* 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.
With Raney nickel In 5,5-dimethyl-1,3-cyclohexadiene for 24 h; Reflux
General procedure: The prepared grades of R-Ni were weighed in water after considering its specific gravity. The residual water was removed using dean stark apparatus. (0043) All the reactions were carried out in a 2-neck round bottom flask, attached with a condenser. Typically, reaction was carried out by stirring and refluxing the reaction mixture of amine and alcohol with pretreated R-Ni in 20ml solvent. After reaction completion, reaction mixture was cooled and filtered using Whatman filter paper 40. The solvent was removed in vacuo. The mixture thus obtained was purified using column chromatography. The purified compounds obtained were characterized by IR, NMR, LC–MS and melting or boiling point. The analytical data obtained of the known compounds are in agreement to the reported literature.
Reference：
[1] Chemistry - A European Journal, 2015, vol. 21, # 27, p. 9656 - 9661
[2] ChemCatChem, 2014, vol. 6, # 3, p. 808 - 814
[3] Chemistry - A European Journal, 2013, vol. 19, # 11, p. 3665 - 3675
[4] Journal of Organic Chemistry, 2011, vol. 76, # 7, p. 2328 - 2331
[5] Tetrahedron Letters, 2007, vol. 48, # 47, p. 8263 - 8265
[6] Journal of the American Chemical Society, 2009, vol. 131, p. 1766 - 1774
[7] Applied Catalysis A: General, 2014, vol. 478, p. 241 - 251
[8] Journal of Organic Chemistry, 2017, vol. 82, # 13, p. 6604 - 6614
[9] Angewandte Chemie - International Edition, 2017, vol. 56, # 46, p. 14702 - 14706[10] Angew. Chem., 2017, vol. 129, # 46, p. 14894 - 14898,5
[11] Green Chemistry, 2012, vol. 14, # 1, p. 226 - 232
2
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Yield
Reaction Conditions
Operation in experiment
92%
With triethylamine In isopropyl alcohol at 20 - 50℃;
50 g of 2-piperazin-1-ylpyrimidine, 60 g of triethylamine and 170 ml of isopropyl alcohol were put into a 100 ml three-necked reaction flask, and 58 g of piperonyl chloride was added dropwise with stirring at room temperature, and the mixture was dropped in 30 minutes, heated to 50 °C, stirring to cool to room temperature, filtration, recovery of mother liquor, filter cake by adding 100ml water beating, pumping, plus 50ml water washing cake. Dried at 50 °C, 71.5 g of piribedil crude and 99.1percent by HPLC. Yield 92percent.
52%
With potassium carbonate In 5,5-dimethyl-1,3-cyclohexadiene at 130℃; for 9 h;
16.4 g of piperazinylpyrimidine was dissolved in 300 ml of xylene, 28 g of potassium carbonate and 18 g of piperonyl chloride were added and the suspension was incubated at reflux temperature (130C) for 9 hours, cooled, extracted with 10percent hydrochloric acid several times,The separated hydrochloric acid solution is washed with ether, the acid solution is transferred to alkaline by potassium carbonate, the organic phase is separated, the aqueous phase is extracted with chloroform, the combined organic phase is dried with potassium carbonate, filtered and the solvent is removed by distillation,20 g of the residual oily organics was obtained and recrystallized from ethanol to give 15 g of product, piribedil, yield 52percent.
