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CAS No. : | 163210-97-7 | MDL No. : | MFCD08234800 |
Formula : | C12H16N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BFFGYMOQOGMTBM-UHFFFAOYSA-N |
M.W : | 220.27 | Pubchem ID : | 15429161 |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P280-P305+P351+P338-P304+P340 | UN#: | |
Hazard Statements: | H302 | Packing Group: | |
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 |
---|---|---|
Stage #1: methyl 4-(piperazin-1-yl)benzoate; cyclobutanone With sodium cyanoborohydride; acetic acid In tetrahydrofuran; water for 6h; Heating / reflux; Stage #2: With potassium carbonate In water | i Methyl 4-(piperazin-l-yl)benzoate (CAS 163210-97-7, 500 mg, 2.27 mmol) was dissolved in THF (10 mL) and water (0.2 mL) with stirring. Cyclobutanone (0.238 g, 3.4 mmol) was added followed by acetic acid (0.5 mL) and sodium cyanoborohydride (0.211 g, 3.4 mmol). The mixture was refluxed for 6 h, cooled and reduced in vacuo. The residue was dissolved in IN HCl (3 mL) and water (12 mL) then washed with ethyl acetate (2 x 10 mL). The aqueous layer was adjusted to pH 10 with potassium carbonate and extracted with ethyl acetate (3 x 10 mL). The combined organics were dried (MgSO4), filtered and reduced in vacuo to give crude methyl ester (0.56 g). | |
With sodium cyanoborohydride; acetic acid In tetrahydrofuran; water for 6h; Heating / reflux; | i Methyl 4-(piperazin-l-yl)benzoate (CAS 163210-97-7, 500 mg, 2.27 mmol) was dissolved in THF (10 mL) and water (0.2 mL) with stirring. Cyclobutanone (0.238 g, 3.4 mmol) was added followed by acetic acid (0.5 mL) and sodium cyanoborohydride (0.211 g, 3.4 mmol). The mixture was refluxed for 6 h, cooled and reduced in vacuo. The residue was dissolved in IN HCl (3 mL) and water (12 mL) then washed with ethyl acetate (2 x 10 mL). The aqueous layer was adjusted to pH 10 with potassium carbonate and extracted with ethyl acetate (3 x 10 mL). The combined organics were dried (MgSO4), filtered and reduced in vacuo to give crude methyl ester (0.56 g). (ii) Methyl ester (0.51 g, assume 1.85 mmol) was suspended in 10% NaOH (3 mL) and water (3 mL) added. The mixture was heated at 8O0C for 2 h, then cooled to O0C. The mixture was acidified to pH 2 with 6N HCl, then cooled for 2 h at -50C. A tan solid was filtered and washed thoroughly with hexane and dried in vacuo to give acid (64) (yield 0.25 g). HPLC-MS 261 [M + H]+. | |
With sodium cyanoborohydride; acetic acid In tetrahydrofuran; water for 6h; | i Methyl 4-(piperazin-l-yl)benzoate (CAS 163210-97-7, 500 mg, 2.27 mmol) was dissolved in THF (10 mL) and water (0.2 mL) with stirring. Cyclobutanone (0.238 g, 3.4 mmol) was added followed by acetic acid (0.5 mL) and sodium cyanoborohydride (0.211 g, 3.4 mmol). The mixture was refluxed for 6 h, cooled and reduced in vacuo. The residue was dissolved in IN HCl (3 mL) and water (12 mL) then washed with ethyl acetate (2 x 10 mL). The aqueous layer was adjusted to pH 10 with potassium carbonate and extracted with ethyl acetate (3 x 10 mL). The combined organics were dried (MgSO4), filtered and reduced in vacuo to give crude methyl ester (0.56 g). |
With sodium cyanoborohydride; acetic acid In tetrahydrofuran; water for 6h; Heating / reflux; | Methyl 4-(piperazin-l-yl)benzoate (CAS 163210-97-7, 500 mg, 2.27 mmol) was dissolved in THF (10 mL) and water (0.2 mL) with stirring. Cyclobutanone (0.238 g, 3.4 mmol) was added followed by acetic acid (0.5 mL) and sodium cyanoborohydride (0.211 g, 3.4 mmol). The mixture was refluxed for 6 h, cooled and reduced in vacuo. The residue was dissolved in IN HCl (3 mL) and water (12 mL) then washed with ethyl acetate (2 x 10 mL). The aqueous layer was adjusted to pH 10 with potassium carbonate and extracted with ethyl acetate (3 x 10 mL). The combined organics were dried (MgSO4), filtered and reduced in vacuo to give crude methyl ester (0.56 g). | |
With sodium cyanoborohydride; acetic acid In tetrahydrofuran; water for 6h; Heating / reflux; | i Methyl 4-(piperazin-l-yl)benzoate (CAS 163210-97-7, 500 mg, 2.27 mmol) was dissolved in THF (10 mL) and water (0.2 mL) with stirring. Cyclobutanone (0.238 g, 3.4 mmol) was added followed by acetic acid (0.5 mL) and sodium cyanoborohydride (0.21 1 g, 3.4 mmol). The mixture was refluxed for 6 h, cooled and reduced in vacuo. The residue was dissolved in IN HCl (3 mL) and water (12 mL) then washed with ethyl acetate (2 x 10 mL). The aqueous layer was adjusted to pH 10 with potassium carbonate and extracted with ethyl acetate (3 x 10 mL). The combined organics were dried (MgSO4), filtered and reduced in vacuo to give crude methyl ester (0.56 g). | |
With sodium cyanoborohydride; acetic acid In tetrahydrofuran; water for 6h; Heating / reflux; | i Methyl 4-(piperazin-l-yl)benzoate (CAS 163210-97-7, 500 mg, 2.27 mmol) was dissolved in THF (10 mL) and water (0.2 mL) with stirring. Cyclobutanone (0.238 g, 3.4 mmol) was added followed by acetic acid (0.5 mL) and sodium cyanoborohydride (0.211 g, 3.4 mmol). The mixture was refluxed for 6 h, cooled and reduced in vacuo. The residue was dissolved in IN HCl (3 mL) and water (12 mL) then washed with ethyl acetate (2 x 10 mL). The aqueous layer was adjusted to pH 10 with potassium carbonate and extracted with ethyl acetate (3 x 10 mL). The combined organics were dried (MgSO4), filtered and reduced in vacuo to give crude methyl ester (0.56 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With hydrogenchloride In 1,4-dioxane; dichloromethane; water at 20℃; for 13h; Cooling with ice; | 125.2 Step 2: Synthesis of methyl 4-(piperazin-1-yl)benzoate 4-(4-(Methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (3g, 9.36mmol) was dissolved in DCM (8mL),HCl.1,4-dioxane (16mL, 48.00mmol, 3mol/L) was added under ice bath and reacted at room temperature for 13h. Part of the solvent was distilled off under reduced pressure, and solids were precipitated. The filter cake was washed with DCM (10 mL×2). Saturated NaHCO3 (120 mL) was added to the filter cake. The pH was adjusted to about 8, and DCM (150 mL×2) was extracted. It was dried over Na2SO4 and concentrated under reduced pressure to obtain a brown solid (1.9 g, 92%). |
