CN111533742A - Method for synthesizing 2-methoxy trimethylpurine diketone by taking cyanamide as raw material - Google Patents
Method for synthesizing 2-methoxy trimethylpurine diketone by taking cyanamide as raw material Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
Abstract
The application discloses a method for synthesizing 2-methoxy trimethylpurine diketone by taking cyanamide as a raw material. The method takes cyanamide as a raw material, and the cyanamide reacts with methanol and hydrochloric acid in total for 8 steps; reacting with ethyl cyanoacetate and sodium methoxide; reacting with dimethyl sulfate; with sodium nitrite, with (NH)4)2S, reacting with ethyl chloroformate; reacting with sodium methoxide to obtain a corresponding intermediate; finally, the product is obtained after the reaction with dimethyl sulfate. The synthesis method provided by the invention has the advantages that the raw materials are easy to obtain. The synthesis line is green and safe, the reaction conditions are not harsh, and the yield is better. The invention provides a reliable and safe synthetic line for the artificial synthesis of 2-methoxy trimethylpurine diketone, and can be used for the industrial production of the compound in the future.
Description
Technical Field
The application relates to the technical field of organic synthesis, in particular to a method for synthesizing 2-methoxy trimethylpurine diketone by taking cyanamide as a raw material.
Background
2-methoxy trimethyl purine diketone belongs to purine alkaloid.
The compound can increase the respiratory center to CO2The sensitivity of (2). It also has exciting effect on respiratory center, and the effect is more obvious in pathological states such as Cheyne-Stoke respiration (Cheyne-Stoke respiration) and premature infant apnea and the condition of using opium to inhibit respiration. When the central nervous system is inhibited by the medicine, the methylxanthine compound with low dosage can show obvious central excitation effect. The methylxanthine compound can relax various smooth muscles, the most important of which is the relaxation of the tracheal smooth muscle, and the effect is particularly obvious in the condition that the tracheal smooth muscle is contracted by using medicaments in clinical asthma and experiments. Under the treatment dosage, the contraction force of human diaphragm can be improved, and the diaphragm fatigue can be reduced.
Additional data indicate that such compounds are specific against the effects of opioid preparations, including analgesia. In addition, it also has diuretic effect.
In nature, alkaloids such as 2-methoxy trimethylpurine diketone are present in plants such as coffee tree, but the content is small. Moreover, it is difficult to extract and separate the extract, and the related processes are complicated.
At present, no method for artificially synthesizing 2-methoxy trimethylpurine diketone is disclosed and reported.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a method for synthesizing 2-methoxy trimethylpurine diketone by taking cyanamide as a raw material. The invention takes cyanamide as a raw material, the cyanamide is a chemical substance, and the molecular formula is NH2And (C) CN. Is easy to dissolve in water, ethanol, ether, benzene, trichloromethane, acetone, etc., and is a common, simple and easily available chemical raw material.
The invention provides a method for synthesizing 2-methoxy trimethylpurine diketone by taking cyanamide as a raw material, which comprises the following steps:
specifically, the synthesis method comprises the following steps:
step 1, cyanamide is used as a raw material and reacts with methanol and hydrochloric acid to obtain an intermediate I, namely methoxy isourea hydrochloride;
step 2, reacting the intermediate I with ethyl cyanoacetate and sodium methoxide to obtain an intermediate II, 6-imine-2-methoxy-5, 6-dihydropyrimidine-4 (3H) -ketone;
step 3, reacting the intermediate II with dimethyl sulfate to obtain an intermediate III, 6-imine-2-methoxy-3-methyl-5, 6-dihydropyrimidine-4 (3H) -ketone;
step 4, reacting the intermediate III with sodium nitrite to obtain an intermediate IV, 6-imine-2-methoxyl-3-methyl-5-nitroso-5, 6-dihydropyrimidine-4 (3H) -ketone;
step 5, reacting the intermediate IV with (NH4)2S to obtain an intermediate V, 5, 6-diimine-2-methoxy-3-methylpyrimidine-4 (3H) -ketone;
step 6, reacting the intermediate V with ethyl chloroformate to obtain an intermediate VI, namely ethyl (4-amino-2-methoxy-1-methyl-6-oxo-1, 6-dihydropyrimidin-5-yl) carbamate;
step 7, reacting the intermediate VI with sodium methoxide to obtain an intermediate VII, 2-methoxy-1-methyl-6, 8-dioxo-1, 6,8, 9-tetrahydropyrurine-7-sodium salt;
and 8, reacting the intermediate VII with dimethyl sulfate to obtain a product, namely 2-methoxy-1, 7, 9-trimethyl-1H-purine-6, 8(7H,9H) -diketone.
