CN112939798B - Preparation method of amantadine - Google Patents
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Abstract
The invention discloses a preparation method of amantadine, belonging to the technical field of organic chemical synthesis, which is characterized by comprising the following steps: using compound adamantane as a starting material, generating an intermediate 1-acetamido adamantane in the presence of acetonitrile, a polyion liquid PIL catalyst and sulfuric acid, and hydrolyzing the intermediate into amantadine in an alcohol and alkali system; the preparation method disclosed by the invention is green and environment-friendly, the post-treatment is convenient, the dosage of sulfuric acid and acetonitrile is greatly reduced by the catalyst polyion liquid, and the post-treatment is simple. The ionic liquid catalyst can be recycled, so that the cost is greatly saved, and the method is suitable for large-scale industrial production.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a preparation method of amantadine.
Background
Adamantane is a structural skeleton of many compounds, and the discovery opens up a new field of chemistry, researches on the synthesis method and physicochemical and biological properties of organic polyhedral compounds, and has been practically applied in the pharmaceutical industry. Among them, the adamantane derivative, amantadine, was the earliest antiviral agent used to inhibit influenza virus. In addition to pharmaceutical applications, amantadine is also an important intermediate in the synthesis of N, N-trimethyl-1-adamantyl ammonium hydroxide (TMADaOH) templating agents.
Currently NOXThe harm to the atmospheric environment becomes an important factor influencing the ecological environment and the sustainable development of the economic society. Control of NO in engine exhaustXThe discharge amount of the catalyst becomes one of the most prominent difficulties in the field of catalytic purification of tail gas at home and abroad. The tail gas catalyst of the diesel vehicle mainly uses vanadium-based SCR to play a role in reducing NOx. Since national VI has higher requirements on the limit and test cycle of the NOx discharged by the diesel vehicle, the vanadium-based catalyst can not meet the requirements. Then, the molecular sieve catalyst is found to have excellent NOx conversion rate and high-temperature thermal stability, so that the molecular sieve catalyst becomes NH for purifying diesel vehicle tail gas3-ideal selection of SCR catalyst. In 1932, McBain J.W. reports the word "molecular sieve" for the first time, and finds that the substance of the molecular sieve can be artificially synthesized, the principle of sieving molecules depends on the unique pore channel structure of the molecular sieve, molecules larger than the pore diameter of the molecular sieve are physically isolated, and the molecules with smaller sizes enter the pore channel without limitation.
Currently, SSZ-13 and SSZ-39 molecular sieves are used as highly efficient, stable, environmentally friendly NOXThe removal SCR catalyst has a huge application prospect, N, N, N-trimethyl-1-adamantyl ammonium hydroxide (TMADAOH) is used as a key raw material-template agent in the production of the molecular sieve SSZ-13, the cost of the template agent accounts for 70-80% of the production cost of the SSZ-13 molecular sieve, and the dosage of the template agent is about to be increased rapidly. However, there are two problems in the current situation: on one hand, the production of the SSZ-13 molecular sieve has high requirements on the quality of a template agent, and metal impurities directly influence the quality of a catalyst, so that the traditional chemical method production cannot meet the requirements easily; on the other hand, the current template agent mainly depends on foreign import, so that the production cost is high, and the application is difficult to expand.
The domestic catalyst market is basically monopolized by foreign enterprises, so that the development of a green preparation technology of the TMADAOH template agent with independent intellectual property rights is realized, the quality of the SSZ-13 molecular sieve is improved, the manufacturing cost is reduced, the foreign monopolization is hopefully broken, and the method has important significance for promoting the leap-type development of China in the field of denitration catalysts, improving the discharge problem of motor vehicle exhaust pollutants and promoting the sustainable development of ecological environment and social economy.
In the course of review of the literature, Rojun, Liyaqiong, in the amantadine Synthesis patent (201010171994.5), mentions adamantane and oxygen in NHPI and Co (OAc)2Oxidizing under the catalysis condition to obtain adamantanol; then, the adamantanol and the urea are subjected to amination reaction at high temperature to obtain a target product, namely amantadine, and the yield can reach 79%.
Davis et al (Synthetic Commun.2006,36(15),2113-2119.) in the study of adamantane diamine preparation proposed that in the presence of Freon adamantane is first dibromo by iron catalysis, then dibromo adamantane reacts with azido trimethylsilane to produce azide, and palladium-carbon catalytic reduction is carried out to produce final product adamantane diamine.
Kovacic et al (J.Am.chem.Soc.1969,91(23), 6457-.
