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CAS No. : | 35134-07-7 | MDL No. : | MFCD01571098 |
Formula : | C6H6O2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KGJDTMQUUPIAEF-UHFFFAOYSA-N |
M.W : | 142.18 | Pubchem ID : | 588315 |
Synonyms : |
|
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 |
---|---|---|
46% | With piperidine In pyridine at 80 - 90℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphorus pentachloride In diethyl ether at 0℃; for 0.25h; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With boron trifluoride diethyl etherate In benzene Heating; |
Yield | Reaction Conditions | Operation in experiment |
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52% | With sodium ethanolate In ethanol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.1% | With trichlorophosphate at 0 - 25℃; for 1h; | Step 1 A three-necked RBF was charged with 3 -methoxythiophene (100 g, 877.19mmol, 1.0 eq), and was added N,N-dimethyl formamide (200mL) followed by drop wise addition of phosphorus (V) oxychloride (98.4 mL, 1052mmol, 1.2eq) at 0° C. The reaction mixture was stirred at 0° C for 1 h. After completion, the reaction mixture was poured into ice-cold water and basified with aqueous sodium hydroxide solution to adjust the pH to -9-10. Precipitated solid was filtered and washed with water to obtain 101g of 3-methoxythiophene-2-carbaldehyde (1); Yield: 81.10%; MS(ES): m/z 143.01 [M+H]+; LCMS: 100%; 1HNMR (400 MHz, DMSO-d6): δ 8.66 (s, 1H), 8.21 (d, J= 6, 1H), 8.04 (d, J= 9.2, 1H), 4.21-4.27 (m, 4H), 2.10-2.13(m, 1H), 1.27-1.31 (m, 3H), 0.88-0.90 (m, 6H). |
73% | Stage #1: 3-methoxy-thiophene With n-butyllithium In tetrahydrofuran at 20℃; for 2h; Heating / reflux; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -10 - 20℃; | A.A.6.a Example A.6; Preparation of intermediate compound 36 To a solution [OF 3-METHOXYTHIOPHENE] (4. [46ML,] 0. [043MOL)] in [60ML] [OF THF, 18. 92ML] (0. [047MOL)] [OF A 2. 5M] solution of butyllithium in tetrahydrofuran were added dropwise at room temperature under nitrogen atmosphere. The reaction was heated to reflux for 2h, then cooled [TO-10C] and DMF (4. [31ML,] 0. [056MOL)] was added dropwise. the resulting reaction mixture was stirred at room temperature overnight. Then a 10% aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl ether. The organic layer was separated, dried [(NA2S04),] filtered and the solvent was evaporated. The residue was purified by short open column chromatography over silica gel (eluent: DCM). The desired fractions were collected and the solvent evaporated. Yielding: 4. 51g (73%) of 3-methoxy-thiophene-2-carbaldehyde [(INTERMEDIATE] compound 30). |
70.1% | Stage #1: 3-methoxy-thiophene With n-butyllithium In tetrahydrofuran for 2h; Inert atmosphere; Reflux; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -10 - 20℃; | 1 Step 1 In a 2 L, 3 -necked round-bottom flask, 3-methoxythiophene (126 g, 1.11 mol) was charged into anhydrous THF (1.5 L) under nitrogen atmosphere. To this reaction mixture, rz-BuLi (486 mL, 1.22 mol) was added dropwise at rt, and the resultant mixture was refluxed for 2 h, cooled to -10 °C followed by dropwise addition ofDMF (105 g, 1.44 mol). Then reaction mixture was allowed to stir at rt overnight until the reaction completion monitored by TLC. To this reaction mixture was added saturated ammonium chloride solution, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (5-15% EtOAc in Hexanes) to obtain 110 g of 3- methoxythiophene- 2-carbaldehyde (1); Yield, 70.1%; NMR (400 MHz, DMSO-r/6): d 9.91 - 9.78 (m, 1H), 8.15 - 7.99 (m, 1H), 7.23 - 7.08 (m, 1H), 3.97 (s, 3H). |
61% | Stage #1: 3-methoxy-thiophene With n-butyllithium In tetrahydrofuran at -78 - 20℃; for 1h; Inert atmosphere; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at 20℃; for 1.5h; Inert atmosphere; | 4.1 First step: 3-methoxythiophene-2-carboxaldehyde (4B) 3-methoxythiophene-2-carbaldehyde3-methoxythiophene (4A) (5g, 43.8mmol) under nitrogen protectionDissolved in tetrahydrofuran (30mL), cooled to -78 ° C,n-Butyllithium (19.3 mL, 48.2 mmol) was added dropwise to the reaction, and the reaction was allowed to rise to room temperature for 1 hour.Further N, N-dimethylformamide (4.8 g, 65.7 mmol)The mixture was added dropwise to the reaction, and the reaction was continued at room temperature for 1.5 hours.The reaction was quenched with saturated aqueous ammonium chloride (30 mL).The aqueous phase was extracted with ethyl acetate (30 mL×3).Wash with saturated sodium chloride (50 mL), dry over anhydrous sodiumAfter the filtrate is concentrated, the crude product is subjected to column chromatography.(petroleum ether/ethyl acetate (v/v) = 20:1 to 10:1)The yellow solid 3-methoxythiophene-2-carboxaldehyde (4B) (3.8 g, yield: 61%) was obtained. |
59.6% | Stage #1: 3-methoxy-thiophene With n-butyllithium In tetrahydrofuran at -78℃; for 1.33333h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran for 2h; | 1.1 (1) Synthesis of Compound Represented by Formula (2b-1) Was synthesized according to the above Reaction Scheme 6, After making a 200 mL round bottom flask vacuum, the compound of formula (2a-1) 5 g and 60 mL of THF were charged, -78 ° C using dry ice 30 mL of n-BuLi was slowly added dropwise over 20 minutes with stirring under agitation. After 1 hour, 5 mL of DMF was added and the reaction was allowed to proceed for another 2 hours. After completion of the reaction, the reaction solution was extracted with dichloromethane, and a small amount of water was removed using magnesium sulfate. The extract was concentrated in vacuo and the concentrated concentrate was purified by silica gel flash chromatography (ethyl acetate: hexane = 1: 6) to obtain 3.71 g (yield: 59.6%) of the compound of the formula (2b-1) |
57% | Stage #1: 3-methoxy-thiophene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere; | 2.2. Synthesis 1: To a solution of 3-methoxythiophene (2g, 17mmol) in anhydrous THF (20mL), 12mL of n-BuLi (1.6M in hexane, 19mmol) was added dropwise under N2 atmosphere at -78°C and the mixture solution was further stirred for 1h. Then, N,N-dimethylformamide (DMF, 1.6mL, 20mmol) was slowly added to the reaction mixture, which was allowed to warm to room temperature. The reaction was terminated by adding small amount of water. The solution was extracted with H2O/CH2Cl2, and the organic layer was concentrated and purified by silica column chromatography with 20% ethylacetate (EtOAc)/hexane as an eluent to give 1 (1.43g, 57%). 1H NMR (250MHz, CDCl3) δ=9.99 (s, 1H), 7.65 - 7.63 (d, J=5Hz, 1H), 6.88 - 6.86 (d, J=5Hz, 1H), 3.99ppm (s, 3H). |
48% | Stage #1: 3-methoxy-thiophene With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In hexane for 0.5h; Heating; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -40 - 20℃; for 0.5h; Stage #3: With hydrogenchloride; water | |
40% | With n-butyllithium In tetrahydrofuran at -78 - 20℃; for 2h; Inert atmosphere; | |
39% | Stage #1: 3-methoxy-thiophene With n-butyllithium In tetrahydrofuran; hexane at 20℃; for 3h; Schlenk technique; Reflux; Inert atmosphere; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -10 - 20℃; Schlenk technique; Reflux; Inert atmosphere; | |
31% | Stage #1: 3-methoxy-thiophene With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In hexane at 20℃; for 0.5h; Inert atmosphere; Reflux; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane; acetonitrile at -40 - 20℃; for 0.5h; Inert atmosphere; | 3-Methoxythiophene-2-carboxaldehyde To a solution of 3-methoxythiophene (1.00 g, 8.76 mmol) and N,N,N’,N’-tetramethylethylenediamine (1.6 mL, 10.5 mmol, 1.2 eq) in hexanes (6 mL) was added a solution of n-BuLi in hexane (2.5 M, 3.0 ml, 7.5 mmol, 0.86 eq) under argon at room temperature. The resulting brown suspension was refluxed for 30 minutes. Anhydrous THF (12 mL) was added and the mixture was cooled to -40 °C in an acetonitrile/dry ice bath. DMF (1.2 mL, 15.6 mmol, 1.8 eq) was added dropwise, and the mixture was allowed to warm to room temperature. After stirring for 30 minutes the mixture was poured into a vigorously stirred 10% aqueous HCl solution (200 mL). The pH of the solution was adjusted to ca. 6 using 5% aqueous Na2CO3 solution and the solution was extracted with diethyl ether (3 x 100 mL). The organic layer was dried (MgSO4), filtered and concentrated to yield a crystalline solid. The crystals were collected by filtration, washed with 50% ether/hexanes, and dried under vacuum (60 °C, 10 mmHg) to provide 337 mg (31%) of product as white crystalline solid: Rf 0.24 (4:1 hexane:EtOAc); 1H NMR (CDCl3) δ 9.99 (s, 1H), 7.64 (dd, 1H), 6.87 (d, 1H), 3.99 (s, 3H). |