More specifically, the reactants of step 1 comprise: HCl methanol solution, cyanamide; the reactants of the step 2 comprise: intermediate I, methanol solution of sodium methoxide and ethyl cyanoacetate;
the reactants of the step 3 comprise: intermediate II, potassium carbonate, dimethyl sulfate solution diluted by methanol; the reactants of the step 4 comprise: intermediate III, glacial acetic acid and sodium nitrite solution; the reactants of the step 5 comprise: intermediate IV, (NH)4)2S solution; the reactants of step 6 comprise: intermediate V, potassium carbonate and ethyl chloroformate; the reactants of the step 7 comprise: intermediate VI, methanol, and a methanol solution of sodium methoxide; the reactants of step 8 comprise: intermediate VII, dimethyl sulfate, acetone and potassium carbonate.
More specifically, the step 4 specifically includes: slowly dripping glacial acetic acid into the solution, generating a large amount of bubbles in the glacial acetic acid adding process, paying attention to prevent material spraying, after the glacial acetic acid is added, slowly dripping sodium nitrite into the solution, stirring for 1h after the dripping is finished, wherein the mass concentration of the sodium nitrite solution is 75%.
More specifically, the reaction conditions of step 5 are as follows: (NH) at-2 to 0 ℃4)2The concentration of the S solution is 40 percent, and the S solution is added dropwise (NH)4)2After the S solution, the temperature was maintained at 0 ℃ for 0.5 h.
More specifically, the reaction conditions in step 6 are as follows: the temperature is-2-0 ℃, and the speed of dripping ethyl chloroformate is 0.5-0.6 g/min.
More specifically, the reaction time of the step 8 is 24-30 hours, and during the reaction time, potassium carbonate and dimethyl sulfate are supplemented once.
More specifically, the reaction time of the step 8 is 5-6 hours, and activated alumina particles need to be added into a reaction bottle and bubbling is carried out continuously.
More specifically, the post-processing step of step 8 is: cooling the reaction to room temperature, carrying out suction filtration, stirring the filter cake with dichloromethane for 1h, carrying out suction filtration, leaching the filter cake with dichloromethane, combining the filtrates, carrying out rotary evaporation to obtain a crude product, pulping with methanol for 3h, cooling to 0 ℃, stirring for 1h, carrying out suction filtration, leaching with cooled methanol, draining, and drying to obtain the product.
Further, the more specific synthetic route of the invention is as follows:
for further clarity and complete explanation of the present invention, a typical and complete technical solution of the present invention is as follows:
step 1, Synthesis of Methoxyisourea hydrochloride
Putting HCl methanol solution and cyanamide into a reaction kettle, cooling to 10 ℃, slowly dripping the HCl methanol solution into the reaction kettle for about 45min, heating to room temperature after dripping, stirring for 12h, sampling, detecting the reaction process (TLC monitoring, potassium permanganate color development), discharging, and directly performing rotary evaporation on the reaction solution to obtain a solid product.
Step 2, 6-imine-2-methoxy-5, 6-dihydropyrimidine-4 (3H) -ketone synthesis
Methoxy isourea hydrochloride, methanol and sodium methoxide methanol solution are added with ethyl cyanoacetate, and the mixture reacts under reflux conditions overnight, and sampling is carried out to detect the reaction progress (TLC monitoring, bromocresol green color development). After the reaction was complete, the next step was carried out directly.