91% | In various solvent(s) at 150℃; for 5h; microwave irradiation; | |
91% | With 1,1,1,3',3',3'-hexafluoro-propanol at 150℃; for 5h; Microwave irradiation; | 4 EXAMPLE 4; To extend the synthetic potential of this deprotection method, this protocol was further expanded to a wide range of N-Boc amines in HFIP. In each case (except as otherwise noted), 1 mmol of protected compound was microwave heated at 150° C. in HFIP (5 mL) for the time shown, and the deprotected compound recovered by chromatography. The results are shown in Table 4. In all cases, the deprotection product was obtained in good to excellent yields. |
91% | With 1,1,1,3',3',3'-hexafluoro-propanol at 150℃; for 5h; Microwave irradiation; | 4 Example 4; To extend the synthetic potential of this deprotection method, this protocol was further expanded to a wide range of N-Boc amines in HFIP. In each case (except as otherwise noted), 1 mmol of protected compound was microwave heated at 150°C in HFIP (5 mL) for the time shown, and the deprotected compound recovered by chromatography. The results are shown in Table 4. In all cases, the deprotection product was obtained in good to excellent yields. |
82.2% | With hydrogenchloride In ethyl acetate at 20℃; | B Step B: methyl 4- (piperazin-1-yl) benzoate To a solution of tert-butyl 4- (4- (methoxycarbonyl) phenyl) piperazine-1-carboxylate[1091](600 mg, 1.9 mmol) in EA (20 mL) was added HCl/EA (20 mL, 4M) , and the mixture was stirred overnight at RT. The reaction mixture filtered, the cake was collected, dried to give the target compound (400 mg, 82.2%) as a yellow solid. MS: M/e 221 (M+1)+. |
With hydrogenchloride In methanol; diethyl ether at 20℃; for 14h; | 1.A Synthesis of 4-Piperazin-1-yl-benzoic acid methyl ester [0111] BINAP (230mg, 0. [37MMOL),] Pd (II) acetate (417mg, 0. [186MMOL),] tBuONa [(1.] 25g, 13mmol), N-boc piperazine (1.9g, 10. [2MMOL)] and THF (40mL) were mixed together and stirred at room temperature for 30min under a nitrogen atmosphere. 4-bromomethyl benzoate (2g, 9. [3MMOL)] in THF [(LOML)] was added to the mixture drop wise and heated at [70°C] for 14h. Excess THF was then evaporated and extracted with ethyl acetate. The crude product was obtained on concentration of the ethyl acetate layer after washing with brine and drying. Flash chromatography on silica gel done eluting with 8% ethyl acetate in petroleum ether yielded pure N-BOC protected product. This intermediate (650mg, 2. [01MMOL)] was dissolved in methanol (20mL) and then [HC1] saturated ether (7mL) was added. The mixture was stirred at room temperature for 14 hours and concentrated. The concentrate was washed with petroleum ether to obtain white solid compound, [4-PIPERAZIN-1-YL-BENZOIC] acid methyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In butan-1-ol for 168h; Heating / reflux; | ||
In butan-1-ol for 168h; Reflux; | ||
With potassium carbonate In butan-1-ol for 177h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In N,N-dimethyl-formamide at 20℃; | ||
With triethylamine In N,N-dimethyl-formamide at 20℃; | ||
at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In hydrogenchloride | 1.B B. B. 4-piperazin-1-yl-benzoic acid hydrochlorid 4-piperazin-1-yl-benzoic acid methyl ester (17 mmol) is dissolved in 6N HCl (25 ml) and heated under reflux for 3 hours. The mixture is cooled in an ice bath to 0-4° C. and the solid material formed is filtered off, washed with acetone and dried (vacuum). A white powder with mp. >240° C. is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In methanol; water; | A. 4-piperazin-1-yl-benzoic acid methyl ester 1-(4-Cyanophenyl)-piperazine (11 mmol) is dissolved in 15 ml of a mixture of concentrated sulfonic acid and methanol (5N) and stirred in a sealed tube at 110 C. for 3 hours. After evaporation of the solvent, the residue is dissolved in water and extracted with ethyl acetate. Addition of sodium carbonate to the water phase until pH=9 results in the precipitation of a white solid which is filtered off and dried (vacuum). A white powder with Rf=0.59 (CH2Cl2/MeOH (+NH3 3N)=9:1) is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; water; In methanol; for 42h;Heating / reflux; | A solution 4-piperazin-1-yl-benzonitrile (1.5g, delta.Ommol) in MeOH (150ml) was saturated with HCI gas. Water (0.17ml) was added and the mixture was heated under reflux for 18 h. The reaction mixture was cooled to r.t. and was resaturated with HCI EPO <DP n="52"/>gas. This was refluxed for a further 24 h. The mixture was concentrated under reduced pressure yielding 4-Piperazin-1-yl-benzoic acid methyl ester (building block E). LCMS purity 90%, m/z 221 [M++H]+. Building block E was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate In acetone at 40 - 50℃; for 5h; | 2 (IV) (37g) in TBME (approx 200ml) is partly reduced in volume under reduced pressure (approx 300mbar) at a maximum temperature of 5O0C. The resulting residue was then treated with absolute acetone (370ml) to eventually produce a solution. Then, postassium carbonate (30.2g) is added to the reaction mixture at a temperature of 40-500C (internal temperature). Then, within 2 hours, propyl iodide (37.1) is added. After 3 hours the reaction mixture is tested by GC to determine the reaction completion. Where the GC indicates that less than 5% (IV) remains the reaction mixture is then reduced in volume at a temperature of 4O0C (internal temperature) and that a reduced pressure of 300mbr. The product is crystallised with TBME (320ml) together with water (270ml) where the reaction mixture is stirred for 5 minutes at a temperature of 4O0C (internal temperature) to produce a clear solution. The upper organic phase is separated and then washed with water (100ml). Then the TBME-phase is reduced in volume at a temperature of 40-5O0C (internal temperature) under reduced pressure of 300mbar where the product (II) precipitates out. The reaction mixture is further agitated at O0C for approximately 2 hours and then filtered. The filter-cake is then washed with cold TBME and dried at a temperature of 5O0C (internal temperature) under reduced pressure of 50mbar for 15 hours. Yield: 37.4g (85% of theory) EPO GC: 99.6F% ((IV) 0.1%, (V) 0.03%, (III) less than 0.01%)Titration: 99.2% (HCI) |