Stage #1: 3-methoxy-thiophene With n-butyllithium Inert atmosphere; Stage #2: N,N-dimethyl-formamide Inert atmosphere; | ||
Stage #1: 3-methoxy-thiophene; N,N-dimethyl-formamide With trichlorophosphate at 0℃; for 1h; Stage #2: With sodium hydroxide In water; N,N-dimethyl-formamide | ||
With n-butyllithium at -78℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 1.) BuLi, tetramethylenediamine / 1.) ether, -60 deg C, 30 min, 2.) ether, -60 deg C, 3 h 2: 76 percent / MnO2 / tetrahydrofuran 3: 56 percent / pyridine/HCl |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1.) BuLi, tetramethylenediamine / 1.) ether, -60 deg C, 30 min, 2.) ether, -60 deg C, 3 h 2: 76 percent / MnO2 / tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 99 percent / BF3*Et2O / benzene / Heating 2: 92 percent / HSiCl3 / benzene / 5 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 99 percent / BF3*Et2O / benzene / Heating 2: benzene / 10 h / 70 °C 3: benzene / 1 h / 50 °C | ||
Multi-step reaction with 2 steps 1: 99 percent / BF3*Et2O / benzene / Heating 2: 97 percent / HSiCl3 / benzene / 1.) 3 h, 40 deg C, 2.) 1 h, r.t. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 99 percent / BF3*Et2O / benzene / Heating 2: benzene / 10 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 46 percent / piperidine / pyridine / 3 h / 80 - 90 °C 2: 73 percent / LiAlH4 / tetrahydrofuran / a) 30 min, 10 deg C, b) 30 min, 40 deg C 3: 70 percent / pyridine / CH2Cl2 / Ambient temperature 4: 1) SnCl4 / 1) CH2Cl2, -8 deg C, 2) up to 3 deg C, 1 h 5: 95 percent / NaBH4 / ethanol / Ambient temperature 6: 36 percent / Raney-Ni W-2 / ethanol; H2O / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 46 percent / piperidine / pyridine / 3 h / 80 - 90 °C 2: 73 percent / LiAlH4 / tetrahydrofuran / a) 30 min, 10 deg C, b) 30 min, 40 deg C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 46 percent / piperidine / pyridine / 3 h / 80 - 90 °C 2: 73 percent / LiAlH4 / tetrahydrofuran / a) 30 min, 10 deg C, b) 30 min, 40 deg C 3: 70 percent / pyridine / CH2Cl2 / Ambient temperature 4: 1) SnCl4 / 1) CH2Cl2, -8 deg C, 2) up to 3 deg C, 1 h 5: 95 percent / NaBH4 / ethanol / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 46 percent / piperidine / pyridine / 3 h / 80 - 90 °C 2: 73 percent / LiAlH4 / tetrahydrofuran / a) 30 min, 10 deg C, b) 30 min, 40 deg C 3: 70 percent / pyridine / CH2Cl2 / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 46 percent / piperidine / pyridine / 3 h / 80 - 90 °C 2: 73 percent / LiAlH4 / tetrahydrofuran / a) 30 min, 10 deg C, b) 30 min, 40 deg C 3: 70 percent / pyridine / CH2Cl2 / Ambient temperature 4: 1) SnCl4 / 1) CH2Cl2, -8 deg C, 2) up to 3 deg C, 1 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.68% | With boron tribromide In dichloromethane at 0 - 25℃; for 1h; | Step 2 A 3L, four-necked RBF was charged with boron tribromide (1.0 M in DCM, 1500mL) followed by drop wise addition of Intermediate (1) (101g, 711.26mmol, 1.0eq) in dichloromethane at 0° C. The reaction mixture stirred at room temperature for 1 h. After completion of reaction, the reaction mixture was transferred into ice-cold water and extracted with dichloromethane. Organic layers were combined, washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the crude material. The crude was purified by silica gel column chromatography (10% ethyl acetate in hexanes) to obtain 78.0 g of 3-hydroxythiophene-2-carbaldehyde (2); Yield: 85.68%; MS(ES): m/z 129.0 [M+H]; LCMS purity: 100%; 1HNMR (400 MHz, DMSO-d6): δ 8.66 (s, 1H), 8.21 (d, J = 6, 1H), 8.04 (d, J = 9.2, 1H), 4.21-4.27 (m, 4H), 2.10-2.13 (m, 1H), 1.27-1.31 (m, 3H), 0.88-0.90 (m, 6H). |
80% | With boron tribromide In dichloromethane at 0 - 20℃; for 14h; | Preparation of 3-hydroxythiophene-2-carbaldehyde (B) To a solution of 3-methoxythiophene-2-carbaldehyde (2 g, 14.1 mmol) was added in DCM (20 mL) at 0 °C and BBr3 (1.43 mL, 15.5 mmol) was added in it. The solution was stirred at room temperature for 14 hours. The reaction mixture was slowly quenched with water (20 mL) and the mixture was extracted with DCM (2 x 50 mL). The combined organic layers were dried over Na2S04, filtered and concentrated. The crude product was purified via flash chromatography (Si02; 5: 1 hexanes:EtOAc) to give 3-hydroxythiophene-2-carbaldehyde as a white solid. (1.5 g, 80 % yield, 1H MR confirmed) |
80% | With boron tribromide In dichloromethane at 0 - 20℃; for 14h; | Preparation of 3-hydroxythiophene-2-carbaldehyde (B) To a solution of 3-methoxythiophene-2-carbaldehyde (2 g, 14.1 mmol) was added in dichloromethane (DCM) (20 mL) at 0 °C and BBr3 (1.43 mL, 15.5 mmol) was added in it. The solution was stirred at room temperature for 14 hours. The reaction mixture was slowly quenched with water (20 mL) and the mixture was extracted with DCM (2 x 50 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated. The crude product was purified via flash chromatography (SiC^; 5: 1 hexanes:EtOAc) to give 3-hydroxythiophene-2-carbaldehyde as a white solid. (1.5 g, 80 % yield, l NMR confirmed) |
80.6% | With boron tribromide In dichloromethane at 0 - 20℃; | 2 Step 2 In a 3 L, 3 -necked round bottom flask, Intermediate (1) (95 g, 669 mmol) was charged with dichloromethane (2 L) at 0 °C. To this reaction mixture, boron tribromide (184 g, 736 mmol) was added dropwise. Then reaction mixture was allowed to stir at rt, and the reaction completion was monitored by TLC. The resultant mixture was poured into crushed ice and ammonium chloride solution. The slurry obtained was filtered through a pad of Celite. The organic phase was separated, and the aqueous layer was extracted several times with dichloromethane. The combined organic layer was dried over sodium sulfate, concentrated under reduced pressure, and crude mixture was purified by silica gel column chromatography using dichloromethane as mobile phase to obtain 69 g of 3-hydroxythiophene-2-carbaldehyde (2); Yield, 80.6%; 'H NMR (400 MHz, DMSO-r/dj: d 11.49 (s, 1H), 9.96 - 9.75 (m, 1H), 8.00 - 7.79 (m, 1H), 6.77 - 6.74 (m, 1H). |
75% | With boron tribromide In dichloromethane at 0 - 20℃; | |
75% | With boron tribromide In n-heptane; dichloromethane at 0 - 20℃; for 24h; Inert atmosphere; | |
74% | With boron tribromide In dichloromethane at 0 - 20℃; Inert atmosphere; | |
71% | With boron tribromide In dichloromethane at 0 - 20℃; treated with MeOH and NH4Cl 10% solution; | A.A.6.b To a solution of intermediate compound 30 (4. [51G,] 0. [0316MOL)] in [215ML] of DCM, 3. [3ML] (0. [0345MOL)] of BBr3 were added at [0C UNDER] nitrogen atmosphere. The reaction was stirred overnight at room temperature. The reaction was cooled to [0C] and additional 0. [52ML] [(0.] [0055MOL)] of BBr3 were added. The reaction was stirred overnight at room temperature, then treated with some drops [OF MEOH] and with a saturated aqueous solution of ammonium chloride. The mixture was filtrated through CELITE and the filtrate organic layer was separated, dried [(NA2S04),] filtered and the solvent was evaporated. The residue was purified by short open column chromatography over silica gel (eluent: DCM/Ethyl acetate 96/4). The desired fractions were collected and the solvent evaporated. Yielding: 2. [91G] [(71%) OF 3-HYDROXY-THIOPHENE-2-CARBALDEHYDE] (intermediate compound [31).] |
48% | With boron tribromide In chloroform at -10 - 50℃; | 4.2 The second step: 3-hydroxythiophene-2-carbaldehyde (4C) 3-hydroxythiophene-2-carbaldehyde3-methoxythiophene-2-carboxaldehyde (4B) (3.5 g, 25 mmol)Dissolved in chloroform (40mL), cooled to -10 ° C, and then boron tribromide(7.4 g, 30 mmol) of a solution of chloroform (20 mL) was added dropwise to the reaction.The reaction was carried out at 50 ° C for 1 hour. Cool, react water (50mL)It was quenched with 2M hydrochloric acid (20 mL).The organic phase was combined, washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.(petroleum ether/ethyl acetate (v/v) = 3:1)Obtained yellow solid 3-hydroxythiophene-2-carbaldehyde (4C)(1.5 g, yield: 48%). |