Step 3, 6-imine-2-methoxy-3-methyl-5, 6-dihydropyrimidine-4 (3H) -ketone synthesis
Cooling the reaction liquid in the previous step to 50 ℃, adding potassium carbonate, slowly dropwise adding a dimethyl sulfate solution (dimethyl sulfate is diluted to be 3 times of the original volume by methanol), dropwise adding for 2 hours, stirring for 0.5 hour, sampling, monitoring the reaction process by a point plate, basically finishing the reaction of the raw materials, and spin-drying the reaction liquid to directly carry out the next step.
Step 4, synthesis of 6-imine-2-methoxy-3-methyl-5-nitroso-5, 6-dihydropyrimidin-4 (3H) -ketone.
Adding water into the reaction residue in the previous step, slowly dropwise adding glacial acetic acid into the mixture, generating a large amount of bubbles in the process of adding glacial acetic acid, paying attention to prevent material spraying, after adding glacial acetic acid, slowly dropwise adding a sodium nitrite solution (37.5g of sodium nitrite is dissolved in 50mL of water), stirring for 1h after dropwise adding, sampling, performing TLC point plate central control, completely reacting the raw materials, sending to HPLC central control, and not detecting the raw materials (the peak time of the product is 11.23 min).
And (3) post-treatment: and (3) transferring the reaction liquid to the condition of 5 ℃, stirring for 0.5h, carrying out suction filtration, leaching the filter cake with water, carrying out suction drying, and drying the material to obtain the product.
And 5, synthesizing 5, 5, 6-diimine-2-methoxy-3-methylpyrimidine-4 (3H) -ketone.
Weighing the compound obtained in the last step and water in a reaction bottle, placing the reaction bottle in a low-temperature tank, cooling to 0 ℃, and adding dropwise (NH)4)2And (3) after the S solution is added dropwise, keeping the temperature at 0 ℃ for reaction for 0.5h, sampling, performing HPLC (high performance liquid chromatography) central control, and not detecting the raw materials (the peak time of the product is 3.63 min).
And (3) post-treatment: suction filtration, washing filter cake with 50ml ice water, vacuum drying product, direct feeding next step. And 6, synthesizing ethyl (4-amino-2-methoxy-1-methyl-6-oxo-1, 6-dihydropyrimidin-5-yl) carbamate.
And (3) placing the product obtained in the last step into a reaction bottle, adding potassium carbonate into the reaction bottle, placing the reaction bottle at the temperature of 0 ℃, stirring, dropwise adding ethyl chloroformate into the reaction bottle for about 1 hour, stirring for 2 hours, sampling, performing HPLC (high performance liquid chromatography) control, and detecting no raw material (the peak time of the product is 3.53 min).
And (3) post-treatment: firstly, carrying out suction filtration, stirring the filter cake with dichloromethane for 2h, carrying out suction filtration, leaching the filter cake with dichloromethane, carrying out spin drying on the filtrate, and directly feeding the obtained product in the next step.
And step 7, synthesizing 2-methoxy-1-methyl-6, 8-dioxo-1, 6,8, 9-tetrahydropyrurine-7-sodium salt.
And (3) placing the compound obtained in the last step into a reaction bottle, adding methanol, adding a sodium methoxide methanol solution, standing overnight under the reflux condition, sampling, and performing HPLC (high performance liquid chromatography) control until no raw material is detected (the peak time of the product is 13.69 min).
And (3) post-treatment: the reaction is firstly cooled to room temperature, and the reaction solution is directly filtered to obtain a solid.
Step 8, synthesis of 2-methoxy-1, 7, 9-trimethyl-1H-purine-6, 8(7H,9H) -diketone.
Placing the compound obtained in the last step into a reaction bottle, adding acetone and potassium carbonate into the reaction bottle, slowly dropwise adding dimethyl sulfate into the reaction bottle at 50 ℃ for about 2 hours, stirring the mixture for 5 hours, then dropping the mixture on a plate, continuously reacting the mixture overnight (wherein a reaction system contains a monomethyl compound), sampling, dropping the plate by TLC (thin-layer chromatography), adding potassium carbonate and dimethyl sulfate into the plate when a small amount of monomethyl is not reacted, 3.5 hours after the potassium carbonate and dimethyl sulfate are added, sampling, dropping the plate by TLC, keeping the amount of monomethyl to be about 1 percent, continuously stirring the mixture for 2 hours, sampling, dropping the plate by TLC, allowing the raw material and the monomethyl to be reacted completely, sending the mixture to HPLC (peak output time of the product is 17.4min) for central control, and detecting the raw material and the monomethyl.