With potassium carbonate In acetone at 50℃; for 3h; | 3 Piperazine (696mmol) , 4-Fluorobenzoic acid methyl ester (1 29mmol) are suspended in Acetonitrile ( 200 ml) and refluxed 24h; the reaction mixture is transferred into TBME (t-Butylmethylether) and diluted brine . The organic phase is washed with brine; a solution with 168 mmol 4-(piperazin-1 -yl) benzoic acid methylester is concentrated at vacuo and TBME replaced by 370 ml acetone ; after addition of 218 mmol K2CO3 and 218 mmol n-propyliodide the reaction mixture is stirred 3h at 50°. After partial evaporation of acetone and replacement by TBME, the organic phase is washed with water and concentrated until 4-(4-propyl-piperazin-1 -yl) benzoic acid methylester cristallised; after filtration is obtained a colourless powder.NMR (CDCI3): 7.9 (d/ 2H), 6.9 (d/ 2H), 3.9 (s/3H), 3.4 (m/4H), 2.6 (m/ 4H), 2.4 (t/2H), 1 .6 (m/2H), 0.9 (t/3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile at 80℃; for 20.25h; | 1 A mixture of piperazine (6Og) in acetonitrile (200ml) was heated to a temperature of 75-8O0C (internal temperature) and then further heated to a temperature of 8O0C once the piperazine was in solution. The mixture was then treated with 4-fluoro-benzoic acid-methyl ester (2Og) within a period of 15 minutes. The reaction mixture was then stirred for about 20 hours. The reaction mixture was then cooled to a temperature of 4O0C and TBME (300ml) and water (200ml) were added at this temperature. Brine (100ml) was then added to the reaction mixture and the 2-phase mixture was stirred for approximately 5 minutes. The water phase was then extracted with TBME (100ml). The combined organic layers were then washed with a further solution of brine (2 x 100ml). The resulting organic phase may be used directly in the next step. GC: 14% of (V). | |
In acetonitrile for 24h; Heating / reflux; | 3 Piperazine (696mmol) , 4-Fluorobenzoic acid methyl ester (1 29mmol) are suspended in Acetonitrile ( 200 ml) and refluxed 24h; the reaction mixture is transferred into TBME (t-Butylmethylether) and diluted brine . The organic phase is washed with brine; a solution with 168 mmol 4-(piperazin-1 -yl) benzoic acid methylester is concentrated at vacuo and TBME replaced by 370 ml acetone ; after addition of 218 mmol K2CO3 and 218 mmol n-propyliodide the reaction mixture is stirred 3h at 50°. After partial evaporation of acetone and replacement by TBME, the organic phase is washed with water and concentrated until 4-(4-propyl-piperazin-1 -yl) benzoic acid methylester cristallised; after filtration is obtained a colourless powder.NMR (CDCI3): 7.9 (d/ 2H), 6.9 (d/ 2H), 3.9 (s/3H), 3.4 (m/4H), 2.6 (m/ 4H), 2.4 (t/2H), 1 .6 (m/2H), 0.9 (t/3H). | |
In acetonitrile at 75 - 80℃; for 20h; | Synthesis of Methyl 4-(piperazin-1-yl)benzoate (3) A mixture of piperazine 2 (60.00 g, 0.70 mol) in acetonitrile (200 mL) was heated to a temperature of75-80 °C. The mixture was then treated with 4-fluoro-benzoic acid-methyl ester 1 (20.00 g, 0.13 mol).After stirring for 20 h, the reaction mixture was cooled to room temperature, and diethyl ether (300mL) and water (200 mL) were added at this temperature. The aqueous layer was extracted with diethylether (200 mL×2). The combined organic layer was washed with brine (50 mL×2), dried over Na2SO4and concentrated to give 3 as a white solid without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In tetrahydrofuran; methanol; Petroleum ether | 1 Synthesis of 4-Piperazin-1-yl-benzoic acid methyl ester Synthesis of 4-Piperazin-1-yl-benzoic acid methyl ester BINAP (230 mg, 0.37 mmol), Pd(II)acetate (417 mg, 0.186 mmol), tBuONa (1.25 g, 13 mmol), N-boc piperazine (1.9 g, 10.2 mmol) and THF (40 mL) were mixed together and stirred at room temperature for 30 min under a nitrogen atmosphere. 4-bromomethyl benzoate (2 g, 9.3 mmol) in THF (10 mL) was added to the mixture drop wise and heated at 70° C. for 14 h. Excess THF was then evaporated and extracted with ethyl acetate. The crude product was obtained on concentration of the ethyl acetate layer after washing with brine and drying. Flash chromatography on silica gel done eluding with 8% ethyl acetate in petroleum ether yielded pure N-BOC protected product. This intermediate (650 mg, 2.01 mmol) was dissolved in methanol (20 mL) and then HCl saturated ether (7 mL) was added. The mixture was stirred at room temperature for 14 hours and concentrated. The concentrate was washed with petroleum ether to obtain white solid compound, 4-Piperazin-1-yl-benzoic acid methyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 20℃; | A solution of methyl 4- (piperazin- l-yl)benzoate (0.687 g, 3.12 mmol), triethylamine (0.870 mL, 6.24 mmol) in dichloromethane (15.0 mL) was treated at room temperature with 2-oxoindoline-5-sulfonyl chloride (0.723 g, 3.12 mmol). The reaction mixture was stirred at room temperature for over night. The yellow solid was filtered and dried to give the final product. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1 H), 7.66 - 7.82 (m, 2 H), 7.46 - 7.63 (m, 2 H), 6.79 - 7.09 (m, 3 H), 3.72 (s, 3 H), 3.55 (s, 2 H), 3.32 - 3.45 (m, 4 H), 2.85 - 3.05 (m, 4 H); LCMS RT = 5.143 min, m/z 416.1 [M+H+] . | |
With triethylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 20 °C 2: sodium hydroxide / water / 6 h / 40 °C 3: triethylamine / acetonitrile / -5 - 20 °C 4: sodium hydroxide / water; methanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 20 °C 2: sodium hydroxide / water / 6 h / 40 °C 3: triethylamine / acetonitrile / -5 - 20 °C 4: sodium hydroxide / water; methanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 20 °C 2: sodium hydroxide / water / 6 h / 40 °C 3: triethylamine / acetonitrile / -5 - 20 °C 4: sodium hydroxide / water; methanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 20 °C 2: sodium hydroxide / water / 6 h / 40 °C 3: triethylamine / acetonitrile / -5 - 20 °C 4: sodium hydroxide / water; methanol / 20 °C 5: dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 20 °C 2: sodium hydroxide / water / 6 h / 40 °C 3: triethylamine / acetonitrile / -5 - 20 °C 4: sodium hydroxide / water; methanol / 20 °C 5: dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 20 °C 2: sodium hydroxide / water / 6 h / 40 °C 3: triethylamine / acetonitrile / -5 - 20 °C 4: sodium hydroxide / water; methanol / 20 °C 5: hydrogenchloride / dichloromethane / 1 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 20 °C 2: sodium hydroxide / water / 6 h / 40 °C 3: triethylamine / acetonitrile / -5 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 20 °C 2: sodium hydroxide / water / 6 h / 40 °C 3: triethylamine / acetonitrile / -5 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 20 °C 2: sodium hydroxide / water / 6 h / 40 °C 3: triethylamine / acetonitrile / -5 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55 mg | With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; Inert atmosphere; | 5.9 Step 9: Methyl 4-(4-((4-(4-chlorophenyl)-1 ,1 -dimethyl-1 ,2,5,6- tetrahydrosilin-3-yl)methyl)piperazin-1 -yl)benzoate 4-(4-Chlorophenyl)-1 , 1 -dimethyl-1 ,2,5,6-tetrahydrosiline-3-carbaldehyde (0.0651 g, 0.25 mmol) and methyl 4-(piperazin-1-yl)benzoate (0.0749g, 0.32 mmol) were dissolved in THF(1.2ml_) at r.t . under N2 atmosphere and stirred for 10 min. NaBH(OAc)3 (0.1563g, 0.74 mmol) was then added and the resulting reaction mixture was stirred at r.t. overnight. The reaction mixture was quenched with a saturated solution of NH4CI (20 mL) and extracted with a solution of 1 :1 EtOAc/hexanes (3x50mL). The combined organic layers was washed with brine (50 mL), dried over Na2S04, and filtered. The filtrate was concentrated and the residue was purified by CombiFlash eluted with 1 %-25% EtOAc/hexanes to give 55 mg pale yellow solid as the product. [00347] 1H NMR (300 MHz, CDCI3): δ 7.90 (d, 2H), 7.25 (d, 2H), 6.98 (d, 2H), 6.80 (d, 2H), 3.85 (3, 3H), 3.25 (m, 4H), 2.85 (s, 2H), 2.36-2.42 (m, 6H), 1.58 (s, 2H), 0.73 (t, 2H), 0.10 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 10h; | 338 Example 338 Preparation of 4-(4-(6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l-(pyridin-3- ylmethyl)-7-(l,3,5-trimethyl-lH-pyrazol-4-yl)-lH-indole-2-carbonyl)piperazin-l- yl)benzoic acid To a solution of 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7-(l,3,5- trimethyl- lH-pyrazol-4-yl)- lH-indole-2-carboxylic acid (25 mg, 0.05 mmol) in DMF (1 mL) at rt were added methyl 4-(piperazin- 1 -yl)benzoate (11 mg, 0.05 mmol), HBTU (70 mg, 0.185 mmol), triethylamine (56 L, 0.4 mmol) and the mixture was stirred at rt for 10 h at which time LC showed complete disappearance of starting carboxylic acid. Water (5 mL) was added to the mixture and it was extracted in CH2CI2 (3x5 mL). The organic layer was dried (anhyd. a2S04) and was evaporated. The crude was taken in DMF (1 mL) and NaH (6 mg, 0.15 mmol) at room temperature and the mixture was stirred for 30 min at ambient temperature. A solution of 3-(bromomethyl)pyridine hydrobromide (15 mg, 0.06 mmol) in DMF (1 mL) was added drop wise to the reaction mixture at room temperature and stirring was continued for additional 2 h. The mixture was diluted with water (4 mL) and extracted in CH2CI2 (3x5 mL). The organic layer was dried (anhyd. Na2S04) and was evaporated. To a solution of crude ester in THF (2 mL) at room temperature was added 2M LiOH (1 mL) the mixture was stirred at the ambient temperature for 10 h. The reaction mixture was evaporated, acidified to pH 7 with 4M HC1, extracted in EtOAc. The organic layer was dried, evaporated and finally purified by the reverse phase HPLC (Phenomenex Gemini CI 8, H2O/CH3CN gradient from 30-70% CH3CN, 0.1% TFA) to give the title compound (37 mg, 95%) as a white solid; MS (ES) 779.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 10 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.2: 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / N,N-dimethyl-formamide / 10 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.2: 2 h / 20 °C 3.1: water; lithium hydroxide / tetrahydrofuran / 10 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 16h; | General Synthesis of Methyl (E)-4-(4-(3-argioacryloyl)piperazin-1-yl)benzoate 5a-i from (E)-3-argioacrylic acid 4a-i General procedure: To (E)-3-argioacrylic acid 4a-i (5 mmol), methyl 4-(piperazin-1-yl)benzoate 3 (5.55 mmol) and TBTU(1.35 g, 5.3 mmol) in acetonitrile (50 mL) was added DBU (4 mL, 5.35 mmol). After stirring 16 h atroom temperature, the resulting white percipitate 5a-i was removed by filtration, dried in vacuo andused in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 16h; | General Synthesis of Methyl (E)-4-(4-(3-argioacryloyl)piperazin-1-yl)benzoate 5a-i from (E)-3-argioacrylic acid 4a-i General procedure: To (E)-3-argioacrylic acid 4a-i (5 mmol), methyl 4-(piperazin-1-yl)benzoate 3 (5.55 mmol) and TBTU(1.35 g, 5.3 mmol) in acetonitrile (50 mL) was added DBU (4 mL, 5.35 mmol). After stirring 16 h atroom temperature, the resulting white percipitate 5a-i was removed by filtration, dried in vacuo andused in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 16h; | General Synthesis of Methyl (E)-4-(4-(3-argioacryloyl)piperazin-1-yl)benzoate 5a-i from (E)-3-argioacrylic acid 4a-i General procedure: To (E)-3-argioacrylic acid 4a-i (5 mmol), methyl 