With boron tribromide Inert atmosphere; | ||
With boron tribromide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-methoxy-thiophene; n-butyllithium In diethyl ether for 1.08333h; Heating / reflux; Stage #2: With hydrogenchloride; water In diethyl ether; N,N-dimethyl-formamide at 0 - 20℃; for 14h; | 42.A 3-Methoxy-2-thiophenecarboxadlehyde was prepared by adding n-butyllithium (10.56 mmol, 2.5M solution in hexane)(Aldrich), without cooling, to a solution of 3-methoxythiophene (1g, 8.8 mmol) (Aldrich) in dry diethyl ether (5 mL) over a period of 5 min. The mixture was gently heated at reflux for 2 h at which time the organolithium compound was transferred, via cannula, to a solution of DMF (23 mmol) in diethyl ether (5 mL) which was cooled in an ice bath. The reaction was stirred at room temperature for 14 h, at which time 1N HCl (10 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (3x25 mL), and the combined organic extracts were dried over magnesium sulfate, and concentrated to yield 3-methoxy-2-thiophenecarboxaldehyde as a pale, yellow solid. The 3-methoxy-2-thiophenecarboxaldehyde was then added to ethynylmagnesium chloride (Aldrich) according to Method A above to yield 3-hydroxy-3-(3-methoxy-2-thiophenyl)-1-propyne. (Yield 151 mg, 0.9 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-methoxy-2-thiophenecarboxaldehyde With boron tribromide-dimethyl sulfide complex In dichloromethane for 18h; Stage #2: With water In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; n-butyllithium In diethyl ether; hexane; N,N-dimethyl-formamide | 42.A Synthesis of rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-(3-methoxy-2-thiophenyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (OO) Step A: 3-Hydroxy-3-(3-methoxy-2-thiophenyl)-1-propyne. 3-Methoxy-2-thiophenecarboxadlehyde was prepared by adding n-butyllithium (10.56 mmol, 2.5M solution in hexane)(Aldrich), without cooling, to a solution of 3-methoxythiophene (1 g,8.8 mmol) (Aldrich) in dry diethyl ether (5 mL) over a period of 5 min. The mixture was gently heated at reflux for 2 h at which time the organolithium compound was transferred, via cannula, to a solution of DMF (23 mmol) in diethyl ether (5 mL) which was cooled in an ice bath. The reaction was stirred at room temperature for 14 h, at which time 1N HCl (10 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (3*25 mL), and the combined organic extracts were dried over magnesium sulfate, and concentrated to yield 3-methoxy-2-thiophenecarboxaldehyde as a pale, yellow solid. The 3-methoxy-2-thiophenecarboxaldehyde was then added to ethynylmagnesium chloride (Aldrich) according to Method A above to yield 3-hydroxy-3-(3-methoxy-2-thiophenyl)-1-propyne. (Yield 151 mg, 0.9 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride In tetrahydrofuran; hexane; acetic acid | 128 Methyl 3-(SR)-[(3-methoxy-thien-2-yl)-methylamino]-2-(SR)-(4-fluorophenyl)-cyclopentane-1-(SR)-carboxylate (Racemic 2,3-cis isomer) EXAMPLE 128 Methyl 3-(SR)-[(3-methoxy-thien-2-yl)-methylamino]-2-(SR)-(4-fluorophenyl)-cyclopentane-1-(SR)-carboxylate (Racemic 2,3-cis isomer) To a solution of methyl 3-(SR)-amino-2-(SR)-(4-fluorophenyl)-cyclopentane-1-(SR)-carboxylate (67 mg, 0.282 mmol) and 3-methoxythiophene-2-carboxaldehyde ›G. Henrico et al., Bull. soc. chim. Fr., 265[(1976)] (40.3 mg, 0.283 mmol) in dry tetrahydrofuran (3 mL) were added glacial acetic acid (17 μL) and sodium triacetoxyborohydride (88 mg, 0.415 mmol). The reaction mixture was stirred overnight at room temperature under an inert atmosphere. The mixture was then evaporated, and residue was purified by flash chromatography eluding with 15% acetone in hexane to obtain 67 mg of the title compound. 400 MHz 1 H NMR (CD3 OD): d 1.80-1.97 (m, 2H), 2.08 (m, 1H), 2.29 (m, 1H), 3.59 (s, 3H), 3.63 (AB q, 2H), 3.64 (s, 3H), 6.85 (d, 1H), 7.08 (m, 2H), 7.16 (d, 1H), 7.24 (m, 2H). Mass spec (NH3 /CI): 364 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium In hexane; N,N-dimethyl-formamide | 19 Synthesis of Compound 19: Example 19 Synthesis of Compound 19: 3-{2-(3-methoxythiophen-2-yl)}acetyl-4-hydroxy-6-methyl-pyrone While stirring 100 ml of ether at -40° C., 40 ml of 2.5 M n-butyllithium/hexane solution was added and then 10.0 g (87.6 mmol) of 3-methoxythiophene added dropwise. Following the dropwise addition, the temperature was raised to 0° C. and stirring carried out for 30 minutes. After re-cooling to -60° C., 7.5 ml of DMF was added dropwise and stirring carried out for 1 hour. The reaction liquid was poured into dilute hydrochloric acid and extracted with ethyl acetate. After drying and concentrating, the residue was recrystallized from ethyl acetate hexane, and 8.93 g (62.8 mmol, 72%) of yellow crystals of the 3-methoxy-2-thiophenealdehyde obtained |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: 3-methoxy-thiophene With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: boron tribromide / dichloromethane / 0 - 20 °C 2: ethanol / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: boron tribromide / dichloromethane / 0 - 20 °C 2: ethanol / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine With sodium sulfate In dichloromethane Stage #2: With sodium tetrahydroborate In methanol; dichloromethane for 1.16667h; Enzymatic reaction; Stage #3: With hydrogenchloride In diethyl ether | 15 [(3-Methoxythiophen-2-yl)methyl]({ 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine Into a vial were added 2-[(9R)-9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine (500 mg, 1.92 mmole), 18 mL CH2C12 and sodium sulfate (1.3 g, 9.6 mmole). The 3- methoxythiophene-2-carboxaldehyde (354 mg, 2.4 mmole) was then added, and the misture was stirred overnight. NaBH4 (94 mg, 2.4 mmole) was added to the reaction mixture, stirred for 10 minutes, and then MeOH (6.0 mL) was added, stirred lh, and finally quenched with water. The organics were separated off and evaporated. The crude residue was purified by a Gilson prep HPLC. The desired fractions collected and concentrated and lyophilized. After lyophilization, residue was partitioned between CH2C12 and 2N NaOH, and the organic layers were collected. After solvent was concentrated to half of the volume, 1.0 eq of iN HC1 in Et20 was added,and majority of solvent evaporated under reduced pressure. The solid obtained was washed several times with Et20 and dried to provide [(3 -methoxythiophen-2-yl)methyl] ( { 2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5] decan-9-yl] ethyl } )amine monohydrochloride (336 mg, 41% yield, m/z 387.0 [M + H]+ observed) as a white solid. The NIVIR for Compound 140 is described herein |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium sulfate In dichloromethane at 20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: trimethyl phosphonoacetate With potassium <i>tert</i>-butylate In tetrahydrofuran at -78℃; for 0.25h; Inert atmosphere; Stage #2: 3-methoxy-2-thiophenecarboxaldehyde In tetrahydrofuran at -78 - 20℃; for 0.5h; Inert atmosphere; | (E)-Methyl 3-(3-methoxythiophene-2-yl)acrylate (S3) A suspension of potassium t-butoxide (821 mg, 7.32 mmol, 2.5 equiv) in THF (20 mL) was cooled to -78 °C in an i-PrOH/dry ice bath. To this suspension was added trimethyl phosphonoacetate (1.33 g, 7.32 mmol, 2.5 equiv). The mixture was stirred at -78 °C for 15 minutes, then a solution of 3-methoxythiophene-2-carboxaldehyde (417 mg, 2.93 mmol) in THF (5 mL) was added dropwise. The resulting homogeneous solution was stirred and allowed to warm to room temperature over 30 minutes. