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CAS No. : | 1124-11-4 | MDL No. : | MFCD00006146 |
Formula : | C8H12N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FINHMKGKINIASC-UHFFFAOYSA-N |
M.W : | 136.19 | Pubchem ID : | 14296 |
Synonyms : |
Ligustrazine;Chuanxiongzine;TMP;NSC 46451;NSC 36080;Chuanxingzine;2,3,5,6-Tetramethylpyrazine
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 41.9 |
TPSA : | 25.78 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.22 cm/s |
Log Po/w (iLOGP) : | 1.99 |
Log Po/w (XLOGP3) : | 1.28 |
Log Po/w (WLOGP) : | 1.71 |
Log Po/w (MLOGP) : | 0.55 |
Log Po/w (SILICOS-IT) : | 2.66 |
Consensus Log Po/w : | 1.64 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.93 |
Solubility : | 1.58 mg/ml ; 0.0116 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.42 |
Solubility : | 5.17 mg/ml ; 0.0379 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.17 |
Solubility : | 0.0921 mg/ml ; 0.000676 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.83 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
65% | Stage #1: With dihydrogen peroxide; acetic acid In water at 70℃; for 8 h; Stage #2: at 125℃; for 3 h; Stage #3: at 20℃; for 5 h; |
In a 500 ml round-bottom flask TMP (13.6 g 100 mmol) was added and dissolved in glacial acetic acid (15 mL) 30 hydrogen peroxide (8 mL 75 mmol) was added and reaced for 4 hours at 70 and 30 hydrogen peroxide (8 mL 75 mmol) was added and then further reacted for 4 hours and monitored by TLC until the reaction product was no longer generated. The resulting material was allowed to return to room temperature then placed in an ice bath adjusted to pH 10 with a solution of 10 sodium hydroxide extracted with chloroform dried over anhydrous sodium sulfate and filtered and concentrated to give crude material of TMP nitric oxide. Without isolation the crude materil was added with acetic anhydride (14.3 mL 150 mmol) heated to 125 with reflux for 3 hours and monitored by TLC until the starting material completely comsumed and the excess acetic anhydride was removed by distillation to give TMP acetyl compound allowed to return to room temperature then placed in an ice bath a solution of 10 sodium hydroxide was added to adjust pH to 12 stirred for 5 hours at room temperature extracted with chloroform dried over anhydrous sodium sulfate filtered and concentrated and the resulting material as separated with column chromatography eluted with ethyl acetate /petroleum ether (11) to give the compound TMP-OH as a white solid (9.88 g 65) . |
65% | at 70℃; for 8 h; | In a 500 ml round-bottom flask, TMP (13.6 g, 100 mmol) was added and dissolved in glacial acetic acid (15 mE), 30percent hydrogen peroxide (8 mE, 75 mmol) was added, and reaced for 4 hours at 70° C., and 30percent hydrogen peroxide (8 mE, 75 mmol) was added and then thrther reacted for 4 hours and monitored by TEC until the reaction product was no longer generated. The resulting material was allowed to return to room temperature then placed in an ice bath, adjusted to pH 10 with a solution of 10percent sodium hydroxide, extracted with chloroform, dried over anhydrous sodium sulfate, and filtered and concentrated to give crude material of TMP nitric oxide. Without isolation, the crude material was added with acetic anhydride (14.3 mE, 150 mmol), heated to 125° C. with reflux for 3 hours, and monitored by TEC until the starting material completely consumed, and the excess acetic anhydride was removed by distillation to give TMP acetyl compound, allowed to return to room temperature then placed in an ice bath, a solution of 10percent sodium hydroxide was added to adjust pH to 12, stirred for 5 hours at room temperature, extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting material as separated with colunm chromatography eluted with ethyl acetate/petroleum ether (1:1) to give the compound TMP-OH as a white solid (9.88 g, 65percent). |
1.85 g | at 90℃; for 6 h; | 2.17 g (16 mmol) of ligustrazine was dissolved in 20 ml of glacial acetic acid. Add 1.8 ml (16 mmol) of 30percent hydrogen peroxide at 90 ° C for 4 h.Then, 1.8 ml (16 mmol) of 30percent hydrogen peroxide was added to continue the reaction for 2 h, and the reaction was completely monitored by TLC.Add an appropriate amount of sodium sulfite to neutralize excess hydrogen peroxide, filter the reaction solution, cool the filtrate to room temperature, and adjust the pH to 10 with 50percent sodium hydroxide.The mixture was extracted with methylene chloride. The organic layer was collected, dried over anhydrous sodium sulfate and dried over anhydrous sodium sulfate. This crude product was added to 1.51 ml (16 mmol) of acetic anhydride, and the mixture was heated to reflux at 550 ° C for 2.5 hr.This black slurry was placed in a solution of 20 ml (THF: MeOH: H 2 O = 3:1:1), 1.92 g (48 mmol) of sodium hydroxide was added portionwise, and the reaction was stirred for 2 h.The organic layer was extracted with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate and filtered.Recovering the solvent under reduced pressureThe crude hydroxyxazine was recrystallized from n-hexane to give 1.85 g of yellow needle crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 80℃; for 4h; Inert atmosphere; | |
With hydrogenchloride; water at 120℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.2% | With dihydrogen peroxide; acetic acid at 70℃; | 2.1 1. Synthesis of Compound 14-1 Weigh 3.04 g of compound 14-0 dissolved in 4 mL of acetic acid, add 1.8 mL of 30% by volume of H 2 O 2 , react at 70 ° C for 4 hours, add 1.8 mL of 30% H 2 O 2 , and continue to heat at 70 ° C overnight. After cooling to room temperature, the system was adjusted to be weakly basic with 50% sodium hydroxide solution, extracted twice with dichloromethane, and the organic phases were combined and dried, filtered, and concentrated to give 3.0 g of white solid compound 14-1, yield: 88.2% . |
82% | With dihydrogen peroxide; acetic acid at 0 - 60℃; | |
78.8% | With dihydrogen peroxide; acetic acid at 94℃; for 12h; | 1.1.1 To a 250 mL three-necked flask were added ligustrazine (15.0 g, 0.1 mol) in this order,30% H2O2 solution (24 mL, 0.2 mol),Glacial acetic acid 15mL,94 reaction 12h,TLC (petroleum ether - ethyl acetate 1: 1) detection reaction is basically complete,Under cooling,PH = 10 was adjusted with 50% NaOH solution,Dichloromethane extraction (3 x 30 mL),The organic phases were combined,After drying over anhydrous Na2SO4,Concentrated under reduced pressure,A tetramethylpyrazine mono-nitroxide white crystal (13.2 g)Yield 78.8%, |
78.8% | With dihydrogen peroxide; acetic acid at 94℃; for 12h; | 1.1 Successively adding 250mL three-necked flask TMP (15.0g, 0.1mol), 30% H2O2Solution (24mL, 0.2mol), acetic acid 15mL, 94 reaction 12h, TLC (petroleum ether - ethyl acetate 1: 1) after detecting the reaction is substantially complete, under cooling, with 50% NaOH solution to adjust pH = 10, dichloro methane was extracted (3 × 30mL), the organic phases were combined, dried over anhydrous Na2SO4And dried under reduced pressure to give white crystals of nitrogen oxides single TMP recovered solvent 13.2g, yield 78.8%. |
70% | With 3,3-dimethyldioxirane In acetone at 25℃; for 0.333333h; | |
68% | With dihydrogen peroxide In water; acetic acid at 70℃; for 8h; | |
61% | With dihydrogen peroxide In acetic acid at 70 - 80℃; for 7.5h; | |
With dihydrogen peroxide; acetic acid | ||
With dihydrogen peroxide; acetic acid | ||
With dihydrogen peroxide; acetic acid at 70℃; for 8h; | ||
With dihydrogen peroxide; acetic acid Heating; | ||
With dihydrogen peroxide; acetic acid at 70℃; for 8h; | ||
With dihydrogen peroxide; acetic acid at 95℃; | ||
With dihydrogen peroxide; acetic acid | ||
With dihydrogen peroxide; acetic acid at 90℃; for 6h; | ||
With dihydrogen peroxide; acetic acid In water at 90℃; for 4h; Inert atmosphere; | ||
With dihydrogen peroxide; acetic acid at 75℃; for 3h; | TMP (1, 10.8 g, 80 mmol) in acetic acid (16 mL) was quickly added toH2O2 (30%, 9 mL), and the mixture was stirred for 3 h at 75C. TLC was performed to detect the product. Sodium hydroxidesolution (50%) was added and the pH was adjusted to 10. Next, the solution was extracted with CHCl3 (50 mL 3), washedand dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a white solid (TMP N-oxide, m). | |
With dihydrogen peroxide; acetic acid at 70℃; for 25h; | 1 preparation of compounds of formula (I) Take ligustrazine 100g at room temperaturePlaced in 500ml three-necked flask,Add 160 mL of glacial acetic acid to dissolve,Under stirring slowly dropping hydrogen peroxide (30%) 85g,About half an hour plus finished,The temperature was raised to 70 ° C,Keep this temperature for 4 hours.Then slowly dropping hydrogen peroxide (30%) 85g,About half an hour plus finished,Continue to maintain the reaction at 70 20 hours,TLC reaction almost completely reacted.The reaction solution was cooled to 0 ° C,Slowly dropping 50% sodium hydroxide solution to adjust the pH to pH> 9,Extract three times with dichloromethane (400 x 3) mL,The combined organic phase,Wet starch with potassium iodide test whether the test does not remove the finished peroxide,Test strips can be white,Dry the organic phase over anhydrous sodium sulfate,Spin dried crude product 110g,The crude product can be used directly for the next step. | |
With dihydrogen peroxide; acetic acid at 70℃; for 8h; | 2.1 (1) In a round bottom flask, add (2) 2,3,5,6-tetramethylpyrazine (1.0 equiv),Dissolve in glacial acetic acid, add 30% H2O2 (1.0-1.1 equiv) dropwise, and stir the reaction at 70 ° C for 4 h.Add 30% H2O2 (1.0~1.1equiv) and continue to react for 4h.The TLC monitoring formula (1) disappeared. After the reaction was completed, the sodium hydroxide aqueous solution was added to adjust the pH to be alkaline, and extracted with DCM.The organic layer was collected, dried and concentrated to give the compound of formula (2) as a white solid. | |