And (3) post-treatment: cooling the reaction to room temperature, carrying out suction filtration, stirring the filter cake with dichloromethane for 1h, carrying out suction filtration, leaching the filter cake with dichloromethane, combining the filtrates, carrying out rotary evaporation to obtain a crude product, pulping with methanol for 3h, cooling to 0 ℃, stirring for 1h, carrying out suction filtration, leaching with cooled methanol, draining, and drying to obtain the product.
For the modification of step 8, the activated alumina particles may be added to the reaction flask while introducing a gas into the reactor to bubble so that the alumina particles are suspended in the solution as much as possible without deposition. The reaction time can be shortened. Specifically, acetone, potassium carbonate and activated alumina particles (with the diameter of 2-2.5 mm) are added into the mixture, dimethyl sulfate is slowly dropped into the mixture at the temperature of 50 ℃ for about 2 hours, then the mixture is aerated for bubbling and stirred for 6 hours, and then the mixture is spotted on a plate, the raw material and the monomethyl react completely, and the mixture is sent to HPLC (high performance liquid chromatography) for central control, and the raw material and the monomethyl are not detected. The post-treatment step is the same as described above.
Has the advantages that: the synthesis method provided by the invention has the advantages that the raw materials are easy to obtain. The synthesis line is green and safe, and the reaction conditions are not harsh. And the yield is better.
The invention provides a reliable and safe synthetic line for the artificial synthesis of 2-methoxy trimethylpurine diketone, and can be used for the industrial production of the compound in the future.
Detailed Description
In order to make the technical solutions of the present application better understood by those skilled in the art, the technical solutions in the embodiments of the present application will be clearly and completely described below in conjunction with the embodiments of the present application, and it is obvious that the described embodiments are only some embodiments of the present application, but not all embodiments.
Example 1
Synthesis of methoxyisourea hydrochloride
1.3M HCl methanol solution (5.5L) and cyanamide (1.5kg,35.7mol) are put into a reaction kettle (30L), cooled to 10 ℃, 6.2M HCl methanol solution (8L) is slowly dripped into the reaction kettle for about 45min, after dripping is finished, the reaction kettle is heated to room temperature, stirred for 12h, then sampling is carried out to detect the reaction process (TLC monitoring, potassium permanganate color development), and the reaction solution is discharged and directly rotary evaporated.
The product was obtained as a solid (3.5kg) in 90% yield.
Example 2
Synthesis of 6-imine-2-methoxy-5, 6-dihydropyrimidine-4 (3H) -one
Methoxy isourea hydrochloride (50g,0.45mol,1eq.) methanol (300mL) and sodium methoxide methanol solution (210mL,1.13mol,2.5eq.) were added to the mixture, ethyl cyanoacetate (61.4g,0.54mol,1.2eq.) was added thereto, the mixture was reacted under reflux overnight, and the progress of the reaction was checked by sampling (TLC monitoring, color development of bromocresol green).
After the reaction was complete, the next step was carried out directly.
Example 3
Synthesis of 6-imine-2-methoxy-3-methyl-5, 6-dihydropyrimidin-4 (3H) -one
Cooling the reaction liquid in the previous step to 50 ℃, adding potassium carbonate (93g,0.68mol,1.5eq.), slowly dropwise adding a dimethyl sulfate solution (66mL,0.68mol,1.5eq.) (the dimethyl sulfate is diluted to 3 times of the original volume by methanol), dropwise adding for about 2h, stirring for 0.5h, sampling, monitoring the reaction process by a point plate, and basically finishing the reaction of the raw materials.
The reaction solution was spin dried and directly subjected to the next step.