4-(piperazin-1-yl)benzoate 3 (5.55 mmol) and TBTU(1.35 g, 5.3 mmol) in acetonitrile (50 mL) was added DBU (4 mL, 5.35 mmol). After stirring 16 h atroom temperature, the resulting white percipitate 5a-i was removed by filtration, dried in vacuo andused in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 3.1: triethylamine / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 3.1: triethylamine / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 3.1: triethylamine / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 3.1: triethylamine / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 3.1: triethylamine / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 3.1: triethylamine / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 3.1: triethylamine / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 3.1: triethylamine / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 3.1: triethylamine / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 3.1: triethylamine / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 3.1: triethylamine / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 3.1: triethylamine / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 16 h / 20 °C 2.1: sodium hydroxide / methanol; water / 7 h / 70 °C 2.2: 1 h / 20 °C / pH 6 - 7 3.1: triethylamine / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 16h; | General Synthesis of Methyl (E)-4-(4-(3-argioacryloyl)piperazin-1-yl)benzoate 5a-i from (E)-3-argioacrylic acid 4a-i General procedure: To (E)-3-argioacrylic acid 4a-i (5 mmol), methyl 4-(piperazin-1-yl)benzoate 3 (5.55 mmol) and TBTU(1.35 g, 5.3 mmol) in acetonitrile (50 mL) was added DBU (4 mL, 5.35 mmol). After stirring 16 h atroom temperature, the resulting white percipitate 5a-i was removed by filtration, dried in vacuo andused in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 16h; | General Synthesis of Methyl (E)-4-(4-(3-argioacryloyl)piperazin-1-yl)benzoate 5a-i from (E)-3-argioacrylic acid 4a-i General procedure: To (E)-3-argioacrylic acid 4a-i (5 mmol), methyl 4-(piperazin-1-yl)benzoate 3 (5.55 mmol) and TBTU(1.35 g, 5.3 mmol) in acetonitrile (50 mL) was added DBU (4 mL, 5.35 mmol). After stirring 16 h atroom temperature, the resulting white percipitate 5a-i was removed by filtration, dried in vacuo andused in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 16h; | General Synthesis of Methyl (E)-4-(4-(3-argioacryloyl)piperazin-1-yl)benzoate 5a-i from (E)-3-argioacrylic acid 4a-i General procedure: To (E)-3-argioacrylic acid 4a-i (5 mmol), methyl 4-(piperazin-1-yl)benzoate 3 (5.55 mmol) and TBTU(1.35 g, 5.3 mmol) in acetonitrile (50 mL) was added DBU (4 mL, 5.35 mmol). After stirring 16 h atroom temperature, the resulting white percipitate 5a-i was removed by filtration, dried in vacuo andused in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 16h; | General Synthesis of Methyl (E)-4-(4-(3-argioacryloyl)piperazin-1-yl)benzoate 5a-i from (E)-3-argioacrylic acid 4a-i General procedure: To (E)-3-argioacrylic acid 4a-i (5 mmol), methyl 4-(piperazin-1-yl)benzoate 3 (5.55 mmol) and TBTU(1.35 g, 5.3 mmol) in acetonitrile (50 mL) was added DBU (4 mL, 5.35 mmol). After stirring 16 h atroom temperature, the resulting white percipitate 5a-i was removed by filtration, dried in vacuo andused in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 16h; | General Synthesis of Methyl (E)-4-(4-(3-argioacryloyl)piperazin-1-yl)benzoate 5a-i from (E)-3-argioacrylic acid 4a-i General procedure: To (E)-3-argioacrylic acid 4a-i (5 mmol), methyl 4-(piperazin-1-yl)benzoate 3 (5.55 mmol) and TBTU(1.35 g, 5.3 mmol) in acetonitrile (50 mL) was added DBU (4 mL, 5.35 mmol). After stirring 16 h atroom temperature, the resulting white percipitate 5a-i was removed by filtration, dried in vacuo andused in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 16h; | General Synthesis of Methyl (E)-4-(4-(3-argioacryloyl)piperazin-1-yl)benzoate 5a-i from (E)-3-argioacrylic acid 4a-i General procedure: To (E)-3-argioacrylic acid 4a-i (5 mmol), methyl 4-(piperazin-1-yl)benzoate 3 (5.55 mmol) and TBTU(1.35 g, 5.3 mmol) in acetonitrile (50 mL) was added DBU (4 mL, 5.35 mmol). After stirring 16 h atroom temperature, the resulting white percipitate 5a-i was removed by filtration, dried in vacuo andused in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium cyanoborohydride; acetic acid / tetrahydrofuran; water / 6 h / Heating / reflux 2.1: sodium hydroxide; water / 2 h / 80 °C 2.2: 0 °C / pH 2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With trimethylaluminum In toluene at 90℃; for 10h; Inert atmosphere; | 3-Chloro-N-(3-cyano-1H-pyrazol-5-yl)-4-((1-methylpiperidin-4-yl)amino)benzamide (23) General procedure: To a stirring solution of compound 22b (0.65g, 2.31mmol) in anhydrous toluene (3mL) were added 20 (0.40g, 2.10mmol) and 2M trimethylaluminum toluene solution (4.20mL, 8.40mmol) under an argon atmosphere. Reaction was stirred at 90°C for 10h. After this period, the reaction was quenched with 95% ethanol (40mL). The solvent was removed in vacuo, and then purified by silica gel column chromatography (EA : MeOH=20 : 1) to afford title compound as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Stage #1: methyl 4-(piperazin-1-yl)benzoate; 2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-5,5-dimethylcyclohex-1-enecarbaldehyde In tetrahydrofuran at 20℃; for 1h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 0 - 20℃; for 16h; | 3 Step 3 To a stirred solution of methyl 4-(piperazin-l-yl)benzoate (389 mg, 1.77 mmol) in THF (10 mL) was added a solution of Intermediate 56-2 (450 mg, 1.77 mmol) in THF (5 mL) at rt. The reaction was stirred for lh, treated with Na(OAc)3BH (1.12 g, 5.31 mmol) at 0 °C, and then warmed to rt. After 16 h, MeOH (10 mL) was added and the reaction was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, dissolved in DCM (20 mL) and washed with sat. aq. NaHCCL (3x10 mL). The organic layer was dried over Na2S04, filtered, and concentrated. The crude product was purified by column chromatography (Si02, EtOAc/pet. ether) to afford methyl 4-(4-((2-(3- (difluoromethyl)bicyclo[ 1.1.1 ]pentan- 1 -yl)-5,5-dimethylcyclohex- 1 -en- 1 - yl)methyl)piperazin-l-yl)benzoate (Intermediate 56-3) (400 mg, 49% yield) as an off-white solid. LC/MS (ESI) m/z 459.2 [M+H]+. [0445] Step 4: Intermediate 56 was prepared following the procedure described in Step 5, Route B for Intermediate 28 using Intermediate 56-3 in place of methyl 2-((lH- pyrrolo[2,3-hJpyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[ I . I . I Jpentan- 1 - yl)cyclohex-l-en-l-yl)methyl)piperazin-l-yl)benzoate. LC/MS (ESI) m/z 445.4 [M+H]+. |