With dihydrogen peroxide; acetic acid at 94℃; for 4h; | 1 Example 1:Preparation of 3,5,6-trimethylpyrazine-2-carbaldehyde Weighed ligustrazine (6.8g, 50mmol),Dissolve it in 50 mL of glacial acetic acid,Add 30% hydrogen peroxide solution(11.25 mL, 100 mmol) was reacted at 94 ° C for 2 h.Then add 30% hydrogen peroxide (11.25mL, 100mmol),Continue to react for 2h,TLC monitors the reaction completely,The reaction solution was cooled to room temperature.Adjust the pH of the reaction solution to 10 with 50% sodium hydroxide solution.At this point, a large amount of white solids will precipitate.Add 3 times of chloroform to extract 3 times.Collecting the resulting chloroform solution together,Dry overnight with anhydrous sodium sulfate,Filter the chloroform solution,Evaporate dry with a rotary evaporatorObtained a white solid,It is a crude product of ligustrazine monoazooxide.The crude product (7.6 g, 50 mmol) was poured into a round bottom flask.Add acetic anhydride,Heating until the ligustrazine monoazo oxide is completely dissolved,Heated back to reflux for 2 h,After TLC is monitored until the reaction is complete,Evaporate the solvent under reduced pressure.Get a black slurry,After the black slurry is cooled to room temperature,Add 20% sodium hydroxide solution (100mL),Adjust the pH to 14,Stir the reaction for 12 h at room temperature.After TLC monitors the reaction,Add diatomaceous earth and filter the solution under low pressure to remove black pigment and insoluble impurities.Add dichloromethane extraction (50mL×3),The resulting dichloromethane solution is collected together.Dry overnight with anhydrous sodium sulfate,Filter the dichloromethane solution,Evaporate dry with a rotary evaporatorObtained a pale yellow solid,It is a crude 2-hydroxymethyl-3,5,6-trimethylpyrazine,The crude product was recrystallized from petroleum ether.Light yellow needle crystals,That is2-hydroxymethyl-3,5,6-trimethylpyrazine pure product yield 66%,Mp 88-89 ° C. | |
With dihydrogen peroxide; acetic acid at 90℃; for 6h; | 1 example 1 Preparation of intermediate compound 1 (2-chloromethyl-3, 5, 6-trimethylpyrazine) Take Ligustrazine 2· 176g (16mmol) dissolved into 20ml glacial acetic acid, add 1.8ml (16mmol) of 30% hydrogen peroxide at 90 ° C for 4h, and then supplement 1.8ml (16mmol) 30% hydrogen peroxide to continue the reaction for 2h, TLC monitoring reaction is complete, add an appropriate amount of sodium sulfite to neutralize excess hydrogen peroxide, the reaction solution was filtered, and the filtrate was cooled at room temperature, adjust the pH at 10 with 50% sodium hydroxide, extract with dichloromethane, collect the organic layer, dehydrate the saturated brine, dry over anhydrous sodium sulfate, and recover the solvent under reduced pressure, obtained white Ligustrazine mono-nitroxide compound crude (2). The crude product is added into 1.51ml (16mmol) of acetic anhydride, heating at 105 ° C for 2.5 h, after TLC was monitored until the reaction has completed, it was evaporated to get dryness under reduced pressure, obtained black slurry of ligustrazine acetylate (3). The next black slurry was placed in a solution of 20 ml (THF: Me0H: H20 = 3:1:1), add 1.92g (48mmol) sodium hydroxide in batches, the reaction was stirred for 2 h, extracted with dichloromethane and organic layer was collected, dehydrated with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent is recovered under reduced pressure and then obtained a crude hydroxyl Ligustrazine, that is re-crystallized from n-hexane, obtained 1.85g of yellow needle crystals (4), the yellow crystal of TMP-0H prepared in the previous step was dissolved into 20 ml of anhydrous tetrahydrofuran, after that add 3.03 g (15.9mmol) Tscl, 2.464 g (24.4mmol) TEA, 0.15 g (12.2mmol) DMAP, stir overnight, extract with methylene chloride, dehydrate the saturated brine, dry over anhydrous sodium sulfate, filter, recover solvent, obtained light yellow chloro-Ligustrazine crude product, appropriate amount of silica gel sample, separation on silica gel column [V (petroleum ether): V (ethyl acetate) = 10:1] and then obtained colorless and transparent chloro- Ligustrazine 1.86g, yield 90.3%. | |
With dihydrogen peroxide; acetic acid at 70℃; for 8h; | ||
With dihydrogen peroxide; acetic acid at 90℃; for 4h; | ||
With dihydrogen peroxide; acetic acid at 70℃; for 10h; | 1 Example 1 Synthesis of Compound TCO-1 (Figure 2) Weighing 10 g (73.5 mmol) of tetramethylpyrazine in 20 ml of acetic acid,Add 8 ml of 30% hydrogen peroxide. Adding oil bath reaction at 70 ° C for 5 hours8.3 ml of 30% (73.5 mmol) of hydrogen peroxide and continue to react for 5 hours.TLC monitors the extent of the reaction and stops the reaction. Cool to room temperature, adjust to saturated sodium hydroxide solutionpH to 10. Extracted with dichloromethane (50ml*5 times),The organic layer was evaporated under reduced pressure using a rotary evaporator to yield white solid (1a-1).20 ml of acetic anhydride (212 mmol) was added thereto to carry out an oil bath at 125 ° C for 2.5 hours.The reaction was complete by TLC. The acetic anhydride was distilled off under reduced pressure to give the crude product (1a-2).Then, the saturated solution of sodium hydroxide was adjusted to pH to 12, stirred at room temperature, and hydrolyzed overnight.The reaction solution was extracted with ethyl acetate (50 ml * 5 times), distilled under reduced pressure, and subjected to wet-column column chromatography.The mobile phase EA: PE (1:1), the fraction was detected by TLC, and the TMP-OH fraction was collected.The same fractions were combined and evaporated under reduced pressure to give a white solid powder 7.5 g.(1a-3, TMP-OH, 49.3 mmol), [M+Na]+=175,The yield was 67%. | |
With dihydrogen peroxide; acetic acid at 70℃; for 8h; | 1.1 (1) In a round bottom flask, add (1) 2,3,5,6-tetramethylpyrazine (ie ligustrazine) (1.0 equiv), dissolve in glacial acetic acid, and add 30% H 2 O 2 dropwise ( 1.0~1.1equiv), stir the reaction at 70 °C for 4h, add 30% H2O2 (1.0~1.1equiv), continue the reaction for 4h, TLC monitoring formula (1) disappears, after the reaction is finished, add sodium hydroxide aqueous solution to adjust the pH It is basic, extracted with DCM, and the organic layer is collected, dried and concentrated to give the compound of formula (2) as a white solid. | |
With dihydrogen peroxide; acetic acid at 70℃; for 10h; | 1.1 Ligustrazine (13.6g, 100mmol), add glacial acetic acid (40mL) and 30% H2O2 (12mL) to the three-necked flask. After heating at 70 ° C for 5 hours, another 30% H2O2 (12 mL) was added and the reaction was continued at reflux for 5 h. The reaction was monitored by TLC. The reaction was cooled to room temperature. The pH was adjusted to 11-12 in a 25% NaOH solution in an ice bath. Dichloromethane was extracted (3 × 250 mL). Anhydrous Na2SO4 was dried, filtered, and the solvent was recovered under reduced pressure to obtain crude product 1. Next, 1 was dissolved in 50 mL of acetic anhydride and heated under reflux for 3 h. A black slurry 2 was obtained. After cooling, add 25% NaOH solution to the ice bath to adjust the pH to 12, dichloromethane extraction (3 x 200 mL), dried over anhydrous Na2SO4, filtered, the solvent was recovered under reduced pressure to obtain a solid, purification by silica gel column chromatography (PE / EtOAc = 6: 1) gave 2-hydroxymethyl-3,5,6-trimethylpyrazine (TMP-OH) as a pale yellow solid with a yield of 58%. | |
With dihydrogen peroxide; acetic acid In water at 90℃; for 6h; | ||
With dihydrogen peroxide; acetic acid at 95℃; for 2h; | ||
With dihydrogen peroxide In acetic acid at 70℃; for 10h; Reflux; | 1.2 (2) Synthesis of (3,5,6-trimethylpyrazin-2-yl)methanol (3) Weigh TMP (500mg, 0.027mmol) and 2ml of hydrogen peroxide, and dissolve it with 2ml of glacial acetic acid in a 25ml round bottom flask.Heated at 70 for 5h in a constant temperature magnetic stirrer,Then put in 1ml of hydrogen peroxide and continue to reflux for 5h,TLC monitors that the reaction is complete. After cooling to room temperature,Adjust the pH to 11-12 with 25% NaOH in an ice bath,At this time, white foam is produced. Then extract with dichloromethane until the extracted organic phase has no fluorescence absorption.Dry with anhydrous Na2SO4, filter, and recover the solvent under reduced pressure.The crude product 1 was obtained by rotary drying. Dissolve crude product 1 in acetic anhydride,Heat to reflux for 3h in a thermostatic magnetic stirrer,TLC monitors that the reaction is complete, and crude product 2 is obtained.After cooling to normal temperature, adjust the pH to 11-12 with 25% NaOH in an ice bath, and monitor the reaction by TLC.Then extract with dichloromethane,Until the extracted organic phase has no fluorescence absorption.Dry with anhydrous Na2SO4, filter, and recover the solvent under reduced pressure.The crude product 3 (3,5,6-trimethylpyrazin-2-yl)methanol was obtained by rotary drying. Column chromatography (petroleum ether: ethyl acetate, 3: 1)4.28 g of white solid (3,5,6-trimethylpyrazin-2-yl)methanol (3) was isolated, and the yield was 72%. | |
With dihydrogen peroxide at 70℃; | 1.1 (1) Using ligustrazine as raw material, oxidizing with 30% hydrogen peroxide at 70°C to obtain mononitroxide, Then, the Boekelheide rearrangement reaction occurs with acid anhydride under heating conditions to obtain a compound that generates methyl acetate at position 2. Hydrolysis reaction is carried out with 20% NaOH aqueous solution to finally obtain 2-hydroxymethyl-3,5,6-trimethylpyrazine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With Oxone In dichloromethane at 25℃; for 24h; | |
53% | With dihydrogen peroxide; acetic acid at 70 - 80℃; for 26.5h; | |
With dihydrogen peroxide; acetic acid |
With Oxone In dichloromethane at 24.9℃; for 24h; | ||
With dihydrogen peroxide; horseradish peroxidase at 37℃; for 1h; aq. phosphate buffer; Enzymatic reaction; | ||
With dihydrogen peroxide In acetic acid at 98℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With potassium permanganate In water | |
55% | With potassium permanganate at 60℃; for 6h; | 2.2 Synthesis of H4pztc A mixture of 2,3,5,6-tetramethylpyrazine (22.1 mmol,3.00 g), potassium hydroxide (52.8 mmol, 2.96 g) was dissolvedin water (250 mL). KMnO4 powder was added to themixture in batches, which was stirred for 6 h at 60 °C tocomplete the oxidization. After that, adequate amount ofethanol was dropped to the mixture and the filtrate wasconcentrated and acidified to acquire the white power. Thenthe oxidation products were recrystallized from 25 mL of20% aq. HCl, yield 55%. 13C NMR (400 MHz, D2O): δ167.53, 145.57. |
46% | With potassium permanganate; Aliquat 336; sodium carbonate In water at 100℃; |
With potassium permanganate | ||