Example 4
Synthesis of 6-imine-2-methoxy-3-methyl-5-nitroso-5, 6-dihydropyrimidin-4 (3H) -one
Adding water (450mL) into the reaction residue in the previous step, slowly dripping glacial acetic acid (200mL) into the reaction residue, generating a large amount of bubbles during the addition of the glacial acetic acid, paying attention to prevent spraying, after the glacial acetic acid is added, slowly dripping a solution of sodium nitrite (37.5g,0.54mol,1.2eq.) into the reaction residue (37.5g of sodium nitrite is dissolved in 50mL of water), stirring for 1h after dripping is finished, sampling, performing central control on a TLC point plate, completely reacting raw materials, sending to HPLC for central control, and not detecting the raw materials (the peak time of the product is 11.23 min).
And (3) post-treatment: and (3) transferring the reaction solution to the condition of 5 ℃, stirring for 0.5h, performing suction filtration, leaching the filter cake with water (200mL), performing suction drying, and drying the material to obtain 49.5g of a product, wherein the yield of the four steps is 60%.
Example 5
Synthesis of 5, 6-diimine-2-methoxy-3-methylpyrimidin-4 (3H) -one
The compound 4(49.5g,0.27mol,1.0eq.) obtained in the previous step and water (75g) were weighed into a reaction flask (500L), placed in a low-temperature tank and cooled to 0 ℃ and added dropwise (NH4)2And (3) dropwise adding the S solution (40% wt, 92g and 2eq), keeping the temperature at 0 ℃ for reacting for 0.5h, sampling, and performing HPLC (high performance liquid chromatography) control until no raw material is detected (the peak time of the product is 3.63 min).
And (3) post-treatment: and (4) performing suction filtration, washing a filter cake by using 50ml of ice water, and directly feeding the product in the next step after vacuum drying, wherein the yield is 80-85%.
Example 6
Synthesis of ethyl (4-amino-2-methoxy-1-methyl-6-oxo-1, 6-dihydropyrimidin-5-yl) carbamate
Putting the product obtained in the last step into a reaction bottle (1L), adding potassium carbonate (55g,0.4mol,1.5eq.), stirring the reaction at 0 ℃, dropwise adding ethyl chloroformate (35.5g,0.33mol,1.2eq.) into the reaction bottle for about 1h, stirring for 2h, sampling, controlling HPLC, and detecting no raw material (the peak time of the product is 3.53 min). . And (3) post-treatment: suction filtration was performed, the filter cake was stirred with dichloromethane (500mL) for 2h, suction filtered, and the filter cake was rinsed with dichloromethane (50 mL).
The filtrate was spin-dried and the product was fed directly to the next step.
Example 7
Synthesis of 2-methoxy-1-methyl-6, 8-dioxo-1, 6,8, 9-tetrahydropyrurine-7-sodium salt
The compound 6(37g,0.15mol,1.0eq.) obtained in the previous step was placed in a reaction flask, methanol (280mL) was added thereto, and a sodium methoxide methanol solution (90mL,0.45mol,3.0eq, 5M) was added thereto, and under reflux conditions overnight, sampling and HPLC control were performed, and no starting material was detected (peak time of product: 13.69 min). And (3) post-treatment: the reaction is first cooled to room temperature and the reaction solution is directly filtered.
27g of solid were obtained in 85% yield.
Example 8
Synthesis of 2-methoxy-1, 7, 9-trimethyl-1H-purine-6, 8(7H,9H) -dione
The compound 7(205g,0.94mol,1.0eq.) obtained in the previous step was placed in a reaction flask, to which acetone (3L) and potassium carbonate (346g,2.51mol,2.7eq.) were added, slowly dropping dimethyl sulfate (290g,2.3mol,2.45eq.) into the mixture at the temperature of 50 ℃ for about 2h, stirring the mixture for 5h, adding potassium carbonate (91g,0.66mol,0.7eq.) and dimethyl sulfate (59.3g,0.47mol,0.5eq.) into the mixture after continuous reaction overnight, sampling, adding a small amount of monomethyl into the mixture after continuous reaction, adding potassium carbonate (91g,0.66mol,0.7eq.) and dimethyl sulfate (59.3g,0.47mol,0.5eq.) into the mixture after continuous reaction, sampling for 3.5h, adding TLC into the mixture, adding monomethyl into the mixture after continuous stirring for about 1h, sampling, adding TLC into the mixture after continuous stirring for 2h, sampling, adding the TLC into the mixture after the TLC and adding the dimethyl sulfate, sending HPLC to the HPLC, and detecting no raw material and monomethyl (the peak time of the product is 17.4 min).
