* 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.
General procedure: To a solution of thiocarbonate 5g (107 mg, 0.200 mmol) in CPME (0.5 mL) were added dropwise a solution of n-Bu3SnH (75.7 mg, 0.260 mmol) and AIBN (6.6 mg, 0.040 mmol) in CPME (1.5 mL) with a syringe pump over 30 min at 90 °C. The resultant mixture was stirred at 90 °C for 30 min and concentrated. The residue was purified by 10percent w/w K2CO3-silica gel flash column chromatography (hexane→hexane/EtOAc=100/1→50/1→20/1) to give the cis-fused cyclized product 6g (53.6 mg, 0.140 mmol, 70percent) and 2.8:1 mixture of cis and trans-fused diastereomers (22.0 mg, 0.0572 mmol, 29percent). These isomers were separated by the repeated column chromatography for spectral analysis.#10;
Reference:
[1] Tetrahedron, 2013, vol. 69, # 10, p. 2251 - 2259
[2] Organic Letters, 2008, vol. 10, # 4, p. 533 - 536
[3] Journal of Organic Chemistry, 1983, vol. 48, # 16, p. 2762 - 2765
2
[ 941-37-7 ]
[ 75-16-1 ]
[ 702-79-4 ]
[ 707-35-7 ]
Reference:
[1] Canadian Journal of Chemistry, 1987, vol. 65, p. 2428 - 2433
3
[ 702-79-4 ]
[ 941-37-7 ]
Yield
Reaction Conditions
Operation in experiment
92%
With aluminum (III) chloride; bromine In 1,2-dichloro-ethane at 15℃;
A) 59.9 g (0.345 mol) of bromine,Anhydrous aluminum trichloride 10 g (0.075 mol)1,2-dichloroethane (37.8 g) was added to the reactor to stir well;B) heating the reaction solution A to 15 ° C;C) 50 g (0.3 mol) of 1,3-dimethyladamantane was added to the mixture obtained in the step (b) to obtain a reaction mixtureIn the liquid B, the reaction process with 5percent sodium hydroxide solution absorption;D) Add 400 g of saturated sodium bisulfite solution to the reaction solution B until the red color in the reaction solution completely disappeared,The organic phase C and the water phase D;E) The organic phase C was washed with 400 g of water and the washed organic phase C was dried with 20 g of anhydrous sodium sulfate;F) the organic phase C obtained in step (e) is distilled off to obtain the crude product E;G) crude product E was distilled under reduced pressure to give 1-bromo-3,5-dimethyl adamantane, yield 92percent, gas chromatography purity ≥ 99percent.
85%
at 150℃; for 3 h; Sealed tube; Inert atmosphere
General procedure: The reactions were carried out in glass ampoules (20 mL) or in a pressure microreactor of stainless steel (17 mL). The results of parallel experiments were identical. Into the microreactor (ampoule) in an argon atmosphere was charged 0.3 mmol of Fe(acac)3, 10 mmol of initial adamantane, 10 mmol of CBr4, and 150 mmol of CH2Br2. The reactor was hermetically closed (the ampoule was sealed) and heated while stirring. On the completion of the reaction the reactor (ampoule) was cooled to room temperature, opened, the solvent was distilled off, the residue was crystallized from hexane or ethanol. Yields are given in respect to converted adamantane (adamantine derivatives) (GLC procedure, internal reference decene; correction factor for adamantane 1.09, for bromoadamantane 1.53). The structure of compounds obtained was proved by comparison with known samples and published data.
Reference:
[1] Patent: CN104592034, 2016, B, . Location in patent: Paragraph 0092-0099
[2] Asian Journal of Chemistry, 2012, vol. 24, # 11, p. 5107 - 5110
[3] Russian Journal of Organic Chemistry, 2015, vol. 51, # 2, p. 184 - 187[4] Zh. Org. Khim., 2015, vol. 51, # 2, p. 196 - 199
[5] Patent: US5061703, 1991, A,
[6] Journal of Medicinal Chemistry, 1963, vol. 6, p. 760 - 763
[7] Patent: WO2008/62472, 2008, A2, . Location in patent: Page/Page column 12-13
[8] Patent: WO2010/15415, 2010, A1, . Location in patent: Page/Page column 16-17
[9] Patent: WO2010/67252, 2010, A1, . Location in patent: Page/Page column 6
[10] Patent: WO2010/83996, 2010, A1, . Location in patent: Page/Page column 20
[11] Patent: WO2006/122238, 2006, A1, . Location in patent: Page/Page column 11
[12] Patent: WO2006/122238, 2006, A1, . Location in patent: Page/Page column 14-15
[13] Patent: WO2007/132476, 2007, A2, . Location in patent: Page/Page column 5; 10; 14; 16
Stage #1: at 20 - 87℃; for 3.75 - 4.33 h; Stage #2: at 35 - 45℃;
Example 4: l-Acetamido-3.5-dimethyladamantane (Ac-NH-DM AD) synthesis; 500 g of l-bromo-3,5-dimethyladamantane and 393 g (500 ml) of acetonitrile were loaded into a 5-liter reactor equipped with condenser, mechanical stirrer, thermometer at 20-250C under nitrogen. After about 15-20 minutes, 806 g of 75percent phosphoric acid was added. After addition of the phosphoric acid, the internal temperature of the reactor rose to 30-320C and a biphasic system was obtained. The biphasic system was warmed to 87+/-2°C over about 30 min (slight reflux) and the temperature maintained for 3-3.5 hrs. A monophasic system was then obtained. At this point, the reaction was complete (sum of 1- hydroxy-3,5-dimethyladamantane and l-bromo-3,5-dimethyladamantane less than 1percent). n-butanol (1000ml) and water (770ml) were added to the monophasic system and the system was cooled to 20-250C. Sodium hydroxide 30percent (337.5g) was added and the temperature rises to 40-450C. Two phases form and the phases were separated at 35-400C. The aqueous phase was discarded and water (385g) was added to the organic phase to form a biphasic system. Then NaOH 30percent (337.5g) was added, while maintaining the temperature at 40-450C and adjusting the pH to 5.5-7. The phases were separated at 40- 45°. The organic phase was concentrated under vacuum (res. pressure 45-50 mrnHg, external temperature 80-850C, internal temperature 40-700C) until a residual volume of 600-650ml was obtained. After cooling to 55-600C, acetone (474g) was added. The <n="22"/>resulting suspension was warmed to reflux (62-63°C) until complete dissolution was obtained. After cooling to 500C, water (2000ml) was slowly added (over about 30min) at 45-500C and crystallization of l-acetamido-S.S-dimethyladamantane occurred. At the beginning some oil separated. Usually spontaneous crystallization occurs, but if not, seeding with about 0.2-0.3percent of solid is necessary. After 1.5-2hrs at 18+/-3°C solid was filtered, washed with water and dried at 45-500C for 15hrs. Dry weight: 435g, Yield: 95.5percent, Purity: 99.84percent by GC.
Reference:
[1] Asian Journal of Chemistry, 2012, vol. 24, # 11, p. 5107 - 5110
[2] Patent: WO2007/126886, 2007, A1, . Location in patent: Page/Page column 20-21
[3] Journal of Medicinal Chemistry, 1963, vol. 6, p. 760 - 763
[4] Patent: WO2010/67252, 2010, A1, . Location in patent: Page/Page column 6-7
[5] Patent: WO2007/132476, 2007, A2, . Location in patent: Page/Page column 6; 10
9
[ 60-35-5 ]
[ 941-37-7 ]
[ 19982-07-1 ]
Yield
Reaction Conditions
Operation in experiment
99%
at 120 - 130℃; Inert atmosphere; Autoclave
General procedure: General procedure for the synthesis of N-(3,5-dimethyladamant-1-yl)acetamides. The stainless steel pressure microreactor (V = 17 mL) or glass vial was charged under argon with 0.3 mmol of manganese-containing catalyst, 10 mmol of 1-bromo-3,5-di-methyladamantane I, and 30 mmol of amide. The reac-tion mixture was heated at 120–130°C for 3–4 h with stirring. After the reaction completed, the rector (vial) was cooled to room temperature and opened. The reaction mixture was washed with water, and then the reaction product was extracted with methylene chloride (3 5 mL). The solvent was removed under a reduced pressure, and the residue was recrystallized. N-(3,5-Dimethyladamant-1-yl)amides II–V were puri-fied by column chromatography (silica gel, eluent – hexane–ethyl acetate).
