85.27% |
With tetra-(n-butyl)ammonium iodide; N-ethyl-N,N-diisopropylamine; In sulfolane; at 95 - 105℃; |
To a reaction flask 24 g (0.06533moles) 2-[[(3aft,4S,6ft,6aS)-6-amino -2,2-dimethyltetrahydro- 3aH-cyclopenta[d][1 ,3]dioxol-4-yl]oxy]-1-ethanol, L-tartaric acid in 40 ml sulfolane, 40 ml (0.296moles) of Nu,Nu-diisopropylethylamine and 2 g of tetra butyl ammonium iodide were charged and the reaction mixture was stirred for 20-25 minutes 10 g (0.04199moles) of 5-amino-4,6- dichloro-2-(propylthio)pyrimidine in 10 ml sulfolane was charged and the reaction mixture was heated to 95C to 105C for 3-4 hours. The reaction mixture was quenched with 150 ml water at 10-15C and stirred for 3 hours at 20-25C. The product obtained was filtered and washed with water and then dried under vacuum at 50-55C for 12 hours. Yield = 15 g. (Efficiency - 85.27%, HPLC - 99%). |
80% |
With triethylamine; In ethylene glycol; at 90 - 100℃;Large scale; |
(1) Add 18L of ethylene glycol, 9.335kg of SM1, 12kg of SM2 and 16.529kg of triethylamine to the 100L reactor, stir and mix;(2) heating the reaction solution to 90 ~ 100 C, the reaction liquid solid dissolved, the color is a yellow clear solution; maintaining this temperature for 8 to 10 hours;(3) TLC detection, the developing agent is ethyl acetate: methanol = 1:1, the color developing agent is ninhydrin ethanol solution, and the color is baked at 150 C;The reaction solution was lowered to below 50 C, and the reaction liquid was a dark brown clear solution; the reaction liquid was poured into a 200 L reaction vessel containing 50 L of ethyl acetate and 50 L of water under stirring at room temperature;The 100 L reaction vessel was rinsed with 10 L of ethyl acetate and 10 L of purified water, and the eluent was poured into a 200 L reaction vessel; the mixture was stirred at room temperature for 30 minutes;Stop stirring, let stand for stratification, and separate the lower aqueous phase; (4) adding 60 L of purified water to the upper organic phase, stirring at room temperature for 30 minutes; stopping the stirring, standing to separate the layers, and separating the lower aqueous phase;(5) The upper organic phase is transferred to a 500 L reaction kettle, and heated to 60-70 C under stirring; in addition, 180 L of isooctane is preheated to 60-70 C, and added to the reaction flask;(6) After adding, slowly cool down to room temperature with stirring and then cool down to 35 ~ 45 C (solid precipitation temperature about 30 ~ 35 C),Slowly cool down to 20 ~ 30 C; keep stirring at 20 ~ 30 C for 1 hour, and then slowly reduce the temperature to 0 ~ 10 C;(7) stirring at 0 to 10 C for 2 hours;(8) centrifugal filtration, the reaction kettle and the filter cake are rinsed with a mixture of 12 L of ethyl acetate and 36 L of isooctane precooled to 0 to 10 C;(9) The filter cake was vacuum dried at 45 to 55 C for 12 to 16 hours to obtain a white powder of Im-1, weighing 11 kg, and the yield was 80%. |
80% |
With triethylamine; In ethylene glycol; at 9 - 100℃; for 0.5h;Large scale; |
3) Operation process(1) Add 18L of ethylene glycol and 9.335kg of SM1 to the 100L reactor.12kg SM2 and 16.529kg triethylamine,Stir and mix;(2) heating the reaction solution to 90 ~ 100 C, the reaction liquid solid dissolved, the color is a yellow clear solution; maintaining this temperature for 8 to 10 hours;(3) TLC detection, the developing agent is ethyl acetate: methanol = 1:1, the color developing agent is ninhydrin ethanol solution, and the color is baked at 150 C;Lower the reaction solution to below 50 C,The reaction solution is a dark brown clear solution;The reaction