49% | Stage #1: methyl 4-(piperazin-1-yl)benzoate; 2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-5,5-dimethylcyclohex-1-enecarbaldehyde In tetrahydrofuran at 20℃; for 1h; Stage #2: With C5H10BO5(1-)*Na(1+) In tetrahydrofuran; methanol at 0 - 20℃; for 16.5h; | 3 Step 3: To a stirred solution of methyl 4-(piperazin-1-yl)benzoate (389 mg, 1.77 mmol) in THF (10 mL) was added a solution of Intermediate 56-2 (450 mg, 1.77 mmol) in THF (5 mL) at rt. The reaction was stirred for 1h, treated with Na(OAc)3BH (1.12 g, 5.31 mmol) at 0 °C, and then warmed to rt. After 16 h, MeOH (10 mL) was added and the reaction was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, dissolved in DCM (20 mL) and washed with sat. aq. NaHCO3 (3×10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, EtOAc/pet. ether) to afford methyl 4-(4-((2-(3- (difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-5,5-dimethylcyclohex-1-en-1- yl)methyl)piperazin-1-yl)benzoate (Intermediate 56-3) (400 mg, 49% yield) as an off-white solid. LC/MS (ESI) m/z 459.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 16h; | 1 Step 1 To a stirred solution of methyl 4-(piperazin-l-yl)benzoate (1.68 g, 7.6 mmol) and Intermediate 22 (2.0 g, 9.15 mmol) in THF (20 mL) was added Na(OAc)3BH (4.8 g, 22.8 mmol) at rt. After 16 h, the reaction was put in an ice batch and quenched with sat. aq. NaHCCh (25 mL). The reaction mixture was extracted with EtOAc (3 x 50 mL), dried over Na SCL, filtered, and concentrated. The crude product was purified by column chromatography (S1O2, EtOAc/pet. ether) to obtain methyl 4-(4-((4,4-dimethyl-2-(3- methylbicyclo [1.1.1 Jpentan- 1 -yl)cyclohex- 1 -en- 1 -yl)methyl)piperazin- 1 -yl)benzoate (Intermediate 39-1) as a white solid (1.5 g, 46% yield). LC/MS (ESI) m/z 423.2[M+H]+. |
46% | With C5H10BO5(1-)*Na(1+) In tetrahydrofuran at 20℃; for 16h; | 1 Step 1: To a stirred solution of methyl 4-(piperazin-1-yl)benzoate (1.68 g, 7.6 mmol) and Intermediate 22 (2.0 g, 9.15 mmol) in THF (20 mL) was added Na(OAc)3BH (4.8 g, 22.8 mmol) at rt. After 16 h, the reaction was put in an ice batch and quenched with sat. aq. NaHCO3 (25 mL). The reaction mixture was extracted with EtOAc (3 x 50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, EtOAc/pet. ether) to obtain methyl 4-(4-((4,4-dimethyl-2-(3- methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Intermediate 39-1) as a white solid (1.5 g, 46% yield). LC/MS (ESI) m/z 423.2[M+H]+. |
46% | With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 16h; | 1 Step 1: To a stirred solution of methyl 4-(piperazin-1-yl)benzoate (1.68 g, 7.6 mmol) and Intermediate 2 (2.0 g, 9.15 mmol) in THF (20 mL) was added Na(OAc)3BH (4.8 g, 22.8 mmol) at rt. After 16 h, the reaction was put in an ice batch and quenched with sat. aq. NaHCO3 (25 mL). The reaction mixture was extracted with EtOAc (3 x 50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, EtOAc/pet. ether) to obtain methyl 4-(4-((4,4-dimethyl-2-(3- methylbicyclo [1.1.1 ]pentan- 1 -yl)cyclohex- 1 -en- 1 -yl)methyl)piperazin- 1 -yl)benzoate (0196) (Intermediate 5-1) as a white solid (1.5 g, 46% yield). LC/MS (ESI) m/z 423.2[M+H]+. |
46% | With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 16h; | Step 1: To a stirred solution of methyl 4-(piperazin-1-yl)benzoate (1.68 g, 7.6 mmol) and 4,4-dimethyl-2-(3-methylbicyclo[l.l.l]pentan-1-yl)cyclohex-1-ene-1- carbaldehyde (2.0 g, 9.15 mmol) in THF (20 mL) was added Na(OAc)3BH (4.8 g, 22.8 mmol) at rt. After 16 h, the reaction was put in an ice batch and quenched with sat. aq. NaHCO3 (25 mL). The reaction mixture was extracted with EtOAc (3 x 50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (S1O2, EtOAc/pet. ether) to obtain methyl 4-(4-((4,4-dimethyl-2-(3- methylbicyclo [1.1.1 ]pentan- 1 -yl)cyclohex- 1 -en- 1 -yl)methyl)piperazin- 1 -yl)benzoate (Intermediate 1-1) as a white solid (1.5 g, 46% yield). LC/MS (ESI) m/z 423.2[M+H]+. |
46% | With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 16h; | Step 1: To a stirred solution of methyl 4-(piperazin-1-yl)benzoate (1.68 g, 7.6 mmol) and 4,4-dimethyl-2-(3-methylbicyclo[l.l.l]pentan-1-yl)cyclohex-1-ene-1- carbaldehyde (2.0 g, 9.15 mmol) in THF (20 mL) was added Na(OAc)3BH (4.8 g, 22.8 mmol) at rt. After 16 h, the reaction was put in an ice batch and quenched with sat. aq. NaHCO3 (25 mL). The reaction mixture was extracted with EtOAc (3 x 50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (S1O2, EtOAc/pet. ether) to obtain methyl 4-(4-((4,4-dimethyl-2-(3- methylbicyclo [1.1.1 ]pentan- 1 -yl)cyclohex- 1 -en- 1 -yl)methyl)piperazin- 1 -yl)benzoate (Intermediate 1-1) as a white solid (1.5 g, 46% yield). LC/MS (ESI) m/z 423.2[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: 4,4-dimethyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)cyclohex-1-ene-1-carbaldehyde With titanium(IV) tetraethanolate In toluene for 0.5h; Stage #2: methyl 4-(piperazin-1-yl)benzoate In toluene at 20℃; for 1h; Stage #3: With sodium tris(acetoxy)borohydride In toluene at 0 - 20℃; for 16h; | 1 Step 1 To a stirred solution of Intermediate 25 (3.5 g, 12.85 mmol) in toluene was added titanium (IV) ethoxide (3.73 g, 16.36 mmol). After 30 min, a