Bayguzina et al (J.org.chem.2018,54(8),1127-1133.) report the selective synthesis of amides by reaction of adamantan-1-ol and nitrile in the presence of a Cu catalyst. Although the yield of the method is relatively high, the amidated raw material is adamantanol, the price is much more expensive than adamantane, and the production cost is high.
Barfield, M. reported a method for synthesizing 1-bromoadamantane by refluxing adamantane in bromine and pouring into carbon tetrachloride for treatment after the reaction is completed. In CN201511018636.X, the mixed solution of adamantane mixed bromine and glacial acetic acid is reported to react at 110 ℃ to obtain a target product, and then the target product is obtained by reacting with urea.
The method has the defects of low atom utilization rate, serious environmental pollution, complex operation, high production cost, relatively low yield and the like.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to design and provide the preparation method of amantadine, which has the advantages of green and environment-friendly reaction process, high yield, simple post-treatment and low production cost.
The technical scheme adopted by the invention is as follows:
a preparation method of amantadine is characterized by comprising the following steps:
(1) Taking a compound adamantane (compound 1) as an initial raw material, and carrying out amidation reaction in the presence of acetonitrile and a polyion liquid catalyst PIL-1 to generate 1-acetamido adamantane (compound 2);
(2) 1-acetamidoadamantane (compound 2) undergoes hydrolysis reaction in a sodium hydroxide and alcohol system to generate the target product amantadine (compound 3).
Further, the salt forming reaction of the step (3) is also included: amantadine was prepared as amantadine hydrochloride (compound 4) to facilitate storage of amantadine.
The reaction equation involved in the invention is as follows:
with the following settings, better yields can be obtained:
in the amidation reaction of step (1):
the polyion liquid catalyst PIL-1 is obtained by adopting the following method: adding 2-vinylpyridine or 4-vinylpyridine into tetrahydrofuran, adding 1, 3-propanesultone, stirring the mixture at room temperature to form a white solid, filtering the white solid, repeatedly washing the white solid with diethyl ether, then drying the solid in vacuum to obtain a pure white solid, adding equivalent sulfuric acid into the obtained solid, and stirring to form an ionic liquid monomer; mixing ionic liquid monomer, ethanol and H2Mixing O and azobisisobutyronitrile to form a solution, adding 1, 3-divinylbenzene and azobisisobutyronitrile into the reaction solution, stirring, standing the mixture to form a white organic gel, drying the gel at room temperature, and grinding the gel into powder to obtain the polyion liquid Catalyst PIL-1.
Further, the polyion liquid catalyst PIL-1 is obtained by adopting the following method: adding 21.0g of 2-vinylpyridine into 40ml of tetrahydrofuran, adding 24.4g of 1, 3-propanesultone, stirring the mixture at room temperature for 72 hours to form a white solid, filtering the white solid, repeatedly washing the white solid by using 30ml of diethyl ether multiplied by 3, then carrying out vacuum drying on the solid at 100 ℃ and 1.0Pa to obtain a pure white solid, adding the same amount of sulfuric acid into the obtained solid, and stirring the mixture at 60 ℃ for 4 hours to form an ionic liquid monomer; mixing ionic liquid monomer 6.28g, ethanol 40mL, 4mLH2O and 0.02g of azobisisobutyronitrile were mixed to form a solution, and after stirring at 70 ℃ for 4 hours, 2.60g of 1, 3-divinylbenzene and 0.02g of azobisisobutyronitrile were added to the reaction solution, followed by stirring for 4 hours, and then the mixture was left to stand at 80 ℃ for 12 hours to form a white organogel, which was dried at room temperature for 12 hours, followed by grinding to a powder, washing the solid with acetone and water until no acidity was detected in the filtrate, and then dried in an oven at 120 ℃ for 12 hours to obtain polyionic liquid catalyst PIL-1.
The solvent is preferably 1, 2-dichloroethane, adamantane: the mol ratio of acetonitrile is 1: 2-3.5, the reaction temperature is 60-65 ℃, and the reaction time is 19 hours; adamantane: the molar ratio of the sulfuric acid is 1: 0.5-1 percent of polyion liquid PIL-1 and 5-12 percent of adamantane by mass,
The optimal process conditions are as follows: the solvent is selected from 1, 2-dichloroethane, adamantane: the mol ratio of acetonitrile is 1:2.5, the reaction temperature is 60 ℃, the reaction time is 19 hours, and the ratio of adamantane: the molar ratio of sulfuric acid is 1: 1, the polyion liquid PIL-1 mass percent can obtain the best yield.
