran; toluene at 110℃; for 10h; Glovebox; Inert atmosphere; | General procedure B: Palladium-catalyzeddiarylmethane derivatives cross-coupling reactionof (hetero)aryl fluorides with benzyltitanium(IV)reagents General procedure: In a glovebox, solid aryl fluorides (0.20 mmol), PdCl2(dppf)2(2 mol%), and L1 (2 mol%) were charged to a dried two-neckround-bottom reaction flask equipped with an addition funnel,and ArCH2Ti(OiPr)3 (0.30 mmol) in 1 cm3toluene:THF(2:1) was added. The mixture was stirred at room temperaturefor 15 min and warmed to 110 °C and was allowed toreact for 10 h and quenched by the addition of 10 cm3water.The solution was extracted with dichloromethane (3 × 30cm3).The combined organic phase was dried over MgSO4and concentrated to dryness under reduced pressures. Theresidue was purified by column chromatography to givethe coupling product. 3aa, 3ba, 3ca, 3da, 3ea, 3fa, 3ga,3 ha, 3ia, 3ja, 3 ka, 3la, 3ma, 3na, 3oa, 3pa, 3qa, 3ra, 3sa,3ta, 3ua, 3va, 3wa, 3xa, 3ya, 3yb, 3yc, 3yd, 3yf, 3yg, 3yh,and 3yj have been reported earlier, and their spectral datamatched with those presented in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; (1-[2-(di-tert-butylphosphanyl)phenyl]-4-methoxypiperidine) In tetrahydrofuran; toluene at 110℃; for 10h; Glovebox; Inert atmosphere; | General procedure B: Palladium-catalyzeddiarylmethane derivatives cross-coupling reactionof (hetero)aryl fluorides with benzyltitanium(IV)reagents General procedure: In a glovebox, solid aryl fluorides (0.20 mmol), PdCl2(dppf)2(2 mol%), and L1 (2 mol%) were charged to a dried two-neckround-bottom reaction flask equipped with an addition funnel,and ArCH2Ti(OiPr)3 (0.30 mmol) in 1 cm3toluene:THF(2:1) was added. The mixture was stirred at room temperaturefor 15 min and warmed to 110 °C and was allowed toreact for 10 h and quenched by the addition of 10 cm3water.The solution was extracted with dichloromethane (3 × 30cm3).The combined organic phase was dried over MgSO4and concentrated to dryness under reduced pressures. Theresidue was purified by column chromatography to givethe coupling product. 3aa, 3ba, 3ca, 3da, 3ea, 3fa, 3ga,3 ha, 3ia, 3ja, 3 ka, 3la, 3ma, 3na, 3oa, 3pa, 3qa, 3ra, 3sa,3ta, 3ua, 3va, 3wa, 3xa, 3ya, 3yb, 3yc, 3yd, 3yf, 3yg, 3yh,and 3yj have been reported earlier, and their spectral datamatched with those presented in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; (1-[2-(di-tert-butylphosphanyl)phenyl]-4-methoxypiperidine) In tetrahydrofuran; toluene at 110℃; for 10h; Glovebox; Inert atmosphere; | General procedure B: Palladium-catalyzeddiarylmethane derivatives cross-coupling reactionof (hetero)aryl fluorides with benzyltitanium(IV)reagents General procedure: In a glovebox, solid aryl fluorides (0.20 mmol), PdCl2(dppf)2(2 mol%), and L1 (2 mol%) were charged to a dried two-neckround-bottom reaction flask equipped with an addition funnel,and ArCH2Ti(OiPr)3 (0.30 mmol) in 1 cm3toluene:THF(2:1) was added. The mixture was stirred at room temperaturefor 15 min and warmed to 110 °C and was allowed toreact for 10 h and quenched by the addition of 10 cm3water.The solution was extracted with dichloromethane (3 × 30cm3).The combined organic phase was dried over MgSO4and concentrated to dryness under reduced pressures. Theresidue was purified by column chromatography to givethe coupling product. 