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (2 × 75 mL). The combined organic extracts were washed with brine (1 × 50 mL), dried over MgSO4, filtered, evaporated under reduced pressure and vacuum dried to yield 540 mg (93%) of product as a tan oil: Rf 0.46 (4:1 hexane:EtOAc); 1H NMR (CDCl3) δ 7.83 (d, 1H), 7.27 (d, 1H), 6.82 (d, 1H), 6.14 (d, 1H), 3.91 (s, 3H), 3.76 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.25 h / -78 °C / Inert atmosphere 1.2: 0.5 h / -78 - 20 °C / Inert atmosphere 2.1: hydrogen; 5% rhodium on activated aluminium oxide / ethyl acetate / 120 h / 1965.21 Torr / Inert atmosphere 3.1: potassium hydroxide / methanol; water / 48 h / 60 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 16 h / 20 °C / Inert atmosphere 5.1: dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.25 h / -78 °C / Inert atmosphere 1.2: 0.5 h / -78 - 20 °C / Inert atmosphere 2.1: hydrogen; 5% rhodium on activated aluminium oxide / ethyl acetate / 120 h / 1965.21 Torr / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.25 h / -78 °C / Inert atmosphere 1.2: 0.5 h / -78 - 20 °C / Inert atmosphere 2.1: hydrogen; 5% rhodium on activated aluminium oxide / ethyl acetate / 120 h / 1965.21 Torr / Inert atmosphere 3.1: potassium hydroxide / methanol; water / 48 h / 60 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.25 h / -78 °C / Inert atmosphere 1.2: 0.5 h / -78 - 20 °C / Inert atmosphere 2.1: hydrogen; 5% rhodium on activated aluminium oxide / ethyl acetate / 120 h / 1965.21 Torr / Inert atmosphere 3.1: potassium hydroxide / methanol; water / 48 h / 60 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 16 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: boron tribromide / dichloromethane; n-heptane / 24 h / 0 - 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: boron tribromide / dichloromethane; n-heptane / 24 h / 0 - 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 °C / Inert atmosphere 3: potassium hexamethylsilazane / toluene; tetrahydrofuran / 2.25 h / -78 - 20 °C / Inert atmosphere 4: toluene-4-sulfonic acid / methanol / Inert atmosphere 5: iodine; potassium carbonate / tetrahydrofuran / 5 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: boron tribromide / dichloromethane; n-heptane / 24 h / 0 - 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 °C / Inert atmosphere 3: potassium hexamethylsilazane / toluene; tetrahydrofuran / 2.25 h / -78 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: boron tribromide / dichloromethane; n-heptane / 24 h / 0 - 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 °C / Inert atmosphere 3: potassium hexamethylsilazane / toluene; tetrahydrofuran / 2.25 h / -78 - 20 °C / Inert atmosphere 4: toluene-4-sulfonic acid / methanol / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In acetonitrile at 20℃; for 2h; Inert atmosphere; | 8: A solution of ethylenediamine (21 mg, 0.35 mmol) in 2mL dry acetonitrile was added dropwise to the solution of 2-formyl-3-methoxythiophene (100 mg, 0.70 mmol) in 3 mL dry acetonitrile with vigorous stirring at room temperature under N2 atmosphere. Precipitation of pale yellow product was observed after around 2 h. Reaction mixture was allowed to stir overnight. Solution was concentrated in vacuum to reduce the volume and allowed to slow evaporation at room temperature to get the pale yellow crystals. Yield: 100mg (93%). Anal. Calc. for C14H16N2O2S2: C, 54.52; H, 5.23; N, 9.08. Found: C, 54.41; H, 5.32; N, 9.16%. ESI-MS: Calc. for C14H16N2O2S2: m/z 308.0653. Found 308.9910 [M+H]+. IR (cm-1, KBr, selected): 1620 (C=N), 1543 (C=N), 1389, 1226. 1H NMR (500MHz, δ, ppm, CDCl3): 8.43 (s, 2H); 7.25 (d, J=5.50Hz, 2H); 6.79 (d, J=5.50Hz, 2H); 3.86 (s, 6H); 3.81 (s, 4H). 13C NMR (125MHz, δ, ppm, CDCl3): 159.09, 153.66, 127.76, 119.20, 115.97, 61.74, 58.65. UV-Vis (THF) λmax/nm (ε/M-1cm-1): 294 (14432). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In acetonitrile at 20℃; for 24h; Inert atmosphere; | 9: A solution of 1,2-diaminobenzene (38 mg, 0.35 mmol) in 2 mL dry acetonitrile was added dropwise to the solution of 2-formyl-3-methoxythiophene (100 mg, 0.70 mmol) in 3mL dry acetonitrile with vigorous stirring at room temperature under N2 atmosphere, yellow solution was obtained. Reaction mixture was stirred for 24 h at same temperature, no precipitate was observed. Solution was concentrated in vacuum to reduce the volume and allowed to slow evaporation at room temperature to get the yellow crystals. Yield: 12 0mg (96%). M. p.: 146°C. Anal. Calc. for C18H16N2O2S2: C, 60.65; H, 4.52; N, 7.86. Found: C, 60.46; H, 4.98; N, 7.83%. ESI-MS: Calc. for C18H16N2O2S2: m/z 356.0653. Found 357.0346 [M+H]+. IR (cm-1, KBr, selected): 1566 (C=N), 1556 (C=C), 1386, 1376, 1251. 1H NMR (400MHz, δ, ppm, CDCl3): 8.24 (d, J=7.32Hz, 1H); 7.74 (d, J=6.12Hz, 1H); 7.63 (d, J=7.32Hz, 1H); 7.46 (m, 2H); 7.15 (d, J=5.52Hz, 1H); 7.04 (d, J=5.52Hz, 1H); 6.77 (d, J=5.48Hz, 1H); 5.66 (s, 2H); 4.09 (s, 3H); 3.83 (s, 3H). 13C NMR (125MHz, δ, ppm, CDCl3): 155.67, 154.96, 146.47, 143.47, 135.39, 127.63, 123.70, 122.52, 122.19, 119.52, 115.92, 115.41, 115.21, 110.50, 108.92, 58.91, 58.70, 39.31. UV-Vis (THF) λmax/nm (ε/M-1cm-1): 304 (14833). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: boron tribromide / dichloromethane / 14 h / 0 - 20 °C 2: potassium carbonate / N,N-dimethyl-formamide / 4 h / 20 °C | ||
Multi-step reaction with 2 steps 1: boron tribromide / dichloromethane / 14 h / 0 - 20 °C 2: potassium carbonate / N,N-dimethyl-formamide / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: boron tribromide / dichloromethane / 14 h / 0 - 20 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 20 °C 3.1: sodium sulfate / dichloromethane / 14 h / 20 °C 3.2: 0.5 h / 20 °C 3.3: 4 h / 20 °C | ||
Multi-step reaction with 3 steps 1.1: boron tribromide / dichloromethane / 14 h / 0 - 20 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 20 °C 3.1: sodium sulfate / dichloromethane / 14 h / 20 °C 3.2: 0.5 h / 20 °C 3.3: 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4h; | Preparation of 3-methoxythiophene-2-carbaldehyde (8) To a solution of 3-hydroxythiophene-2-carbaldehyde (0.2 g, 1.56 mmol), K2CO3 (150 mg, 3.12 mmol) and Iodomethane (244 mg, 1.72 mmol) was added in DMF (5 mL). The solution was stirred at room temperature for 4 hours. The reaction mixture was poured onto water (20 mL) and the mixture was extracted with EA (2 x 50 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated. The crude product was purified via flash chromatography (S1O2; 10: 1 hexanes:EtOAc) to give 3-methoxythiophene-2-carbaldehyde as a white solid. (0.2 g, 80 % yield, LCMS confirmed) |
With potassium carbonate In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With cetyltrimethylammonim bromide In water for 20h; Reflux; | 2.2. Synthesis 2: To a solution of 2-aminothiophenol (1.4 g, 11.6 mmol) and 1(1.5 g, 10.5 mmol) in H2O (15 mL), cetyl trimethylammonium bromide(CTAB; 0.19 g, 0.53 mmol) was added and refluxed for 20 h. Then, thereaction mixture was extracted with H2O/EtOAc, and the organic layerwas concentrated and purified by recrystallization with ethanol to give2 (2 g, 69%). 1H NMR (400 MHz, CDCl3) δ=8.00 - 7.98 (d, J=8 Hz,1 H), 7.87 - 7.85 (d, J=8 Hz, 1 H), 7.46 - 7.42 (m, 1 H), 7.41 - 7.40 (d,J=4 Hz, 1 H), 7.33 - 7.29 (m, 1 H), 6.95 - 6.94 (d, J=4 Hz, 1 H),4.09 ppm (s, 3 H); 13C NMR (100 MHz, CDCl3, 25 °C)=158.18, 152.61,135.11, 132.07, 128.27, 126.23, 124.44, 122.44, 121.45, 116.23,115.61, 59.19 ppm; MALDI-TOF-MS m/z: cald. for C12H9NOS2: 247.01[M]+; found: 247.76. |
60.4% | With cetyltrimethylammonim bromide In water for 2h; Reflux; | 1.2 (2) Synthesis of Compound Represented by Formula 2c-1 Was synthesized according to the above Reaction Scheme 7, [Formula 2b-1] 4 g of 2-aminobenzenethiol (3.5 g) and 500 mg of CTAB in 200 mL After the reaction mixture was poured into a round bottom flask, 130 mL of water And the mixture was refluxed for 2 hours. After the reaction was completed, the reaction solution was removed using a vacuum distillation apparatus, then extracted with dichloromethane, and then the residual water was removed using magnesium sulfate. The extract was concentrated in vacuo, and the concentrated concentrate was purified by silica gel flash chromatography (ethyl acetate: hexane = 1: 6) to obtain the compound of the formula (2c-1) (4.2 g, yield 60.4% . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: cetyltrimethylammonim bromide / water / 2 h / Reflux 2: boron tribromide / dichloromethane; acetone / 20 h / -78 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: cetyltrimethylammonim bromide / water / 20 h / Reflux 2: boron tribromide / dichloromethane / 20 h / -78 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: cetyltrimethylammonim bromide / water / 2 h / Reflux 2: N-Bromosuccinimide / dichloromethane / 0.5 h / 0 °C | ||