With potassium permanganate; sodium hydroxide In water at 20℃; for 26h; Reflux; | Preparation of 2,3,5,6-pyrazinetetracarboxylic acid (11) Tetramethylpyrazine (10) and sodium hydroxide are suspended in hot deionized water. Hot potassium permanganate (KMnO4) solution is then slowly added after which the mixture is stirred for a further 2 hours at room temperature prior to refluxing for 24 hours. The solution is cooled to room temperature using an ice bath and ethanol is then added to the mixture to destroy any excess KMflO4. The volume of solution is reduced and then cooled to allow crystallization of the product over a period of 24 hours. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.6% | With palladium on activated charcoal; ammonium formate In water at 80 - 90℃; for 4h; | 3 Example 3 10.0 g of butanedione monooxime,1.0 g of palladium on carbon was added to 134 ml of water,And then stirred to a temperature of 80 to 90 ° C.67.4 g of ammonium formate (HCOONH4) was added in batches,After adding ammonium formate,Continue stirring for 4 hours.After the reaction is complete,The palladium carbon was removed by suction filtration under a Buchner funnel,The filtrate was extracted three times with dichloromethane (CH2Cl2)Combine organic phase,Dried over anhydrous sodium sulfate,filter,And concentrated under reduced pressure to give 5.7 g of tetramethylpyrazine,The yield was 84.6%. |
With hydrogenchloride; tin Behandlung des entstandenen Methyl-<α-amino-aethyl>-ketons mit Alkalien; | ||
With hydrogenchloride; tin(ll) chloride Behandlung des entstandenen Methyl-<α-amino-aethyl>-ketons mit Alkalien; |
With potassium hydroxide; mercury dichloride | ||
With sodium hydroxide; zinc | ||
With hydrogenchloride; tin(ll) chloride Destillation des Reaktionsprodukts mit Quecksilber(II)-chlorid und Natronlauge; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With carbonylchlorohydrido(4,5-bis((diisopropylphosphino)methyl)acridine)ruthenium(II); ammonia In toluene at 150℃; for 36h; Inert atmosphere; Glovebox; | |
With aluminium oxide catalysts; ammonia at 400℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With air; sodium acetate In methanol at 60℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.6 % Chromat. | With diammonium phosphate In water for 24h; Ambient temperature; | |
With ammonium acetate at 85℃; for 4h; | ||
With ammonium acetate In water at 25℃; Ea; other ammonium salts; var. solvents, temperature and pressure; effect of high pressure; effect of propylene glycol; effect of nicotinamide adenine dinucleotide and flavin adenine dinucleotide as hydrogen acceptors; |
With sodium hydroxide; ammonium phosphate; ammonium citrate In water at 85℃; for 5h; phosphate buffer, pH 7.2; reaction in acetate buffer, pH 7.2; addition of MeOH and EtOH; effects of a buffer and solvent on tetramethylpyrazine formation in a 3-hydroxy-2-butanone-ammonium hydroxide system; | ||
With ammonium acetate In water | 7 EXAMPLE 7 EXAMPLE 7 Acetoin (7.92 g, 0.09 moles), ammonium acetate (21 g, 0.27 moles), and 2 ml of water are processed in an assembly as depicted in the drawing Figure. The assembly is evacuated to a reduced pressure of about 30 mm Hg. The reaction mixture is heated at 115° C. and refluxed for 4 hours. Crystalline product sublimed on the cooled cone. After cooling the system and releasing pressure, and after disassembly, the product is collected and washed with water. 3.7 g of a crystalline product are obtained. Analyses indicate the product is tetramethylpyrazine. The product has a melting point of from 83° C. to 85° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 30℃; Reflux; | Ligustrazine 10mmol,Dibenzoyl peroxide (BPO) 0.5mmol in a single-mouth flask,Add solvent 10ml of carbon tetrachloride and stir at 30°C. NBS (1.77 g, 10 mmol) was added portionwise, followed by stirring at reflux. After the TCL reaction was completed, the reaction mixture was filtered while hot, and 10 ml of a saturated aqueous solution of sodium hydrogencarbonate was added. The filtrate was extracted twice with 10 ml of dichloromethane, and the residue was purified by column chromatography to give Compound 2 (1.98 g, yield 92%). |
75% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane | |
72.8% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 75℃; for 10h; Incandescent irradiation; | 1.1.3 1.3 Synthesization of 2-bromomethyl-3, 5, 6-trimethylpyrazine Equation: [Show Image] Reaction steps: Adding raw material of ligustrazine (20g, 0.147 mol), NBS (26.75g, 0.15 mol), benzoperoxide (0.05 g, 0.0002 mol), and CCl4 (75 mL) into a 250mL three-necked bottle in turn, wherein the solution appears orange and turbid, irradiating with incandescent lamp, heating to 75°C with oil bath, processing circumfluence for 10 hours, wherein TLC [V(petroleum ether):V(ethyl acetate) = 2:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material = 0.4, Rf of product = 0.6), and the reaction solution appears purple, filtering out formed succinimide to obtain purple filtrate, recycling CCl4 under reduced pressure to obtain a purple viscous liquid, distilling under reduced pressure, collecting a cut fraction under 99-101°C / 2mmHg to obtain 23g colorless liquid of 2-bromomethyl-3, 5, 6-trimethylpyrazine, solidifying after cooling, m.p. 41.2-44°C, a yield is 72.8%. |
70% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane Reflux; Irradiation; | 1 The preparation of 2-bromomethyl-3,5,6-trimethylpyrazine intermediate Dehydrated tetramethylpyrazine 10 g was dissolved into CCl4 60 ml and then NBS 9.17 g was added at a molar ratio of tetramethylpyrazine to NBS=1:0.7 (a minute amount of benzoylperoxide can be added as radical initiator). Reaction was carried out under reflux under the illumination of an incandescent lamp for 10-12 h. The reaction sample was cooled and condensed, and the excess tetramethylpyrazine was sucked away at reduced pressure in 60-70° C. water bath. The residue was kept in a fridge for standing and a pale red half-oily substance 7.75 g was obtained with a yield of 70%. |
70% | With N-Bromosuccinimide In tetrachloromethane Reflux; Irradiation; | 1 The preparation of 2-bromomethyl-3,5,6-trimethyl pyrazine intermediate The preparation of 2-bromomethyl-3,5,6-trimethyl pyrazine intermediate [0106] Dehydrated tetramethylpyrazine 10 g was dissolved into CCl4 60 ml and then NBS 9.17 g was added at a mole ratio of tetramethylpyrazine to NBS=1:0.7 (a minute amount of benzoylperoxide can be added as radical initiator). Reaction was carried out under reflux under the illumination of an incandescent lamp for 10-12 h. The reaction sample was cooled and condensed, and the excess tetramethylpyrazine was sucked away at a reduced pressure in 60-70° C. water bath. The residue was kept in a fridge for standing and a pale red half-oily substance 7.75 g was obtained with a yield of 70%. |
70% | With N-Bromosuccinimide In tetrachloromethane for 12h; Irradiation; Reflux; | 1.1 (1) Synthesis of 2-bromomethyl-3,5,6-trimethylpyrazine (4): In a 250 mL round bottom flask was added 20.0 g(348 mmol) of TMP,After 18.2 g (103 mmol) of N-bromosuccinimide (NBS) was dissolved in 80 mL of CCl4 to dissolve the starting material,60W incandescent lamp irradiation and reflux 12h,After the reaction was completed by TLC, the filtrate was filtered off with suction and the filtrate was evaporated to dryness. The crude product was purified by silica gel column chromatography with V (petroleum ether): V (ethyl acetate) = 12: 1 to obtain 15.4g of white solid with a yield of 70% |
70% | With N-Bromosuccinimide In tetrachloromethane Irradiation; Reflux; | 1 Example 1 Preparation of intermediate bromotetramethylpyrazine (TMP-Br) Weigh TMP · 3H2O in an appropriate amount of 2-3 times the amount of toluene and stir to dissolve, heat to reflux for 10-12h, and perform dehydration treatment in the water separator to obtain anhydrous TMP.Take an appropriate amount of anhydrous TMP and dissolve it in CCl4 with stirring, and then put into NBS according to the molar ratio TMP: NBS = 1: 0.7-0.9.Under full irradiation of an incandescent lamp, heat and reflux for 10 hours. At the end of the reaction, the reaction solution is purplish red. The resulting succinimide is suspended on it, cooled, filtered, concentrated under reduced pressure in a water bath at 60-80 and pumped Excess ligustrazine,A purple-red semi-oil TMP-Br was obtained, Yield: 70%. |
63.6% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 75℃; for 10h; Irradiation; | 1.1 Synthesis of 2-bromomethyl-3,5,6-trimethylpyrazine In the 250ml three-necked flask in turn add raw materials anhydrous ligustrazine(20 g, 0.147 mol), NBS (26.75 g,0.15 mol),Benzoyl peroxide(0.058, 0.0002 mol), solvent ccl4,The solution was orange yellow turbidity,Incandescent light,The oil bath is warmed to 75 ° C,Reflux reaction for 10 hours,TLC [V (petroleum ether): V (ethyl acetate) = 2: 1 as developing solvent] showed complete reaction (raw material Rf = 0. 4, product Rf = 0. 6)The reaction solution was purple,The resulting succinimide was removed by filtration,Purple red filtrate,Decompression recovery CC14 after the purple-colored viscous liquid,After vacuum distillation,Collect product 99 ~ 101 ° C / 2mmHg fraction,2-bromomethyl-3,5,6-trimethylpyrazine as colorless liquid, cooled and cured, m.p. 41. 2 to 44 ° C in a yield of 63.6%. |
60% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane Reflux; | 1 Specific steps are as follows: 32mL CCl4 added 2,3,5,6_ tetramethylpyrazine 8.7g (63 · 7mmol) of the reaction flask,Then 11.54 g (64.8 mmol) of N-bromosuccinimide (NBS)23 mg of benzoyl peroxide,The mixture was stirred at 200W incandescent lamp reflux reaction 8_9h;After the reaction was cooled to 5 ° C or less,The succinimide was removed by suction filtration to obtain 13.0 g of a tan oil,The crude product was isolated by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1, v / v) to give pure 2-Bromomethyl-3,5,6-trimethylpyrazine (1) 8.3 g as a white to pale pink solid with a yield of 60%. |
58.3% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 65℃; for 10h; Irradiation; | |
53.2% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 80℃; | 1 Synthesis of compound IND-003 (FIG. 2) TMP (15 g, 110.3 mmol) was dissolved in 250 mL of carbon tetrachloride, then NBS (20 g, 112.4 mmol) and a catalytic amount of benzoyl peroxide were added respectively. The reaction was heated to 80° C. overnight. After the reaction was completed, an appropriate amount of water was added, and the resulting mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate. The solvent was evaporated to dryness under reduced pressure. The resulting material was separated via column chromatography (ethyl acetate: petroleum ether=1:9) to give TMP-Br as a pale white solid (12.6 g, 53.2%). ESI-MS: [M+H]+ m/z 217.0. 1H-NMR:(300 MHz, CDCl3) δ: 4.67 (s, 2H), 2.53 (s, 6H), 2.41 (s, 3H). |
52% | With N-Bromosuccinimide; dibenzoyl peroxide at 70℃; for 10h; | |
50% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 75℃; for 10h; Irradiation; | 3 4. Preparation of 2-bromomethyl-3,5,6-trimethylpyrazine Ligustrazine (20.0 g, 0.147 mol), NBS (26.8 g, 0.151 mol), a catalyst benzoyl peroxide (0.058 g, 0.232 mmol) and a solvent CCl4 (75.0 mL) are sequentially added into a 250 ml three-necked bottle, irradiating with an incandescent lamp is performed, heating is performed to 75° C. in an oil bath, and a reaction is performed for a period of 10 hours. Filtering is performed to remove the solvent from filter liquor to obtain a concentrate. Purification is performed by column chromatography to obtain 15.8 g of light-yellow solid, i.e., 2-bromomethyl-3,5,6-trimethylpyrazine, wherein the yield is 50%. |