3aa, 3ba, 3ca, 3da, 3ea, 3fa, 3ga,3 ha, 3ia, 3ja, 3 ka, 3la, 3ma, 3na, 3oa, 3pa, 3qa, 3ra, 3sa,3ta, 3ua, 3va, 3wa, 3xa, 3ya, 3yb, 3yc, 3yd, 3yf, 3yg, 3yh,and 3yj have been reported earlier, and their spectral datamatched with those presented in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; (1-[2-(di-tert-butylphosphanyl)phenyl]-4-methoxypiperidine) In tetrahydrofuran; toluene at 110℃; for 10h; Glovebox; Inert atmosphere; | General procedure B: Palladium-catalyzeddiarylmethane derivatives cross-coupling reactionof (hetero)aryl fluorides with benzyltitanium(IV)reagents General procedure: In a glovebox, solid aryl fluorides (0.20 mmol), PdCl2(dppf)2(2 mol%), and L1 (2 mol%) were charged to a dried two-neckround-bottom reaction flask equipped with an addition funnel,and ArCH2Ti(OiPr)3 (0.30 mmol) in 1 cm3toluene:THF(2:1) was added. The mixture was stirred at room temperaturefor 15 min and warmed to 110 °C and was allowed toreact for 10 h and quenched by the addition of 10 cm3water.The solution was extracted with dichloromethane (3 × 30cm3).The combined organic phase was dried over MgSO4and concentrated to dryness under reduced pressures. Theresidue was purified by column chromatography to givethe coupling product. 3aa, 3ba, 3ca, 3da, 3ea, 3fa, 3ga,3 ha, 3ia, 3ja, 3 ka, 3la, 3ma, 3na, 3oa, 3pa, 3qa, 3ra, 3sa,3ta, 3ua, 3va, 3wa, 3xa, 3ya, 3yb, 3yc, 3yd, 3yf, 3yg, 3yh,and 3yj have been reported earlier, and their spectral datamatched with those presented in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; (1-[2-(di-tert-butylphosphanyl)phenyl]-4-methoxypiperidine) In tetrahydrofuran; toluene at 110℃; for 10h; Glovebox; Inert atmosphere; | General procedure B: Palladium-catalyzeddiarylmethane derivatives cross-coupling reactionof (hetero)aryl fluorides with benzyltitanium(IV)reagents General procedure: In a glovebox, solid aryl fluorides (0.20 mmol), PdCl2(dppf)2(2 mol%), and L1 (2 mol%) were charged to a dried two-neckround-bottom reaction flask equipped with an addition funnel,and ArCH2Ti(OiPr)3 (0.30 mmol) in 1 cm3toluene:THF(2:1) was added. The mixture was stirred at room temperaturefor 15 min and warmed to 110 °C and was allowed toreact for 10 h and quenched by the addition of 10 cm3water.The solution was extracted with dichloromethane (3 × 30cm3).The combined organic phase was dried over MgSO4and concentrated to dryness under reduced pressures. Theresidue was purified by column chromatography to givethe coupling product. 3aa, 3ba, 3ca, 3da, 3ea, 3fa, 3ga,3 ha, 3ia, 3ja, 3 ka, 3la, 3ma, 3na, 3oa, 3pa, 3qa, 3ra, 3sa,3ta, 3ua, 3va, 3wa, 3xa, 3ya, 3yb, 3yc, 3yd, 3yf, 3yg, 3yh,and 3yj have been reported earlier, and their spectral datamatched with those presented in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; (1-[2-(di-tert-butylphosphanyl)phenyl]-4-methoxypiperidine) In tetrahydrofuran; toluene at 110℃; for 10h; Glovebox; Inert atmosphere; | General procedure B: Palladium-catalyzeddiarylmethane derivatives cross-coupling reactionof (hetero)aryl fluorides with benzyltitanium(IV)reagents General procedure: In a glovebox, solid aryl fluorides (0.20 mmol), PdCl2(dppf)2(2 mol%), and L1 (2 mol%) were charged to a dried two-neckround-bottom reaction flask equipped with an addition funnel,and ArCH2Ti(OiPr)3 (0.30 mmol) in 1 cm3toluene:THF(2:1) was added. The mixture was stirred at room temperaturefor 15 min and warmed to 110 °C and was allowed toreact for 10 h and quenched by the addition of 10 cm3water.The solution was extracted with dichloromethane (3 × 30cm3).The combined organic phase was dried over MgSO4and concentrated to dryness under reduced pressures. Theresidue was purified by column chromatography to givethe coupling product. 