In the hydrolysis reaction of step (2):
the solvent is ethylene glycol, 1-acetamidoadamantane: molar ratio of sodium hydroxide 1: 6-8; the reaction temperature is 130-135 ℃, and the reaction time is 10-12 hours.
The optimal process conditions are as follows: the solvent is selected from glycol, 1-acetamidoadamantane: molar ratio of sodium hydroxide 1: 6, the reaction temperature is 135 ℃, and the reaction time is 12 hours.
In the salt-forming reaction of the step (3):
the solvent is 1, 2-dichloroethane, amantadine: the molar ratio of hydrochloric acid is 1: 3-5 ℃, the reaction temperature is selected to be 40-50 ℃, and the reaction time is 3-5 hours.
The optimal process conditions are as follows: the solvent is selected from 1, 2-dichloroethane, amantadine: the molar ratio of hydrochloric acid is 1: 5, the reaction temperature is selected to be 50 ℃, and the reaction time is 3 hours. The best yield can be obtained.
The invention has the following beneficial effects:
the applicant finds a new reaction system aiming at the defects existing in the reaction in the existing amantadine synthesis, and gives consideration to the problems of environmental protection, yield, production cost and the like, and tests of the applicant show that the system adopting the acetonitrile/polyion liquid catalyst PIL-1 has the following remarkable technical effects:
(1) The polyion liquid catalyst PIL-1 greatly reduces the using amount of sulfuric acid, simplifies post-treatment and reduces the discharge of three wastes.
(2) Lower cost: the raw material adamantane is low in price, and the consumption of a small amount of acetonitrile and sulfuric acid is reduced, so that the production cost is reduced, and the method is more suitable for industrial production.
(3) And better yield: by adopting an acetonitrile/PIL system and adjusting related production processes, the reaction yield can be effectively improved, and the effect contrast of the embodiment is shown in detail.
The invention is further described with reference to the following figures and detailed description.
Drawings
FIG. 1 is an infrared spectrum of PIL-1 prepared in example 1;
FIG. 2 is a scanning electron micrograph of PIL-1 prepared in example 1;
FIG. 3 is a NMR spectrum of 1-acetamidoadamantane prepared in example 2 of the present invention: (1H NMR, 400M, solvent deuterated chloroform);
FIG. 4 is a mass spectrum of amantadine prepared in inventive example 3;
FIG. 5 is a NMR spectrum of amantadine hydrochloride prepared in example 4 of the present invention: (1H NMR,400M, solvent heavy water).
Detailed Description
Example 1: synthesis of polyion liquid catalyst PIL-1
2-vinylpyridine (21.0g,0.2mol) (or 4-vinylpyridine (21.0g,0.2mol)) was added to 40ml of tetrahydrofuran, 1, 3-propanesultone (24.4g,0.2mol) was added and the mixture was stirred at room temperature (usually 25 ℃) for 72h to form a white solid. It was filtered, washed repeatedly with diethyl ether (30 ml. times.3), and the solid was dried under vacuum (100 ℃ C., 1.0Pa) to give a pure white solid (yield 90%). The solid obtained was added with an equal amount of sulfuric acid and stirred at 60 ℃ for 4h to form ionic liquid monomer.
The reaction equation is as follows:
ionic liquid monomer (6.28g, 20mmol), 40mL ethanol, 4mLH2O and 0.02g of azobisisobutyronitrile were mixed to form a solution, and after stirring at 70 ℃ for 4 hours, 1, 3-divinylbenzene (2.60g, 20mmol) and azobisisobutyronitrile (0.02g) were added to the reaction solution, followed by stirring for another 4 hours. Then, the mixture was kept standing at 80 ℃ for 12 hours to form a white organogel. The gel was dried at room temperature for 12h, then ground to a powder and the solid washed with acetone and water until no acidity was detected in the filtrate. And drying in an oven at 120 ℃ for 12h to obtain the polyion liquid catalyst PIL-1.
The polymerization equation is as follows:
and (3) product structure characterization:
the acidity of PIL-1 was measured by neutralization titration to be 4.3 mmol/g. Compared with the common heterogeneous acid, the PIL-1 has higher acid value. On the other hand, the hydrophobic BET surface decreases with increasing 1, 3-divinylbenzene content. The polyion liquid has a BET surface area of 523m2/g。
Infrared analysis: as shown in FIG. 1, at 1049cm-1Here, the infrared spectrum of PIL-1 showed the absorbability of the sulfonic acid group, confirming the acidic group possessed thereby. Attribution of other functional groups in the infrared spectrum: C-C (1250 cm)-1),Ar-H(3150cm-1),C=O(1740cm-1) And OH (3400 cm) -1)。
Scanning electron microscope: as shown in fig. 2, the Scanning Electron Microscope (SEM) image showed that the obtained particles had an irregular spherical structure and a particle diameter of about 0.2 to 0.5 μm. The particles are interconnected without distinct boundaries. The particles were uniform, indicating good copolymerization during the synthesis. Such a crosslinked structure makes the recovery of the polyionic liquid very simple, requiring only a filtration operation.