solution of methyl 4-(piperazin- 1 -yl) benzoate (2.35 g, 10.71 mmol) in toluene (20 mL) was added and the resulting reaction mixture was stirred at rt for 1 h. The reaction mixture was then cooled to 0 °C, and Na(OAc)3BH (6.9 g, 32.72 mmol) was added and the reaction was warmed to rt. After 16 h, the reaction was quenched with water (100 mL) at 0°C, and MTBE (200 mL) was added after 30 min. The reaction mixture was filtered over Celite and the collected solid was washed with DCM (2 x 100 mL). The combined organic layers were washed with sat. aq. NaHCCL, brine, dried over Na SCL, filtered and concentrated. The crude product was column chromatography (S1O2, EtOAc/pet. ether) to afford methyl 4-(4-((4,4-dimethyl-2-(3- (trifluoromethyl)bicyclo [1.1.1 J pen tan- 1 -yl)cyclohex- 1 -en- 1 -yl)methyl)piperazin- 1 - yl)benzoate (Intermediate 41-1) (3.2 g, 63% yield) as a white solid. LC/MS (ESI) m/z 477.3 [M+H]+. |
63% | Stage #1: 4,4-dimethyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)cyclohex-1-ene-1-carbaldehyde With titanium(IV) tetraethanolate In toluene for 0.5h; Stage #2: methyl 4-(piperazin-1-yl)benzoate In toluene at 20℃; for 1h; Stage #3: With C5H10BO5(1-)*Na(1+) In toluene at 0 - 20℃; for 16h; | 1 Step 1: To a stirred solution of Intermediate 25 (3.5 g, 12.85 mmol) in toluene was added titanium (IV) ethoxide (3.73 g, 16.36 mmol). After 30 min, a solution of methyl 4-(piperazin-1-yl) benzoate (2.35 g, 10.71 mmol) in toluene (20 mL) was added and the resulting reaction mixture was stirred at rt for 1 h. The reaction mixture was then cooled to 0 °C, and Na(OAc)3BH (6.9 g, 32.72 mmol) was added and the reaction was warmed to rt. After 16 h, the reaction was quenched with water (100 mL) at 0°C, and MTBE (200 mL) was added after 30 min. The reaction mixture was filtered over Celite and the collected solid was washed with DCM (2 x 100 mL). The combined organic layers were washed with sat. aq. NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude product was column chromatography (SiO2, EtOAc/pet. ether) to afford methyl 4-(4-((4,4-dimethyl-2-(3- (trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1- yl)benzoate (Intermediate 41-1) (3.2 g, 63% yield) as a white solid. LC/MS (ESI) m/z 477.3 [M+H]+. |
63% | Stage #1: 4,4-dimethyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)cyclohex-1-ene-1-carbaldehyde With titanium(IV) tetraethanolate In toluene for 0.5h; Stage #2: methyl 4-(piperazin-1-yl)benzoate In toluene at 20℃; for 1h; Stage #3: With sodium tris(acetoxy)borohydride In toluene at 0 - 20℃; for 16h; | Step 1: To a stirred solution of 4,4-dimethyl-2-(3-(trifluoromethyl)bicyclo[l.l.l]pentan-1-yl)cyclohex-1-ene-1-carbaldehyde (3.5 g, 12.9 mmol) in toluene was added titanium (IV) ethoxide (3.73 g, 16.4 mmol). After 30 min, a solution of methyl 4-(piperazin-1-yl) benzoate (2.35 g, 10.71 mmol) in toluene (20 mL) was added and the resulting reaction mixture was stirred at rt for 1 h. The reaction mixture was then cooled to 0 °C, and Na(OAc)3BH (6.9 g, 32.72 mmol) was added and the reaction was warmed to rt. After 16 h, the reaction was quenched with water (100 mL) at 0°C, and MTBE (200 mL) was added. The reaction mixture was filtered over Celite and the collected solid was washed with DCM (2 x 100 mL). The combined organic layers were washed with sat. aq. NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (S1O2, EtOAc/pet. ether) to afford methyl 4-(4-((4,4- dimethyl-2-(3-(trifluoromethyl)bicyclo[ 1.1.1 ]pentan- 1 -yl)cyclohex- 1 -en- 1 - yl)methyl)piperazin-1-yl)benzoate (Intermediate 47-1) (3.2 g, 63% yield) as a white solid. LC/MS (ESI) m/z 477.3 [M+H]+. |
63% | Stage #1: 4,4-dimethyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)cyclohex-1-ene-1-carbaldehyde With titanium(IV) tetraethanolate In toluene for 0.5h; Stage #2: methyl 4-(piperazin-1-yl)benzoate In toluene at 20℃; for 1h; Stage #3: With sodium tris(acetoxy)borohydride In toluene at 0 - 20℃; for 16h; | Step 1: To a stirred solution of 4,4-dimethyl-2-(3-(trifluoromethyl)bicyclo[l.l.l]pentan-1-yl)cyclohex-1-ene-1-carbaldehyde (3.5 g, 12.9 mmol) in toluene was added titanium (IV) ethoxide (3.73 g, 16.4 mmol). After 30 min, a solution of methyl 4-(piperazin-1-yl) benzoate (2.35 g, 10.71 mmol) in toluene (20 mL) was added and the resulting reaction mixture was stirred at rt for 1 h. The reaction mixture was then cooled to 0 °C, and Na(OAc)3BH (6.9 g, 32.72 mmol) was added and the reaction was warmed to rt. After 16 h, the reaction was quenched with water (100 mL) at 0°C, and MTBE (200 mL) was added. The reaction mixture was filtered over Celite and the collected solid was washed with DCM (2 x 100 mL). The combined organic layers were washed with sat. aq. NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (S1O2, EtOAc/pet. ether) to afford methyl 4-(4-((4,4- dimethyl-2-(3-(trifluoromethyl)bicyclo[ 1.1.1 ]pentan- 1 -yl)cyclohex- 1 -en- 1 - yl)methyl)piperazin-1-yl)benzoate (Intermediate 47-1) (3.2 g, 63% yield) as a white solid. LC/MS (ESI) m/z 477.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 50℃; Inert atmosphere; | 1.3 3. In a 250 ml three-necked flask, add 7.54 g of compound (4), 21.8 g of compound (5), 17.5 g of potassium carbonate, 100 ml of N'N-dimethylformamide, and heat to 50 ° C under nitrogen atmosphere for reaction. TLC monitoring After the reaction was completed, ice water was added thereto, and the mixture was extracted three times with ethyl acetate. The organic phase was combined and dried to give the compound (6) 15.50 g, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 50℃; Inert atmosphere; | 2.3 3. In a 250 ml three-necked flask, compound (4) 7.94 g, compound (5) 33 g, potassium carbonate 25 g, and N'N-dimethylformamide 150 ml were sequentially added, and the mixture was heated to 50 ° C under a nitrogen atmosphere, and the reaction was monitored by TLC. After the end of the reaction, ice water was added, and the mixture was