14.76 g
With triethylamine In isopropyl alcohol at 20 - 50℃; for 2.5 h;
ake 10g about 89.7percent content of piperazine pyrimidine, 12g triethylamine, 34ml isopropanol into 100ml three reaction flask, dropping peppermint chloride at room temperature under stirring, dropping over 30 minutes. Heated to 50 , incubated for 2 hours, cooled to room temperature with stirring, filtered, the mother liquor was recovered, the filter cake was added 20ml water beating, suction filtration, plus 10ml water washing cake. 50 drying, get piribedil crude 16.6g, HPLC analysis content of 99.2percent. Yield 92percent; 16g of crude piribedil (99.2percent), 0.3g of activated charcoal and 42ml of absolute ethanol were added into a 100ml single-necked flask and heated to the reflux temperature for 0.5 hour. The activated carbon was removed by hot filtration and the filtrate was cooled and crystallized under stirring to obtain a white Crystalline solid. Filtered, rinsed with a small amount of anhydrous ethanol, and dried to obtain 14.76g of the first crystal product of piribedil, the content of which was 99.90percent by HPLC and the refined yield was 90.33percent.
Reference：
[1] Patent: CN106432212, 2017, A, . Location in patent: Paragraph 0010; 0019
[2] Patent: CN106432212, 2017, A, . Location in patent: Paragraph 0016
[3] Patent: CN107216318, 2017, A, . Location in patent: Paragraph 0022; 0025; 0028
[4] Patent: CN107266429, 2017, A, . Location in patent: Paragraph 0022; 0025; 0028
3
[ 94-53-1 ]
[ 20980-22-7 ]
[ 3605-01-4 ]
Yield
Reaction Conditions
Operation in experiment
85%
With tris(pentafluorophenyl)borate; phenylsilane In dibutyl ether at 140℃; for 24 h; Schlenk technique; Inert atmosphere; Green chemistry
In the same procedure as in Example 1, The reaction mixture was then heated at 140 ° C for 24 h and cooled to room temperature. The resulting white crystals were isolated by the same post-treatment to yield 85percent yield.The obtained product was subjected to nuclear magnetic resonance spectroscopy and nuclear magnetic resonance spectroscopy to confirm that the obtained product was 2- [4- (1,3-benzodioxol-5-ylmethyl) _ Base] pyrimidine, that ie piribedil. [0050] In a 10 mL Schlenk reaction tube (Beijing Xinwei Er Glass Instrument Co., Ltd., F891410 reaction tube, Capacity 10mL, Grinding mouth 14/20) was added 0.005 mmol of tris (pentafluorophenyl) boron, The inside of the tube is replaced with argon, Then, 1.5 mL of n-butyl ether and 2.0 mmol of phenyl silane were added under argon atmosphere and stirred (using an IKA magnetic stirrer, RCT basic, Stirring speed of 500 rpm). Followed by the addition of 0.5 mmol of 1- (2-pyrimidinyl) piperazine and 1.0 mmol ofd piperic acid. After heating at 100 ° C for 20 h, the mixture was cooled to room temperature. Quenched with sodium hydroxide solution (3M; 3 mL) Ethyl acetate (3 mL) was added, After stirring at room temperature for 3 h, Ethyl acetate extraction (2 mL x 3), The organic phase was dried over anhydrous sodium sulfate, Filtration, organic phase through the rotary evaporator (Swiss step Qi Co., Ltd., BUCHI Rotary Evaporator R-3) Concentrated, And then through the column (Beijing Xin Wei Er Glass Instrument Co., Ltd., C383040C with sand plate storage column chromatography column, 35/20, φ30mm, effective length: 500ml) Chromatography to obtain white crystal products, Yield 41percent. The resulting product was subjected to 1H-NMR (400 MHz, CDCl3) and nuclear magnetic resonance spectroscopy 13C-NMR (101 MHz, CDCl3) analysis, The resulting spectra are shown in Figure 1-2. The resulting product was confirmed to be 2- [4- (1,3-benzodioxol-5-ylmethyl) piperazin-1-yl] pyrimidine, i.e piribedil
With triethylamine In ethanol at 95 - 100℃; for 1 h;
The intermediate intermediate piperonyl piperazine, 360 ml of absolute ethanol and 120 ml of triethylamine were placed in a 1000 ml three-necked reaction flask and heated to 95 ° C to 100 ° C with stirring. A mixed solution of 70 g of dichloropyrimidine and 360 ml of absolute ethanol was added dropwise, and the mixture was incubated at 95 ° C to 100 ° C for 1 hour, distilled under reduced pressure, and about 400 ml of ethanol and triethylamine solution were removed, cool to room temperature and filter. Atmospheric distillation, remove the ethanol and triethylamine about 250ml, cooled to room temperature, filter the solid, add water, beating, pumping filter, to get piribedil crude 160g, content 92percent, the total yield of 80percent.