solution was poured into a 200 L reaction vessel containing 50 L of ethyl acetate and 50 L of water under stirring at room temperature;The 100 L reaction kettle was rinsed with 10 L of ethyl acetate and 10 L of purified water.The eluent was poured into a 200 L reaction kettle; stirred at room temperature for 30 minutes; the stirring was stopped, and the layer was allowed to stand.Divide the lower aqueous phase;(4) Add 60 L of purified water to the upper organic phase, stir at room temperature for 30 minutes; stop stirring, let stand for stratification, and separate the lower layer.water box;(5) Transfer the upper organic phase to a 500L reactor and heat to 60-70 C with stirring; in addition, 180 L of isooctane pre-Heat to 60 ~ 70 C, added to the reaction flask;(8) After adding, slowly cool down to room temperature with stirring and firstly cool to 35-45 C (solid precipitation temperature about 30-35 C).Slowly cool down to 20 ~ 30 C; keep stirring at 20 ~ 30 C for 1 hour, and then slowly reduce the temperature to 0 ~ 10 C;(8) stirring at 0 to 10 C for 2 hours;(9) Centrifugal filtration, the reaction kettle and filter cake are mixed with 12 L of ethyl acetate pre-cooled to 0-10 C and 36 L of isooctane.Rinsing(10) The filter cake is dried under vacuum at 45-55 C for 12 to 16 hours to obtain a white powder of Im-1, weighing 11 kg, yield80%. |
77.3% |
With 1,8-diazabicyclo[5.4.0]undec-7-ene; N-ethyl-N,N-diisopropylamine; In ethylene glycol; at 120 - 125℃; |
To a mixture of 4,6-dichloro-2-(propylthio)-5-pyrimidinamine (25.0 gm, 0.105 mol)) in ethylene glycol (125 ml), 2-[(3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-SaH-cyclopentalcdll .Sl-dioxol^-ylJoxy}- -ethanol, L- tartaric acid (1 :1 ) (42.41 gm; 0.115 mol) was added 1 , 8-bicyclo [5.4.0] undec-7-ene (1.25 gm), followed by addition of diisopropyl ethylamine (61.06 gm; 0.472 mol) at 20-25C. Reaction mixture was heated at 120-125C stirred and maintained at same temperature for 4-5 hours, until completion of reaction (monitored by TLC). After completion of reaction, resulting mass was cooled to 20-30 C, diluted with water (500 ml). 2-[((3aR,4S,6R,6aS)-6- [5-amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino}-2,2- dimethyltetrahydro-3aH-cyclopenta[d] [1 ,3] dioxol-4-yl)oxy]-1 -ethanol compound was extracted as oil from reaction mass twice with MDC (250 ml), followed by washing of MDC layer with water (500 ml). MDC was evaporated at 35-40C under reduced pressure to produce 42.5 gm of 2- [((Sa ^S.eR.eaSJ-e-ilS-amino-e-chloro^-ipropylthioJ^-pyrimidinylJamino}- 2,2-dimethyltetrahydro-3aH-cyclopenta[cd [1 ,3] dioxol-4-yl)oxy]-1-ethanol as oil. Obtained oil was dissolved in ethyl acetate (75.0 ml), stirred and the solution was heated at 50C, followed by addition of n-heptane (500.0 ml) at 50C and maintained for 30 min. The resulting isolated suspensions was gradually cooled to room temperature then cooled to 20-25C and maintained at 20-25C for 30-40 min. Obtained solid was filtered, washed with n-heptane (50.0 ml), suck dried and dried at 50-55C to afford white solid of 2-[((3a 4S,6 ,6aS)-6-[5-amino-6-chloro-2-(propylthio)-4- pyrimidinyl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d] [1 ,3] dioxol-4- yl)oxy]-1-ethanol. [Yield = 34.0 gm (77.30%); purity (HPLC): 99.1 %] |
77% |
With ethylene glycol; triethylamine; In 1,2-dimethoxyethane; at 100℃; for 9.0h;Industrial scale; |