30.5% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 77℃; for 3h; | 1 Example 1: Synthesis of compound D-TBN Weigh tetramethylpyrazine (ΤΜΡ) (10g , 73.5 mmol) was dissolved in 150 ml of carbon tetrachloride and NBS was added (19.6 g, 110.3 mmol) , Catalytic amount of benzoyl peroxide 10mg, warmed to 77 ° C reaction 3KTLC monitoring reaction , After the reaction is over , Cooled to room temperature, suction filtered, the filter cake washed with a small amount of CC14 2-3 times, the filtrate was concentrated under reduced pressure rotary evaporator, the crude product Column chromatography , To obtain a white solid compound 1 (4.80 g, yield 30.5%). |
With N-Bromosuccinimide In tetrachloromethane for 12h; Reflux; Irradiation; | ||
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 12h; | ||
With N-Bromosuccinimide In tetrachloromethane for 12h; Reflux; UV-irradiation; | ||
With tetrachloromethane; N-Bromosuccinimide for 12h; Irradiation; Reflux; | ||
With N-Bromosuccinimide In tetrachloromethane at 95℃; for 1h; Irradiation; | ||
With N-Bromosuccinimide; dibenzoyl peroxide for 24h; Reflux; | ||
With N-Bromosuccinimide In tetrachloromethane at 95℃; for 2h; | 1 Example 1: preparation of 2-bromomethyl-3,5,6-trimethylpyrazine intermediate ( compound B) Weigh 20.00g (0.15mol) of anhydrous TMP, 23.54gNBS (0.15mol, before use finely) into 250mL three-necked flask, 100mLCCl4As the reaction solvent, 4 85W incandescent lamp illumination, 95 reflux 2h.TLC [V (petroleum ether) :V (acetone) = 3] Detection reaction is substantially complete; After cooling filtration, the filtrate was collected, solvent is recovered under reduced pressure to give a viscous purple liquid (content of 60% by count), spare. | |
With N-Bromosuccinimide In tetrachloromethane at 95℃; for 1h; | 1 Example 1 Preparation of 2-Aromomethyl-3,5,6-trimethylpyrazine intermediate 2-O methyl -3, 5, 6-trimethyl pyrazine synthetic process optimization ". xu Kuo, wang Penglong, han Qiujun, and the like. Anhui medicine, 2013,17 (9): 1467-1470 the method for preparing [...]. Weighing 20.00g (0.15mol) no water ligustrazine, 23.54gNBSN-bromo succinimide (0.15mol, front porphyrization) in 250 ml three-necked bottle, 100mLCCl4as the reaction solvent, 4 lamps 85W incandescent lamp irradiation, 95 °C reflux reaction 1h. TLC[V (petroleum ether): V (acetone) the =3 [...] 1] detection reaction substantially completely; after cooling cvvhdf, collect filtrate, pressure reducing and recovering the solvent, to be purple-red viscous liquid (according to the content of 60% meter). HRMS (ESI) m/z: 216.00135 [M+H]+, the theoretical calculation: C8H11BrN2: 216.00851. | |
With N-Bromosuccinimide; dibenzoyl peroxide at 20℃; | ||
With N-Bromosuccinimide In tetrachloromethane at 95℃; Irradiation; | 1 Example 1 Preparation of intermediate compound 1 (2-bromomethyl-3,5,6-trimethylpyrazine) According to "intermediate 2-bromomethyl-3,5,6-trimethyl pyrazine synthesis process optimization. "Anhui Pharmaceutical, 2013,17 (9): 1467-1470" method of preparation. Weigh 20.00g (0.15mol) anhydrous tetramethylpyrazine, 23.54g N-bromosuccinimide (0.15mol, finely ground before use) placed in 250mL three-necked flask, 100mL CCl4 as a reaction solvent, four 85W incandescent lamp irradiation, 95 °C reflux reaction 1h. TLC [V (petroleum ether): V (acetone) = 3: 1]. The reaction was basically complete. After cooling, the reaction mixture was filtered and the filtrate was collected. The solvent was recovered under reduced pressure to give a purple-red viscous liquid (content: 60%). | |
With N-Bromosuccinimide In tetrachloromethane for 12h; Reflux; Irradiation; | 2-(Bromomethyl)-3,5,6-trimethylpyrazine (TMP-Br): TMP.3H2O (0.26 mol) was dissolved in benzene(120 mL) and refluxed for 10 h. After concentrating the solution, white solids (TMP) were obtained.TMP (0.15 mol) was dissolved in carbon tetrachloride (100 mL) and NBS (0.12 mol) was added inportions. The mixture was refluxed and illuminated by four 60 W tungsten light bulbs. After 12 h, thebrown liquid was filtered and dried in vacuum. A brown crude oily product was obtained (TMP-Br),which was not purified further, as it caused a strong mucous membrane irritation. Yield: 70%. | |
Multi-step reaction with 4 steps 1: acetic acid; dihydrogen peroxide / 8 h / 70 °C 2: 3 h / 120 °C / Reflux 3: sodium hydroxide; water / ethanol / 1 h / 25 °C 4: phosphorus tribromide / dichloromethane / 1 h / 0 - 25 °C | ||
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 45 - 70℃; for 10h; | ||
With N-Bromosuccinimide In tetrachloromethane at 95℃; for 1h; Microwave irradiation; | 1 Embodiment 1 compound 2 - bromo methyl - 3, 5, 6 - trimethyl pyrazine (compound 1) preparation According to the "" intermediate 2 - bromomethyl - 3, 5, 6 - trimethyl pyrazine synthesis process optimization ". [...], [...], [...], and the like. Anhui medical, 2013, 17 (9): 1467 - 1470" method. Weighing 20.00 g (0.15 µM) water-free Rhizoma Chuanxiong hydrochlorothizide, 23.54 g NBS N - bromosuccinimide (0.15 µM, for the ground before) is placed on the 250 ml [...], 100 ml CCl4 as the reaction solvent, 4 lamp 85 W incandescent lamp irradiation, 95 °C reflux reaction 1 h. TLC [V (petroleum ether): V (acetone)=3:1] detection reaction substantially completely; after cooling filtered, collecting the filtrate, the solvent is recovered under reduced pressure, a red viscous liquid (content of 60% meter). | |
Multi-step reaction with 4 steps 1: acetic acid; dihydrogen peroxide / 8 h / 70 °C 2: 3 h / 120 °C 3: sodium hydroxide; water / ethanol / 1 h / 25 °C 4: phosphorus tribromide / dichloromethane / 1 h / 0 - 20 °C | ||
Multi-step reaction with 4 steps 1: acetic acid; dihydrogen peroxide / 10 h / 70 °C 2: 3 h / Reflux 3: sodium hydroxide; water / pH 12 / Cooling with ice 4: phosphorus tribromide / tetrahydrofuran / 0.5 h / 0 °C | ||
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 10h; Irradiation; Reflux; | 2.1 Step (1): Compound 1-0 (20g, 147mmol), N-bromosuccinimide (26.7g, 150mmol) andBenzoyl peroxide (50mg, 0.2mmol) was dissolved in carbon tetrachloride (70ml), irradiated by incandescent lamp, refluxed for 10 hours,After the reaction is over, filter and concentrate to obtain crude product 1-2, which is directly put into the next reaction. | |
With N-Bromosuccinimide; Benzoyl bromide In tetrachloromethane for 10h; Irradiation; Reflux; | 2.1 step (1) Compound 1-0 (20g, 147mmol),N-bromosuccinimide (26.7g, 150mmol) and benzoyl peroxide (50mg, 0.2mmol) are dissolved in carbon tetrachloride (70ml),Illuminated by incandescent lamps,Reflux for 10 hours,After the reaction,filter,Concentrate to get crude product 1-2,Go directly to the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With selenium(IV) oxide In water at 105℃; for 5h; | |
67.2% | With selenium(IV) oxide | |
41% | With selenium(IV) oxide In 1,4-dioxane at 110℃; for 6h; | 1 Preparation of Compound (1): 136 mg (1 mmol) of ligustrazine was added to 8 mL of 1,4-dioxane.Further, 224 mg (2 mmol) of SeO2 was added, and the mixture was reacted at 110 ° C for 6 hours, filtered, and evaporated to dryness under reduced pressure.Purification by column chromatography (ethyl acetate: petroleum ether 1:15),2,4-dialdehyde-3,5-dimethylazine was obtained in a yield of 41%. |
37.9% | With selenium(IV) oxide In 1,4-dioxane at 110℃; for 6h; | 2 Example 2: Synthesis of compound 5-OH-D-TBN TMP (25g, 183.82mmol) was dissolved in 250mL of 1,4-dioxane was added selenium dioxide (40.8g, 367.64 mmol), was heated to 110 deg.] C, the reaction 6h. After completion of the reaction, the reaction solution was filtered, an appropriate amount of silica gel was added to the filtrate, the solvent was evaporated under reduced pressure, column chromatography (ethyl acetate: petroleum ether = 1: 15) to give a tan solid Compound 3 (11.4g, 37.9 %). |
37.9% | With selenium(IV) oxide In 1,4-dioxane at 110℃; for 6h; | 4 Synthesis of Compound IND-008 (FIG. 3) TMP (25 g, 183.8 mmol) was dissolved in 250 mL of 1,4-dioxane, and selenium dioxide (40.8 g, 367.6 mmol) was added, and the reaction was heated to 110° C. for 6 hours. After the reaction was completed, the reaction solution was filtered, and an appropriate amount of silica gel was added to the filtrate. The solvent was evaporated to dryness under reduced pressure. The residue was separated by column chromatography (ethyl acetate: petroleum ether=1:15) to give 3,6-dimethyl pyrazine-2,5-dicarbaldehyde (Compound 2) as a brownish solid (11.4 g, 37.9%). ESI-MS: [M+H]+ m/z 165.0. 1H-NMR:(300 MHz, CDCl3) δ: 10.22 (s, 2H), 2.92(s, 6H). |
35.6% | With selenium(IV) oxide at 84℃; for 2h; | |
30% | With selenium(IV) oxide In 1,4-dioxane at 107℃; for 3h; | 15 Example 15. Synthesis of compound MT-009A TMP (6.8 g 50 mmol) was dissolved in dioxane (100 mL) selenium dioxide (11.1 g 100 mmol) was added and the reaction was heated to 107 for 3 hours and monitored by TLC. After the reaction was complete the reaction mixture was filtered with cooling the filtrate was distilled off the solvent and added with an appropriate amount of 100-200 mesh silica gel and the sample was loaded and separated on a silica gel column (CH2Cl2as eluent) to give the compound MT-009A as a pale yellow solid (2.46g 30) . |
30% | With selenium(IV) oxide In 1,4-dioxane at 107℃; for 3h; | 15 Synthesis of Compound MT-009A TMP (6.8 g, 50 mmol) was dissolved in dioxane (100 mE), selenium dioxide (11.1 g, 100 mmol) was added, and the reaction was heated to 107° C. for 3 hours and monitored by TEC. Afier the reaction was complete, the reaction mixture was filtered with cooling, the filtrate was distilled oil the solvent and added with an appropriate amount of 100-200 mesh silica gel, and the sample was loaded and separated on a silica gel column (CH2C12 as eluent) to give the compound MT-009A as a pale yellow solid (2.46 g, 30%). |
26% | With selenium(IV) oxide In 1,4-dioxane; water for 5h; Heating; | |
With selenium(IV) oxide In 1,4-dioxane at 110℃; for 6h; | ||