Reference：
[1] Patent: CN106432212, 2017, A, . Location in patent: Paragraph 0010; 0020
5
[ 20980-22-7 ]
[ 93-54-9 ]
[ 3605-01-4 ]
Yield
Reaction Conditions
Operation in experiment
76%
With trifuran-2-yl-phosphane; palladacycle; lithium hydroxide In neat (no solvent) at 120℃; for 24 h; Inert atmosphere; Molecular sieve
General procedure: An oven dried Schlenk tube was charged with LiOH (1.5 mmol), pre-catalyst (1.5*10-2 mmol), P(2-Fur)3 (3*10-2 mmol) and activated 4 Å MS (100 mg). The tube was connected to a vacuum line under argon and purged three times. To the reaction mixture, sulfanilamide (3.0 mmol) and arylalcohol (6.0 mmol) were added. The Schlenk tube was closed with PTFE stopper and the reaction mixture was stirred at 120 °C for 24 h. At the end of the reaction time, the reaction mixture was cooled to room temperature, diluted with methanol (5 mL), and the tube was washed with methanol three more times (3*2 mL). The methanol solution was concentrated under vacuum and the crude was subjected to flash column chromatography on silica gel using ethyl acetate and n-hexane mixtures to afford the N-alkylated product.
With potassium carbonate In tetrahydrofuran for 2 h; Reflux
250 ml of a three-necked flask was added 50 g of piperonyl piperazine, 26 g of dichloropyrimidine, 330 ml of tetrahydrofuran and 65 g of potassium carbonate, and the mixture was heated under reflux for 2 hours. The mixture was cooled and cooled, and 1600 ml of distilled water was added thereto, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a dark red viscous liquid (56.3 g). Add 40ml of anhydrous ethanol, dissolve, slightly cold, add activated carbon 40g, reflux 30 minutes, hot filter, cooling, precipitation of white solid, filtration, 40 °C vacuum drying to get 30.2 g of white crystalline powder, yield 44percent.
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 16, p. 9144 - 9155
[2] Patent: CN106432212, 2017, A, . Location in patent: Paragraph 0015
7
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Reference：
[1] ChemCatChem, 2018, vol. 10, # 6, p. 1235 - 1240
[2] Chemistry - A European Journal, 2017, vol. 23, # 9, p. 2217 - 2224
[3] Tetrahedron Letters, 2006, vol. 47, # 15, p. 2549 - 2552
[4] Patent: US2005/215788, 2005, A1, . Location in patent: Page/Page column 1; 2
To a solution of ethyl 2-(4-methylpiperazin-1-yl)pyrimidine ethyl ester prepared in Step a was added 4-bromo-1,2-methylenedioxybenzene, the compound IV130.6g was added and the temperature was raised to reflux Reaction 4h, After the reaction, the reaction solution has a degree of vacuum of not less than 0.09 MPa, At a temperature of 40~50 ° C under reduced pressure to remove ethyl acetate, The residue was added with 200 mL of purified water and stirred for 20 min, filter, piribedil crude weight 192.1g; c, purification of piribedil: The crude piribedil was added to the reactor, then 1.15 L of anhydrous ethanol was added, heated to dissolve, and activated charcoal 9.6g, continue to heat for 30min, the reaction after the hot filter, the filtrate naturally cooled to room temperature, room temperature crystallization 2h, filter, filter cake placed at 40~45 °C temperature drying 8h, get piribedil finished product 127.6g.