(1) In 50 L reaction kettle are respectively added with a 10.80 L glycol, 5.601 kg FTG - SM1, 7.200 kg FTG - SM2 and 7.933 kg triethylamine, stirring and mixing;(2) The reaction liquid heating to 100 C, reaction liquid solid-dissolving, color is the yellow clear solution; to maintain this temperature reaction 9 h;(3) TLC detection (developing solvent: ethyl acetate/methanol=1:1, developer is ninhydrin ethanol solution, 150 C baking sheet color); FTG - SM2 raw material point disappears then the reaction completely. The reaction liquid is dropped to 50 C following, the reaction solution is a dark brown clear solution; under stirring at room temperature the reaction liquid pouring 25.00 L ethyl acetate and 25.00 L water of 100 L glass reactor; then 3.80 L ethyl acetate and 3.80 L purified water leaching 50 L glass reactor, showering liquid is poured into the 100 L glass reactor; room temperature stirring 30 min; stop stirring, layered, separating out the lower aqueous phase;(4) The upper organic phase further 28.80 L purified water, room temperature stirring 30 min; stop stirring, layered, separating out the lower aqueous phase;(5) The upper organic phase is concentrated under reduced pressure to no longer have a liquid outflow, temperature 50 C; to obtain brown sticks the thick oil objects;(6) For the brown sticks the thick oil-like 28.80 L methanol dissolved, add 360 g activated carbon, 50 C stirring 30 min; filtering, the filtrate into 100 L glass reactor; and then to 100 L glass reactor by adding 28.80 L methanol, stirring and heating to 50 C;(7) Under mixing to preheat to the 50 C of 28.80 L purified water by adding 100 L glass reactor, maintaining the temperature 50 C;(8) stirring cooling to 25 C, thermal insulation stirring 1 h;(9) Dropped to 10 C to continue stirring 2 h;(10) Filtering, reactor and the filter cake is pre-cooled to 10 C of 14.40 L methanol and 7.20 L purified water mixed solvent leaching;(11) Filtering cake 55 C decompression drying 16 h, getting white powder 6.187 kg, yield 77%. |
Ca.95% |
With sodium hydrogencarbonate; In water; at 100℃; for 0.14h; |
A flask was charged with 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (25 g), <strong>[376608-65-0]2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol L-tartaric acid salt</strong> (42.5 g), water (75 mL) and sodium bicarbonate (53 g). The mixture was heated to about 100 C. and maintained at the same temperature for about 14 hours and completion of the reaction was monitored by TLC. After completion of reaction, the mixture was cooled to 60 C. followed by addition of ethyl acetate (25 mL), water (175 mL) and n-hexane (375 mL). The mixture was stirred for about 7 hours. The solid obtained was isolated by filtration and washed with water (50 mL). The wet compound and water (500 mL) were charged into round bottom flask and stirred for overnight. The solid was isolated by filtration and washed with water (50 mL) and was subjected to drying under vacuum at 60 C. for 9 hours to afford the title compound in about 95% yield having HPLC purity of about 98.5%. |
30 g |
With triethylamine; In methanol; at 99 - 105℃; for 22.0h;Autoclave; |
2-[[(3aS,4R,6S,6aR)-4-amino-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][l,3]- dioxol-6-yl]oxy]ethanol in the form of the L-tartrate (32.6 g, 89 mmol) and 4.6-dichloro-2- (propylthio)-pyrimidin-5 -amine (20.5 g, 86 mmol, compound Ilia) were dissolved in methanol (80 ml). Triethylamine (60 ml; 430 mmol) was added to the solution. Then, the reaction mixture was heated up to approximately 99 to 105 C in a pressure vessel and agitated for 22 hours. After that, the cooled reaction mixture was diluted with ethyl acetate (90 ml) and the mixture was concentrated by evaporation of a great part of the solvents at a reduced pressure. The concentrated mixture was diluted with 90 ml of ethyl