Example 2: synthesis of 1-acetamidoadamantane (Compound 2)
Polyionic liquid PIL-1(1g) was added to a mixture of acetonitrile (7.533g, 0.1835mol) and adamantane (10g, 0.0734mol) in 1, 2-dichloroethane (32ml), and 98% sulfuric acid (7.193g, 0.0734mol) was slowly added dropwise with stirring at 60 ℃ for a total reaction time of 19 h. After the reaction is finished, removing the acid catalyst by suction filtration, then carrying out reduced pressure distillation at 10 ℃, carrying out vacuum-0.09 MPa, distilling until the temperature in the bottle is 60 ℃ and the vacuum-0.1 MPa, putting the bottle after no fraction is evaporated into the receiving bottle into a water bath for cooling, beginning to dropwise add 200g of deionized water at the temperature of 10 ℃ in the bottle, finishing dropwise adding after 1h, and keeping the temperature in the bottle at 10 ℃ and continuing stirring for 1 h. Turning off the stirring, filtering, rinsing the solid with water to finally obtain 13.335g of a product with the GC purity of 99 percent and the yield of 94 percent. The theoretical yield was 14.187 g.
And (3) product structure confirmation:1H NMR(400MHz,CDCl3)δ5.14(s,1H),2.11(s,3H),2.03(d,J=2.8Hz,6H),1.95(s,3H),1.72(s,6H).
the reaction equation involved is as follows:
alternatives 2-1 to 2-23:
the preparation method was the same as example 2, the starting material adamantane was charged in an amount of 10g, the theoretical yield was 14.187g, and the reaction temperature, the reaction solvent, and the molar ratio of the reaction raw materials were adjusted as shown in Table 1.
Tables 1,
As shown in the above table, in the synthesis of 1-acetamidoadamantane, the reaction temperature, the reaction solvent, the reaction time and the molar ratio of the reaction raw materials, the amount of polyionic liquid PIL-1 used had an effect on the yield of the reaction:
(1) from the data in alternatives 2-1 to 2-5 and example 2, it can be seen that the reaction yield of 1, 2-dichloroethane as the solvent is the highest when the other reaction conditions are the same and only the solvent is changed;
(2) from the data in the alternatives 2-5 to 2-9, it can be seen that the reaction yield is the highest when the reaction time is 19h, only the reaction time is changed when other reaction conditions are the same;
(3) it can be seen from the data in alternatives 2-10 to 2-13 that the reaction yield is affected by an increase or decrease in temperature, and thus the reaction yield is highest when the reaction temperature is 60 ℃ under the same other reaction conditions;
(4) it can be seen from the data in alternatives 2-14 to 2-19 that when the other reaction conditions were the same, the molar ratio of adamantane to acetonitrile was changed to 1: the reaction yield was highest at 2.5.
(5) From the data in the alternative examples 2-17 and 2-20 to 2-23, it can be seen that when other reaction conditions are the same, the mass percentage of the polyion liquid to adamantane is 10%, and the mass percentage of adamantane is: the molar ratio of the sulfuric acid is 1: the reaction yield was highest at 1.
(6) From the data in alternatives 2-24, it can be seen that the yield reached 89% when increasing the amount of acetonitrile and sulfuric acid, and that the polyionic liquid PIL-1 can use much less acetonitrile and sulfuric acid.
In summary, the optimal process conditions are:
the solvent is selected from dichloroethane, adamantane: the molar ratio of acetonitrile is 1:2.5, and the molar ratio of adamantane: the molar ratio of sulfuric acid is 1: 1, the reaction temperature is selected to be 60 ℃, the reaction time is 19 hours, and the best yield can be obtained when the mass percentage of the polyion liquid PIL-1 and the adamantane is 10%.
Example 3: synthesis of amantadine (Compound 3)
The product 1-acetamidoadamantane (13.329g, 0.0689mol) prepared above was added to a mixture of ethylene glycol (20ml) and particulate sodium hydroxide (16.536g, 0.4134mol), heated at 135 ℃ for 12 hours, quenched after the reaction was completed by the addition of 50ml deionized water, and stirred for 1 h. By CH2Cl2(20 ml. times.5) and the organic layer was yellow, then washed with deionized water (20 ml. times.3). The product was 9.379g as a yellow-brown solid. GC purity 99%. yield 90%. Theoretical yield 10.421 g.