extracted three times with ethyl acetate, and the organic phase was combined and dried to give a compound (6) 14.41 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sodium sulfide nonahydrate; ammonium chloride / tetrahydrofuran; water / 2 h / 50 °C 2: sodium carbonate / <i>tert</i>-butyl alcohol / 50 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.94 g | With sodium carbonate In <i>tert</i>-butyl alcohol for 50h; Reflux; | 1.2; 2.2 Take the next step of compound (2) 6.05g, add 30ml of t-butanol, 6.2g of compound (3) and 6.2g of sodium carbonate in 100ml.After the completion of the feeding, the reaction was heated to reflux for 50 h, and the reaction was monitored by TCL. The reaction was completed, and the reaction mixture was cooled and diluted with ethyl acetate.Further, it was washed with water, dried, and rotated to obtain a substance (4): 7.94 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 50 °C / Inert atmosphere 2: sodium; ammonia / methanol; 1,2-dimethoxyethane / 12 h / 0 - 50 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 50 °C / Inert atmosphere 2: sodium; ammonia / methanol; 1,2-dimethoxyethane / 12 h / 0 - 50 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; | C Step C: methyl 4- (4- (2- (5-amino-2- (furan-2-yl) -7H-pyrazolo [4, 3-e] [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yl) -2-phenylpropanoyl) piperazin-1-yl) benzoate A mixture of the product of step B (80 mg, 0.32 mmol) , 2- (5-amino-2- (furan-2-yl) -7H-pyrazolo [4, 3-e] [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yl) -2-phenylpropanoic acid (100 mg, 0.26 mmol) , HATU (100 mg, 0.26 mmol) and DIEA (100 mg, 0.78 mmol) in DMF (10 mL) was stirred overnight at RT. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (50 mL x 3) . The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (petroleum ether/EtOAc = 1: 1 100%EtOAc) to give the target compound (100 mg, 65%) as a yellow solid. MS: M/e 592 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: tris-(dibenzylideneacetone)dipalladium(0); XPhos; caesium carbonate / toluene / 2 h / 120 °C 2: hydrogenchloride / ethyl acetate / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 2: sodium hydroxide; water / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 2: sodium hydroxide; water / methanol 3: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 2: sodium hydroxide; water / methanol 3: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 2: sodium hydroxide; water / methanol 3: HATU; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 15 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 2: sodium hydroxide; water / methanol 3: HATU; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 15 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 2: sodium hydroxide; water / methanol 3: HATU; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 15 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: titanium(IV) tetraethanolate / toluene / 0.5 h 1.2: 1 h / 20 °C 1.3: 16 h / 0 - 20 °C 2.1: water; lithium hydroxide monohydrate / tetrahydrofuran; methanol / 16 h / 20 - 30 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sodium tris(acetoxy)borohydride / tetrahydrofuran / 16 h / 20 °C 2: lithium hydroxide monohydrate; water / tetrahydrofuran; methanol / 16 h / 30 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: sodium tris(acetoxy)borohydride / tetrahydrofuran / 16 h / 20 °C 2: lithium hydroxide monohydrate; water / tetrahydrofuran; methanol / 16 h / 30 °C 3: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane / 16 h / 20 - 35 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium tris(acetoxy)borohydride; acetic acid In tetrahydrofuran; ethanol at 60℃; for 18h; | 125.3 Step 3: Synthesis of methyl 4-(4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)benzoate Dissolve methyl 4-(piperazin-1-yl)benzoate (1.04g, 4.72mmol), 4-(trifluoromethyl)benzaldehyde (0.8mL, 6.00mmol) in THF/EtOH (6mL/6mL) Add AcOH (1.3mL, 23.00mmol), STAB (4.80g, 23.00mmol), and react at 60°C for 18h. Add saturated NaHCO3 solution (60mL) to the reaction solution, adjust the pH to about 8, extract with EtOAc (100mL×2), dry with anhydrous Na2SO4, and concentrate under reduced pressure. The concentrated solution is separated by silica gel column chromatography (eluent: PE/ EtOAc (v/v)=3/1) to obtain a brown solid (1.6 g, 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos / toluene / 19 h / 110 °C / Inert atmosphere 2: hydrogenchloride / dichloromethane; 1,4-dioxane; water / 13 h / 20 °C / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sodium tris(acetoxy)borohydride; acetic acid / tetrahydrofuran; ethanol / 18 h / 60 °C 2: lithium hydroxide monohydrate; water; methanol / tetrahydrofuran / 48 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: sodium tris(acetoxy)borohydride; acetic acid / tetrahydrofuran; ethanol / 18 h / 60 °C 2: lithium hydroxide monohydrate; water; methanol / tetrahydrofuran / 48 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 17 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 60 °C 2: sodium hydroxide / methanol; water / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 60 °C 2: sodium hydroxide / methanol; water / 2 h / 20 °C 3: 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 / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With HBTU; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; | Methyl 4-(4-(3-(3,4-dihydroxyphenyl)acryloyl)piperazin-1-yl) benzoate General procedure: To a mixture of the caffeic acid (1 mmol) in dry THF (4 mL) was added HOBt (1.2 mmol), HBTU (1.2 mmol) and DIEA (1.5 mmol). The reaction mixture was stirred at room temperature. The reaction was terminated when the caffeic acid was finished by TLC control. Purified by column chromatography. |
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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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