With 1,4-dioxane; selenium(IV) oxide at 110℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In a 500 ml round-bottom flask TMP (13.6 g 100 mmol) was added and dissolved in glacial acetic acid (15 mL) 30 hydrogen peroxide (8 mL 75 mmol) was added and reaced for 4 hours at 70 and 30 hydrogen peroxide (8 mL 75 mmol) was added and then further reacted for 4 hours and monitored by TLC until the reaction product was no longer generated. The resulting material was allowed to return to room temperature then placed in an ice bath adjusted to pH 10 with a solution of 10 sodium hydroxide extracted with chloroform dried over anhydrous sodium sulfate and filtered and concentrated to give crude material of TMP nitric oxide. Without isolation the crude materil was added with acetic anhydride (14.3 mL 150 mmol) heated to 125 with reflux for 3 hours and monitored by TLC until the starting material completely comsumed and the excess acetic anhydride was removed by distillation to give TMP acetyl compound allowed to return to room temperature then placed in an ice bath a solution of 10 sodium hydroxide was added to adjust pH to 12 stirred for 5 hours at room temperature extracted with chloroform dried over anhydrous sodium sulfate filtered and concentrated and the resulting material as separated with column chromatography eluted with ethyl acetate /petroleum ether (11) to give the compound TMP-OH as a white solid (9.88 g 65) . | |
65% | With dihydrogen peroxide; acetic acid; at 70℃; for 8h; | In a 500 ml round-bottom flask, TMP (13.6 g, 100 mmol) was added and dissolved in glacial acetic acid (15 mE), 30% hydrogen peroxide (8 mE, 75 mmol) was added, and reaced for 4 hours at 70 C., and 30% hydrogen peroxide (8 mE, 75 mmol) was added and then thrther reacted for 4 hours and monitored by TEC until the reaction product was no longer generated. The resulting material was allowed to return to room temperature then placed in an ice bath, adjusted to pH 10 with a solution of 10% sodium hydroxide, extracted with chloroform, dried over anhydrous sodium sulfate, and filtered and concentrated to give crude material of TMP nitric oxide. Without isolation, the crude material was added with acetic anhydride (14.3 mE, 150 mmol), heated to 125 C. with reflux for 3 hours, and monitored by TEC until the starting material completely consumed, and the excess acetic anhydride was removed by distillation to give TMP acetyl compound, allowed to return to room temperature then placed in an ice bath, a solution of 10% sodium hydroxide was added to adjust pH to 12, stirred for 5 hours at room temperature, extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting material as separated with colunm chromatography eluted with ethyl acetate/petroleum ether (1:1) to give the compound TMP-OH as a white solid (9.88 g, 65%). |
1.85 g | With dihydrogen peroxide; acetic acid; at 90℃; for 6h; | 2.17 g (16 mmol) of ligustrazine was dissolved in 20 ml of glacial acetic acid. Add 1.8 ml (16 mmol) of 30% hydrogen peroxide at 90 C for 4 h.Then, 1.8 ml (16 mmol) of 30% hydrogen peroxide was added to continue the reaction for 2 h, and the reaction was completely monitored by TLC.Add an appropriate amount of sodium sulfite to neutralize excess hydrogen peroxide, filter the reaction solution, cool the filtrate to room temperature, and adjust the pH to 10 with 50% sodium hydroxide.The mixture was extracted with methylene chloride. The organic layer was collected, dried over anhydrous sodium sulfate and dried over anhydrous sodium sulfate. This crude product was added to 1.51 ml (16 mmol) of acetic anhydride, and the mixture was heated to reflux at 550 C for 2.5 hr.This black slurry was placed in a solution of 20 ml (THF: MeOH: H 2 O = 3:1:1), 1.92 g (48 mmol) of sodium hydroxide was added portionwise, and the reaction was stirred for 2 h.The organic layer was extracted with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate and filtered.Recovering the solvent under reduced pressureThe crude hydroxyxazine was recrystallized from n-hexane to give 1.85 g of yellow needle crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: aq. H2O2; acetic acid / 8 h / 70 °C 2: 3 h / Heating 3: 64 percent / aq. NaOH 4: SOCl2 / CH2Cl2 / 2.5 h | ||
Multi-step reaction with 4 steps 1.1: dihydrogen peroxide; acetic acid / 95 °C 2.1: 2 h / Reflux 3.1: sodium hydroxide 4.1: thionyl chloride / dichloromethane / 2.5 h / 0 °C 4.2: 0.08 h | ||
Multi-step reaction with 4 steps 1: acetic acid; dihydrogen peroxide / 6 h / 90 °C 2: 2 h / 105 °C 3: sodium hydroxide / water; methanol; tetrahydrofuran / 1 h 4: p-toluenesulfonyl chloride; triethylamine; dmap / tetrahydrofuran / 12 h / 25 °C |
Multi-step reaction with 4 steps 1.1: dihydrogen peroxide; acetic acid / water / 4 h / 90 °C / Inert atmosphere 2.1: 105 °C / Inert atmosphere 3.1: sodium hydroxide / water; tetrahydrofuran; methanol / 1 h / 20 °C 4.1: thionyl chloride / dichloromethane / 2.5 h / 0 °C 4.2: 0.08 h / 0 °C | ||
Multi-step reaction with 4 steps 1: acetic acid; dihydrogen peroxide / 6 h / 90 °C 2: 2 h / 105 °C 3: sodium hydroxide / methanol; tetrahydrofuran; water 4: triethylamine; dmap; p-toluenesulfonyl chloride / tetrahydrofuran / 12 h | ||
With N-chloro-succinimide; dibenzoyl peroxide In tetrachloromethane at 20℃; for 10h; Inert atmosphere; Reflux; | ||
Multi-step reaction with 4 steps 1: acetic acid; dihydrogen peroxide / water / 6 h / 90 °C 2: 2 h / 105 °C 3: sodium hydroxide; water / methanol; tetrahydrofuran / 1 h 4: p-toluenesulfonyl chloride; dmap; triethylamine / tetrahydrofuran / 12 h | ||
Multi-step reaction with 4 steps 1: dihydrogen peroxide; acetic acid / 2 h / 95 °C 2: 2.5 h / 140 °C 3: sodium methylate / methanol / 0.5 h / 20 °C 4: thionyl chloride / dichloromethane / 2.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen In acetic acid | 2 Scheme 2 To a solution of 2-1 (5 g, 36.7 mmol) in acetic acid (75 [ML)] was added [PT02] (450 mg). After stirring the reaction mixture under [H2] atmosphere overnight, the mixture was flushed with nitrogen, filtered and concentrated. To a solution of the bis-acetate salt (9.63 g, 36.7 mmol) in methanol (20 mL) was added 5N [NAOH] (40 [ML,] 200 mmol). Methanol was removed under vacuum, and the mixture was extracted with [CH2CL2.] The organic layer was dried and concentrated to give 2-2 (4.26 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium diisopropyl amide In tetrahydrofuran | II 2-(2-Hydroxy-4-phenyl-3-buten-1-yl)-3,5,6-trimethylpyrazine STR10 EXAMPLE II 2-(2-Hydroxy-4-phenyl-3-buten-1-yl)-3,5,6-trimethylpyrazine STR10 To a solution of lithium diisopropylamide (1.5 Molar, 73.3 mL, 0.11 mole) in 150 mL of tetrahydrofuran at -78° C. is added slowly a solution of tetramethylpyrazine (13.6 g, 0.1 mole) in 100 mL of tetrahydrofuran. The mixture is allowed to warm to room temperature and then cooled to -78° C. A solution of cinnamaldehyde (14.5 g, 0.11 mole) in 100 mL of tetrahydrofuran is added dropwise over 15 minutes. The reaction product mixture is then worked up according to the procedures of Example I to provide the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium diisopropyl amide In tetrahydrofuran | V 2-(2-Hydroxy-4-p-methoxyphenyl-3-buten-1-yl)-3,5,6-trimethylpyrazine STR13 EXAMPLE V 2-(2-Hydroxy-4-p-methoxyphenyl-3-buten-1-yl)-3,5,6-trimethylpyrazine STR13 To a solution of lithium diisopropylamide (1.5 Molar, 73.3 mL, 0.11 mole) in 150 mL of tetrahydrofuran at -78° C. is added slowly a solution of tetramethylpyrazine (13.6 g, 0.1 mole) in 100 mL of tetrahydrofuran. The mixture is allowed to warm to room temperature and then cooled to -78° C. A solution of p-methoxycinnamaldehyde (17.8 g, 0.11 mole) in 100 mL of tetrahydrofuran is added dropwise over 15 minutes. The reaction product mixture is then worked up according to the procedures of Example I to provide the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26 g (70%) | With mercury; lithium diisopropyl amide In tetrahydrofuran | I 2-(3-Hexyl-2-hydroxy-4-phenyl-3-buten-1-yl)3,5,6-trimethylpyrazine STR9 EXAMPLE I 2-(3-Hexyl-2-hydroxy-4-phenyl-3-buten-1-yl)3,5,6-trimethylpyrazine STR9 To a solution of lithium diisopropylamide (1.5 Molar, 73.3 mL, 0.11 mole) in 150 mL of tetrahydrofuran at -78° C. is added slowly a solution of tetramethylpyrazine (13.6 g, 0.1 mole) in 100 mL of tetrahydrofuran. The mixture is allowed to warm to room temperature and then cooled to -78° C. A solution of α-hexylcinnamaldehyde (23.7 g, 0.11 mole) in 100 mL of tetrahydrofuran is added dropwise over 15 minutes. The solution is allowed to warm to room temperature, and then poured into an ice/dilute hydrochloric acid mixture. The organic layer is separated and washed with saturated solutions of sodium bicarbonate and sodium chloride. The solution is dried over anhydrous magnesium sulfate. After filtration of drying agent and evaporation of solvent, a yield of 40 g of crude material is obtained. A volatile fraction in the crude material is removed by distillation at below 85° C. under 0.15 torr of mercury. The residue is crystallized from a mixture of ethyl acetate-hexane. The product is obtained as a fine needle, M.P. 61°-62° C. Yield 26 g (70%). NMR and IR confirm the structure. Anal. Calc. for C23 H32 N2 O: C,78.37;H,9.15;N,7.95. Found: C,78.37;H,9.14;N,7.83. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; nitrogen In dichloromethane | 5 Example 5 Example 5 To a 300 ml volume flask equipped with a reflux condenser and a tube for introducing nitrogen gas, there were added 3.00 g (0,022 mole) of 2,3,5,6-tetramethyl pyrazine, 28.31 g (0.264 mole) of pyridine-3-aldehyde and 41.76 g (0.264 mole) of butyric anhydride and the contents of the flask were heated for 7 hours at 230° C. while passing nitrogen gas. After completion of the reaction and cooling down to about room temperature, an aqueous solution of sodium hydroxide (25.34 g NaOH/100 ml H2 O) was added and the mixture was stirred. To the mixture, there was added 130 ml of methylene chloride, followed by stirring and allowing to stand overnight. Since solids were precipitated out in the methylene chloride phase, the solids were filtered after removing the water phase. The solids were dried and then recrystallized from dimethylformamide (DMF) to give 4.34 g (yield 40.11%) of 2,3,5,6-tetrakis[2-(3-pyridyl)vinyl]pyrazine as needles of orange color. The melting point of the resulting 2,3,5,6-tetrakis[2-(3-pyridyl)vinyl]pyrazine was 300°-302° C. The resulting crystal was confirmed to be the desired compound by mass spectroscopic and NMR spectroscopic measurements. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nitrogen In ethanol; decalin | 8 Example 8 Example 8 To a 500 ml volume flask equipped with a reflux condenser and a tube for introducing nitrogen gas, there were added 3.00 g (0,022 mole) of 2,3,5,6-tetramethyl pyrazine, 39.63 g (0.264 mole) of p-formylbenzoic acid, 59.80 g (0,264 mole) of benzoic anhydride and 150 ml of decalin and the contents of the flask were refluxed for 5 hours while passing nitrogen gas. After completion of the reaction, the reaction system was allowed to stand overnight to give yellow solids. An amount of 200 ml of ethanol was added and the mixture was stirred for 2 hours. The solids precipitated were filtered and then dried to give 30.63 g of 2,3,5,6-tetrakis[2-(4-benzoyloxycarbonylphenyl) vinyl]pyrazine as yellow solids. The resulting solids were confirmed to be the intended compound by mass spectroscopic and NMR spectroscopic measurements. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nitrogen In ethanol; decalin | 6 Example 6 Example 6 To a 500 ml volume flask equipped with a reflux condenser and a tube for introducing nitrogen gas, there were added 3.00 g (0.022 mole) of 2,3,5,6-tetramethyl pyrazine, 32.24 g (0.264 mole) of p-hydroxybenzaldehyde, 59.80 g (0.264 mole) of benzoic anhydride and 100 ml of decalin and the contents of the flask were refluxed for 7 hours while passing nitrogen gas. After completion of the reaction and cooling down to about 50 ° C., 200 ml of ethanol was added and the mixture was allowed to stand overnight. The solids precipitated were dried and then recrystallized from DMF-ethanol mixed solvent to give 11.28 g (yield 52.96%) of 2,3,5,6-tetrakis[2-(4-benzoyloxyphenyl)vinyl]pyrazine as yellow needles. The melting point of the resulting 2,3,5,6-tetrakis[2-(4-benzoyloxyphenyl)vinyl]pyrazine was 249°-251° C. The resulting crystal was confirmed to be the intended compound by mass spectroscopic and NMR spectroscopic measurements. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.5% | In water | 3 EXAMPLE 3 EXAMPLE 3 Acetoin (3.52 g 0.04 moles), diammonium phosphate (6 g 0.045 moles) in 5 ml of water are heated in a flask immersed in an oil bath which is maintained at a temperature of 125° C. for 6 hours. The pyrazine product is isolated by following the procedures of Example 1. 1.4 g of a crystalline product is obtained. Analyses indicate that the product is tetramethylpyrazine. The product has a melting point of from 84° C. to 85° C. The calculated yield is 55.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In acetone shaking (room temp., 5 min), NMR monitoring; solvent removal (dry N2), drying (vac.); elem. anal.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In dichloromethane-d2 shaking (25°C); solvent removal (N2, vac.); elem. anal.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In dichloromethane-d2 shaking (25°C); solvent removal (N2, vac.); elem. anal.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.1% | With sodium hydroxide In water | 1.1.1 1.1 Neutralization of ligustrazine hydrochloride Weighing 50g of ligustrazine hydrochloride salt and dissolving into 125mL water, wherein the solution is clear and transparent, and pH is 3-4. Weighing 13.1g NaOH and dissolving into 65mL water, neutralizing the ligustrazine hydrochloride salt with the foregoing prepared 20% NaOH solution, keeping stirring, measuring pH, wherein white solid is separated out continuously, neutralizing until pH is about 8, processing with vacuum filtration to obtain a large amount of white solid, drying in an oven, 33.6g white needle-like solid ligustrazine trihydrate is obtained, wherein a yield is 61.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium permanganate In water at 50℃; for 10h; | 1 Synthesis of compound OLB-3 Ligustrazine (13.6 g, 100.0 mmol) was dissolved in water (300 mL), potassium permanganate (31.6 g, 200.0 mmol) was added in batches, and stirred at 50°C for 10 hours. After the reaction, it was cooled, adjusted to pH 3 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product TMA (10.3 g, 62%). |
57.8% | With potassium permanganate In water at 50℃; for 10h; | 1 Synthesis of compound IND-003 (FIG. 2) P (13.6 g, 100.0 mmol) was dissolved in 300 mL of water, KMnO4 (31.6 g, 200.0 mmol) was added in portions, and the reaction was heated to 50° C. for 10 hours. After the reaction was completed, the resulting material was cooled and extracted with ethyl acetate. The organic phase was discarded, and the aqueous phase was adjusted to pH 3 with 10% hydrochloric acid and extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 3,5,6-trimethylpyrazine-2-carboxylic acid as a yellow solid (Compound 1) (9.6 g, 57.8%). ESI-MS: [M+H]+ m/z 167.0. |
52% | With potassium permanganate In water at 60℃; | 2 The specific synthesis steps are as follows: In a 500 mL two-necked flask, 6.8 g (50 mmol) of 2,3,5,6-tetramethylpyrazine and 150 mL of water were added,Stirring heated to 60 ° C,Then a suspension of 15.8 g (100 mmol) of potassium permanganate and 100 mL of water was added portionwise to the above solution,The mixture was cooled to room temperature and suction filtered. The filter cake was washed with water. The filtrate was adjusted to pH 1-2 with 3N hydrochloric acid and extracted with chloroform. The organic phases were combined, dried over anhydrous sodium sulfate overnight, filtered and concentrated under reduced pressure Dry to dryness in vacuo to give an off-white solid4.32g, yield 52% |
50% | With potassium permanganate; water | Ethyl 3,5,6-Trimethylpyrazine-2-carboxylate (1) To200 mL of water was added TMP (15 g, 110 mmol) andKMnO4 (21 g, 133 mmol). The mixture was stirred at 50°C for10 h, followed by cooling to room temperature. The mixturewas filtered and the residue was washed with H2O (5 mL).The filtrate was extracted with ethyl acetate (3×100 mL) and the remaining water layer was acidified to pH 2-3 with dilutehydrochloric acid. The water layer was extracted with ethylacetate (5×100 mL). The combined organic layers were driedover Na2SO4. Solvent was removed in vacuo. To the residue(approximately 4.5 g, 271 mmol) in ethanol (110 mL) was addedEDCI (7.76 g, 405 mmol) and 4-(dimethylamino)-pyridine(DMAP, 1.8 g, 147 mmol). The mixture was stirred at roomtemperature for 5 h and then the mixture was acidified to pH 5with dilute hydrochloric acid. Ethanol was removed in vacuo.The residue was extracted with ethyl acetate (3×50 mL). Thecombined organic layers were dried over Na2SO4. Removalof solvent in vacuo gave a residue. The residue was purifiedby column chromatography eluting with petroleum ether andethyl acetate (4 : 1) to afford compound 1 as a colorless oil(4.4 g, 84% yield). MS (ESI): m/z 194.9 [M+H]+. 1H-NMR(CDCl3, 300 MHz) δ: 1.44 (t, J=7.1 Hz, 3H, CH3), 2.57 (d,J=2.1 Hz, 6H, CH3), 2.75 (s, 3H, CH3), 4.47 (q, J=7.1 Hz, 2H,CH2). Anal. Calcd for C10H14N2O2·0.25H2O: C, 60.44; H, 7.35; N, 14.10. Found: C, 60.14; H,7.20; N, 14.28. |
50.82% | With potassium permanganate In water at 35 - 40℃; for 10h; | 2 2. Preparation of 3,5,6-trimethylpyrazine-2-formic acid 10 g (73.42 mmol) of tetramethyl pyrazine is weighed and added into a 250 ml three-necked bottle, 100 ml of water is added into the three-necked bottle, heating is carried out to 35-40° C., 11.6 g of KMnO4 is added into the three-necked bottle with stirring, and a reaction is carried out for a period of 10 h while the temperature is preserved. Extraction with ethyl acetate is carried out, drying is carried out, and then, a solvent is removed to obtain 6.2 g of light-yellow solid, wherein the yield is 50.82%. |
48% | With potassium permanganate In water at 50℃; for 12h; | |
47.8% | With potassium permanganate In water at 20 - 55℃; | |
47.8% | With potassium permanganate In water at 37℃; for 24h; | 2 Example 2 Preparation of intermediate compound 2 (3,5,6-trimethylpyrazine-2-carboxylic acid) According to "Synthesis of new ligustrazine derivatives and their anticancer activity. "Northwest Pharmaceutical Journal, 29 (1): 58-64" method of preparation. 10.0 g (73.53 mmol) of tetramethylpyrazine was suspended in 100.0 mL of distilled water and 11.62 g (73.53 mmol) of potassium permanganate was weighed in 3 batches and stirred at 37 ° C for 24 h. The mixture was cooled and suction filtered. The filtrate was adjusted to pH 1 to 2 with 360 mg · L -1 hydrochloric acid and then extracted three times with ethyl acetate. The ethyl acetate layer was collected and dried over anhydrous sodium sulfate. Concentration to dryness under reduced pressure and recrystallization of acetone gave a white solid, yield: 47.8%. |
With potassium permanganate In water at 35℃; for 24h; | ||
With potassium permanganate In water at 50℃; for 10h; | ||
With potassium permanganate | ||
With potassium permanganate In water at 65℃; for 24h; | ||
With potassium permanganate In water at 35℃; for 24h; | 4.1 (1) Preparation of tetramethylpyrazine acid 8.4% KMnO4 aqueous solution (containing KMnO4 25.28 g) was added dropwise to 15.2 g of tetramethylpyrazine. The addition was completed within 60 minutes. The reaction temperature was controlled at 35 DEG C., and the reaction was carried out for 24 hours. The filtrate was concentrated under reduced pressure and cooled in an ice water bath. Diluted hydrochloric acid was adjusted to pH 1 and the refrigerator was refrigerated overnight. The mixture was extracted with chloroform, concentrated under reduced pressure, and recrystallized from 95% ethanol to obtain the pale yellow crystalline powder Chuanxiongzinic acid. | |
With potassium permanganate In water at 37℃; for 24h; | 4.1.1 3,5,6-Trimethylpyrazine-2-carboxylic acid 3,5,6-trimethylpyrazine-2-carboxylic acid was obtained according to our previous study [22]. In brief, TMP (10.000g) was suspended in 100mL distilled water and KMnO4 (11.618g) was added in three batches. Then the mixture was stirred at 37°C for 24h. After completion of the reaction, the mixture was cooled, filtered, and the pH of the filtrate was adjusted to 1 to 2 with 36% hydrochloric acid and then extracted 3 times with ethyl acetate. The layer was collected and dried over anhydrous sodium sulfate, and the solvent was evaporated under vacuum. Finally, the target compound was recrystallized from acetone. | |
With potassium permanganate In water at 75℃; for 2.333h; | ||
Multi-step reaction with 4 steps 1: acetic acid; dihydrogen peroxide / 4 h / 90 °C 2: 2.5 h / 105 °C 3: sodium hydroxide / tetrahydrofuran; methanol; water / 1 h / 20 °C 4: potassium permanganate; water / N,N-dimethyl-formamide / 12 h / 30 °C | ||
With potassium permanganate at 37℃; for 4h; | ||
With potassium permanganate In water at 37℃; for 24h; | ||
With potassium permanganate In water at 37℃; for 24h; | 1 Example 1 Preparation of ligustrazine Ligustrazine10.0g suspended inIn 100mL of distilled water, add 11.618g KMnO4 in three portions, and stir at 37 ° C for 24h.When the reaction is complete,Cool the reaction solution,Filtration, the filtrate was adjusted to pH 1-2 with 36% hydrochloric acid,It was then extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and recrystallized from acetone. | |