The reaction equation involved is as follows:
and (3) product structure confirmation:
the mass spectrum of amantadine prepared in example 3 is shown in figure 4 and the following table:
Peak List
m/z | z | Abund |
57.1 | 3460.08 | |
58.1 | 1 | 1234.92 |
77.1 | 2261.54 | |
79.1 | 2 | 1168.77 |
91.1 | 1573.23 | |
93.1 | 1460 | |
94.1 | 1 | 50565.85 |
95.1 | 1 | 4909.31 |
108.1 | 2381.85 | |
151.2 | 1 | 9740.69 |
。
alternatives 3-1 to 3-8:
the preparation method was the same as example 3, 10g of raw material 1-acetamidoadamantane was charged, the theoretical yield was 7.825g, the reaction temperature, the reaction solvent and the molar ratio of the reaction raw materials were adjusted, and the influence on the reaction was measured, as shown in Table 2.
TABLE 2,
As shown in the above table, in the synthesis of amantadine, the reaction temperature, the reaction solvent, the reaction time, and the reaction ratio of the reaction raw materials have an influence on the yield of the reaction:
(1) from the data in the alternatives 3-1 to 3-5 and the examples, it can be seen that the reaction yield is the highest when the solvent is changed only when the other reaction conditions are the same;
(2) it can be seen from the data in alternatives 3-5 to 3-7 that the reaction yield is the highest when the reaction temperature is changed to 135 ℃ only when the other reaction conditions are the same;
(3) as can be seen from the data in alternatives 3-7 to 3-9, the reaction yield was highest when the reaction time was 12 hours, when the other reaction conditions were the same;
(4) it can be seen from the data in alternatives 3-8, 3-9, and 3-11 that, when the other reaction conditions were the same, the molar ratio of the starting material to the sodium hydroxide was 1: the reaction yield is highest when 6 hours;
To sum up: the optimal process conditions are as follows: the solvent is selected from glycol, 1-acetamidoadamantane: the molar ratio of sodium hydroxide is 1:6, the reaction temperature is 135 ℃, and the reaction time is 12 hours, so that the optimal yield can be obtained.
Example 4: synthesis of amantadine hydrochloride (Compound 4)
The product amantadine (9.275g, 0.0613mol) prepared above was dissolved in dichloromethane (20ml), 5N hydrochloric acid (61ml, 0.3065mol) was added and stirred at 50 ℃ for 3 h. After the reaction, the layers were separated and extracted to leave an aqueous layer, and the aqueous layer was washed with 10ml of 3 dichloromethane and spin-dried. Then the mixture is put into a vacuum drying oven and dried at 60 ℃. The time duration is about 24 h. 11.046g of a pale yellow solid are obtained, with a theoretical yield of 11.506g and a yield of 96%.
The structure of the product is confirmed:1H NMR(400MHz,D2O)δ3.61(s,2H),3.55(s,1H),2.06(s,3H),1.77(s,6H),1.70–1.39(m,6H)。
the reaction equation involved is as follows:
alternative examples 4-1 to 4-5:
the preparation method was the same as example 4, 10g of amantadine as a raw material, 12.410 as a theoretical yield, adjusting the reaction temperature, the reaction solvent and the molar ratio of the reaction raw materials, and testing the influence thereof on the reaction, as shown in Table 3.
TABLE 3,
As shown in table 3:
(1) from the data in alternatives 4-1, 4-2, and examples, it can be seen that the reaction yield was the highest for dichloroethane as the solvent when the other reaction conditions were the same, with only the solvent being changed;
(2) It can be seen from the data in alternatives 4-2 and 4-3 that the reaction yield was the highest at 50 ℃ with only the reaction temperature being changed when the other reaction conditions were the same;
(3) as can be seen from the data in alternatives 4-3 and 4-4, the reaction yield was highest when the reaction time was 3 hours, as other reaction conditions were the same;
(4) it can be seen from the data in alternatives 4-4, 4-5 that, when the other reaction conditions were the same, the ratio of starting material to hydrochloric acid was 1: the reaction yield is highest when 5 hours;
to sum up: the optimal process conditions are as follows: the solvent is selected from dichloroethane, amantadine: the molar ratio of the hydrochloric acid is 1:5, the reaction temperature is selected to be 50 ℃, and the optimal yield can be obtained with the reaction time of 3 hours.