Multi-step reaction with 2 steps 1: cetyltrimethylammonim bromide / water / 20 h / Reflux 2: N-Bromosuccinimide / dichloromethane / 1 h / 0 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: cetyltrimethylammonim bromide / water / 2 h / Reflux 2: N-Bromosuccinimide / dichloromethane / 0.5 h / 0 °C 3: tetrakis(triphenylphosphine) palladium(0) / toluene / 20 h / Inert atmosphere; Reflux | ||
Multi-step reaction with 3 steps 1: cetyltrimethylammonim bromide / water / 20 h / Reflux 2: N-Bromosuccinimide / dichloromethane / 1 h / 0 °C / Inert atmosphere 3: tetrakis(triphenylphosphine) palladium(0) / toluene / 10 h / Reflux; Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: cetyltrimethylammonim bromide / water / 2 h / Reflux 2: N-Bromosuccinimide / dichloromethane / 0.5 h / 0 °C 3: tetrakis(triphenylphosphine) palladium(0) / toluene / 20 h / Inert atmosphere; Reflux 4: boron tribromide / dichloromethane; acetone / 20 h / -78 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: cetyltrimethylammonim bromide / water / 2 h / Reflux 2: N-Bromosuccinimide / dichloromethane / 0.5 h / 0 °C 3: boron tribromide / dichloromethane / 20 h / -78 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: cetyltrimethylammonim bromide / water / 2 h / Reflux 2: N-Bromosuccinimide / dichloromethane / 0.5 h / 0 °C 3: boron tribromide / dichloromethane / 20 h / -78 °C 4: tetrakis(triphenylphosphine) palladium(0) / toluene / 15 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: cetyltrimethylammonim bromide / water / 2 h / Reflux 2: N-Bromosuccinimide / dichloromethane / 0.5 h / 0 °C 3: tetrakis(triphenylphosphine) palladium(0) / toluene / 20 h / Inert atmosphere; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: cetyltrimethylammonim bromide / water / 2 h / Reflux 2: N-Bromosuccinimide / dichloromethane / 0.5 h / 0 °C 3: tetrakis(triphenylphosphine) palladium(0) / toluene / 20 h / Inert atmosphere; Reflux 4: boron tribromide / dichloromethane; acetone / 20 h / -78 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: boron tribromide / dichloromethane / 14 h / 0 - 20 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 20 °C 3.1: sodium sulfate / dichloromethane / 14 h / 20 °C 3.2: 0.5 h / 20 °C 3.3: 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.3 g | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; (R)-2-(9-(D4-pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine With sodium sulfate In dichloromethane at 20℃; for 14h; Stage #2: With sodium tetrahydroborate In dichloromethane at 20℃; for 0.5h; Stage #3: With methanol In dichloromethane at 20℃; for 4h; | Preparation of (R)-N-((3-methoxythiophen-2-yl)methyl)-2-(9-(D4-pyridin-2-yl)-6- oxaspirof 4.5 ]decan-9-yl)ethanamine To a solution of 3-methoxythiophene-2-carbaldehyde (600 mg, 4.8 mmol), (R)-2-(9-(D4- pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine (1.2 g, 6.2 mmol) and Na2SC>4 (2.8 g, 20 mmol) was added in dichloromethane (DCM) (15 mL) and the mixture was stirred at room temperature for 14 hours. NaBH4 (200 mg, 4.9 mmol) was added in it and the mixture was stirred at room (0388) temperature for 0.5 hour. MeOH (5 mL) was added in it. The solution was stirred at room (0389) temperature for 4 hours. The reaction mixture was poured onto water (20 mL) and the mixture was extracted with EA (2 x 50 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated. The crude product was purified Pre-HPLC to give (R)-N-((3-methoxythiophen-2- yl)methyl)-2-(9-(D4-pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine as a colorless clear liquid. (0.3 g, 12 % yield). HPLC purity was 99.4%. LC-MS: [M+H]=391. NMR (MeOD): 7.16 (d, 1H), 6.86 (d, 1H), 3.77-3.72 (m, 5H), 3.67 (S, 2H), 2.48-2.37 (m, 3H), 2.01 -1.86 (m, 3H), 1.75-1.38 (m, 9H), 1.10-1.08 (m, 1H), 0.75-0.68 (m, 1H). (FIG. 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: cetyltrimethylammonim bromide / water / 20 h / Reflux 2: N-Bromosuccinimide / dichloromethane / 1 h / 0 °C / Inert atmosphere 3: tetrakis(triphenylphosphine) palladium(0) / toluene / 10 h / Reflux; Inert atmosphere 4: N-Bromosuccinimide / dichloromethane / 1 h / 0 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: cetyltrimethylammonim bromide / water / 20 h / Reflux 2: N-Bromosuccinimide / dichloromethane / 1 h / 0 °C / Inert atmosphere 3: tetrakis(triphenylphosphine) palladium(0) / toluene / 10 h / Reflux; Inert atmosphere 4: N-Bromosuccinimide / dichloromethane / 1 h / 0 °C / Inert atmosphere 5: boron tribromide / dichloromethane / 20 h / -78 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-(9-(pyridin-2-yl)-6-oxaspiro[4.6]undecan-9-yl)ethanamine With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane for 0.333333h; | 14.7 Step 7: N-((3-Methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.6]undecane-9- Ethylamine (14H) 9-(Pyridin-2-yl)-6-oxaspiro[4.6]undecyl-9-yl)ethylamine (14G)(0.5 g, 2.0 mmol) was dissolved in dichloromethane (15 mL).Further sodium sulfate (1.3 g, 7.5 mmol)And 3-methoxythiophene-2-carboxaldehyde (0.28 g, 3.0 mmol)The reaction was added and the reaction was continued overnight at room temperature. Sodium borohydride (0.09 g, 2.0 mmol)After the reaction was added, the reaction was stirred for 20 minutes, and then methanol (10 mL) was added.The reaction was stirred for 1 hour. The reaction was quenched with water (30 mL).The aqueous phase was extracted with dichloromethane (30 mL×4).Wash with saturated sodium chloride (30 mL), dry over anhydrous sodiumAfter the filtrate is concentrated, the crude product is analyzed by column chromatography.(dichloromethane/methanol (v/v) = 50:1 to 20:1)Obtaining a yellow oily liquidN-((3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.6]undec-9-yl)ethylamine (14H)(0.5g, yield: 30%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.7% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-(9-(4-fluorobenzyl)-6-oxaspiro[4.5]decan-9-yl)ethanamine With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane at 20℃; for 1h; | 15.4 Fourth step: 2-(9-(4-fluorobenzyl)-6-oxaspiro[4.5]decane-9-yl)-N-((3-methoxythiophen-2-yl)methyl )ethylamine (15E) The compound 2-(9-(4-fluorobenzyl)-6-oxaspiro[4.5]decane-9-yl)ethylamine (15D)(0.800g, 2.75mmol), 3-methoxythiophene-2-carbaldehyde(0.600 g, 4.22 mmol) dissolved in dichloromethane (10 mL)In the middle, anhydrous sodium sulfate (2.000 g, 14.080 mmol) was added.Stir at room temperature overnight.Add sodium borohydride (0.170 g, 4.470 mmol)After stirring at room temperature for 1 hour, 3 ml of anhydrous methanol was added and stirred for 2 hours.20 mL of water was added to the reaction mixture, and extracted with ethyl acetate (10 mL × 3).The organic phases were combined and washed with saturated brine (30 mL×1).The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated.Silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 2:1-3:1),Obtained a yellow oily product2-(9-(4-fluorobenzyl)-6-oxaspiro[4.5]decane-9-yl)-N-((3-methoxythiophen-2-yl)methyl)ethylamine ( 15E)(490 mg, yield: 42.