And (3) post-treatment: cooling the reaction to room temperature, carrying out suction filtration, stirring the filter cake with dichloromethane (2.5L) for 1h, carrying out suction filtration, leaching the filter cake with dichloromethane (0.5L), combining filtrates, carrying out rotary evaporation to obtain 253g of crude product, pulping with methanol (300mL) for 3h, cooling to 0 ℃, stirring for 1h, carrying out suction filtration, leaching with cooled methanol (50mL), and carrying out suction drying.
Drying gave 155g of product in 74% yield.
Example 9
Synthesis of 2-methoxy-1, 7, 9-trimethyl-1H-purine-6, 8(7H,9H) -dione (modified)
Placing the compound 7(205g,0.94mol,1.0eq.) obtained in the last step into a reaction flask, adding acetone (3L), potassium carbonate (437g,3.17mol,3.4eq.) and active alumina particles (the diameter is 2-2.5 mm, and the total volume is 100ml), slowly dropwise adding dimethyl sulfate (349.3g,2.77mol,2.95eq.) into the reaction flask at 50 ℃, carrying out bubbling for about 2h, then carrying out plate addition after stirring for 6h, finishing reaction of the raw material and the monomethyl group, and sending to HPLC (high performance liquid chromatography) for central control, wherein the raw material and the monomethyl group are not detected (the peak time of the product is 17.4 min).
And (3) post-treatment: cooling the reaction to room temperature, carrying out suction filtration, stirring the filter cake with dichloromethane (2.5L) for 1h, carrying out suction filtration, leaching the filter cake with dichloromethane (0.5L), combining filtrates, carrying out rotary evaporation to obtain a crude product of 258g, pulping with methanol (300mL) for 3h, cooling to 0 ℃, stirring for 1h, carrying out suction filtration, leaching with cooled methanol (50mL), and carrying out suction drying.
Drying gave 158g of product in 75% yield.
The above description is only exemplary, or preferred, embodiments of the present application, and is not intended to limit the present application.
Claims (9)
1. A method for synthesizing 2-methoxy trimethylpurine diketone by taking cyanamide as a raw material is characterized in that a synthetic line of the product is as follows:
2. the method for synthesizing 2-methoxy trimethylpurine diketone by using cyanamide as a raw material according to claim 1, which is characterized by comprising the following steps:
step 1, cyanamide is used as a raw material and reacts with methanol and hydrochloric acid to obtain an intermediate I, namely methoxy isourea hydrochloride;
step 2, reacting the intermediate I with ethyl cyanoacetate and sodium methoxide to obtain an intermediate II, 6-imine-2-methoxy-5, 6-dihydropyrimidine-4 (3H) -ketone;
step 3, reacting the intermediate II with dimethyl sulfate to obtain an intermediate III, 6-imine-2-methoxy-3-methyl-5, 6-dihydropyrimidine-4 (3H) -ketone;
step 4, reacting the intermediate III with sodium nitrite to obtain an intermediate IV, 6-imine-2-methoxyl-3-methyl-5-nitroso-5, 6-dihydropyrimidine-4 (3H) -ketone;
step 5, reacting the intermediate IV with (NH4)2S to obtain an intermediate V, 5, 6-diimine-2-methoxy-3-methylpyrimidine-4 (3H) -ketone;
step 6, reacting the intermediate V with ethyl chloroformate to obtain an intermediate VI, namely ethyl (4-amino-2-methoxy-1-methyl-6-oxo-1, 6-dihydropyrimidin-5-yl) carbamate;
step 7, reacting the intermediate VI with sodium methoxide to obtain an intermediate VII, 2-methoxy-1-methyl-6, 8-dioxo-1, 6,8, 9-tetrahydropyrurine-7-sodium salt;
and 8, reacting the intermediate VII with dimethyl sulfate to obtain a product, namely 2-methoxy-1, 7, 9-trimethyl-1H-purine-6, 8(7H,9H) -diketone.