Example 5: amplification experiment
Putting 48ml of acetonitrile, 50g of adamantane, 150g of dichloroethane and 15 g of polyion liquid PIL into a 500ml glass reaction bottle, slowly dropwise adding 36g of sulfuric acid, heating to 58-60 ℃ for reacting for 19h, and then turning off the heating and stirring;
and (3) carrying out reduced pressure distillation at the temperature of 14 ℃ in the bottle, carrying out vacuum-0.09 MPa, distilling to the temperature of 60 ℃ in the bottle, carrying out vacuum-0.1 MPa, placing the reaction bottle in a water bath for cooling, beginning to drop 500ml of deionized water at the temperature of 10 ℃ in the bottle, finishing dropping after 2h (stopping dropping after the temperature is up to 40 ℃ in the dropping period, reducing the dropping speed and keeping the temperature below 20 ℃), continuing stirring for 1h at the temperature of 14 ℃ in the bottle after finishing dropping, stopping stirring, beginning to carry out suction filtration, pulping the wet product with 500ml of deionized water, leaching the solid to finally obtain 65.260g of solid, wherein the GC purity is 99%, and the total yield is 92%. Theoretical yield 70.935 g.
Through the amplification experiment, the following results can be seen: the reaction has better yield under the optimized condition, is obviously superior to the following comparative examples, the reaction system is easy to amplify, the synthesis process is green and environment-friendly, the post-treatment is convenient, the catalyst polyion liquid PIL-1 overcomes the defect of common liquid acid, the use of a large amount of sulfuric acid and acetonitrile is greatly reduced, and the method has the characteristics of simple post-treatment, little environmental pollution, high selectivity, recoverability, cost saving, environmental friendliness and the like, and is suitable for large-scale industrial production.
Comparative example 1:
in the literature (Russian Journal of Organic Chemistry,54(8),1127 (1133)), the reaction progress affecting the experimental time, temperature and concentration of the catalyst and reagents was varied in order to increase the conversion of adamantanol and the yield of amide.
The method was tested: adding 10% of CuBr2To a mixture of adamantanol (10g, 0.0656mol), acetonitrile (13.464g, 0.328mol) and 1, 2-dichloroethane (32ml) was added. Heated to 60 ℃ and stirred for 8 h. After the reaction was completed, 6.983g (55%) of a solid was obtained.
The method has low yield compared with the patent, and the cost of raw material adamantanol is high.
The reaction equation involved is as follows:
comparative example 2:
described in the literature (Journal of Chemical Research,36 (9); 539- 2.12H2Amides are prepared from alcohols and nitriles in the presence of O. The method was tested:
acylaminoadamantane: mixing 10% KAl (SO)4)2.12H2O was added to a mixture of adamantanol (10g, 0.0656mol), acetonitrile (13.464g, 0.328mol) and 1, 2-dichloroethane (32 ml). Heated to 60 ℃ and stirred for 5 h. The reaction was terminated to obtain 5.332g (42%) of a solid.
The method has low yield compared with the patent, and the cost of raw material adamantanol is high.
The reaction equation involved is as follows:
comparative example 3:
98% sulfuric acid (178ml, 3.3488mol) was slowly added to adamantane (10g, 0.0734mol), acetonitrile (93ml, 1.7826mol) and tert-butanol (10g, 0.1394mol) in a mixture at 60-65 ℃ for 2.0-2.5 h. Stirred at 60-65 ℃ for 18h, then cooled to 5 ℃ and quenched with water and extracted with dichloromethane (120 ml). The organic layer was washed with water and evaporated to give a cream white solid. Yield 11.349g (80%).
The process requires the consumption of large amounts of sulfuric acid, the production of waste acid, and the addition of tert-butanol increases costs.
The reaction equation involved is as follows:
comparative example 4:
10% g of perfluorosulfonic acid resin was added to a mixture of acetonitrile (15mL, 0.2811mol) and adamantane (10g, 0.0734mol), and the reaction mixture was stirred at 60-70 ℃ for 10 hours. The solid acid, Nafion-H, was filtered and the solvent was then removed under vacuum to give a white solid. Yield: 6.384g (45% yield)
The method has the advantages of low yield and high reaction cost.
The reaction equation involved is as follows:
comparative example 5:
to a mixture of acetonitrile (15mL, 0.2811mol) and adamantane (10g, 0.0734mol) was added 10% g of silica-Supported Sulfuric Acid (SSA) and the reaction mixture was stirred at 90 ℃ for 10 h. After the reaction was complete, cooled to room temperature, the reaction mixture was filtered to remove the SSA catalyst, the organic phase was washed with 1M aqueous NaOH (80mL), and then the solvent was removed under reduced pressure to give a white solid. The crude product is obtained and purified by distillation or column chromatography. Yield: 9.505 g. (yield 67%)
The method has the advantages of complex process, low yield and high reaction cost.