94%
at 125℃;
Compound (IV) (60 g, 0.247 mol)Mix with acetamide (116.6 g, 1.974 mol).The oil bath was heated to 125°C and incubated for 4~5h.Stop the reaction. Cool, add 600ml of dichloromethane and 300ml of drinking water,Stir well, stand and separate the liquid. The aqueous phase is extracted once more with 300 ml of dichloromethane.Combine the organic phases. 600ml of drinking water is washed twice and the organic phase is concentrated to dryness under reduced pressure and recrystallized from water.Drying under reduced pressure gave compound (III) as a white solid (GC> 98.0percent, yield 94percent).
1548 g
at 150℃; Inert atmosphere
Followed by the addition of 1.8 kg of starting material,Acetamide 2.2 kg,Nitrogen protection.The reaction solution was heated to 150 ° C and stirred for 6 to 7 hours.3.6 L of water was slowly added,Stirring was continued for 5 to 10 minutes,Further 1.8 L of methylene chloride was added, Standing for 3 to 5 minutes,The organic layer was separated,Repeat the above procedure twice.To the organic layer was added 1.8 L of water,Stirring for 5 to 10 minutes,Standing for 3 to 5 minutes,Abandoned water layer.To the organic layer was added 1.8 L of saturated sodium chloride,Stirring for 5 to 10 minutes, standing for 3 to 5 minutes,Abandoned water layer. 500 g of anhydrous sodium sulfate was added to the organic layer, and the mixture was stirred and dried for 2 hours.In the water bath temperature of 40 ~ 45 , vacuum ≤-0.090MPa, the vacuum distillation of the solvent, 1 - acetylamino - 3 -1548 g of dimethyl adamantane.
Reference:
[1] Russian Journal of General Chemistry, 2015, vol. 85, # 7, p. 1771 - 1772[2] Zh. Obshch. Khim., 2015, vol. 85, # 7, p. 1210 - 1211,2
[3] Patent: CN104557567, 2018, B, . Location in patent: Paragraph 0038; 0049; 0062; 0063; 0070; 0077
[4] Patent: WO2008/62472, 2008, A2, . Location in patent: Page/Page column 13-17
[5] Patent: CN104529791, 2016, B, . Location in patent: Paragraph 0049; 0050
10
[ 941-37-7 ]
[ 19982-07-1 ]
Reference:
[1] Patent: WO2007/132476, 2007, A2,
11
[ 941-37-7 ]
[ 41100-52-1 ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: at 20 - 90℃; for 1 h; Inert atmosphere Stage #2: With hydrogenchloride In water at 20 - 110℃; for 4 h; Inert atmosphere
24 g of 1-bromo-3,5-dimethyladamantane and 36 g of urethane were placed in a reaction flask,Add 240 ml98percent formic acid,Stirring at room temperature dissolved,Argon protection,The reaction was heated to 90 ° C for 1 hour.Cooled to room temperature,The formic acid was distilled off under reduced pressure,Then add the mass concentration of 10percent hydrochloric acid 60 ml,And the mixture was heated to 110 ° C and reacted for 4 hours. Cooled to 0 ° C, the crystal analysisOut, to be complete crystallization,Filtering to obtain memantine hydrochloride.GC purity: 99.0percent, Yield: 85percent.
Stage #1: at 120℃; for 4 h; Stage #2: With sodium hydroxide In 1-methyl-pyrrolidin-2-one at 120℃; for 6 h; Stage #3: With hydrogenchloride In 1-methyl-pyrrolidin-2-one; water at 25℃; for 16 h;
A 5 L flask was charged with 300.00 g of 1-bromo-3,5-dimethyladamantane (1233.7 mmol), urea 296.37 g (4934.6 mmol) and NMP 600 mL were added, and the mixture was stirred at 120 ° C. for 4 hours (yellow solution). The reaction solution was cooled to room temperature, 1500 mL of NMP and 493.46 g (12336.5 mmol) of sodium hydroxide were added, and the mixture was stirred at 120 ° C. for 6 hours (light yellow slurry). After cooling the reaction solution to room temperature, 2000 mL of water was added and the solution was transferred to a 10 L flask, 3400 mL of water and 1500 mL of toluene were further added and vigorously stirred for 20 minutes.The mixture was allowed to stand for 1 hour, and separated into an aqueous layer and an organic layer.The aqueous layer was returned to a 10 L flask, 1500 mL of toluene was added and vigorously stirred for 20 minutes. The mixture was allowed to stand for 20 minutes, and the aqueous layer was removed (pH 12.5).The organic layers were combined, 900 mL of water was added, vigorously stirred for 20 minutes, allowed to stand for 20 minutes, and the aqueous layer was removed. The obtained organic layer was cooled to 15 ° C. or lower, 137.44 g (1357.0 mmol) of concentrated hydrochloric acid was added, and the mixture was stirred at 25 ° C. for 16 hours.The obtained slurry was suction filtered, the cake was washed twice with 300 mL of toluene, and the obtained memantine hydrochloride wet crystals were dried under reduced pressure to obtain 258.62 g of memantine hydrochloride (yield 97percent, GC Purity 99.8percent)
Reference:
[1] Patent: JP2017/39656, 2017, A, . Location in patent: Paragraph 0035
General procedure: General procedure for the synthesis of N-(3,5-dimethyladamant-1-yl)acetamides. The stainless steel pressure microreactor (V = 17 mL) or glass vial was charged under argon with 0.3 mmol of manganese-containing catalyst, 10 mmol of 1-bromo-3,5-di-methyladamantane I, and 30 mmol of amide. The reac-tion mixture was heated at 120–130°C for 3–4 h with stirring. After the reaction completed, the rector (vial) was cooled to room temperature and opened. The reaction mixture was washed with water, and then the reaction product was extracted with methylene chloride (3 5 mL). The solvent was removed under a reduced pressure, and the residue was recrystallized. N-(3,5-Dimethyladamant-1-yl)amides II–V were puri-fied by column chromatography (silica gel, eluent – hexane–ethyl acetate). N-(3,5-Dimethyladamantan-1-yl)formamide (II). Yield 78percent, mp 69–70°C (hexane). Physico-chemical constants and NMR spectral data correspond to the literature data [7].
Reference:
[1] Russian Journal of General Chemistry, 2015, vol. 85, # 7, p. 1771 - 1772[2] Zh. Obshch. Khim., 2015, vol. 85, # 7, p. 1210 - 1211,2
[3] Patent: WO2010/15415, 2010, A1, . Location in patent: Page/Page column 16-17
[4] Patent: WO2010/83996, 2010, A1, . Location in patent: Page/Page column 20-21
Intermediate 3 Preparation of (3,5-Dimethyl-adamantan-1-yl)-acetyl chloride (3,5-Dimethyl-adamantan-1-yl)-acetic acid; The bromide (24.32 g, 100 mmol) in dichloroethane was added into 90% H2SO4 solution at 10 C. (cold water bath). The reaction mixture was stirred at 10 C. for 1 hr. Then BF3 etherate (2.84 g, 20 mmol) was added dropwise in 30 minutes via a syringe. The reaction mixture was stirred at 10-15 C. for 2 more hours with additional BF3 etherate was added until complete consumption of the starting bromide before pouring onto ice. The water was adjusted to pH=9 followed by extraction with ether. The aqueous layer was acidified with HCl to pH=3 followed by extraction with ether, dried, removal of organic solvent to give solid product, which was taken on directly to the next step. 1H NMR (300 MHz, CD3Cl3), 2.13 (s, 2H),1.74 (s, 1H), 1.02-1.38 (m, 12H), delta 0.82(s, 6H),
A) A mixture of <strong>[941-37-7]1-bromo-3,5-dimethyladamantane</strong> (10 g, 0.04 mol)Anhydrous ethanol 40ml,10% sodium hydroxide solution 80 ml was added to a dry reactor,To obtain a mixed solution F;B) heating the mixed liquid F in step (a) to 70 C to obtain a reaction solution G;C) Step (b) The reaction solution G was poured into 350 g of ice water at -5 C to precipitate a white solid H to obtain a mixed solution I;D) step (c) mixed solution I to give 1-hydroxy-3,5-dimethyl adamantane,Yield 85%Gas chromatography purity ? 99%.
With sodium hydroxide; In water; for 4h;Reflux;
Add 3L of deionized water and 120g of intermediate 1 to a 3L three-necked flask. 600 ml of 1 M aqueous sodium hydroxide solution was added dropwise. The mixture was subjected to an antipyretic reflux reaction for 4 hours, adjusted to pH 7 with dilute hydrochloric acid, and extracted with ethyl acetate (200 ml 3). Combine the organic layers, After washing with ice water, Dry over anhydrous sodium sulfate, Filtering, The filtrate is concentrated, The obtained intermediate 2 was used directly in the next reaction.
Example 12 A coupling reaction of <strong>[941-37-7]1-bromo-3,5-dimethyladamantane</strong> (Compound A100, product of Aldrich) is caused in m-xylene by the addition of metal sodium, whereby 3,3',5,5'-tetramethyl-1,1'-biadamantane (Compound A101) is obtained.
