* 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.
Reference：
[1] Journal of Organic Chemistry, 1991, vol. 56, # 2, p. 678 - 683
2
[ 707-36-8 ]
[ 75-05-8 ]
[ 19982-07-1 ]
Yield
Reaction Conditions
Operation in experiment
97.05%
Stage #1: With sulfuric acid In acetic acid at 20 - 75℃; for 4 h; Stage #2: With water In acetic acid; toluene at 5 - 25℃; for 0.75 h;
Example 1 Synthesis of 1-acetamido adamantane ; Pilot Process on Laboratory Scale The 1-chloro-3,5-dimethyladamantane (viscous liquid), the acetonitrile and the glacial acetic acid are fed into a 2 litre glass reactor at room temperature. The solution is heated to Ti=70+/-5° C. and, maintaining this temperature, the sulfuric acid is added dropwise over at least four hours while maintaining the temperature range. During the dropwise addition of the acid, the reaction is exothermic. At the end of the addition, the mixture is left at Ti=70+/-5° C. and the end of the reaction is monitored by GC. The mixture is then cooled to Ti=25+/-5° C. In the round bottom quench flask the water, cooled to 5/10° C., and the extraction toluene are prepared. While maintaining the T<25° C. the mixture in the reactor is poured into the water-toluene system. Agitation is applied for 15 minutes then the phases are allowed to separate for at least 30 minutes. The very acid aqueous phase is drawn off and discarded, and the organic phase is washed first with water then with a 10percent potassium bicarbonate solution. The phases are again allowed to separate for at least 30 minutes. The lower aqueous phase is discarded and the toluene solution is completely clarified by filtering through a dicalite panel. The clear filtrate is fed into the flask where the subsequent hydrolysis is carried out. The toluene is concentrated by concentration under vacuum until a stirrable residue is obtained. This residue is used as such for the next step. Yield obtained=162.15 g 1-acetamido-3,5-dimethyl-adamantane (white solid). Theoretical yield=167.07 g equal to a yield=97.05percent. Melting point 113-114° C. GC purity >99.0percent.
97.05%
Stage #1: at 20 - 75℃; for 4 h; Stage #2: at 20 - 30℃;
RAW MATERIALS d(g/ml) g ml mols MR 1-CHLORO-3,5-DIMETHYLADAMANTANE 150.0 0.755 1.00 ACETONITRILE 0.782 215.05 275.0 5.239 6.95 SULFURIC ACID 95-97 percent 1.83 305.28 165.9 3.0192 4.00 GLACIAL ACETIC ACID 1.05 288.75 275.0 4.808 6.37 DEION. WATER (QUENCHING) 1500.0 1500.0 TOLUENE (EXTRACTION) 0.87 1305.0 1500.0 DEION. WATER (WASHING) 1.00 750.0 750.0 10 percent KHCO3 SOL. (WASHING) 750.0 Pilot process on laboratory scale The 1-chloro-3,5-dimethyladamantane (viscous liquid), the acetonitrile and the glacial acetic acid are fed into a 2 litre glass reactor at room temperature. The solution is heated to Ti = 70+/-5°C and, maintaining this temperature, the sulfuric acid is added dropwise over at least four hours while maintaining the temperature range. During the dropwise addition of the acid, the reaction is exothermic. At the end of the addition, the mixture is left at Ti = 70+/-5°C and the end of the reaction is monitored by GC. The mixture is then cooled to Ti = 25+/-5°C. In the round bottom quench flask the water, cooled to 5/10°C, and the extraction toluene are prepared. While maintaining the T<25°C the mixture in the reactor is poured into the watertoluene system. Agitation is applied for 15 minutes then the phases are allowed to separate for at least 30 minutes. The very acid aqueous phase is drawn off and discarded, and the organic phase is washed first with water then with a 10percent potassium bicarbonate solution. The phases are again allowed to separate for at least 30 minutes. The lower aqueous phase is discarded and the toluene solution is completely clarified by filtering through a dicalite panel. The clear filtrate is fed into the flask where the subsequent hydrolysis is carried out. The toluene is concentrated by concentration under vacuum until a stirrable residue is obtained. This residue is used as such for the next step. Yield obtained = 162.15 g 1-acetamido-3,5-dimethyl-adamantane (white solid). Theoretical yield = 167.07 g equal to a yield = 97.05percent. Melting point 113-114°C. GC purity > 99.0percent.
With hydrogenchloride; sodium hydroxide; urea In water
EXAMPLE 1 1-amino-3,5-dimethyl-adamantane hydrochloride 1.99 grams of 1-chloro-3,5-dimethyl-adamantane were heated with 0.9 gram urea for about 40 minutes at 220° C. The heating was carried out in a closed vessel in an oil bath with a thermostat. After cooling, the reaction product was pulverized and made into a paste with 50 ml. water. The water phase was brought to a pH between 3 and 5 by dropwise addition of concentrated HCl. The acidified water phase was extracted with two 10-ml. ether portions. Next the water phase was brought to a pH between 12 and 13 by addition of sodium hydroxide, and stirred for 5 minutes. After stirring, the alkaline water phase was extracted with four portions of ether, 10 ml. each. The combined ether extracts were dried over potassium hydroxide. By bubbling dried hydrogen chloride through the solution, 1-amino-3,5-dimethyl-adamantane hydrochloride was precipitated. The yield was 1.7 grams (78percent of the theoretical yield). The product did not melt until 300° C.