The reaction equation involved is as follows:
comparative example 6:
to a mixture of acetonitrile (15mL, 0.2811mol) and adamantane (10g, 0.0734mol) was added FeCl in an amount of 10% g3·6H2O, the reaction mixture was stirred at 145 ℃ for 6 h. After completion of the reaction, ice water (50ml) was added to the reaction mixture, and the mixture was stirred for 1.0 h. Extraction was carried out with methylene chloride (120 ml). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was removed under vacuum to give a white solid. Yield: 4.965 g. (yield 35%)
The method has the advantages of low yield, large amount of required acetonitrile and high reaction cost.
The reaction equation involved is as follows:
comparative example 7:
32mL of dichloromethane was added to a round-bottom flask to which 10g (0.0734mol) of adamantane and 0.5g of sodium dodecylbenzenesulfonate had been added, followed by stirring, and mixed acid (prepared by adding 36mL of 98% concentrated sulfuric acid to 17mL of fuming nitric acid) was slowly dropped into the flask via a constant pressure dropping funnel in an ice-water bath for about 20 min. The temperature of the circulating cooling pump is 0 ℃, and the reaction lasts for 18 h. And absorbing the tail gas by using a sodium hydroxide aqueous solution. After the reaction was completed, 10.638g of a pale yellow solid was obtained by workup, GC purity 53%, yield 40%. The method hydrolyzes the reaction into a large amount of adamantanol, resulting in very low purity.
Taking the molar ratio of the adamantanol nitrate and the urea obtained in the previous step as 1:6, adding a small amount of solvent as far as possible, heating to the specified temperature of 140 ℃, and stirring for 1 h. After the reaction was complete 4.325g of a white solid with a GC purity of 98% was obtained.
The method has low total output, uses a large amount of liquid acid, generates waste acid to cause certain pollution, and is not suitable for technological production.
The reaction equation involved is as follows:
and (3) analysis:
(1) the invention adopts an adamantane/acetonitrile/PIL-1/sulfuric acid system, can obviously solve the problems (high cost and large solid waste) of the existing adamantanol system, and the cost of the adamantanol used in the comparative examples 1 and 2 is higher than that of the adamantane.
(2) Experiments show that in the system of adamantane/acetonitrile/PIL-1/sulfuric acid, the yield of the system is influenced by a plurality of factors, mainly the molar ratio of the compounds; the selection of reaction solvent, the control of reaction temperature and time, the mass percent of PIL-1 and the like have great influence on the yield of the reaction, and the yield can be improved to more than 95 percent by optimizing reaction conditions.
(3) In the alcohol-base system, the experiment shows that the yield of the alcohol-base system in the example 3 is influenced by a plurality of factors, mainly the molar ratio of the compounds; the selection of reaction solvent, the control of reaction temperature and time and the yield of the reaction have great influence, and the yield can be improved by more than 90 percent by optimizing reaction conditions.
(4) Experiments show that in the hydrochloric acid system, the yield of the hydrochloric acid system in example 4 is influenced by a plurality of factors, mainly the molar ratio of the compounds; the selection of reaction solvent, the control of reaction temperature and time and the yield of the reaction have great influence, and the yield can be improved to more than 95 percent by optimizing reaction conditions.
Claims (9)
1. A preparation method of amantadine is characterized by comprising the following steps:
(1) taking compound adamantane as an initial raw material, and carrying out amidation reaction in the presence of acetonitrile and a polyion liquid catalyst PIL-1 to generate 1-acetamido adamantane;
The polyion liquid catalyst PIL-1 is obtained by adopting the following method: adding 2-vinylpyridine or 4-vinylpyridine into tetrahydrofuran, adding 1, 3-propane sultone, stirring the mixture at room temperature to form a white solid, filtering the white solid, repeatedly washing the white solid with diethyl ether, then drying the solid in vacuum to obtain a pure white solid, adding equivalent sulfuric acid into the obtained solid, and stirring to form an ionic liquid monomer; mixing ionic liquid monomer, ethanol and H2Mixing O and azobisisobutyronitrile to form a solution, adding 1, 3-divinylbenzene and azobisisobutyronitrile into the reaction solution, stirring, standing and storing the mixture to form white organic gel, drying the gel at room temperature, and grinding the gel into powder to obtain the polyion liquid catalyst PIL-1;
(2) 1-acetamido adamantane is subjected to hydrolysis reaction in a sodium hydroxide and alcohol system to generate the target product amantadine.