Example 4: l-Acetamido-3.5-dimethyladamantane (Ac-NH-DM AD) synthesis; 500 g of l-bromo-3,5-dimethyladamantane and 393 g (500 ml) of acetonitrile were loaded into a 5-liter reactor equipped with condenser, mechanical stirrer, thermometer at 20-250C under nitrogen. After about 15-20 minutes, 806 g of 75% phosphoric acid was added. After addition of the phosphoric acid, the internal temperature of the reactor rose to 30-320C and a biphasic system was obtained. The biphasic system was warmed to 87+/-2C over about 30 min (slight reflux) and the temperature maintained for 3-3.5 hrs. A monophasic system was then obtained. At this point, the reaction was complete (sum of 1- hydroxy-3,5-dimethyladamantane and l-bromo-3,5-dimethyladamantane less than 1%). n-butanol (1000ml) and water (770ml) were added to the monophasic system and the system was cooled to 20-250C. Sodium hydroxide 30% (337.5g) was added and the temperature rises to 40-450C. Two phases form and the phases were separated at 35-400C. The aqueous phase was discarded and water (385g) was added to the organic phase to form a biphasic system. Then NaOH 30% (337.5g) was added, while maintaining the temperature at 40-450C and adjusting the pH to 5.5-7. The phases were separated at 40- 45. The organic phase was concentrated under vacuum (res. pressure 45-50 mrnHg, external temperature 80-850C, internal temperature 40-700C) until a residual volume of 600-650ml was obtained. After cooling to 55-600C, acetone (474g) was added. The <n="22"/>resulting suspension was warmed to reflux (62-63C) until complete dissolution was obtained. After cooling to 500C, water (2000ml) was slowly added (over about 30min) at 45-500C and crystallization of l-acetamido-S.S-dimethyladamantane occurred. At the beginning some oil separated. Usually spontaneous crystallization occurs, but if not, seeding with about 0.2-0.3% of solid is necessary. After 1.5-2hrs at 18+/-3C solid was filtered, washed with water and dried at 45-500C for 15hrs. Dry weight: 435g, Yield: 95.5%, Purity: 99.84% by GC.
With sulfuric acid; at 5 - 50℃;
Example-2: Preparation of N-acetamido-3,5-dimethyl adamantane[78] Charge l-bromo-3,5-dimethyl adamantane (100 gm) at 25-300C. Charge Acetonitrile(100 ml) at 25-300C. Cool reaction mixture to 5C. Add cone. H2SO4 (200 ml) drop wise at 5-200C. Raise temperature of reaction mixture to 25C. Maintain 25-300C temperature of reaction mixture for 3 hours. Heat the reaction mixture to 45C. Maintain reaction mixture at 45-500C for 8 hours . Cool reaction mixture to 300C. Add reaction mixture into ice cold water. Add Toluene to reaction mass. Add sodium hydrosulfite (1 gm). Stir reaction mixture for 15 min. Settle the layers. Separate aqueous layer. Toluene layer is washed with DM water. Settle the layers. Separate aqueous layer. Combine aqueous layers. Stir aqueous layer with toluene. Settle the layers. Separate aqueous layer. Combine toluene layers. Toluene layer is washed with 2% Sodium bicarbonate solution.Distill out toluene under vacuum till volume of reaction mass remains 200-250 ml up to temp 6O0C. Cool reaction mixture to 300C. Further, cool reaction mixture to 0-50C. Maintain it at 0-50C for 1 hr. Filter the solid at 0-50C. Wash solid with chilled toluene at 0-50C. Dry the solid under vacuum at 45-500C. 2nd crop is isolated from mother liquor.[79] Results:- [80] Dry wt:- 75.0 g[81] Yield (%w/w):- 0.75[82] Purity:- 99.8%
736 gm of Sulphuric acid was taken into a one litre 4-necked round bottom flask at room temperature (25-35 C). Nitrogen purging was applied and coled to 10-15 C. 100ml of acetonitrile was added over 30-60 minutes followed by lOOgms of l-Bromo-3,5-dimethyl adamantane and 100ml of acetonitrile. Slowly the temperature was raised to 20-25C. The reaction was maintained at 20-25 C for 15 hrs and monitored for completion. The reaction mass was quenched into 2500ml of DM water at a temperature below 10C. 750ml of dichloromethane was added at below 10 C and stirred for 30minutes. The organic and aqueous layers were separated at 5-10 C and the aqueous layer was extracted with 750ml of dichloromethane. The organic layer was washed with 500ml of 10% NaHCO3 at below 20 C followed by 500ml of D M Water. Carbon treatment was given with usual workup and dichloromethane was distilled off completely. 80ml of Cyclohexane was added to the semi-solid mass and distilled of cyclohexane completely under vacuum to get semi-solid. <n="12"/>(Weight: 70-80gms). Cyclohexane (80ml) was added to the semi-solid and stirred for 15min. at RT. The reaction mass was filtered and washed with cyclohexane (20ml). The compound l-Acetamido-3, 5 -dimethyl adamantane obtained was dried at 45-50C for 4-8 hrs till LOD is not more than 3.0%. Yield 81gms Purity by GC: 99.8%
With sulfuric acid; In hexane; at 5 - 10℃; for 4h;
In a 1L flask, add 50 mL of concentrated sulfuric acid, start stirring, add about 24.4 gl, 50 mL of n-hexane at about 5~10 C, stir rapidly, add 45 mL of formic acid dropwise, 1h drop, keep the temperature at 5~10 C The reaction was carried out for 3 h . The reaction mixture was poured into ice water to give 500 ml of ice-water mixture, which was stood, and the white solid was filtered, dried, dissolved in diethyl ether, and extracted with 0.1 M sodium hydroxide (100 mL X3). Acidified with dilute hydrochloric acid,Drying gave a white precipitate of 19.1 g.
Compound A4 is then brominated with bromine into 3'-bromo-3,5-dimethyl-1,1'-biadamantane (Compound A5). Compound (A5) is reacted with <strong>[941-37-7]1-bromo-3,5-dimethyladamantane</strong> to obtain 1,3-bis-(3,5-dimethyl-1-adamantyl)adamantane (Compound A6).
1-acetamido-3,5-dimethyladamantane p-toluenesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51.2%
To a solution of l-Bromo-3,5-dimethyl adamantane (100 gm) in acetonitrile (370 ml), sulphuric acid (760 ml) was added slowly at a temperature of 10-150C over 4hrs under nitrogen atmosphere. Temperature of the reaction mass was slowly raised over 2 hrs and maintained at 20-250C for 12 hrs under nitrogen purging. Nitrogen purging was continued for further 4 hrs. Reaction mass was transferred into a mixture of toluene (1000 ml) and ice (3.0 Kg) at temperature below 100C. Temperature of reaction mass was raised, maintained for 30 min at 25 -3O0C and allowed to settle for 15 min. Layers were separated and the <n="13"/>aqueous layer was extracted with toluene (1800 ml), dried over sodium sulfate, treated with activated carbon (5 gm) and filtered. Clear filtrate was collected and toluene was distilled off under vacuum below 5O0C. The obtained residue was dissolved in ethanol (80 ml) and p-toluene sulfonic acid (90.8 gm) was added in 4 lots at temperature of 25-35C over 30 min. Reaction mass was maintained for 60 min and diisopropyl ether (240 ml) was added over 30 min. Reaction mixture was maintained at 25-35C for 30 min, cooled and maintained at 0-5C for 1 hr. Product was filtered, wet cake was washed with chilled diisopropyl ether. (50 ml) and dried at a temperature of 45-500C for 4 hrs. The dried product (100 gm) was dissolved in methylene chloride (150 ml) and acetone (300 ml) was added slowly over 30 min. Reaction mixture was maintained at 25 - 3O0C for 30 min. Cooled the mass to 10-150C and maintained for 60 min. The precipitated product was filtered, wet cake was washed with chilled acetone (50 ml) and dried at 45-5O0C. Yield: 51.2%.
Weighing 100g 1 - bromo - 3, 5 - dimethyl adamantane with 63.34g ammonium acetate is added to containing 500 ml N, N - dimethyl formamide in the reaction vessel, stirring, heated to 150 C, reaction, thermal insulation 5.5h, stopping the reaction. Lowering the temperature to 5 C, adding 5L 2 mol/L hydrochloric acid, stirring 30min, a large amount of white solid precipitated, filtering, cake purified water washing to pH>5, 70 C vacuum drying 2h, to obtain white solid 79.85g, yield 90%, purity 99.9% (GC).