3aa, 3ba, 3ca, 3da, 3ea, 3fa, 3ga,3 ha, 3ia, 3ja, 3 ka, 3la, 3ma, 3na, 3oa, 3pa, 3qa, 3ra, 3sa,3ta, 3ua, 3va, 3wa, 3xa, 3ya, 3yb, 3yc, 3yd, 3yf, 3yg, 3yh,and 3yj have been reported earlier, and their spectral datamatched with those presented in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; (1-[2-(di-tert-butylphosphanyl)phenyl]-4-methoxypiperidine) In tetrahydrofuran; toluene at 110℃; for 10h; Glovebox; Inert atmosphere; | General procedure B: Palladium-catalyzeddiarylmethane derivatives cross-coupling reactionof (hetero)aryl fluorides with benzyltitanium(IV)reagents General procedure: In a glovebox, solid aryl fluorides (0.20 mmol), PdCl2(dppf)2(2 mol%), and L1 (2 mol%) were charged to a dried two-neckround-bottom reaction flask equipped with an addition funnel,and ArCH2Ti(OiPr)3 (0.30 mmol) in 1 cm3toluene:THF(2:1) was added. The mixture was stirred at room temperaturefor 15 min and warmed to 110 °C and was allowed toreact for 10 h and quenched by the addition of 10 cm3water.The solution was extracted with dichloromethane (3 × 30cm3).The combined organic phase was dried over MgSO4and concentrated to dryness under reduced pressures. Theresidue was purified by column chromatography to givethe coupling product. 3aa, 3ba, 3ca, 3da, 3ea, 3fa, 3ga,3 ha, 3ia, 3ja, 3 ka, 3la, 3ma, 3na, 3oa, 3pa, 3qa, 3ra, 3sa,3ta, 3ua, 3va, 3wa, 3xa, 3ya, 3yb, 3yc, 3yd, 3yf, 3yg, 3yh,and 3yj have been reported earlier, and their spectral datamatched with those presented in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; (1-[2-(di-tert-butylphosphanyl)phenyl]-4-methoxypiperidine) In tetrahydrofuran; toluene at 110℃; for 10h; Glovebox; Inert atmosphere; | General procedure B: Palladium-catalyzeddiarylmethane derivatives cross-coupling reactionof (hetero)aryl fluorides with benzyltitanium(IV)reagents General procedure: In a glovebox, solid aryl fluorides (0.20 mmol), PdCl2(dppf)2(2 mol%), and L1 (2 mol%) were charged to a dried two-neckround-bottom reaction flask equipped with an addition funnel,and ArCH2Ti(OiPr)3 (0.30 mmol) in 1 cm3toluene:THF(2:1) was added. The mixture was stirred at room temperaturefor 15 min and warmed to 110 °C and was allowed toreact for 10 h and quenched by the addition of 10 cm3water.The solution was extracted with dichloromethane (3 × 30cm3).The combined organic phase was dried over MgSO4and concentrated to dryness under reduced pressures. Theresidue was purified by column chromatography to givethe coupling product. 3aa, 3ba, 3ca, 3da, 3ea, 3fa, 3ga,3 ha, 3ia, 3ja, 3 ka, 3la, 3ma, 3na, 3oa, 3pa, 3qa, 3ra, 3sa,3ta, 3ua, 3va, 3wa, 3xa, 3ya, 3yb, 3yc, 3yd, 3yf, 3yg, 3yh,and 3yj have been reported earlier, and their spectral datamatched with those presented in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; (1-[2-(di-tert-butylphosphanyl)phenyl]-4-methoxypiperidine); lithium chloride In tetrahydrofuran; toluene at -10℃; for 24h; Glovebox; Inert atmosphere; | General procedure C: Palladium-catalyzeddiarylmethane derivatives cross-coupling reactionof (hetero)aryl fluorides with functionalizedbenzyltitanium(IV) reagents General procedure: In a glovebox, (hetero)aryl fluorides (0.20 mmol),PdCl2(dppf)2 (5 mol%), LiCl (0.20 mmol) and L1 (5 mol%)were charged to a dried two-neck round-bottom reactionflask equipped with an addition funnel, and ArCH2Ti(OiPr)3(0.40 mmol) in 1 cm3toluene:THF (2:1) was added. Themixture was stirred at - 10 °C for 24 h and quenched by theaddition of 10 cm3water. The solution was extracted withdichloromethane (3 × 30 cm3).The combined organic phasewas dried over MgSO4and concentrated to dryness under reduced pressures. The residue was purified by column chromatographyto give the coupling product. 3yk, 3ym, 3dm,3lm, 3za, and 4 have been reported earlier, and their spectraldata matched with those presented in the literature. Products3ye, 3yi, 3yl, and 3fm are novel compounds. |
Tags: 321-38-0 synthesis path| 321-38-0 SDS| 321-38-0 COA| 321-38-0 purity| 321-38-0 application| 321-38-0 NMR| 321-38-0 COA| 321-38-0 structure
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P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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