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-(9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)ethanamine With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane for 1h; | 18.3 The third step: 2-(9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)-N-((3-methoxythiophen-2-yl) )methyl)ethylamine (18D) The compound 2-(9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)ethylamine (18C)(0.400g, 1.45mmol),3-methoxythiophene-2-carboxaldehyde (0.310 g, 2.180 mmol) dissolved in dichloromethane (10 mL)Anhydrous sodium sulfate (1.03 g, 7.254 mmol) was added.Stir at room temperature overnight.Sodium borohydride (0.083 g, 2.200 mmol) was added and stirred at room temperature for 1 hour.Add 3 ml of anhydrous methanol and stir for 2 hours.20 mL of water was added to the reaction mixture, and extracted with ethyl acetate (10 mL × 3).The organic phases were combined and washed with saturated brine (30 mL×1).The organic phase was dried over colorless sodium sulfate, filtered, evaporated and evaporated.EA/PE=2/1-3/1 gives yellow oily product2-(9-(4-Fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)-N-((3-methoxythiophen-2-yl)methyl) Ethylamine(18D) (66 mg, yield: 11%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-amino-N-(6-oxaspiro[4.5]decan-9-yl)-N-(p-tolyl)acetamide With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane for 0.166667h; | 25.1 First step: 2-(((3-methylthien-2-yl)methyl)amine)-N-(6-oxaspiro[4.5]decane-9-yl)-N-(p-tolyl) )acetamide (25A) 2-Amino-N-(6-dioxaspiro[4.5]decane-9-yl)-N-(p-tolyl)acetamide (24F)(0.3 g, 0.99 mmol) dissolved in dichloromethane (10 mL)Further sodium sulfate (0.7 g, 5.0 mmol)And 3-methoxythiophene-2-carbaldehyde(0.21 g, 1.5 mmol) was added to the reaction and allowed to react at room temperature overnight.Sodium borohydride (0.057 g, 1.5 mmol)After the addition of the reaction, the reaction was stirred for 10 minutes, and then methanol (10 mL) was added.The reaction was stirred for 1 hour. The reaction was quenched with water and the aqueous phase was dichloromethane(20mL × 3) extraction, combined organic phase, with saturated sodium chloride solution (30mL)Wash, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate.Column chromatography on crude material (dichloromethane/methanol (v/v) = 50:1)Obtained a yellow oily liquid 2-(((3-methylthiophen-2-yl)methyl)amine)-N-(6-oxaspiro[4.5]decane-9-yl)-N-(p-tolyl) )acetamide (25A)(0.15 g, yield: 35%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-(2-(6-oxaspiro[4.5]decan-9-yl)pyridin-3-yl)ethanamine With magnesium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane for 1h; | 27.1 first step:2-(2-(6-oxaspiro[4.5]decane-9-yl)pyridin-3-yl)-N-((3-methoxythiophen-2-yl)methyl)ethylamine (27A) 2-(2-(6-oxaspiro[4.5]decane-9-yl)pyridin-3-yl)ethylamine (26I)(0.20 g, 0.77 mmol), 3-methoxythiophene-2-carbaldehyde(0.16 g, 1.2 mmol) dissolved in dichloromethane (10 mL)Add magnesium sulfate (0.46 g, 3.84 mmol) and stir at room temperature overnight.Sodium borohydride (44 mg, 1.15 mmol) was added and stirred at room temperature for 1 hour.Anhydrous methanol (3 mL) was added and stirred for 2 hours. Water (20 mL) was added to the reaction solution.Extracted with ethyl acetate (10 mL × 3),The organic phases were combined and washed with brine (30 mL).The organic phase was dried over colorless sodium sulfate and filtered and evaporated.Column chromatography of crude product (ethyl acetate:Petroleum ether (v/v) = 1/10-1/1) purified by column chromatography,Concentrated to dryness to give a light yellow oil2-(2-(6-oxaspiro[4.5]decane-9-yl)pyridin-3-yl)-N-((3-methoxythiophen-2-yl)methyl)ethylamine (27A )(0.22 g, yield 74%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.1% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane for 0.333333h; | 2.1 First step: (S)-N-((3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane -9-yl)ethylamine (2A) S)-2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethylamine (Intermediate 1) (1.0 g, 3.62 mmol)Soluble in dichloromethane (15 mL),Further sodium sulfate (2.57g, 18.1mmol)And 3-methoxythiophene-2-carboxaldehyde(0.64 g, 4.52 mmol) was added to the reaction and the mixture was reacted overnight at room temperature. Sodium borohydride(0.17 g, 4.52 mmol) was added to the reaction, and the reaction was stirred for 20 minutes.Further methanol (10 mL) was added and the reaction was stirred for 1 hour.The reaction was quenched with water (30 mL) andEtOAcEtOAcThe combined organic layers were washed with saturated sodiumAfter filtration, the filtrate was concentrated, and the crude product was subjected to column chromatography.(dichloromethane/methanol (v/v) = 50:1 to 20:1) to obtain a yellow oily liquid(S)-N-((3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl )ethylamine (2A)(0.8g, yield: 57.1%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.4% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-(10-(pyridin-2-yl)-6-oxaspiro[4.6]undecan-10-yl)ethanamine With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane for 0.333333h; | 32.2 Second step: N-((3-methoxythiophen-2-yl)methyl)-2-(10-(pyridin-2-yl)-6-oxaspiro[4.6] Monoalkyl-10-yl)ethylamine (33C) 2-(10-(Pyridin-2-yl)-6-oxaspiro[4.6]undec-10-yl)ethylamine (33B) (0.5 g, 1.82 mmol) was dissolved in dichloromethane (15 mL) in,Further sodium sulfate (1.3 g, 7.5 mmol)And 3-methoxythiophene-2-carboxaldehyde(0.35 g, 2.46 mmol) was added to the reaction, which was reacted overnight at room temperature.Sodium borohydride (0.14 g, 3.64 mmol) was added to the reaction.The reaction was stirred for 20 minutes, then methanol (10 mL) was added and the mixture was stirred for 1 hour.The reaction was quenched with water (30 mL) andEtOAcEtOAcThe combined organics were washed with saturated sodium chloride (30 mL)Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate.Column chromatography on crude product (dichloromethane/methanol (v/v) = 50:1 to 20:1)Obtained a yellow oily liquid N-((3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.6]undecane-9- Ethylamine (33C)(0.52g, yield: 71.4%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-amino-N-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetamide With magnesium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane at 20℃; for 1h; | 39.1 First step: 2-(((3-methylthien-2-yl)methyl)amino)-N-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9 -yl)acetamide (39A) 2-Amino-N-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetamide (38I)(0.30g, 1.04mmol),3-methoxythiophene-2-carbaldehyde (0.22 g, 1.55 mmol)Dissolved in dichloromethane (10mL), added magnesium sulfate(0.62 g, 5.18 mmol), stirred at room temperature overnight.Sodium borohydride (59 mg, 1.55 mmol) was added and stirred at room temperature for 1 hour.Anhydrous methanol (3 mL) was added and stirred for 2 hours. Add water (20 mL) to the reaction solutionExtracted with ethyl acetate (10 mL × 3) and combined with organic phase.It was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate.Filtration and evaporation, crude product column chromatography(ethyl acetate: petroleum ether (v/v) = 1/10-1/1) was purified by column chromatography and concentrated to dryness to give pale yellow oil.2-(((3-Methylthiophen-2-yl)methyl)amino)-N-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)B Amide (39A)(0.20 g, yield 50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-(6-fluorospiro[chroman-2,1'-cyclopentan]-4-yl)ethanamine With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane for 2h; | 1.4 the fourth step: 2-(6-fluorospiro[benzofuran-2,1'-cyclopentyl]-4-yl)-N-((3-methoxythiophen-2-yl)methyl)ethylamine(1E) 2-(6-fluorospiro[chroman-2,1'-cyclopentan]-4-yl)-N-((3- Methoxythiophen-2-yl)methyl)ethanamine2-(6-Fluorospiro[benzofuran-2,1'-cyclopentyl]-4-yl)ethylamine 1D (0.3 g, 1 mmol) at room temperatureSoluble in dichloromethane (10 mL),3-methoxythiophene-2-aldehyde (0.2 g, 1 mmol) was added in sequence.Sodium sulfate (1 g, 10 mmol) was stirred at room temperature overnight. Add methanol (3 mL),Sodium borohydride (0.05 g, 1 mmol) was added and reacted for 2 h.Water (20 mL) was added to the system and extracted with dichloromethane (30 mL×3).The organic phases were combined and washed with a saturated aqueous brine (50 mL×1).Dry over anhydrous sodium sulfate and concentrate the filtrate.Separation and purification by column chromatography (dichloromethane / methanol (v / v) = 30:1) to give a yellow liquid product2-(6-Fluorospiro[benzofuran-2,1'-cyclopentyl]-4-yl)-N-((3-methoxythiophen-2-yl)methyl)ethylamine 1E ( 0.4 g, yield 75%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-(12-(pyridin-2-yl)-1,4-dioxadispiro[4.0.46.45]tetradecan-12-yl)ethan-1-amine With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane for 0.333333h; | 47.9 Ninth step: N-((3-methoxythiophen-2-yl)methyl)-2-(12-(pyridin-2-yl)-1,4-dioxaspiro [4.0.46.45] Tetradecyl-12-yl)ethyl-1-amine (47J) 2-(12-(Pyridin-2-yl)-1,4-dioxaspiro[4.0.46.45]tetradecyl-12-yl)ethyl-1-amine (47I) (0.316 g, 1.0mmol)Soluble in dichloromethane (20mL), then sodium sulfate(1.3 g, 10.5 mmol) and 3-methoxythiophene-2-carboxaldehyde (0.142 g, 1.0 mmol)The reaction was added and the reaction was continued overnight at room temperature. Sodium