To 100g of <strong>[941-37-7]1-bromo-3,5-dimethyl adamantane</strong> and 86g of urea, adding 80ml of 80wt% formic acid, heating to 80C and holding for 3 hours. Cooling to the room temperature and adding 95ml of concentrated hydrochloric acid to hydrolyze at 80C for about 1 hour. Adjusting with 30% sodium hydroxide to a pH of 12, extracting with toluene twice, combining the organic layers and washing with water. Concentrating under reduced pressure to yield a limpid yellow solution as the 1-amino-3,5-dimethyl adamantane crude. To the crude, adding 150ml of ethanol and concentrated hydrochloric acid, heating to dissolve and crystallizing to yield white solid. Drying the solid and re-crystallizing with ethanol to yield 61.0g of pure Memantine Hydrochloride. The yield of product is 68.8% (GC 99.5%). 1HNMR (CDCl3, 400MHZ): delta0.833 (6H, singlet), 1.156 (2H, quartet), 1.328 (4H, quartet), 1.683 (4H, quartet), 1.869 (2H, broad signal), 2.179 (1H, broad signal), 8.28(3H, broad signal). MS (Q-Tof micro, ESI+): 179(M+), 164, 122, 108, 93 and 55. Element Analysis (C12H21N.HCl): actual results (calculated value%): C 66.77(66.80), H 10.40(10.28), N 6.48(6.49), Cl 16.39(16.43); To 100g of 1-bromo-3, 5-dimethyl adamantane and 86g of urea, adding 72ml of 94wt% formic acid, heating to 120C and holding for 2 hours. Cooling to the room temperature and adding 385ml of 10% hydrochloric acid to hydrolyze at 100C for about 1 hour. Adjusting with 30% sodium hydroxide solution to a pH of 12, extracting with butyl acetate twice, combining the organic layers and washing with water. Concentrating under reduced pressure to yield a limpid yellow solution as 1-amino-3,5-dimethyl adamantane crude. To the crude, adding 150ml of ethanol and concentrated hydrochloric acid, heating to dissolve and crystallizing to yield white solid. Drying the solid and re-crystallizing with water to yield 60.4g of pure Memantine Hydrochloride. The yield is 68.1 % (GC 99.1 %).
To 100g of 1-bromo-3, 5-dimethyl adamantane and 86g of urea, adding 80ml of 80wt% formic acid, heating to 80C and holding for 3 hours. Cooling to the room temperature and adding 75ml of 85% phosphoric acid to hydrolyze at 80C for 1 hour. Adjusting with 10% potassium hydroxide aqueous solution to a pH of 12. Extracting with toluene twice, combining the organic layers and washing with water. Concentrating under reduced pressure to yield a limpid yellow solution as 1-amino-3,5-dimethyl adamantane crude. To the crude, adding 150ml of ethanol and concentrated hydrochloric acid, heating to dissolve and crystallizing to yield a white solid. Drying the solid and re-crystallizing with ethanol to yield 61.0g of pure Memantine Hydrochloride. The yield is 68.8% (GC 99.5%). 1HNMR (CDCl3, 400MHZ): delta0.833 (6H, singlet), 1.156 (2H, quartet), 1.328 (4H, quartet), 1.683(4H, quartet), 1.869 (2H, broad signal), 2.179 (1H, broad signal), 8.28 (3H, broad signal). MS (Q-Tof micro, ESI+): 179(M+), 164, 122, 108, 93 and 55. Element Analysis (C12H21N.HCl): actual results (calculated value%): C 66.77 (66.80), H 10.40 (10.28), N 6.48(6.49) and Cl 16.39(16.43)
To 100g of 1-bromo-3, 5-dimethyl adamantane and 86g of urea, adding 72ml of 94wt% formic acid, heating to 120C and holding for 2 hours. Cooling to the room temperature and adding 385ml of 10% hydrochloric acid to hydrolyze at 100C for about 1 hour. Adjusting with 30% sodium hydroxide solution to a pH of 12, extracting with butyl acetate twice, combining the organic layers and washing with water. Concentrating under reduced pressure to yield a limpid yellow solution as 1-amino-3,5-dimethyl adamantane crude. To the crude, adding 150ml of ethanol and concentrated hydrochloric acid, heating to dissolve and crystallizing to yield white solid. Drying the solid and re-crystallizing with water to yield 60.4g of pure Memantine Hydrochloride. The yield is 68.1 % (GC 99.1 %).
3-(3, 5-Dimethyl-1-adamantyl)propionitrile A solution of <strong>[941-37-7]1-bromo-3,5-dimethyladamantane</strong> (1.0 g, 4.11 mmol), acrylonitrile (436 mg, 8.22 mmol) and 1,1'-azobis(cyclohexanecarbonitrile) (50 mg, 0.21 mmol) in dry toluene (12 mL) was treated with tri-n-butyltin hydride (1.44 g, 4.93 mmol) at room temperature, refluxed for 3.5 h, cooled, diluted with ether (30 mL), washed with 0.2-M NH4OH (30 mL), water (10 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography [SiO2, CH2Cl2-hexane (0:100 to 100:0)] to give the product (771 mg, 86%) as a colourless oil: IR numax (liquid film)/cm-1 2899, 2841, 2247, 1545 and 1359; NMR deltaH (400 MHz, CDCl3) 0.81 (6H, s), 1.0-1.2 (6H, m), 1.25-1.35 (6H, m), 1.53 (2H, t, J 4.2 Hz), 2.05-2.10 (1H, m) and 2.27 (2H, tJ 4.2 Hz).
Example 3 Synthesis of 3,5-Dimethyl-1-adamantyl Acetate 2.486 (10.2 mmoles) of <strong>[941-37-7]3,5-dimethyl-1-bromoadamantane</strong> is refluxed for 16 hours with 2.034 g (20.7 mmoles) of potassium acetate in 10 mL of acetic acid. The solution is poured over 100 grams of ice, allowed to melt, and extracted with 3*10 mL of diethyl ether. The combined ether extracts are washed with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride, then dried over sodium sulfate. The solvent is removed under vacuum, yielding 1.521 (67%) of the desired product, a colorless oil. TLC: Rf=0.68 (silica plate: eluant hexane 90%, ethyl acetate 10%). 1H-NMR (CDCl3, 500 Mhz): 0.858 (s, 6H), 1.115 (d, 2H, J=12.4 Hz), 1.177 (d, 2H, J=12.4 Hz), 1.260 (d, 2H, J=12.3 Hz), 1.367 (d, 2H, J=12.3 Hz), 1.714 (d, 2H, J=11.6 Hz), 1.766 (d, 2H, J=11.6 Hz), 1.939 (s, 2H), 1.976 (s, 3H), 2.191 (m, 1H).
With potassium acetate; In acetic acid;
Example 3 Synthesis of 3,5-dimethyl-1-adamantyl acetate 2.486 (10.2 mmoles) of <strong>[941-37-7]3,5-dimethyl-1-bromoadamantane</strong> is refluxed for 16 hours with 2.034 g (20.7 mmoles) of potassium acetate in 10 mL of acetic acid. The solution is poured over 100 grams of ice, allowed to melt, and extracted with 3*10 mL of diethyl ether. The combined ether extracts are washed with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride, then dried over sodium sulfate. The solvent is removed under vacuum, yielding 1.521 (67%) of the desired product, a colorless oil. TLC: Rf=0.68 (silica plate: eluant hexane 90%, ethyl acetate 10%). 1 H-NMR (CDCl3, 500 Mhz): 0.858 (s, 6H), 1.115 (d, 2H, J=12.4 Hz), 1.177 (d, 2H, J=12.4 Hz), 1.260 (d, 2H, J=12.3 Hz), 1.367 (d, 2H, J=12.3 Hz), 1.714 (d, 2H, J=11.6 Hz), 1.766 (d, 2H, J=11.6 Hz), 1.939 (s, 2H), 1.976 (s, 3H), 2.191 (m, 1H).
With zinc(II) chloride; In dichloromethane; at 20℃; for 72h;
Intermediate 5 Preparation of 2-Adamantan-1-yl-2-methyl-propionyl chloride 2-Adamantan-1-yl-2-methyl-propionic acid methyl ester; The methyl ester was prepared via the route described in Tetrahedron Letters, 1978, 17, 1455-1458. Thus 1-bromoadamantane (6.17 g, 28.7 mmol), (1-methoxy-2-methylprop-1-enyloxy)-trimethylsilane (5.5 g, 31.6 mmol), and ZnCl2 (300 mg) in DCM (40 ml) was stirred at rt for 3 days. The reaction was monitored for the disappearance of the bromide by LCMS and worked up according to the literature reference.