2. The method for preparing amantadine according to claim 1, characterized by further comprising the step (3) of salt formation: amantadine is prepared as amantadine hydrochloride to facilitate storage of amantadine.
3. The method for preparing amantadine according to claim 1, characterized in that the polyion liquid catalyst PIL-1 is obtained by the following method: adding 21.0 g of 2-vinylpyridine into 40ml of tetrahydrofuran, adding 24.4 g of 1, 3-propane sultone, stirring the mixture at room temperature for 72 hours to form a white solid, filtering the white solid, repeatedly washing the white solid with 30ml of ✖ 3, then drying the solid at 100 ℃ under 1.0 Pa in vacuum to obtain a pure white solid, adding the same amount of sulfuric acid into the obtained solid, and stirring the solid at 60 ℃ for 4 hours to form an ionic liquid monomer; mixing ionic liquid monomer 6.28g, 40mL ethanol, 4mLH 2O and 0.02g of azobisisobutyronitrile were mixed to prepare a solution, and after stirring at 70 ℃ for 4 hours, 2.60g of 1, 3-divinylbenzene and 0.02g of azobisisobutyronitrile were addedAdding the mixture into the reaction liquid, stirring for 4h, standing and storing the mixture at 80 ℃ for 12h to form white organic gel, drying the gel at room temperature for 12h, then grinding the gel into powder, washing the solid with acetone and water until no acidity is detected in the filtrate, and drying the solid in an oven at 120 ℃ for 12h to obtain the polyion liquid catalyst PIL-1.
4. The method for preparing amantadine according to claim 1, characterized in that in the amidation reaction in step (1): the solvent is 1, 2-dichloroethane, adamantane: the mol ratio of acetonitrile is 1: 2-3.5, the reaction temperature is 60-65 ℃, and the reaction time is 19 hours; adding sulfuric acid, adamantane: the molar ratio of sulfuric acid is 1: 0.5-1, and the mass percentage of the polyion liquid catalyst PIL-1 to the adamantane is 5-12%.
5. The process for producing amantadine according to claim 4, characterized in that in the amidation reaction in step (1): the solvent is selected from 1, 2-dichloroethane, adamantane: the mol ratio of acetonitrile is 1:2.5, the reaction temperature is 60 ℃, the reaction time is 19 hours, sulfuric acid, adamantane: the molar ratio of sulfuric acid is 1: 1, the mass percentage of the polyion liquid catalyst PIL-1 and the adamantane is 10%.
6. The method for preparing amantadine according to claim 1, characterized in that in the hydrolysis reaction of the step (2): the solvent is ethylene glycol, 1-acetamidoadamantane: molar ratio of sodium hydroxide = 1: 6-8; the reaction temperature is 130-135 ℃, and the reaction time is 10-12 hours.
7. The method of claim 6, wherein the hydrolysis reaction of step (2) comprises: the solvent is selected from glycol, 1-acetamidoadamantane: molar ratio of sodium hydroxide = 1: 6, the reaction temperature is 135 ℃, and the reaction time is 12 hours.
8. The method for preparing amantadine according to claim 2, characterized in that in the salt-forming reaction of step (3): the solvent is 1, 2-dichloroethane, amantadine: the molar ratio of hydrochloric acid = 1: 3-5 ℃, the reaction temperature is selected to be 40-50 ℃, and the reaction time is 3-5 hours.
9. The process for preparing amantadine according to claim 8, characterized in that in the salt-forming reaction of step (3): the solvent is selected from 1, 2-dichloroethane, amantadine: the molar ratio of hydrochloric acid = 1: 5, the reaction temperature is selected to be 50 ℃, and the reaction time is 3 hours.
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Publication number | Priority date | Publication date | Assignee | Title |
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CN103965068A (en) * | 2013-01-25 | 2014-08-06 | 上海医药工业研究院 | 1-amide adamantane preparation method |
CN109265357A (en) * | 2018-09-06 | 2019-01-25 | 赵旭萌 | A kind of synthetic method of amantadine hydrochloride |
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CN109265357A (en) * | 2018-09-06 | 2019-01-25 | 赵旭萌 | A kind of synthetic method of amantadine hydrochloride |
Non-Patent Citations (1)
Title |
---|
盐酸金刚烷胺的合成;何建勋等;《中国医药工业杂志》;20130110(第01期);全文 * |
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