Reference：
[1] Patent: CN106749204, 2017, A, . Location in patent: Paragraph 0012; 0013; 0014; 0015
10
[ 120-57-0 ]
[ 20980-22-7 ]
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[ 3605-01-4 ]
Reference：
[1] Archiv der Pharmazie, 1993, vol. 326, # 4, p. 241 - 242
11
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Reference：
[1] Archiv der Pharmazie, 1993, vol. 326, # 4, p. 241 - 242
To 1 kg powder having a Piribedil purity of 98 wt % in a 15 L flask equipped with a heating pack and mechanical stirrer one liter of distilled water was added. The mixture was heated to 100 C. Five liters of 95 wt % ethanol aqueous solution was slowly added into the flask while stirring, and the temperature of the mixture contained in the flask was dropped to about 60 C. upon completion of the 95 wt % ethanol. The temperature was increased to 75 C. by heating, and another five liters of 95 wt % ethanol aqueous solution was slowly added into the flask while maintaining the temperature at 75 C. by heating, thereby the opaque mixture was turned into a clear liquid. The hot clear liquid was filtered, and the resulting hot filtrate was cooled with an ice bath, so that a crystal was formed therein. The crystal was recovered by filtration and dried in vacuo to obtain 0.92 kilogram of a white crystallized solid having a Piribedil purity of 99.8 wt %. The Piribedil purity of 99.8 wt % was determined by differential scanning calorimetry (DSC) and high performance liquid chromatography (HPLC).
Among the compounds which are of prior knowledge as derivatives of piperazine having the above-mentioned coronary blood flow increasing action are the following: ... 1-BENZYL-4-(3,4,5-TRIMETHOXYBENZOYL)PIPERAZINE [Farmatsiya (Sofia), vol. 19, p. 31 (1969)], 1-(1,5-DIMETHYL-5-HYDROXYHEXYL)-4-METHYLPIPERAZINE [Chemical Abstracts, vol. 74, 22882y (1971)], 1-(1,5-DIMETHOXY-5-HYDROXYHEXYL)-4-MORPHOLINOCARBONYLMETHYL-PIPERAZINE [Chemical Abstracts, vol. 74, 22882y (1971)], 1-(P-FLUOROPHENYLCARBONYLPROPYL)-4-PIPERONYLPIPERAZINE [Chemical Abstracts, vol. 74, 88056j (1971)], 1-(2-PYRIMIDYL)-4-PIPERONYLPIPERAZINE [Journal of Medical Chemistry, vol. 11, p. 1151 (1968)], 1-BENZHYDRYL-4-ACETONYLPIPERAZINE DIHYDROCHLORIDE [French Patent No. 7,009,523; Japanese Early Disclosure of Patent Application No. 46-2931/1971], 3,4-dihydroxy-alpha-[4-(2-methoxyphenyl)-1-piperazinylmethyl]-benzyl alcohol [Arzneimittel Forshung, vol. 19, p. 1698 (1969)].
5
[ 120-57-0 ]
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Yield
Reaction Conditions
Operation in experiment
With formic acid; at 100 - 140℃;
Preferably, the Piribedil product having a Piribedil purity of 98 wt % or lower is prepared from a method comprising reacting 1-(2-pyrimidinyl)piperazine and piperonal in the presence of formic acid as a reducing agent at a temperature of 100-140 C
In o-xylene; at 150℃; for 30.0h;Inert atmosphere; Sealed tube;
General procedure: Dried pressure tube was charged with magnetic stir bar and50 mg of PdSiO2 catalysts (1 mol% with respect to amine). Then,1.0 mL o-xylene was added, followed by the addition of 0.5 mmolof amine and 1 mmol of benzyl alcohol. The pressure tube wasflushed with argon was closed with screw cap. Then it was placedin the preheated aluminum block and reaction was allowed to progressfor 30 h at 150 C. After completion of the reaction, pressuretube was removed from aluminum block and cooled down to roomtemperature. The catalyst was filtered out by ciliate and reactionproducts were analyzed by GC-MS and the corresponding amineswere purified by column chromatography. The yields of selectedamines were determined by GC analysis using n-hexadecane asstandard. For this purpose, after completion of the reaction, nhexadecane(100 mL) as standard was added to the reaction pressuretube and the reaction products were diluted with ethyl acetate followed by filtration using plug of silica and then subjected GCanalysis.