B. Preparation of 1-(2-Bromoethyl)-3,5-dimethyl Adamantane (II) Mix 1.4 mol of <strong>[941-37-7]1-bromo-3,5-dimethyl adamantane</strong> (I) in hexane with 0.6 mol of aluminum bromide at -75 C. Subsequently, pass ethylene through the solution for 20-30 minutes, stir for 5 min., and pour the reaction mixture onto ice water. Extract with ether, dry the organic phase and evaporate to dryness. Recrystallize the residue from methanol. (Yield: 48%).
1-N-cyclohexylamino-3,5-dimethyl-adamantane hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
EXAMPLE 8 1-N-cyclohexyl-3,5-dimethyl-adamantane hydrochloride 2.43 grams of <strong>[941-37-7]1-bromo-3,5-dimethyl adamantane</strong> and 1.86 grams of N,N'-dicyclohexylurea were heated to 190 C. in a closed vessel for 45 minutes. The cooled product was worked up as in Example 5. 1.52 Grams of 1-N-cyclohexylamino-3,5-dimethyl-adamantane hydrochloride was isolated. Yield: 51% of the theoretical yield.
1-N-methylamino-3,5-dimethyl-adamantane hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
In water;
EXAMPLE 2 1-N-methylamino-3,5-dimethyl-adamantane hydrochloride 2.43 grams of <strong>[941-37-7]1-bromo-3,5-dimethyl-adamantane</strong> was heated with 1.36 grams of N,N'-dimethylurea for 35 minutes at 160 C. The warming was performed in a closed container in an oil bath with a thermostat. The cooled reaction product was treated with water, and the 1-N-methylamino-3,5-dimethyl-adamantane hydrochloride isolated as described in Example 1. Yield: 1.41 grams (72% of theoretical yield) Melting point: 257 C.
EXAMPLE 2; PREPARATION OF 1-N-FORMYL-3,5-DIMETHYL ADAMANTANE (FORMULA Vl); 64 liters of formamide was taken into a reactor and 2.55 kg of the 1-bromo- 3,5-dimethyl adamantane of Formula III obtained above was added to it. The reaction mass was heated to a temperature of 157 C and maintained for 14 hours. Reaction completion was checked using gas chromatography. After the reaction is completed, the reaction mass was cooled to 28 C. The reaction mass was then further cooled to 4 C and maintained for 4.25 hours. 37.5 liters of chilled water was added to the reaction mass slowly below 5 C. Then 37.5 liters of dichloromethane was added to the reaction mass. The temperature of the reaction mass was raised to 25 C. The reaction mass was filtered over a celite bed and the bed was washed with 12.5 liters of dichloromethane. The filtrate was taken into another reactor and stirred at 25 C for 10 minutes. The layers were separated and the aqueous layer was extracted with 15 liters of dichloromethane in 2 equal lots. The combined dichloromethane layer was washed with 51 liters of 10% sodium bicarbonate solution in 2 equal lots. The dichloromethane layer was EPO <DP n="13"/>dried over sodium sulphate and distilled under vacuum at a temperature of 40 C to yield 2.3 kg of the title compound in the form of a residue.Purity by GC: 76.4 %,1 ,3-dimethyl adamantane: 0.11 %, 1-hydroxy-3,5-dimethyl adamantane: 21.28%
With formamide; at 155℃; for 8h;Product distribution / selectivity;
EXAMPLE 7; PREPARATION OF 1-N-FORMYL-3.5-DIMETHYL ADAMANTANE (FORMULA VI); 13 liters of bromine was taken into a reactor and 8.3 kg of 1,3-dimethyl adamantane was added to it at 30 C. The reaction mass was maintained at 30 C for 24 hours. Reaction completion was checked using a gas chromatographic technique. 200 liters of formamide was taken in another reactor and the reaction mass from the previous reactor was added to it. The previous reactor was rinsed with 8 liters of formamide and added to the reaction mass. The temperature of the reaction mass was raised to 155 C. The reaction mass was maintained at 155 C for 8 hours. Reaction completion was checked using gas chromatography. After the reaction was completed, the reaction mass was cooled to 4 C and maintained for 1.5 hours. 125 liters of chilled water was added to the reaction mass at 4 C. 125 liters of dichloromethane was added to the reaction mass and the EPO <DP n="16"/>temperature was raised to 25 C. The reaction mass was then filtered over a celite bed and the bed was washed with 42 liters of dichloromethane. The filtrate was allowed to settle and the organic layer was separated. The aqueous layer was extracted with 124.5 liters of dichloromethane in two equal lots. The combined dichloromethane layer was washed with 166 liters of 10% aqueous solution of sodium bicarbonate in two equal lots. The dichloromethane layer was dried over sodium sulfate and distilled atmospherically to dryness at 40 C to yield 18.2 kg of the title compound.Purity by GC: 96.29% 1 ,3-dimethyl adamantane: less than 0.004%.1-hydroxy-3,5-dimethyl adamantane: 2.81 %.<strong>[941-37-7]1-bromo-3,5-dimethyl adamantane</strong>: 0.05%.
A 0.25 l round-bottorn three-necked flask, equipped with reflux condenser, oil ventile, mechanical stirrer, thermometer, and dropping funnel is charged with <strong>[941-37-7]1-bromo-3,5-dimethyladamantane</strong> (5.00 g, 20.56 mmol), iron(III)sulphate (84 mg, 0.21 mmol) and dimethylformamide (6.00 ml). The reaction mixture is cooled to 5 - 10 C with stirring. Sulphuric acid (96 %, 8.87 ml, 166.4 mmol) is added drop wise, keeping the temperature at 5 - 10C. After completion of addition the resulting suspension is treated with chloroacetonitrile (4.19 g, 55.50 mmol) at 5 C and then heated to 70 - 80 C for 30 min. The reaction mixture is allowed to cool to room temperature and hydrolyzed with water (50 ml). After cooling to 5 C and stirring for further 30 min. the residue is separated and washed in a stream of water (150 ml) and dried under reduced pressure (40 C, 72 h, 25 mbar) to yield 3.52 g (13.76 mmol, 66.9 %) of 2-chloro-N-(3,5-dimethyl-adamantan-1-yl)-acetamide as described above.
66.9%
Example 6; Preparation of 2- Chloro-N-(3.5-dimethyl-adamantan-1-yl) acetamide (Method 6); A 0.25 I round-bottom three-necked flask, equipped with reflux condenser, oil ventile, mechanical stirrer, thermometer, and dropping funnel is charged with 1-bromo-3,5- dimethyladamantane (5.00 g, 20.56 mmol), iron(lll)sulphate (84 mg, 0.21 mmol) and dimethylformamide (6.00 ml). The reaction mixture is cooled to 5 - 10 0C with stirring. Sulphuric acid (96 %, 8.87 ml, 166.4 mmol) is added drop wise, keeping the temperature at 5 - 10 C. After completion of addition the resulting suspension is treated with chloroacetonitrile (4.19 g, 55.50 mmol) at 5 0C and then heated to 70 - 80 0C for 30 min. The reaction mixture is allowed to cool to room temperature and hydrolyzed with water (50 ml). After cooling to 5 0C and stirring for further 30 min. the residue is separated and washed in a stream of water (150 ml) and dried under reduced pressure (40 0C, 72 h, 25 mbar) to yield 3.52 g (13.76 mmol, 66.9 %) of 2-chloro-N-(3,5-dimethyl-adamantan-1-yl)-acetamide as described above.
61.4%
A 0.25 l round-bottom three-necked flask, equipped with reflux condenser, oil ventile, mechanical stirrer, thermometer, and dropping funnel is charged with <strong>[941-37-7]1-bromo-3,5-dimethyladamantane</strong> compound (5.00 g, 20.56 mmol), iron(III)sulphate (84 mg, 0.21 mmol), dimethylformamide (6.00 ml), chloroacetonitrile (4.19 g, 55.50 mmol), and acetic acid (9.23 g, 153.73 mmol). The reaction mixture is cooled to 5 - 10 C with stirring. Sulphuric acid (96 %, 8.87 ml, 166.4 mmol) is added drop wise, keeping the temperature at 5 - 10 C. After completion of addition the resulting suspension is heated to 80 C for about 90 min. The reaction mixture is allowed to cool to room temperature and hydrolyzed with water (50 ml). After cooling to 5 C and stirring for further 30 min. the residue is separated and washed in a stream of water (150 ml) and dried under reduced pressure (40 C, 72 h, 25 mbar) to yield 3.23 g (12.63 mmol, 61.4 %) of 2-chloro-N-(3,5-dimethyl-adamantan-1-yl)-acetamide as a colourless powder as described above.