borohydride(0.049 g, 1.30 mmol) was added to the reaction, and the reaction was stirred for 20 minutes.Further methanol (10 mL) was added and the reaction was stirred for 1 hour. The reaction water (30mL)After quenching, the aqueous phase was extracted with dichloromethane (30 mL×4), and the organic phase was combined.Washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered and evaporated.Get yellow oil Liquid N-((3-methoxythiophen-2-yl)methyl)-2-(12-(pyridin-2-yl)-1,4-dioxaspiro[4.0.46.45]tetradecane Ethyl-12-yl)ethyl-1-amine (47J) (0.15 g, yield 34%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: boron tribromide / chloroform / -10 - 50 °C 2.1: potassium hydroxide / water; acetonitrile / 1 h / 0 - 20 °C 3.1: sodium sulfate / dichloromethane / 20 °C 3.2: 0.17 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: boron tribromide / chloroform / -10 - 50 °C 2: potassium carbonate / N,N-dimethyl-formamide / 6 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: boron tribromide / chloroform / -10 - 50 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 6 h / 80 °C 3.1: sodium sulfate / dichloromethane / 20 °C 3.2: 0.17 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium sulfate / dichloromethane / 20 °C 1.2: 0.33 h 2.1: 1,2-dichloro-ethane / 3 h / 20 °C 2.2: 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium sulfate / dichloromethane / 20 °C 1.2: 0.33 h 2.1: 1,2-dichloro-ethane / 3 h / 20 °C 2.2: 16 h / 20 °C 3.1: hydrogenchloride / ethyl acetate / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: boron tribromide / chloroform / -10 - 50 °C 2: potassium carbonate / N,N-dimethyl-formamide / 2 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: boron tribromide / chloroform / -10 - 50 °C 2.1: potassium hydroxide / water; acetonitrile / 1 h / 0 - 20 °C 3.1: sodium sulfate / dichloromethane / 20 °C 3.2: 0.33 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: boron tribromide / chloroform / -10 - 50 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 100 °C 3.1: sodium sulfate / dichloromethane / 20 °C 3.2: 0.17 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: boron tribromide / chloroform / -10 - 50 °C 2: potassium hydroxide / water; acetonitrile / 1 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.2% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-((8,9-trans)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-8-yl)ethanamine With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane at 20℃; for 1h; | 50.7 Step 7: 2-((8,9 trans)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decane-8-yl)-N-((3-methoxy) Thiophen-2-yl)methyl)ethylamine (50H) The compound 2-((8,9 trans)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decane-8-yl)ethylamine (50G) (0.500g, 1.704mmol), 3-methoxythiophene-2-carbaldehyde(0.315 g, 2.215 mmol) dissolved in dichloromethane(20 mL), anhydrous sodium sulfate (1.21 g, 8.521 mmol) was added.Stir at room temperature overnight. Add sodium borohydride(0.097 g, 2.556 mmol) was stirred at room temperature for 1 hour.Add 3 ml of anhydrous methanol and stir for 2 hours. Water (20 mL) was added to the reaction solution.Extract with ethyl acetate (10 mL × 3), and combine the organic phases.And washed with saturated saline (30 mL × 1),The organic phase is dried over colorless sodium sulphate, filtered, evaporated and evaporated.EA/PE=2/1-3/1 gives yellow oily product2-((8,9 trans)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decane-8-yl)-N-((3-methoxythiophen-2- Methyl)ethylamine(50H) (380 mg, yield: 55.2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-(6-(pyridin-2-yl)-3-oxaspiro[bicyclo[3.1.0]n-hexane-2,1'-cyclopentan]-6-yl)ethylamine With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane for 0.166667h; | 59.16 Step 16: N-((3-Methoxythiophen-2-yl)methyl)-2-(6-(pyridin-2-yl)-3-oxaspiro[bicyclo[3.1.0] n-Hexane-2,1'-cyclopentane]-6-yl)ethylamine (59R) 2-(6-(Pyridin-2-yl)-3-oxaspiro[bicyclo[3.1.0]n-hexane-2,1'-cyclopentane]-6-yl)ethylamine (59P) ( 0.07 g, 0.27 mmol) was dissolved in dichloromethane (10 mL).Further, sodium sulfate (0.19 g, 1.4 mmol) and 3-methoxythiophene-2-carbaldehyde (0.077 g, 0.54 mmol) were added to the reaction, and the reaction was carried out at room temperature overnight.. Sodium borohydride (0.015 g, 0.41 mmol) was added to the reaction, and the reaction was stirred for 10 minutes, then methanol (5 mL) was added and the mixture was stirred for 1 hour.The reaction was quenched with water (20 mL) andEtOAc.The combined organic phases were washed with a saturated sodium chloride solution (20 mL).Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate.Column chromatography (dichloromethane/methanol (v/v) = 50:1 to 20:1) afforded a yellow oily liquid N-((3-methoxythiophen-2-yl)methyl)-2- (6-(pyridin-2-yl)-3-oxaspiro[bicyclo[3.1.0]]Alkano-2,1'-cyclopentane]-6-yl)ethylamine (59R) (0.023 g, yield: 22%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 3-(3-isopropoxyphenyl)-3-(pyridin-2-yl)propan-1-amine With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane for 0.333333h; | 61.6 Step 6: 3-(3-Isopropoxyphenyl)-N-((3-methoxythiophen-2-yl)methyl)-3-(pyridin-2-yl)propyl-1- Amine (61G) 3-(3-Isopropoxyphenyl)-3-(pyridin-2-yl)propyl-1-amine (61F) (0.41 g, 1.5 mmol) was dissolved in dichloromethane.Further sodium sulfate (1.3 g, 7.5 mmol)And 3-methoxythiophene-2-carboxaldehyde(0.23 g, 1.6 mmol) was added to the reaction, and the mixture was stirred at room temperature overnight.Sodium borohydride (0.09 g, 2.0 mmol) was added to the reaction.The reaction was stirred for 20 minutes, and then methanol (10 mL) was added and the mixture was stirred for 1 hour.The reaction was quenched with water (30 mL) andEtOAc.The organic phase was combined and washed with saturated sodium chloride (30 mL).Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate.Column chromatography on crude product (dichloromethane/methanol (v/v) = 50:1 to 20:1)Obtaining a yellow oily liquid3-(3-Isopropoxyphenyl)-N-((3-methoxythiophen-2-yl)methyl)-3-(pyridin-2-yl)propyl-1-amine(61G) (0.05g, yield: 8%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-(2-(pyridin-2-yl)bicyclo[2.2.2]octan-2-yl)ethanamine With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane for 2h; | 65.8 Step 8: N-((3-Methoxythiophen-2-yl)methyl)-2-(2-(pyridin-2-yl)bicyclo[2.2.2]oct-2-yl)ethylamine (65I) 2-(2-(Pyridin-2-yl)bicyclo[2.2.2]oct-2-yl)ethylamine 65H(0.20 g, 0.90 mmol) was dissolved in dichloromethane (10 mL).To this was added 3-methoxythiophen-2- aldehyde (0.15 g, 1 mmol), anhydrous sodium sulfate (0.5 g). Reactive overnight at room temperature,Add 3 mL of methanol and sodium borohydride (0.05 g, 1.35 mmol) and continue stirring for 2 h.Water (20 mL) was added, and extracted with dichloromethane (20 mL×2).Wash with a saturated aqueous solution of brine (30 mL×1) and dry over anhydrous sodium sulfate.Filtration, concentration of the filtrate, column chromatography (dichloromethane / methanol = 30:1)Made a yellow oilN-((3-Methoxythiophen-2-yl)methyl)-2-(2-(pyridin-2-yl)bicyclo[2.2.2]oct-2-yl)ethylamine65I (0.14 g, 50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-2-en-9-yl)ethanamine With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane for 0.333333h; | 66.11 Eleventh step: N-((3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-2- Ace-9-yl)ethylamine (66L) 2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-2-en-9-yl)ethylamine (66K)(0.34 g, 1.3 mmol) dissolved in dichloromethane (15 mL)Further sodium sulfate (1.3 g, 10.5 mmol)And 3-methoxythiophene-2-carboxaldehyde(0.22 g, 1.6 mmol) was added to the reaction, and the reaction was carried out overnight at room temperature.Sodium borohydride (0.074 g, 2.0 mmol) was added to the reaction.The reaction was stirred for 20 minutes, methanol (10 mL) was further added, and the mixture was stirred for 1 hour.The reaction was quenched with water (30 mL) andEtOAcEtOAcThe combined organic layers were washed with saturated sodium chloride (30 mL), filtration, concentration of the filtrate, and crude column chromatography(dichloromethane/methanol (v/v) = 50:1 to 20:1) to obtain a yellow oily liquidN-((3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-2-ene-9-yl Ethylamine (66L) (0.05g, yield: 10%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.5% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-(4'-(pyridin-2-yl)tetrahydrospiro[bicyclo[3.1.0]hexane-3,2'-pyran]-4'-yl)ethanamine With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane for 0.333333h; | 68.6 Step 6: N-((3-Methoxythiophen-2-yl)methyl)-2-(4'-(pyridin-2-yl)tetrahydrooxaspiro[bicyclo[3.1.0]hexane -3,2'-pyran]-4'-yl)ethylamine (68F) 2-(4'-(Pyridin-2-yl)tetrahydrooxaspiro[bicyclo[3.1.0]hexane-3,2'-pyran]-4'-yl)ethylamine (68E) (0.30 g, 1.3mmol)Dissolved in dichloromethane (15 mL), then sodium sulfate (1.3 g, 10.5 mmol)And 3-methoxythiophene-2-carboxaldehyde (0.22 g, 1.6 mmol) was added to the reaction.The reaction was carried out overnight at room temperature. Sodium borohydride (0.074 g, 2.0 mmol) was added Into the reaction, the reaction was stirred for 20 minutes, and then methanol (10 mL) was added.The reaction was stirred for 1 hour. The reaction was quenched with water (30 mL). The aqueous phase was extracted with dichloromethane (30 mL×4).Wash with saturated sodium chloride (30 mL), dry over anhydrous sodiumAfter concentrating the filtrate, the crude product was purified by column chromatography (dichloromethane/methanol (v/v) = 50:1 to 20:1) to give a yellow oil. N-((3-methoxythiophen-2-yl)methyl)-2-(4'-(pyridin-2-yl)tetrahydrooxaspiro[bicyclo[3.1.0]hexane-3, 2'-Pyrano]-4'-yl)ethylamine (68F) (0.22 g, yield: 42.5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.2% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-[2-(2-pyridyl)-11-oxadispiro[3.1.46.34]tridecan-2-yl]ethanamine With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane for 0.166667h; | 70.7 Step 7:N-((3-methoxythiophen-2-yl)methyl)-2-(2-(pyridin-2-yl)-11-oxaspiro[3.1.46.34]tridec-2-yl ) Ethyl-1-amine (70H) 2-[2-(2-Pyridinyl)-11-oxadispiro[3.1.46.34]tridec-2-yl]ethylamine (70G)(0.30 g, 0.99 mmol) dissolved in dichloromethane (10 mL)Further sodium sulfate (0.71 g, 4.9 mmol)And 3-methoxythiophene-2-carboxaldehyde(0.21 g, 1.5 mmol) was added to the reaction and allowed to react at room temperature overnight.Sodium borohydride (0.056 g, 1.5 mmol) was added to the reaction and stirred The reaction was stirred for 10 minutes, then methanol (10 mL) was added and the mixture was stirred for 1 hour.The reaction was quenched with water (30 mL) andEtOAcEtOAcThe combined organic phases were washed with a saturated sodium chloride solution (30 mL).Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The crude product was purified by column chromatography (dichloromethane/methanol (v/v) = 50:1 to 20:1) to give a white solid liquid.N-((3-methoxythiophen-2-yl)methyl)-2-(2-(pyridin-2-yl)-11-oxaspiro[3.1.46.34]tridec-2-yl ) Ethyl-1-amine (70H)(0.15 g, yield: 35.2%). |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-(9-(pyridin-2-yl)-2,6-dioxaspiro[4.5]decan-9-yl)ethanamine With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane for 0.333333h; | 6.7 Step 7:N-((3-methylthien-2-yl)methyl)-2-(9-(pyridin-2-yl)-2,6-dioxaspiro[4.5]decane-9-yl)ethylamine (6H) 2-(9-(Pyridin-2-yl)-2,6-dioxaspiro[4.5]decane-9-yl)ethylamine (6G)(1.6 g, 6.1 mmol) dissolved in dichloromethane (15 mL)Further sodium sulfate (4.3 g, 30.5 mmol)And 3-methoxythiophene-2-carboxaldehyde (1.3 g, 9.1 mmol) was added to the reaction.The reaction was carried out overnight at room temperature. Sodium borohydride (0.35 g, 9.1 mmol) was added to the reaction.The reaction was stirred for 20 minutes, then additional methanol (10 mL) was added and the mixture was stirred for 1 hour.The reaction was quenched with water (30 mL).The combined organic phases were washed with a saturated sodium chloride solution (30 mL).Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate.Column chromatography on crude product (dichloromethane/methanol (v/v) = 50:1 to 20:1)Obtaining a yellow oily liquidN-((3-methylthiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-2,6-dioxaspiro[4.5]Decane-9-yl)ethylamine compound 6H. | |
Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-(9-(pyridin-2-yl)-2,6-dioxaspiro[4.5]decan-9-yl)ethanamine With sodium sulfate In dichloromethane at 25℃; for 48h; Stage #2: With sodium tetrahydroborate In methanol at 0 - 25℃; for 16h; | 1.1 Step 1: Preparation of Compound 1 The compound L1 (305.0 mg, 1.2 mmol) was dissolved in dichloromethane (8.0 mL) at 25° C., and the compound 3-methoxy-2-thiophen-carbaldehyde (247.9 mg, 1.7 mmol) and anhydrous sodium sulfate (165.1 mg, 1.2 mmol) were sequentially added. After reaction for 48 hours, the reaction solution was concentrated in vacuum. Methanol (8.0 mL) was added to the concentrate, and the temperature was lowered to 0° C., and then sodium borohydride (52.8 mg, 1.4 mmol) was added, and the reaction was continued at 25° C. for 16 hours. After the reaction was completed, 5 ml of water was added to quench the reaction. The reaction solution was filtered, the filter residue was washed with ethyl acetate (30 mL), and the filtrate was concentrated in vacuum. The concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane/ethyl acetate=1/1 to dichloromethane/methanol=5/1) to give compound 1. MS m/z: 389.1 [M+1]. 1H NMR (400 MHz, CDCl3) δ 8.58-8.55 (m, 1H), 7.67-7.62 (m, 1H), 7.32-7.28 (m, 1H), 7.15-7.12 (m, 1H), 7.06-7.04 (d, J=8 Hz, 1H), 6.79-6.77 (d, J=8 Hz, 1H), 3.87-3.67 (m, 9.5H), 3.55-3.53 (d, J=8.0 Hz, 0.5H), 3.18-3.15 (d, J=12.0 Hz, 0.5H), 2.85-2.83 (d, J=8.0 Hz, 0.5H), 2.55-2.42 (m, 2H), 2.20-2.12 (m, 1H), 2.05-1.77 (m, 6H), 1.41-1.35 (m, 0.5H), 1.27-1.11 (m, 0.5H). |
Yield | Reaction Conditions | Operation in experiment |
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40% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; 2-(9-(prop-1-yn-1-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane for 0.333333h; | 9.4 Fourth step: N-((3-methylthien-2-yl)methyl)-2-(9-(prop-1-yn-1-yl)-6-oxaspiro[4.5]decane- 9-yl)ethylamine (9E) 2-(9-(prop-1-yn-1-yl)-6-dioxaspiro[4.5]decane-9-yl)ethylamine (9D)(0.6 g, 2.7 mmol) dissolved in dichloromethane (15 mL)And then sodium sulfate (1.9g, 13.5mmol) and 3-methoxythiophene-2-carboxaldehyde(0.57 g, 4 mmol) was added to the reaction and allowed to react at room temperature overnight.Sodium borohydride (0.15 g, 4 mmol) was added to the reaction.The reaction was stirred for 20 minutes, then methanol (15 mL) was added and the mixture was stirred for 1 hour.The reaction was quenched with water (30 mL).The aqueous phase was extracted with dichloromethane (30 mL x 3) and organic phases were combined.Wash with saturated sodium chloride solution (30 mL), dry over anhydrous sodiumAfter the filtrate is concentrated, the crude product is subjected to column chromatography.(dichloromethane/methanol (v/v) = 50:1 to 20:1)Obtaining a yellow oily liquidN-((3-methylthien-2-yl)methyl)-2-(9-(prop-1-yn-1-yl)-6-oxaspiro[4.5]decane-9-yl) Ethylamine (9E)(0.4 g, yield: 40%). |
Yield | Reaction Conditions | Operation in experiment |
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59.3% | Stage #1: 3-methoxy-2-thiophenecarboxaldehyde; (9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)methanamine With sodium sulfate In dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In dichloromethane at 20℃; for 1h; | 10.8 Step 8: N-((9-(4-Fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)methyl)-1-(3-methoxythiophene- 2-yl)methylamine (10I) The compound (9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)methylamine (10H)(0.250 g, 0.957 mmol), 3-methoxythiophene-2-carbaldehyde(0.204 g, 1.430 mmol) was dissolved in dichloromethane (10 mL)Anhydrous sodium sulfate (0.679 g, 4.780 mmol) was added.Stir at room temperature overnight. Add sodium borohydride (0.060 g, 1.600 mmol)After stirring at room temperature for 1 hour, 3 ml of anhydrous methanol was added and stirred for 2 hours.Water (20 mL) was added to the reaction mixture, and ethyl acetate (10 mL×3)The organic phases were combined and washed with saturated brine (30 mL×1).The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated and evaporated.EA/PE=2/1-3/1 gives yellow oily productN-((9-(4-fluorophenyl)-6-oxaspiro[4.5]dec-8-en-8-yl)methyl)-1-(3-methoxythiophen-2-yl) Methylamine (10I)(220 mg, yield: 59.3%). |