Reference：
[1] Patent: US4122193, 1978, A,
[2] Patent: JP2017/105721, 2017, A,
[3] Patent: WO2006/122238, 2006, A1,
4
[ 707-36-8 ]
[ 77287-34-4 ]
[ 351329-88-9 ]
Reference：
[1] Organic Process Research and Development, 2007, vol. 11, # 2, p. 268 - 269
[2] Patent: WO2006/122238, 2006, A1, . Location in patent: Page/Page column 13
Example 1 Synthesis of 1-acetamido adamantane ; Pilot Process on Laboratory Scale The 1-chloro-3,5-dimethyladamantane (viscous liquid), the acetonitrile and the glacial acetic acid are fed into a 2 litre glass reactor at room temperature. The solution is heated to Ti=70+/-5 C. and, maintaining this temperature, the sulfuric acid is added dropwise over at least four hours while maintaining the temperature range. During the dropwise addition of the acid, the reaction is exothermic. At the end of the addition, the mixture is left at Ti=70+/-5 C. and the end of the reaction is monitored by GC. The mixture is then cooled to Ti=25+/-5 C. In the round bottom quench flask the water, cooled to 5/10 C., and the extraction toluene are prepared. While maintaining the T<25 C. the mixture in the reactor is poured into the water-toluene system. Agitation is applied for 15 minutes then the phases are allowed to separate for at least 30 minutes. The very acid aqueous phase is drawn off and discarded, and the organic phase is washed first with water then with a 10% potassium bicarbonate solution. The phases are again allowed to separate for at least 30 minutes. The lower aqueous phase is discarded and the toluene solution is completely clarified by filtering through a dicalite panel. The clear filtrate is fed into the flask where the subsequent hydrolysis is carried out. The toluene is concentrated by concentration under vacuum until a stirrable residue is obtained. This residue is used as such for the next step. Yield obtained=162.15 g 1-acetamido-3,5-dimethyl-adamantane (white solid). Theoretical yield=167.07 g equal to a yield=97.05%. Melting point 113-114 C. GC purity >99.0%.
97.05%
RAW MATERIALS d(g/ml) g ml mols MR 1-CHLORO-3,5-DIMETHYLADAMANTANE 150.0 0.755 1.00 ACETONITRILE 0.782 215.05 275.0 5.239 6.95 SULFURIC ACID 95-97 % 1.83 305.28 165.9 3.0192 4.00 GLACIAL ACETIC ACID 1.05 288.75 275.0 4.808 6.37 DEION. WATER (QUENCHING) 1500.0 1500.0 TOLUENE (EXTRACTION) 0.87 1305.0 1500.0 DEION. WATER (WASHING) 1.00 750.0 750.0 10 % KHCO3 SOL. (WASHING) 750.0 Pilot process on laboratory scale The 1-chloro-3,5-dimethyladamantane (viscous liquid), the acetonitrile and the glacial acetic acid are fed into a 2 litre glass reactor at room temperature. The solution is heated to Ti = 70+/-5C and, maintaining this temperature, the sulfuric acid is added dropwise over at least four hours while maintaining the temperature range. During the dropwise addition of the acid, the reaction is exothermic. At the end of the addition, the mixture is left at Ti = 70+/-5C and the end of the reaction is monitored by GC. The mixture is then cooled to Ti = 25+/-5C. In the round bottom quench flask the water, cooled to 5/10C, and the extraction toluene are prepared. While maintaining the T<25C the mixture in the reactor is poured into the watertoluene system. Agitation is applied for 15 minutes then the phases are allowed to separate for at least 30 minutes. The very acid aqueous phase is drawn off and discarded, and the organic phase is washed first with water then with a 10% potassium bicarbonate solution. The phases are again allowed to separate for at least 30 minutes. The lower aqueous phase is discarded and the toluene solution is completely clarified by filtering through a dicalite panel. The clear filtrate is fed into the flask where the subsequent hydrolysis is carried out. The toluene is concentrated by concentration under vacuum until a stirrable residue is obtained. This residue is used as such for the next step. Yield obtained = 162.15 g 1-acetamido-3,5-dimethyl-adamantane (white solid). Theoretical yield = 167.07 g equal to a yield = 97.05%. Melting point 113-114C. GC purity > 99.0%.