61.4%
Example 5; Preparation of 2- Chloro-N-(3,5-dimethyl-adamantan-1-yl) acetamide (Method 5); A 0.25 I round-bottom three-necked flask, equipped with reflux condenser, oil ventile, mechanical stirrer, thermometer, and dropping funnel is charged with 1-bromo-3,5- dimethyladamantane compound (5.00 g, 20.56 mmol), iron(lll)sulphate (84 mg, 0.21 mmol), dimethylformamide (6.00 ml), chloroacetonitrile (4.19 g, 55.50 mmol), and acetic acid (9.23 g, 153.73 mmol). The reaction mixture is cooled to 5 - 10 0C with stirring. Sulphuric acid (96 %, 8.87 ml, 166.4 mmol) is added drop wise, keeping the temperature at 5 - 10 0C. After completion of addition the resulting suspension is heated to 80 0C for about 90 min. The reaction mixture is allowed to cool to room temperature and hydrolyzed with water (50 ml). <n="12"/>After cooling to 5 0C and stirring for further 30 min. the residue is separated and washed in a stream of water (150 ml) and dried under reduced pressure (40 0C, 72 h, 25 mbar) to yield 3.23 g (12.63 mmol, 61.4 %) of 2-chloro-N-(3,5-dimethyl-adamantan-1-yl)-acetamide as a colourless powder as described above.
With dimanganese decacarbonyl; at 120 - 130℃;Inert atmosphere; Autoclave;
General procedure: General procedure for the synthesis of N-(3,5-dimethyladamant-1-yl)acetamides. The stainless steel pressure microreactor (V = 17 mL) or glass vial was charged under argon with 0.3 mmol of manganese-containing catalyst, 10 mmol of 1-bromo-3,5-di-methyladamantane I, and 30 mmol of amide. The reac-tion mixture was heated at 120-130C for 3-4 h with stirring. After the reaction completed, the rector (vial) was cooled to room temperature and opened. The reaction mixture was washed with water, and then the reaction product was extracted with methylene chloride (3 5 mL). The solvent was removed under a reduced pressure, and the residue was recrystallized. N-(3,5-Dimethyladamant-1-yl)amides II-V were puri-fied by column chromatography (silica gel, eluent - hexane-ethyl acetate).
94%
at 125℃;
Compound (IV) (60 g, 0.247 mol)Mix with acetamide (116.6 g, 1.974 mol).The oil bath was heated to 125C and incubated for 4~5h.Stop the reaction. Cool, add 600ml of dichloromethane and 300ml of drinking water,Stir well, stand and separate the liquid. The aqueous phase is extracted once more with 300 ml of dichloromethane.Combine the organic phases. 600ml of drinking water is washed twice and the organic phase is concentrated to dryness under reduced pressure and recrystallized from water.Drying under reduced pressure gave compound (III) as a white solid (GC> 98.0%, yield 94%).
92.4%
at 70 - 160℃; for 6h;Inert atmosphere;
Add 120g of <strong>[941-37-7]1-bromo-3,5-dimethyladamantane</strong> to the first reactor, stir, then add 144g of acetamide,After adding, stop stirring, close the feeding port, and evacuate,Nitrogen was replaced 3 times. Turn on stirring, turn on the heating device, first heat up to 70 ,The solid melts into a viscous liquid, continue to heat up to 160 , turn off nitrogen,Incubate for 6 hours.Turn on the cooling device to cool the reaction liquid to 70 ,Quickly add 300g of purified water to the reactor, add it, continue to cool to room temperature, add 450g of methylene chloride,Stir to dissolve. Add 300g of purified water and 450g of dichloromethane to the second reaction kettle, and then transfer the reaction liquid from the first reaction kettle to the second reaction kettle,Stir for 15min, let stand, separate the liquid, extract the upper aqueous phase once with 120g dichloromethane, stir for 15min, let stand,Liquid separation. Combine the organic phases, add 300 g of purified water, stir for 15 min, let stand, and separate the aqueous phase.Transfer the organic phase into the first spinner flask,The temperature is controlled at 20 C, and the vacuum degree is -0.06MPa or more under reduced pressure until no solvent is distilled off, and the distillation is continued for 0.5 hours to obtain an off-white solid. Transfer the solids to the beating bucket,Add 240g of n-heptane, stir, control the temperature of the liquid to 0-15 , stir for 0.5 hours,Suction filtration.Put the filter cake into the decompression oven, control the temperature at 45 (outside temperature), vacuum degree above -0.08MPa and vacuum dry to constant weight,That is, 1-acetamido-3,5-dimethyladamantane solid. Packed in double plastic bags and weighed1-acetylamino-3,5-dimethyladamantane solid(100.9 g, yield 92.4%).
at 25 - 140℃; for 3 - 5h;Product distribution / selectivity;
l-Bromo-3,5-dimethyl adamantane (60.0 g) was added to reaction vessel followed by addition of acetamide (145.72 g) at 25-300C. The reaction mixture was stirred and then heated at 130-1400C and heating was maintained for 3-4 Hrs. The reaction mixture was cooled to 20-250C and toluene (300 mL) was added. Reaction mixture was stirred at 25-300C for 1 Hr. Water (600 mL) was added at 25-300C and stirred for 1 Hr. After stirring the layers were settled for 30 minutes and then separated out. The organic (Toluene) layer was kept and to the aqueous layer, toluene (150 mL) was added at 25-300C and stirred for 1 Hr and after stirring layers were settled and separated out. Further, to the aqueous layer, toluene (150 mL) was added at 25-300C and stirred for 1 Hr and after stirring layers were settled and separated out. Total toluene layers were collected and dried over anhydrous sodium sulfate and toluene layer was distilled under pressure below 600C. Methanol (300 mL) was added to the residue and methanol was distilled under pressure below 600C. The residue was cooled upto 25-300C and then stirred vigorously and water (500 mL) was added during vigorous stirring. The reaction mixture was cooled upto 5-100C for 2 Hrs. The solid was filtered under reduced pressure at 10-150C and washed with chilled (10-150C) water and then dried under reduced pressure at 50-550C for 2 Hrs to afford the title compound l-acetamido-3,5-dimethyl adamantane.; Example 2 (b): Preparation of l-Acetamido-3,5-dimethyI adamantane with 5.0 equivalent of acetamide <n="15"/>l-Bromo-3 ,5 -dimethyl adamantane (60.0 g) was added to reaction vessel followed by addition of acetamide (72.85 g) at 25-300C. The reaction mixture was stirred and then heated at 130-1400C and heating was maintained for 3-5 Hrs. The reaction mixture was cooled to 80-850C and toluene (300 mL) was added. Reaction mixture was stirred at 25-300C for 1 Hr. Water (600 mL) was added to the reaction mixture at 25-300C and stirred for 1 Hr. After stirring the layers were settled for 30 minutes and then separated out. The organic (Toluene) layer was kept and to the aqueous layer, toluene (150 mL) was added at 25-300C and stirred for 1 Hr and after stirring layers were settled and separated out. Further, to the aqueous layer, toluene (150 mL) was added at 25-300C and stirred for 1 Hr and after stirring layers were settled and separated out. Total toluene layers were collected and dried over anhydrous sodium sulfate and toluene layer was distilled under pressure below 60 C. Methanol (300 mL) was added to the residue and methanol was distilled under pressure below 600C. The residue was cooled upto 25-300C and then stirred vigrously and water (500 mL) was added during vigorous stirring. The reaction mixture was cooled upto 5-100C for 2 Hrs. The solid was filtered under reduced pressure at 10-150C and washed with chilled (10-150C) water and then dried under reduced pressure at 50-550C for 2 Hrs to afford the title compound l-acetamido-3,5-dimethyl adamantane.; Example 3 (b): Preparation of Memantine Base (One pot synthesis) l~Bromo-3,5-dimethyl adamantane (60.0 g) was added to reaction vessel followed addition of acetamide (87.42 g) the reaction mixture was stirred and heated at 130-1400C for 3 to 5 Hrs. The reaction mixture was cooled up to 80- 850C and then toluene (300 mL) was added to reaction mixture and stirred for 1 Hr. The reaction mixture was treated with water (600 mL) and stirred for lhr. The reaction mixture was filtered and washed with toluene. The organic layer was separated and toluene was distilled out at temperature range 105-130C.Cool to 105-1150C and the reaction mass was again treated with DEG(270 mL) at 105-1150C maintaing 105-1150C for 2 hrs. Again distill out toluene at 130-140C.Cool at 105-1150C and add sodium hydroxide (78 g) was added at 105-1150C. The reaction mixture was stirred and then heated at 155-1700C and heating was maintained for 10 Hrs. The reaction mixture was cooled to 80-850C and water (200 mL) was added within 1 Hr. Reaction mixture was stirred for 30 minutes and toluene (400 mL) was added to the reaction mixture and further stirred for 1 Hr. After stirring the layers were settled for 30 minutes and then separated out. The organic (Toluene) layer was kept and to the aqueous layer, toluene (50 mL) was added and stirred for 1 Hr and after stirring layers were settled and separated out. Total toluene layers were collected and water (500 ml) was added to it and stirred for 1 Hr at 25-300C. After stirring the layers were settled for 30 minutes and then separated out to afford the title compound Memantine Base.; Example 6: Preparation of Memantine Hydrochloride (One pot synthesis). l-Bromo-3, 5 -dimethyl adamantane (60.0 g) was added to reaction vessel followed addition of acetamide (87.42 g) the reaction mixture was stirred and heated at 130-1400C for 3 to 5 Hrs. The reaction mixture was cooled up to 80- 850C and then toluene (300 mL) was added to reaction mixt...