85%
With Raney nickel; In 5,5-dimethyl-1,3-cyclohexadiene; for 24.0h;Reflux;
General procedure: The prepared grades of R-Ni were weighed in water after considering its specific gravity. The residual water was removed using dean stark apparatus. (0043) All the reactions were carried out in a 2-neck round bottom flask, attached with a condenser. Typically, reaction was carried out by stirring and refluxing the reaction mixture of amine and alcohol with pretreated R-Ni in 20ml solvent. After reaction completion, reaction mixture was cooled and filtered using Whatman filter paper 40. The solvent was removed in vacuo. The mixture thus obtained was purified using column chromatography. The purified compounds obtained were characterized by IR, NMR, LC-MS and melting or boiling point. The analytical data obtained of the known compounds are in agreement to the reported literature.
With tris(pentafluorophenyl)borate; phenylsilane; In dibutyl ether; at 140℃; for 24.0h;Schlenk technique; Inert atmosphere; Green chemistry;
In the same procedure as in Example 1, The reaction mixture was then heated at 140 C for 24 h and cooled to room temperature. The resulting white crystals were isolated by the same post-treatment to yield 85% yield.The obtained product was subjected to nuclear magnetic resonance spectroscopy and nuclear magnetic resonance spectroscopy to confirm that the obtained product was 2- [4- (1,3-benzodioxol-5-ylmethyl) _ Base] pyrimidine, that ie piribedil. [0050] In a 10 mL Schlenk reaction tube (Beijing Xinwei Er Glass Instrument Co., Ltd., F891410 reaction tube, Capacity 10mL, Grinding mouth 14/20) was added 0.005 mmol of tris (pentafluorophenyl) boron, The inside of the tube is replaced with argon, Then, 1.5 mL of n-butyl ether and 2.0 mmol of phenyl silane were added under argon atmosphere and stirred (using an IKA magnetic stirrer, RCT basic, Stirring speed of 500 rpm). Followed by the addition of 0.5 mmol of 1- (2-pyrimidinyl) piperazine and 1.0 mmol ofd piperic acid. After heating at 100 C for 20 h, the mixture was cooled to room temperature. Quenched with sodium hydroxide solution (3M; 3 mL) Ethyl acetate (3 mL) was added, After stirring at room temperature for 3 h, Ethyl acetate extraction (2 mL x 3), The organic phase was dried over anhydrous sodium sulfate, Filtration, organic phase through the rotary evaporator (Swiss step Qi Co., Ltd., BUCHI Rotary Evaporator R-3) Concentrated, And then through the column (Beijing Xin Wei Er Glass Instrument Co., Ltd., C383040C with sand plate storage column chromatography column, 35/20, φ30mm, effective length: 500ml) Chromatography to obtain white crystal products, Yield 41%. The resulting product was subjected to 1H-NMR (400 MHz, CDCl3) and nuclear magnetic resonance spectroscopy 13C-NMR (101 MHz, CDCl3) analysis, The resulting spectra are shown in Figure 1-2. The resulting product was confirmed to be 2- [4- (1,3-benzodioxol-5-ylmethyl) piperazin-1-yl] pyrimidine, i.e piribedil
With triethylamine; In isopropyl alcohol; at 20 - 50℃;
50 g of 2-piperazin-1-ylpyrimidine, 60 g of triethylamine and 170 ml of isopropyl alcohol were put into a 100 ml three-necked reaction flask, and 58 g of piperonyl chloride was added dropwise with stirring at room temperature, and the mixture was dropped in 30 minutes, heated to 50 C, stirring to cool to room temperature, filtration, recovery of mother liquor, filter cake by adding 100ml water beating, pumping, plus 50ml water washing cake. Dried at 50 C, 71.5 g of piribedil crude and 99.1% by HPLC. Yield 92%.