At room temperature, to a reactor equipped with a mechanical stirrer and a reflux cold energy device,Add 1-chloro-3,5-dimethyl adamantane 88g in sequenceFormamide 140g, plus,After the end of the exothermic process, it was warmed to 80 C and stirred for 6 hours.The reaction was cooled to room temperature, and concentrated by hydrolysis with concentrated hydrochloric acid for 5 hours to cool down.The reaction solution is adjusted to a pH of 12 to 14 with a sodium hydroxide solution.Add 200 ml of ethanol to extract twice, combine the ethanol phase, add concentrated hydrochloric acid to form a salt,Filter, dry,The white crystalline solid memantine hydrochloride 63.0 g was obtained in a yield of 80.9%, and the GC purity was 99.2%.
78%
With hydrogenchloride; sodium hydroxide; urea; In water;
EXAMPLE 1 1-amino-3,5-dimethyl-adamantane hydrochloride 1.99 grams of 1-chloro-3,5-dimethyl-adamantane were heated with 0.9 gram urea for about 40 minutes at 220 C. The heating was carried out in a closed vessel in an oil bath with a thermostat. After cooling, the reaction product was pulverized and made into a paste with 50 ml. water. The water phase was brought to a pH between 3 and 5 by dropwise addition of concentrated HCl. The acidified water phase was extracted with two 10-ml. ether portions. Next the water phase was brought to a pH between 12 and 13 by addition of sodium hydroxide, and stirred for 5 minutes. After stirring, the alkaline water phase was extracted with four portions of ether, 10 ml. each. The combined ether extracts were dried over potassium hydroxide. By bubbling dried hydrogen chloride through the solution, 1-amino-3,5-dimethyl-adamantane hydrochloride was precipitated. The yield was 1.7 grams (78% of the theoretical yield). The product did not melt until 300 C.
at 152℃; for 10h;Product distribution / selectivity;
EXAMPLE 5; PREPARATION OF 1-N-FORMYL-3.5-DIMETHYL ADAMANTANE (FORMULA Vl); 10 g of 1-chloro-3,5-dimethyl adamantane of Formula VII prepared above was taken into a round bottom flask and 250 ml of formamide was added to it. The reaction mass was heated to 152 C and maintained at that temperature for 10 hours. The reaction mass was then cooled to 10 C, and 150 ml of water chilled to a temperature of 5 C was added to it slowly. Then 150 ml of dichloromethane was added to it and the temperature of the reaction mass was brought up to 28 C. The reaction mass was filtered through a celite bed and the celite bed was washed with 50 ml of dichloromethane. The filtrate was transferred into a separating funnel and the organic layer was separated. The aqueous layer was extracted with 150 ml of dichloromethane in two equal lots. The combined organic layer was washed with 200 ml of 10% sodium bicarbonate solution in two equal lots. The organic layer was dried over sodium sulphate and distilled under vacuum at 38 C to yield 9.6 g of the title compound. Purity by GC: 77.35%.
With thionyl chloride; In 1,2-dichloro-ethane; at 50℃; for 2h;
3,5-Dimethyl-1-adamantanol prepared as described above adding 54 g of thionyl chloride to the 1,2-dichloroethane solution,Heat to 50 C for 2 hours, cool to room temperature, add 200ml of water, phase separation, organic phase 100ml water wash, dry, concentrated to yield light yellow oil product 1-chloro-3,5-dimethyl adamantane 54g, yield 90%, GC purity 99.8%
With hydrogenchloride; In water; at 28℃; for 21h;
EXAMPLE 4; PREPARATION OF I-CHLORO-S.delta-DIMETHYL ADAMANTANE (FORMULA VII); 15 g of 1-hydroxy-3,5-dimethyl adamantane was taken into a round bottom flask and 300 ml of 36% aqueous hydrochloric acid was added to it. The reaction mass was stirred at 28 C for 21 hours. The reaction mass was kept for layer separation. The upper layer was separated to yield 13.0 g of the title compound in the form of crude. Purity by GC: 99.88%.
1-amino-3,5-dimethyladamantane trifluoroacetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With methyl carbamate; at 75 - 84℃; for 28.5h;
In a container having an internal volume of 50 mL equipped with a stirring device, a thermometer and a reflux condenser, 3.00 g (12.3 mmol) of <strong>[707-36-8]1-chloro-3,5-dimethyladamantane</strong>, 1.39 g (18.5 mmol) of methyl carbamate and 7.03 g (61.7 mmol) of trifluoroacetic acid were added and reacted at 75 to 84 C. with stirring. After 28.5 hours, n-hexane was added to the obtained reaction solution, followed by extraction with water and stirring at 0 to 5 C. for 30 minutes. The precipitated solid was filtered, washed with water and dried to obtain 2.30 g of a salt of 1-amino-3,5-dimethyladamantane and trifluoroacetic acid as a slightly yellowish white solid (yield: 64%).
Take 1-chloro-3,5-dimethyl adamantane 50g into a three-neck bottle, Add 250ml of formamide, Heat to 150 C for 6 hours. Cool to room temperature and add to cold water. Extract with 300 ml of dichloromethane, wash the dichloromethane solution with saturated sodium chloride solution, and dry. The white solid product was concentrated to give 49.5 g of N-formyl-3,5-dimethyl-1-adamantamine in a yield of 95%.
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