1548 g
In dichloromethane; water; at 150℃;Inert atmosphere;
Followed by the addition of 1.8 kg of starting material,Acetamide 2.2 kg,Nitrogen protection.The reaction solution was heated to 150 C and stirred for 6 to 7 hours.3.6 L of water was slowly added,Stirring was continued for 5 to 10 minutes,Further 1.8 L of methylene chloride was added, Standing for 3 to 5 minutes,The organic layer was separated,Repeat the above procedure twice.To the organic layer was added 1.8 L of water,Stirring for 5 to 10 minutes,Standing for 3 to 5 minutes,Abandoned water layer.To the organic layer was added 1.8 L of saturated sodium chloride,Stirring for 5 to 10 minutes, standing for 3 to 5 minutes,Abandoned water layer. 500 g of anhydrous sodium sulfate was added to the organic layer, and the mixture was stirred and dried for 2 hours.In the water bath temperature of 40 ~ 45 , vacuum ?-0.090MPa, the vacuum distillation of the solvent, 1 - acetylamino - 3 -1548 g of dimethyl adamantane.
Example 6: Preparation of Memantine Hydrochloride (One pot synthesis). l-Bromo-3, 5 -dimethyl adamantane (60.0 g) was added to reaction vessel followed addition of acetamide (87.42 g) the reaction mixture was stirred and heated at 130-1400C for 3 to 5 Hrs. The reaction mixture was cooled up to 80- 850C and then toluene (300 mL) was added to reaction mixture and stirred for 1 Hr. The reaction mixture was treated with water (600 mL) and stirred for lhr. The reaction mixture was filtered and washed with toluene. The organic layer was separated and toluene was distilled out at temperature range 105-1300C and then cool to 105-1150C and the reaction mass was again treated with DEG(260 mL) at 105-1150C maintaining 105- 1150C for 2 hrs. Again distill out toluene at temperature 130-140C.Cool at 105-1150C and add sodium hydroxide (78 g) was added at 105-1150C. The reaction mixture was stirred and then heated at 155-1700C and heating was maintained for 10 Hrs. The <n="18"/>reaction mixture was cooled to 80-850C and water (200 niL) was added within 1 Hr. Reaction mixture was stirred for 30 minutes and toluene (400 mL) was added to the reaction mixture and further stirred for 1 Hr. After stirring the layers were settled for 30 minutes and then separated out. The organic (Toluene) layer was kept and to the aqueous layer, toluene (50 mL) was added and stirred for 1 Hr and after stirring layers were settled and separated out. Total toluene layers were collected and water (500 ml) was added to it and stirred for 1 Hr at 25-300C. After stirring the layers were settled for 30 minutes and then separated out. Distilled out toluene (350 mL) under reduced pressure below 6O0C, add (1.2 g) charcoal and heat at 50-600C for 20 to 30 minutes. The reaction mixture was filtered and washed with toluene (2 X 50 mL). The toluene layer was cooled to 10-150C and aqueous HCl (18-22 mL) was added drop wise with in 1 hr at 10-150C and stirred for 30 minutes. The reaction mixture was cooled 5-1O0C and maintain for lhr. The product was filtered and washed with chilled acetone (5 x 50 mL), the product was dried under vacuum at 80-900C for 15 hrs - 20 lirs. to obtain 25- 35g of the title compound i.e. memantine hydrochloride with more than 99% purity and having individual known impurities like l-Bromo-3,5-dimethyladamantane, 1- Hydroxy-3,5-dimethyladamantane, l-(N)-Acetamido-3,5-dimethyl adamantane, 1- Amino-3,5-dimethyladamantane less than 0.10% and unknown impurities less than 0.10%. The total impurities is less than 0.5%.
Preparation of Compound of Formula H - X = Br; Compound of formula III, wherein X is bromo, (20 gms, 0.0823 moles) was stirred with N,N-dimethylformamide (200ml). Potassium phthalimide (22.85 gm, 0.123 moles) was added at 25-300C and the contents were stirred for 10 minutes. The reaction mass was heated to 1300C, further stirred for 6 hours at 1300C and then cooled to ambient temperature. The reaction mass was quenched in ice-water (500 ml) and extracted with methylene chloride. The organic phase was separated, washed with water, dried over sodium sulphate and concentrated under reduced pressure below 350C to yield the title compound (20.0 gm, 78.64%).
With dimanganese decacarbonyl; at 120 - 130℃;Inert atmosphere; Autoclave;
General procedure: General procedure for the synthesis of N-(3,5-dimethyladamant-1-yl)acetamides. The stainless steel pressure microreactor (V = 17 mL) or glass vial was charged under argon with 0.3 mmol of manganese-containing catalyst, 10 mmol of 1-bromo-3,5-di-methyladamantane I, and 30 mmol of amide. The reac-tion mixture was heated at 120-130C for 3-4 h with stirring. After the reaction completed, the rector (vial) was cooled to room temperature and opened. The reaction mixture was washed with water, and then the reaction product was extracted with methylene chloride (3 5 mL). The solvent was removed under a reduced pressure, and the residue was recrystallized. N-(3,5-Dimethyladamant-1-yl)amides II-V were puri-fied by column chromatography (silica gel, eluent - hexane-ethyl acetate). N-(3,5-Dimethyladamantan-1-yl)formamide (II). Yield 78%, mp 69-70C (hexane). Physico-chemical constants and NMR spectral data correspond to the literature data [7].
at 22 - 75℃;Inert atmosphere;Product distribution / selectivity;
Example 1[007O] A clean enameled reactor is inerted by purging 3 times with nitrogen. Temperature in the reactor is adjusted to 2O0C. 1.22 kmol of 1 ,3- dimethyladamantan is introduced into the reactor under nitrogen atmosphere. Consequently, 3.66 kmol of bromine is introduced into the reactor under constant agitation at 90 rpm. The reaction mass is heated up to 8O0C in approximately 8 hours under constant agitation at 90 rpm. The reaction mass is agitated for another 6 hours at 80C.105577P502PC [0071] A second reactor is prepared and the atmosphere in the reactor is inerted by purging the reactor 3 times with nitrogen. 7.9 kmol of formamide is introduced under nitrogen atmosphere at 22C into the reactor. Consequently, formamide is heated up to 75C under constant agitation at 100 rpm. The reaction mass in the first reactor is slowly, over a time period of 4 hours, transferred into the reactor containing formamide. The resulting mixture is agitated for 2 hours. After the preceding of 2 hours of agitation, the reactor is immediately cooled to 120C. Methylene chloride is introduced to this reactor at 12C. Immediately thereafter, bisulfite solution is prepared in a third reactor at 200C and consequently cooled down to 1O0C. Slowly, over a time period of 2-3 hours, the bisulfite solution is transferred under constant agitation at 100 rpm into the second reactor containing the reaction mass. After 15 minutes two phases are formed; the brown upper phase containing the product and the aqueous layer phase containing the salts. The two phases are separated. Separately, a sodium bicarbonate solution is prepared and introduced into the brown organic phase. After 30 minutes, the mass is rinsed with Water for Injection. 7.06 kmol of hydrochloric acid is introduced to the resulting reaction mass and is heated to until reflux (T=98- 108C). The resulting slurry is cooled immediately to 80C within 2.5 hours. The output is memantine HCI.
Example 4Preparation of 1-amino-3,5-dimethyladamantane hydrochloride[0065] <strong>[941-37-7]1-bromo-3,5-dimethyladamantane</strong> as prepared in Example 3, is treated with an excess of formamide and heated to 120 0C for 3 to 5 h. The reaction mixture is cooled and diluted with methylene chloride. This mixture is washed 4 times with a 30% sodium hydroxide solution. The organic layer is concentrated via distillation followed by addition of water. The distillation is continued to remove the organic layer, and the mixture is then cooled to below 800C. The N-formyl-1-amino-3,5-dimethyladamantane intermediate, which is optionally isolated, is then hydrolyzed by addition of a 37% hydrochloric acid solution. The reaction mixture is heated to reflux for about 3 h, and the reaction mixture is then cooled to 5 0C to yield crude 1-amino-3,5- dimethyladamantane hydrochloride which is isolated by centrifugation and washed with water followed by ethyl acetate. The crude 1-amino-3,5-dimethyladamantane hydrochloride is then reprecipitated to yield the title compound.