52%
With potassium carbonate; In 5,5-dimethyl-1,3-cyclohexadiene; at 130℃; for 9.0h;
16.4 g of piperazinylpyrimidine was dissolved in 300 ml of xylene, 28 g of potassium carbonate and 18 g of piperonyl chloride were added and the suspension was incubated at reflux temperature (130C) for 9 hours, cooled, extracted with 10% hydrochloric acid several times,The separated hydrochloric acid solution is washed with ether, the acid solution is transferred to alkaline by potassium carbonate, the organic phase is separated, the aqueous phase is extracted with chloroform, the combined organic phase is dried with potassium carbonate, filtered and the solvent is removed by distillation,20 g of the residual oily organics was obtained and recrystallized from ethanol to give 15 g of product, piribedil, yield 52%.
With triethylamine; In isopropyl alcohol; at 50℃; for 4.5h;
Taking 10 g about 89.7% content piperazine pyrimidine, 12 g triethylamine, 34 ml isopropanol into 100 ml three port into reaction, stirring at the room temperature under the chlorosilane dropping pepper, in 30 minutes in the transfusion. Heating to 50 C, thermal insulation 4 hours, stirring under cooling to room temperature, filter, recovery mother liquor, in the filter cake by adding 20 ml water beating, filtering, adding 10 ml water washes filters cake. 50 C drying, the crude product shall piribedil 16.6 g, HPLC analysis content 99.2%. Yield 92%
14.76 g
With triethylamine; In isopropyl alcohol; at 20 - 50℃; for 2.5h;
ake 10g about 89.7% content of piperazine pyrimidine, 12g triethylamine, 34ml isopropanol into 100ml three reaction flask, dropping peppermint chloride at room temperature under stirring, dropping over 30 minutes. Heated to 50 , incubated for 2 hours, cooled to room temperature with stirring, filtered, the mother liquor was recovered, the filter cake was added 20ml water beating, suction filtration, plus 10ml water washing cake. 50 drying, get piribedil crude 16.6g, HPLC analysis content of 99.2%. Yield 92%; 16g of crude piribedil (99.2%), 0.3g of activated charcoal and 42ml of absolute ethanol were added into a 100ml single-necked flask and heated to the reflux temperature for 0.5 hour. The activated carbon was removed by hot filtration and the filtrate was cooled and crystallized under stirring to obtain a white Crystalline solid. Filtered, rinsed with a small amount of anhydrous ethanol, and dried to obtain 14.76g of the first crystal product of piribedil, the content of which was 99.90% by HPLC and the refined yield was 90.33%.
With triethylamine; In ethanol; at 95 - 100℃; for 1.0h;
The intermediate intermediate piperonyl piperazine, 360 ml of absolute ethanol and 120 ml of triethylamine were placed in a 1000 ml three-necked reaction flask and heated to 95 C to 100 C with stirring. A mixed solution of 70 g of dichloropyrimidine and 360 ml of absolute ethanol was added dropwise, and the mixture was incubated at 95 C to 100 C for 1 hour, distilled under reduced pressure, and about 400 ml of ethanol and triethylamine solution were removed, cool to room temperature and filter. Atmospheric distillation, remove the ethanol and triethylamine about 250ml, cooled to room temperature, filter the solid, add water, beating, pumping filter, to get piribedil crude 160g, content 92%, the total yield of 80%.