Multi-step reaction with 4 steps 1: dihydrogen peroxide; acetic acid 3: sodium hydroxide 4: potassium permanganate / water / 0.67 h / 20 °C | ||
With potassium permanganate at 60℃; | 1.1 The preparation method of ligustrazine memantine I includes the following steps: (1) Dissolve ligustrazine (II) (1eq) in water, stir at 60 and slowly add KMnO4 (2eq). After TLC monitors the reaction is complete, filter the mixed solution and wash the residue with hot water (30-40) , Combine the filtrate, extract with ethyl acetate, discard the organic phase, and adjust the aqueous phase to pH = 3 with 10% (w/w) aqueous hydrochloric acid solution, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and reduce It was evaporated to dryness under pressure to obtain 3,5,6-trimethylpyrazine-2-carboxylic acid (III) as a yellow-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; nitric acid In methanol | 1 2.1 Synthesis of tetramethylpyrazine nitrate dihydrate The crystals of 1:1:2 complex of TMP (2,3,5,6-tetramethylpyrazine -Aldrich), nitric acid and water were obtained by slow isothermal crystallization from non-dried methanol using equimolar amounts of TMP and nitric acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium permanganate In water at 70 - 90℃; for 4h; | 3,6-dimethyl-2,5-pyrazinedicarboxylic acid (5). The KMnO4 (15.8 g, 0.1 mol) was added to 150 mL distilled water in the flash, added with tetramethylpyrazine 4 (2.72 g, 20 mmol) at 70 °C, then heated to 90 °C and reaction for 4 h. The mixture was filtered and the solid MnO2 cake was washed with 50 mL water. The filtrate was concentrated to 30 mL by rotary evaporation, cooled and acidified dropwise with conc. H2SO4. The crude precipitate was recrystallized from 20 mL water to obtain compound 5 in 50% yield.1H NMR (CDCl3, 300 MHz, TMS): δ = 2.85 (s, 6H, -CH3); m.p.171 °C. |
With potassium permanganate In water at 100℃; | ||
With potassium permanganate In water for 4h; | 1.2 Compound (V, tetramethylpyrazine) with a mass concentration of 10%The potassium permanganate aqueous solution is oxidized for 4 hours, then hot filtered.The filter cake is washed with warm water.The combined filtrates were concentrated by rotary evaporation.After cooling to room temperature, adjust the pH to 3 with concentrated sulfuric acid.The filter cake was filtered by suction for about 6 hours.Obtaining the compound (VI, 3,6-dimethyl-2,5-pyrazinedicarboxylic acid);Adding SOCl2 to compound (VI),Heating and refluxing for about 6h,Excess SOCl2 is removed by vacuum filtration,Finally obtaining a pale yellow solid compound (VII,3,6-dimethyl-2,5-pyrazinedicarboxylic acid chloride) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With zinc trifluoroacetate monohydrate In ethanol; acetonitrile | Compound II was synthesized while attempting to prepare zinc(II) 1,5-naphthalene disulfonate with Me4Pyz in the inner sphere of the metal. In order to prepare compound II, a solution of Me4Pyz (0.19 g,1.39 mmol) and Zn(CF3COO)2*H2O (0.21 g,0.68 mmol) in MeCN (10 mL) was added to a solution of naphthalene disulfonic acid (0.25 g, 0.68 mmol) in CH3CN-C2H5OH (8 mL, 1 : 1) under stirring. The settled fine crystalline precipitate was filtered out, washed with ethanol, and dried in air. The reaction product was dissolved in acetonitrile + dimethylformamide (1 : 1.5) under heating, filtered out, and the solution was allowed to stand for 24 h in a closed vessel. The settled prismatic crystals were separated from the mother solution, washed with a small amount of ethanol, and dried in air. According to elemental analysis, the crystals corresponded to the composition(Me4PyzH)2(1,5Nds). For C26H32N4O6S2, anal. calcd. (%): N, 10.00; C,55.71; H, 5.71; S, 11.43.Found (%): N, 9.82; C, 54.68; H, 5.86; S, 11.18. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: Tetramethylpyrazine With potassium permanganate In ethanol at 50℃; for 10h; Stage #2: ethanol With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | In ethanol Reflux; Inert atmosphere; | 3.4. General Procedure for the Preparation of 9a-9c General procedure: To a stirring solution of 5 (3.9 g, 0.02 moL) dissolved in ethanol (30 mL) sodium (0.01moL), piperazine (0.01 moL), and ligustrazine (0.01 moL) were added, respectively. The reaction mixture was refluxed for 6-8 h. After being poured into ethanol, the reaction mixture was filtered to get crude materials, which was washed with ethanol and recrystallized with water to give the target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium In tetrahydrofuran at 23℃; for 72h; Inert atmosphere; Schlenk technique; | |
71% | With potassium In tetrahydrofuran at 20℃; for 48h; Inert atmosphere; | 1 Under an argon atmosphere,Using 60 mL of tetrahydrofuran as a solvent,5.09 g (37.4 mmol) of 2,3,5,6-tetramethylpyrazine and 14.3 mL (112.3 mmol) of chlorotrimethylsilane were cut into 0.5 to 1.0 cm square pieces of metal potassium (4.39 g , 112.3 mmol).After stirring at room temperature for 48 hours,The supernatant of the reaction solution was fractionated and concentrated,By subjecting the obtained pale blue solid to sublimation purification under reduced pressure condition,7.41 g ofA white powder was obtained (yield 71%). |
71% | In tetrahydrofuran at 20℃; for 48h; Inert atmosphere; | 1 Production of Reducing Agent 2,3,5,6-Tetramethyl 1,4-bis (trimethylsilyl) -1,4-dihydropyrazine Tetrahydrofuran (60 mL) in an argon atmosphereWith 2,3,5,6-tetramethylpyrazine (5.09 g, 37.4 mmol) and chlorotrimethylsilane (14.3 mL, 112.3 mmol) as a solvent.Was suspended in a solvent, and a piece of metal potassium (4.39 g, 112.3 mmol) cut into 0.5 cm-1.0 cm nuclei was added and mixed.After stirring at room temperature for 48 hours, the supernatant of the reaction solution is separated and concentrated.The obtained pale blue solid was sublimated and purified under reduced pressure conditions to obtain 7.41 g of white powder (yield 71%).From the 1H NMR spectrum of the obtained product,The obtained product is of 2,3,5,6-tetramethyl 1,4-bis (trimethylsilyl) -1,4-dihydropyrazine (hereinafter referred to as "Si-Me4-DHP") represented by the chemical formula C14H30N2Si2. It was confirmed that there was.Here, Me represents a methyl group (CH3) (the same applies hereinafter). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With ammonia In ethanol; water; N,N-dimethyl-formamide at 20℃; Sonication; Darkness; | 2.2. Synthesis of complex {Ag2(tpyz)(L)}_n (1) General procedure: AgNO3 (34.2 mg, 0.2 mmol), tpyz (38 ml, 0.2 mmol) and H2L(313.6 mg, 0.2 mmol) were took place in CH3CN-DMF (N,Ndimethylformamide)mixed solvent (6 ml, v/v: 3/3) under stirring.Then, ammonia (14 M, 10 d) was dropped into the mixture to give aclear solution under ultrasonic treatment (160 W, 40 KHz, 30 min) atroom temperature. The resultant solution was allowed to evaporateslowly in darkness at room temperature for several days to giveirregular-yellow crystals of 1 (Yield: 32%, based on Ag). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: Tetramethylpyrazine With n-butyllithium In tetrahydrofuran; hexane at -25 - 20℃; Inert atmosphere; Stage #2: acetylferrocene With acetic anhydride; acetic acid In tetrahydrofuran; hexane at 120℃; for 2h; Inert atmosphere; | 1 Preparation of 2-methyl-2-ferrocenylvinyl-3,5,6-trimethylpyrazine (C1) To the flask were added tetramethylpyrazine (898 mg) and dry tetrahydrofuran (10 mg) at room temperature under nitrogen atmosphereML), and dissolved by stirring. To the reaction mixture was added the same amount of butyllithium in hexane at -25 & lt; 0 & gt; CSolution, followed by addition of acetyl ferrocene (1.254 g) in tetrahydrofuran and stirring at room temperature for 1 hour;The acetic acid-acetic anhydride solution (10 mL) was then added to the reaction mixture, and the reaction was heated at 120 ° C for 2 hours. After completion of the reaction, water was added to the flask, and the layers were separated. The organic layer was separated, the aqueous layer was extracted with ethyl acetate, and the organic phase was washed with waterSodium bicarbonate solution, saturated brine, dried over anhydrous Na2S04, filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography over silica gelOr recrystallized from ethyl acetate to give 1. 713 g of red crystals in 90% yield, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 80℃; for 24h; | 1 Take ligustrazine 272 mg (2.0 mmol) and dissolve in 15 mL of anhydrous CCl4 solution.Add a catalytic amount of benzoyl peroxide,Slowly add 778 mg (4.4 mmol) of N-bromosuccinimide, react at 80 ° C for 24 h, stop the reaction, add 20 mL of water, layer, extract with CCl4, dry, filter, evaporate under reduced pressure, and recover solvent. Purification by silica gel column chromatography (V petroleum ether: ethyl acetate = 9:1) gave Intermediate (II). The yield was 54%. |
Multi-step reaction with 3 steps 1: selenium(IV) oxide / 1,4-dioxane / 6 h / 110 °C 2: sodium tetrahydroborate / 1,2-dichloro-ethane / 3 h / 20 °C 3: phosphorus tribromide / dichloromethane / 3 h / 0 °C | ||
Multi-step reaction with 3 steps 1: selenium(IV) oxide / 1,4-dioxane / 6 h / 110 °C 2: sodium tris(acetoxy)borohydride / dichloromethane / 4 h / 20 °C 3: phosphorus tribromide / dichloromethane / 3 h / 0 °C |