24 g of <strong>[941-37-7]1-bromo-3,5-dimethyladamantane</strong> and 36 g of urethane were placed in a reaction flask,Add 240 ml98% formic acid,Stirring at room temperature dissolved,Argon protection,The reaction was heated to 90 C for 1 hour.Cooled to room temperature,The formic acid was distilled off under reduced pressure,Then add the mass concentration of 10% hydrochloric acid 60 ml,And the mixture was heated to 110 C and reacted for 4 hours. Cooled to 0 C, the crystal analysisOut, to be complete crystallization,Filtering to obtain memantine hydrochloride.GC purity: 99.0%, Yield: 85%.
With hydrogen bromide; In water; for 0.666667h;Inert atmosphere;
General procedure: In a screw cap test tube were placed with 1-adamantanol (316 mg, 2.07 mmol) and aqueous HBr (47%, 10 mL). The mixture was shaken vigorously for 40 min. The solid was collected by filtration and washed several times with water. The crude bromide 5e (389 mg, 1.81 mmol, 87%) was dried in vacuo and used without further purification. Commercially available bromides 5e and 5f were also used for examination.
With silver(l) oxide; In chloroform; for 1.83333h;Reflux;
Phenylphosphinic acid (0.568 g, 4 mmol) and <strong>[941-37-7]1-bromo-3,5-dimethyladamantane</strong> (2.334 g, 9.6 mmol) were dissolved in chloroform (40 ml). This reaction mixture was refluxed. Then, silver oxide (2.22 g, 9.6 mmol) was added in five equal portions, over 50 min. This solution was refluxed for an additional 1 h. After, the solvents were removed, the residue was treated with diethylether and filtered through celite. The filtrates were concentrated. The residue was purified by column chromatography using diethylether as eluent. 3,5-dimethyladamantyl hydrogenophenylphosphinate Colorless oil : 31P NMR (121 MHz, CDCl3) delta 14.4 (s); 1H NMR (300 MHz, CDCl3) delta 7.40 - 7.61 (m, 2 H) 7.72 - 7.84 (m, 3 H), 6.80 (d, J = 553 Hz, 1H), 2.23 - 2.10 (m, 3 H), 2.05 - 1.90 (m, 4 H), 1.45 - 1.32 (m, 4 H), 1.04 (s, 2 H), 0.91 (s, 6 H)
With dimanganese decacarbonyl; at 120 - 130℃;Inert atmosphere; Autoclave;
General procedure: General procedure for the synthesis of N-(3,5-dimethyladamant-1-yl)acetamides. The stainless steel pressure microreactor (V = 17 mL) or glass vial was charged under argon with 0.3 mmol of manganese-containing catalyst, 10 mmol of 1-bromo-3,5-di-methyladamantane I, and 30 mmol of amide. The reac-tion mixture was heated at 120-130C for 3-4 h with stirring. After the reaction completed, the rector (vial) was cooled to room temperature and opened. The reaction mixture was washed with water, and then the reaction product was extracted with methylene chloride (3 5 mL). The solvent was removed under a reduced pressure, and the residue was recrystallized. N-(3,5-Dimethyladamant-1-yl)amides II-V were puri-fied by column chromatography (silica gel, eluent - hexane-ethyl acetate).
With dimanganese decacarbonyl; at 120 - 130℃;Inert atmosphere; Autoclave;
General procedure: General procedure for the synthesis of N-(3,5-dimethyladamant-1-yl)acetamides. The stainless steel pressure microreactor (V = 17 mL) or glass vial was charged under argon with 0.3 mmol of manganese-containing catalyst, 10 mmol of 1-bromo-3,5-di-methyladamantane I, and 30 mmol of amide. The reac-tion mixture was heated at 120-130C for 3-4 h with stirring. After the reaction completed, the rector (vial) was cooled to room temperature and opened. The reaction mixture was washed with water, and then the reaction product was extracted with methylene chloride (3 5 mL). The solvent was removed under a reduced pressure, and the residue was recrystallized. N-(3,5-Dimethyladamant-1-yl)amides II-V were puri-fied by column chromatography (silica gel, eluent - hexane-ethyl acetate).
2.9Og (8.2 mmol) of urea, 2.96 g (49.4 mmol) of urea and 4 mL of N, N-dimethylimidazolidinone were added, and the mixture was stirred at 140 C for 2 hours (colorless transparent liquid). From 1 H NMR analysis of the reaction solution,Formation of 1-carbamide 3,5-dimethyladamantane was confirmed (conversion 51%)
A 5 L flask was charged with 300.00 g of <strong>[941-37-7]1-bromo-3,5-dimethyladamantane</strong> (1233.7 mmol), urea 296.37 g (4934.6 mmol) and NMP 600 mL were added, and the mixture was stirred at 120 C. for 4 hours (yellow solution). The reaction solution was cooled to room temperature, 1500 mL of NMP and 493.46 g (12336.5 mmol) of sodium hydroxide were added, and the mixture was stirred at 120 C. for 6 hours (light yellow slurry). After cooling the reaction solution to room temperature, 2000 mL of water was added and the solution was transferred to a 10 L flask, 3400 mL of water and 1500 mL of toluene were further added and vigorously stirred for 20 minutes.The mixture was allowed to stand for 1 hour, and separated into an aqueous layer and an organic layer.The aqueous layer was returned to a 10 L flask, 1500 mL of toluene was added and vigorously stirred for 20 minutes. The mixture was allowed to stand for 20 minutes, and the aqueous layer was removed (pH 12.5).The organic layers were combined, 900 mL of water was added, vigorously stirred for 20 minutes, allowed to stand for 20 minutes, and the aqueous layer was removed. The obtained organic layer was cooled to 15 C. or lower, 137.44 g (1357.0 mmol) of concentrated hydrochloric acid was added, and the mixture was stirred at 25 C. for 16 hours.The obtained slurry was suction filtered, the cake was washed twice with 300 mL of toluene, and the obtained memantine hydrochloride wet crystals were dried under reduced pressure to obtain 258.62 g of memantine hydrochloride (yield 97%, GC Purity 99.8%)
1-amino-3,5-dimethyladamantane trifluoroacetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With methyl carbamate; at 72 - 94℃; for 29h;
In a container having an internal volume of 300 mL equipped with a stirring device, a thermometer and a reflux condenser,20 mmol (101 mmol) of <strong>[941-37-7]1-bromo-3,5-dimethyladamantane</strong>,11.4 g (152 mmol) of methyl carbamate and 58.0 g (509 mmol) of trifluoroacetic acid were added,The reaction was carried out at 72 to 94 C. with stirring. After 29 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 19.5 g of a salt of 1-amino-3,5-dimethyladamantane and trifluoroacetic acid as a slightly yellowish white solid (yield: 66%).
1-(3,5-dimethyladamantan-1-yl)propan-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
General procedure: A solution of 43 g (0.2 mol) of 1-bromoadamantane in 260 mL of methylene chloride was cooled to -10 C, and 61.9 g (0.23 mol) of aluminum bromide was added. The mixture was stirred for 0.5 h, 44 mL (40 g, 0.42 mol) of isopropenyl acetate was added over a period of 2 h, and the mixture was stirred for 0.5 h, poured onto 200 g of ice, and made weakly alkaline reaction by adding sodium carbonate (106 g, 1 mol) and sodium metabisulfite (38 g, 0.2 mol). The organic layer was separated, and the aqueous layer was extracted with methylene chloride (3 × 50 mL). The extracts were combined with the organic phase, the solvent was distilled off, and the residue was distilled under reduced pressure. Yield 31.9 g (83%), bp 110-112 C (4 mm). 1H NMR spectrum (DMSO-d6), delta, ppm: 1.50-1.80 m (12H, CH2), 1.94 s (3H, CH), 2.10 s (3H, CH3), 2.16 s (2H, CH2CO).
With tris-(dibenzylideneacetone)dipalladium(0); XPhos; In toluene; at 100℃; for 24h;
Aniline (10 mol), 1-Bromo-3,5-dimethyladamantane (10 mol), Pd2 (dba) 3 (0.1 mol) and XPhos (0.1 mol) were placed in toluene and heated to 100 C and stirred for 24 hours. Ethyl acetate was added to the solution and the mixture was washed twice with water to extract an organic layer. The extracted organic layer was distilled under reduced pressure and purified by column chromatography to obtain Intermediate J-1.