With C48H55ClN2Pd; sodium t-butanolate; In 1,2-dimethoxyethane; at 20℃; for 16.0h;Inert atmosphere; Sealed tube;
In the N2 environment, compound 1o (1.0mmol, 1.0equiv), compound 2o (1.2equiv), Pd-NHC-1 (2mol%), sodium tert-butoxide (1.2equiv), 4mL ethylene glycol dimethyl ether, The mouth of the bottle was sealed and stirred for 16 hours under nitrogen at room temperature. Dilute with water, extract with ethyl acetate 3 times, spin dry under reduced pressure, and dry with anhydrous sodium sulfate. After silica gel column chromatography, a white solid is obtained with a yield of 98% (292.1 mg).
44%
With potassium carbonate; In tetrahydrofuran; for 2.0h;Reflux;
250 ml of a three-necked flask was added 50 g of piperonyl piperazine, 26 g of dichloropyrimidine, 330 ml of tetrahydrofuran and 65 g of potassium carbonate, and the mixture was heated under reflux for 2 hours. The mixture was cooled and cooled, and 1600 ml of distilled water was added thereto, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a dark red viscous liquid (56.3 g). Add 40ml of anhydrous ethanol, dissolve, slightly cold, add activated carbon 40g, reflux 30 minutes, hot filter, cooling, precipitation of white solid, filtration, 40 C vacuum drying to get 30.2 g of white crystalline powder, yield 44%.
With trifuran-2-yl-phosphane; palladacycle; lithium hydroxide; In neat (no solvent); at 120℃; for 24.0h;Inert atmosphere; Molecular sieve;
General procedure: An oven dried Schlenk tube was charged with LiOH (1.5 mmol), pre-catalyst (1.5*10-2 mmol), P(2-Fur)3 (3*10-2 mmol) and activated 4 Å MS (100 mg). The tube was connected to a vacuum line under argon and purged three times. To the reaction mixture, sulfanilamide (3.0 mmol) and arylalcohol (6.0 mmol) were added. The Schlenk tube was closed with PTFE stopper and the reaction mixture was stirred at 120 C for 24 h. At the end of the reaction time, the reaction mixture was cooled to room temperature, diluted with methanol (5 mL), and the tube was washed with methanol three more times (3*2 mL). The methanol solution was concentrated under vacuum and the crude was subjected to flash column chromatography on silica gel using ethyl acetate and n-hexane mixtures to afford the N-alkylated product.
In ethyl acetate; for 4.0h;Reflux; Green chemistry;
To a solution of ethyl 2-(4-methylpiperazin-1-yl)pyrimidine ethyl ester prepared in Step a was added 4-bromo-1,2-methylenedioxybenzene, the compound IV130.6g was added and the temperature was raised to reflux Reaction 4h, After the reaction, the reaction solution has a degree of vacuum of not less than 0.09 MPa, At a temperature of 40~50 C under reduced pressure to remove ethyl acetate, The residue was added with 200 mL of purified water and stirred for 20 min, filter, piribedil crude weight 192.1g; c, purification of piribedil: The crude piribedil was added to the reactor, then 1.15 L of anhydrous ethanol was added, heated to dissolve, and activated charcoal 9.6g, continue to heat for 30min, the reaction after the hot filter, the filtrate naturally cooled to room temperature, room temperature crystallization 2h, filter, filter cake placed at 40~45 C temperature drying 8h, get piribedil finished product 127.6g.
With C34H52BrN3OPd; In 1,4-dioxane; at 90℃; for 3.0h;Inert atmosphere; Schlenk technique;
Under a nitrogen atmosphere, take 0.5 mol% of the new nitrogen heterocyclic carbene ring palladium compound prepared in Example 1, KOtBu (1.5 equivalent) and 1 mL of dioxane into the Schlenk reaction tube, and then add 0.5 mmol of dichloropyrimidine and 0.75 mmol of morpholine. The reaction was stirred at 90C for 3 hours, the solvent was removed under reduced pressure, and the obtained was separated by flash column chromatography to obtain pure anti-Parkinson drug Piribedil with a yield of 92%. The hydrogen NMR spectrum is shown in Figure 2, and the NMR carbon spectrum is shown As shown in Figure 3.
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