3. The method for synthesizing 2-methoxy trimethylpurine diketone with cyanamide as raw material according to claim 1,
the reactants of the step 1 comprise: HCl methanol solution, cyanamide;
the reactants of the step 2 comprise: intermediate I, methanol solution of sodium methoxide and ethyl cyanoacetate;
the reactants of the step 3 comprise: intermediate II, potassium carbonate, dimethyl sulfate solution diluted by methanol;
the reactants of the step 4 comprise: intermediate III, glacial acetic acid and sodium nitrite solution;
the reactants of the step 5 comprise: intermediate IV, (NH)4)2S solution;
the reactants of step 6 comprise: intermediate V, potassium carbonate and ethyl chloroformate;
the reactants of the step 7 comprise: intermediate VI, methanol, and a methanol solution of sodium methoxide;
the reactants of step 8 comprise: intermediate VII, dimethyl sulfate, acetone and potassium carbonate.
4. The method for synthesizing 2-methoxy trimethylpurine diketone by using cyanamide as a raw material according to claim 1, wherein the step 4 specifically comprises: slowly dripping glacial acetic acid into the solution, generating a large amount of bubbles in the glacial acetic acid adding process, paying attention to prevent material spraying, after the glacial acetic acid is added, slowly dripping sodium nitrite into the solution, stirring for 1h after the dripping is finished, wherein the mass concentration of the sodium nitrite solution is 75%.
5. The method for synthesizing 2-methoxy trimethylpurine diketone by using cyanamide as raw material according to claim 1, characterized in that the reaction conditions of the step 5 are as follows: (NH) at-2 to 0 ℃4)2The concentration of the S solution is 40 percent, and the S solution is added dropwise (NH)4)2After the S solution, the temperature was maintained at 0 ℃ for 0.5 h.
6. The method for synthesizing 2-methoxy trimethylpurine diketone by using cyanamide as raw material according to claim 1, characterized in that the reaction conditions of the step 6 are as follows: the temperature is-2-0 ℃, and the speed of dripping ethyl chloroformate is 0.5-0.6 g/min.
7. The method for synthesizing 2-methoxy trimethylpurine diketone by using cyanamide as a raw material according to claim 1, wherein the reaction time of the step 8 is 24-30 hours, and during the reaction, the potassium carbonate and the dimethyl sulfate are supplemented once.
8. The method for synthesizing 2-methoxy trimethylpurine diketone by using cyanamide as a raw material according to claim 1, wherein the reaction time of the step 8 is 5-6 hours, and active alumina particles are added into a reaction bottle and continuously bubbled.
9. The method for synthesizing 2-methoxy trimethylpurine diketone by using cyanamide as a raw material according to claim 1, wherein the post-treatment step of the step 8 is as follows: cooling the reaction to room temperature, carrying out suction filtration, stirring the filter cake with dichloromethane for 1h, carrying out suction filtration, leaching the filter cake with dichloromethane, combining the filtrates, carrying out rotary evaporation to obtain a crude product, pulping with methanol for 3h, cooling to 0 ℃, stirring for 1h, carrying out suction filtration, leaching with cooled methanol, draining, and drying to obtain the product.
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| CN115466219A (en) * | 2022-07-28 | 2022-12-13 | 中国科学院天津工业生物技术研究所 | Preparation method of 1- [3- (2-amino-4-ethyl-1H-imidazole-5-yl) propyl ] guanidine |
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|---|---|---|---|---|
| CN115466219A (en) * | 2022-07-28 | 2022-12-13 | 中国科学院天津工业生物技术研究所 | Preparation method of 1- [3- (2-amino-4-ethyl-1H-imidazole-5-yl) propyl ] guanidine |
| CN115466219B (en) * | 2022-07-28 | 2023-09-08 | 中国科学院天津工业生物技术研究所 | Preparation method of 1- [3- (2-amino-4-ethyl-1H-imidazol-5-yl) propyl ] guanidine |
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