Multi-step reaction with 3 steps 1: selenium(IV) oxide / 1,4-dioxane / 6 h / 110 °C 2: sodium tetrahydroborate / 1,2-dichloro-ethane / 20 °C 3: phosphorus tribromide / dichloromethane / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37.4% | In ethanol at 50℃; for 0.666667h; | Protocatechuic acid (PA, 1.54 g, 0.01mol) was dissolved in absolute ethyl alcohol (7.5 mL)and ligustrazine (TMP, 0.68 g, 0.005 mol) was dissolved in absolute ethyl alcohol (3.5 mL) at40°C. The solution of ligustrazinewas added into the solution of protocatechuic acid, and thenthemixture was refluxed for 40min at 50°C.After cooling, the crude productwas precipitated.The crystal of the complex (II) was obtained after crystallization in 100 mL water-ethanol(1:1) solvent system at room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.2% | Stage #1: 3-amino-butan-2-one With acetic acid for 1.3h; Stage #2: With potassium bromate; sodium hydrogensulfite | S2; S3; S4; S5; S6; S7 Example 4 S2, adding the aromatization catalyst and glacial acetic acid to the reaction vessel and stirring for 1.3 hours, followed by filtration to obtain filtrate A,Wherein the weight ratio of the aromatization catalyst to the main material is 37.5: 39, and the aromatization catalyst is composed of potassium bromate and sodium bisulfiteAnd the volume to weight ratio of glacial acetic acid and potassium bromate was 3.5: 1 (ml / g)S3, the filtrate A concentration 32min to get solution B, concentration temperature of 30 ;S4, add water to solution B for 30min, then add ethyl acetate for extraction, take the upper solution to be dissolvedLiquid C, wherein the volume ratio of solution B, water and ethyl acetate is 16: 145: 255;S5, the solution C was distilled under reduced pressure for 35 min to obtain solution D;S6, the solution D water after cooling down crystallization to get mixed material E, solution D and water volume ratio of 1: 1;S7, the mixed material E filtered to get ligustrazine crystal |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.87% | With ammonia; In methanol; water; N,N-dimethyl-formamide; at 40℃; for 0.5h;Sonication; | General procedure: A mixture of AgNO3 (33.4 mg, 0.2 mmol), pyrazine (pyz) (16.0 mg, 0.2 mmol) and <strong>[603-11-2]3-nitrophthalic acid</strong> (H2npth) (42.2 mg, 0.2 mmol) were dissolved in methanol-H2O-DMF (N,N-dimethylformamide) solvents (6 mL, v/v/v = 1:1:1) in the presence of ammonia (0.5 mL, 14 M) under ultrasonic treatment (160 W, 40 kHz, 30 min) at 40 C. The resultant colorless solution was allowed to evaporate slowly at room temperature in the dark. Colorless crystals of compound 1 were obtained after several days. The crystals were isolated by filtration, washed with deionized water and dried in air. Yield based on silver is 58.71%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.03% | With ammonia; In water; at 100℃; for 72h;Autoclave; High pressure; | General procedure: A mixture of AgNO3 (33.4mg, 0.2mmol), H2npth (42.2mg, 0.2mmol), pyz (16mg, 0.2mmol) and H2O (10mL) was stirred for a few minutes, then sealed in a 25mL Teflon-lined stainless steel autoclave and heated at 100C for 72h. After cooling to room temperature, pale yellow crystals were obtained in a yield of 51.91% based on Ag. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In methanol; at 20℃; for 336h; | General procedure: The preparation of co-crystals 1e3 was conducted through solutioncrystallization experiments. Co-crystal 1 was obtained usingthe following procedure: MP (0.25 mmol, 23.5 mg) and <strong>[636-46-4]4-HIPA</strong>(0.5 mmol, 91.1 mg), in a 1:2 stoichiometric ratio, were dissolvedin separate beakers in 15 mL of methanol, and subsequently combinedtogether. The resulting solutionwas left to evaporate at roomtemperature. Two weeks later, colorless block-like co-crystals of 1were obtained. (yield87%, based on 2-methylpyrazine) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.7% | With phosphoric acid In acetonitrile for 8h; Darkness; Reflux; | 1 Preparation process of compound formula II Dissolve 0.1 ml of 2,3,5,6-tetramethylpyridazine in 50 ml of acetonitrile, heat to reflux, and add dropwise under dark conditions.0.4mol of methyl iodide and 0.2mol of phosphoric acid were reacted for 8 hours and then cooled to room temperature. Ether was added dropwise until precipitation ceased. Filtration, washing of the filter cake with acetone, recrystallization from ethanol-ether, dried to yield 17.3 g, yield 69.7. %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.2% | With phosphoric acid In acetonitrile for 12h; Darkness; Reflux; | 1 Preparation process of compound formula III Dissolve 0.1 ml of 2,3,5,6-tetramethylpyridazine in 50 ml of acetonitrile, heat to reflux, and add dropwise under dark conditions.0.1 lmol of cyclopropyl methyl bromide and 0.12 mol of phosphoric acid were reacted for 12 hours and then cooled to room temperature. Ether was added dropwise until precipitation ceased. Filtration, washing of the filter cake with acetone, recrystallization from ethanol-ether, and drying yielded 13.6 g of solid. The rate is 47.2% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In acetonitrile; at 110℃; for 92h; | General procedure: A mixture of AgNO3 (0.051 g, 0.3 mmoL), H2ntph (0.063 g, 0.3mmol) and pyz (0.024 g, 0.3 mmoL) were dissolved in H2O/acetonitrile(10 mL, 1:1), after stirred for 20 min in air and then the mixturewas transferred to a 25 mL stainless steel reactor and heatedto 110 C for 72 h. And then the reaction system was cooled toroom temperature, colorless needle crystals of 1 were obtained.Yield based on Ag: 72%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 23℃; for 4h; Inert atmosphere; | 2.2.2. Synthesis of TSP2 (Fig. 1b) A solution of 2,3,5,6-tetramethylpyrazine (50 mg, 0.37 mmol) in DMF (5 mL) was added slowly to (1,5 g, 7.4 mmol) 4-hexyloxybenzaldehyde and (0.84 g, 7.4 mmol) KOtBu in DMF (45 mL). After 4 h stirring under nitrogen at 23°C water (25 mL) was added, the product extracted with ethyl acetate (3*15 mL). The pooled organic solutions were washed with water, brine, and dried (MgSO4).Recrystallization from dichloromethane/methanol gave 299 mg (91%) of a pure orange solid with m.p. 185°C. 1H NMR (CDCl3,400 MHz): δ (ppm) = 7.89 (d, 3J = 15.5 Hz, 4H), 7.60 (d, 3J = 8.7 Hz,8H), 7.40 (d, 3J = 15.5 Hz, 4H), 6.94 (d, 3J = 8.7 Hz, 8H), 4.01 (t, 8H),1.81 (m, 8H), 1.49 (m, 8H), 1.37 (m, 16H), 0.92 (t, 12H); 13C NMR(CDCl3, 75 MHz): δ (ppm) = 159.6, 144.9, 134.8, 129.7, 128.8, 120.2,114.7, 68.1, 31.6, 29.3, 25.8, 22.6, 14.1. FD-MS: m/z (g/mol) = 888.1 (100%) [M+]; IR (ATR): ~ν(cm-1) = 2928, 2852, 1603, 1508, 1243, 1171,962, 812, 797; UV-vis (CH2Cl2): λmax = 390 nm, κ = 60389 cm2/mmol;fluorescence (CH2Cl2): λmax = 446 nm; elemental analysis:C60H76N2O4 (M = 889.27 g/mol): calcd.: C 81.04%, H 8.61%, N 3.15%,found: C 81.49%, H 8.13%, N 3.14% |
Multi-step reaction with 2 steps 1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide 2: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In acetonitrile; at 90℃; for 72h;Sealed tube; High pressure; | 0.020 g (0.10 mmol) H2ntp, 0.025 g (0.05 mmol) UO2(Ac)2·2H2Oand 0.013 g (0.10 mmol) tmp were dissolved in 3.0 mL H2O and 1.0 mLacetonitrile. The resultant solution was further stirred for 30 min. Thenthe mixture was placed in a 15 mL tightly closed glass vessel and heatedat 90 C under autogenous pressure for 3 days. After cooling to roomtemperature, the yellow block-like crystals of 1 were obtained afterfiltration, washed with EtOH for several times and then dried in vacuumoven at 40 C. Yield 65% based on UO2Ac2·2H2O. The experimentalPXRD pattern of sample 1 coincides well with the simulatedpattern from single crystal X-ray diffraction (Fig. S1a). Anal. Calcd(Found %) for 1 C40H40O24N7U2 (Mr=1478.85): C 32.50, H 2.57, N 6.64; found: C 32.45, H 2.53, N 6.57 (%). FT-IR date (cm-1, KBr):3340(w), 3085(w), 2930(w), 1622(vs), 1537(s), 1404 (vs), 937(m),778(m). There are three steps of weightlessness for compound 1, thesolid sample reduce 2.4% weight up to 150 C because of the loss of oneH2O molecule. The next lost weight stage occurs at 200-260 C withweight reduction of 18.1%, which belongs to one H2tmp ligand. As thetemperature fall in the range of 300-500 C, the third weight loss stepfinishes with main weight reduction of 56.5%. (Figs. S2a, S3a). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.7% | In ethanol; toluene at 20℃; | Synthesis of co-crystal 1 2,3,5,6-TMP (0.37 mmol, 50 mg) and 3,5-DNS (0.37 mmol, 84.40 mg), in a 1:1 molar ratio, were respectively dissolved in 15 mL toluene and 15 mL ethanol at room tem- perature to obtain solutions 1 and 2 . Solution 1 was slowly added to solution 2 , followed by filtrating the mixture and slow evap- oration. Two weeks later, yellow crystals were obtained with the yield of 38.7%. IR (KBr pellet, cm -1 ): 3312, 3083, 2916, 2583, 2166, 20 62, 16 6 6, 1625, 1500, 1420, 1333, 1280, 1220, 1187, 1083, 10 0 0, 916, 812, 780, 583, 531. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.2% | In ethanol; toluene at 20℃; | Synthesis of co-crystal 1 General procedure: 2,3,5,6-TMP (0.37 mmol, 50 mg) and 3,5-DNS (0.37 mmol, 84.40 mg), in a 1:1 molar ratio, were respectively dissolved in 15 mL toluene and 15 mL ethanol at room tem- perature to obtain solutions 1 and 2 . Solution 1 was slowly added to solution 2 , followed by filtrating the mixture and slow evap- oration. Two weeks later, yellow crystals were obtained with the yield of 38.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.9% | In ethanol; toluene at 20℃; | Synthesis of co-crystal 1 General procedure: 2,3,5,6-TMP (0.37 mmol, 50 mg) and 3,5-DNS (0.37 mmol, 84.40 mg), in a 1:1 molar ratio, were respectively dissolved in 15 mL toluene and 15 mL ethanol at room tem- perature to obtain solutions 1 and 2 . Solution 1 was slowly added to solution 2 , followed by filtrating the mixture and slow evap- oration. Two weeks later, yellow crystals were obtained with the yield of 38.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.7% | Stage #1: Tetramethylpyrazine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Stage #2: chloro-trimethyl-silane In tetrahydrofuran; hexane at -78 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; acetonitrile at 20℃; for 24h; | 3.1. Preparation of ASA-TMP cocrystal ASA-TMP cocrystal was obtained via both liquid-assisted grinding(LAG) (Song et al., 2015) and slurry methods (Sun and Hou, 2008; Zhanget al., 2007) at ambient temperature. The LAG method was performed bymixing a 1:1 stoichiometric amount of ASA (36.03 mg, 0.2 mmol) andTMP (27.24 mg, 0.2 mmol) along with a few drops of methanol in a 2 mLgrinding jar, using a stainless steel milling ball (5 mm in diameter) at afrequency of 20 Hz on a vibrating apparatus (GT300, Beijing GrinderInstrument Co., Ltd, China). Different stoichiometric ratios between thetwo drugs were not attempted in this work.The slurry method was performed by suspending 4.0 mmol of ASA(720.6 mg) and TMP (544.8 mg) in 1 mL acetonitrile with a magneticstirring bar at 200 rpm. The solid was separated by filtration after 24 hand dried under vacuum for 24 h at ambient temperature.Single crystals of ASA-TMP were grown by slow evaporation of 5 mLof saturated ethyl acetate solution of both ASA and TMP by suspending198 mg ASA and 150 mg TMP at room temperature. After ultrasonicatingthe suspension for 20 min, a clear solution was obtained byfiltration and collected in a clean glass vial. The vial was covered withparaffin film with 8 holes made to allow slow evaporation of ethyl acetatein a fume hood undisturbed. After about 7 days, colorless blockshapedsingle crystals of ASA-TMP suitable for single crystal X-raydiffraction experiment were obtained. |
Tags: 1124-11-4 synthesis path| 1124-11-4 SDS| 1124-11-4 COA| 1124-11-4 purity| 1124-11-4 application| 1124-11-4 NMR| 1124-11-4 COA| 1124-11-4 structure
A1151623[ 126400-81-5 ]
2,3,5,6-Tetramethylpyrazine hydrochloride
Reason:
A1496633[ 848645-86-3 ]
2,3,5,6-Tetramethylpyrazine phosphate
Reason: Free-salt
A299581[ 126400-81-5 ]
2,3,5,6-Tetramethylpyrazine hydrochloride
Reason: Free-salt
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