acetate and 180 ml of water and the extraction was performed. The top organic phase was separated and concentrated by evaporation of most of the solvents at a reduced pressure. The agitated concentrated mixture was diluted with heptane (140 ml) at an elevated temperature (60 - 70C) and the agitated mixture was then left to crystallize. After cooling down to 0C the beige-colored product was removed by filtration and washed with a small amount of heptane. After drying in vacuo, 30 g of the intermediate IVa with the HPLC purity higher than 98.5% was obtained. MW of 418.94 (C17H27CIN4O4S) was then verified with the use of HR MS. The obtained compound IVa (28.5 g; 68 mmol) was stirred up in a mixture of 90 ml of methanol and 15 ml of water. 36% hydrochloric acid (20 ml, ca. 240 mmol) was then added to the suspension. The obtained solution was then agitated at the temperature of ~35C for 3.5 hours. In an evaporator the mixture was then concentrated by distillation of most of the more volatile solvent. The concentrated mixture was diluted with 130 ml of water and then, being stirred, it was neutralized by a dropwise addition of a 5% aqueous solution of NaOH (ca. 150 ml). The mixture was agitated overnight. The next day it was cooled down to 0C, the grayish crystalline product was filtered off and washed with a small amount of water. After drying in vacuo, 25.5 g of the compound Va was obtained (80% relative to Ilia) with the HPLC purity of 99.5%. MW of 378.87 (C14H23C1N404S) was then verified with the use of HR MS. The water content measured using the Karl Fischer method is 4.8 %. |
|
With N-ethyl-N,N-diisopropylamine; at 128℃; for 6.0h;Green chemistry; |
Example-1: Preparation of 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)- pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4- yl)oxy)ethanol (III) To a mixture of diisopropylethylamine (1000 ml) and 4,6-dichloro-2-(propylthio)-pyrimidin- 5-amine (200 gm), 2-[[(3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H- cyclopenta[l,3]dioxol-4-yl]oxy]-ethanol.L-tartaric acid (340 gm) was added at 30C and heated toa temperature of 128C. The reaction mixture was maintained for 6 hours at 128C. The progress of the reaction was monitored by HPLC. On completion of the reaction, the reaction mass was cooled to 75C and distilled under vacuum to remove diisopropylethylamine. Methanol (300 ml) was added to the reaction mass at a temperature of 30C followed by slowly addition of water (3000 ml) for 2 hours. The contents were then stirred for about 4 hours, filtered, washed with water (1200 ml) and dried. Yield: 1.5 gm |
110 g |
With triethylamine; at 100℃; for 11.0h;Inert atmosphere; |
To a solution of 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (III) can be prepared as disclosed in CN1270590A, CN1680340A Method obtained or commercialized) 106g <strong>[376608-65-0]2-[[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-cyclopenta-3aH-[d][1,3]dioxolan-4-yl]oxy]ethanol L-tartaric acid salt</strong> (II, commercially available as disclosed in the method disclosed in CN 101143864A), 120 g of triethylamine and 136 g of triethylamine; The reaction mixture was heated to 100 C with stirring under nitrogen for about 11 hours and then cooled to about 40 C; The organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated. The concentrate was crystallized from isopropyl acetate / isooctane (1/3, v / v) to give 110 g of the title compound (IV). |
|
With sodium tosylate; N-ethyl-N,N-diisopropylamine; sodium iodide; In 1,4-dioxane; at 100℃; for 10.0h;Inert atmosphere; |
25 mol of 1,4-dioxane, 1.5 mol of TG-SM-3, 1 mol of TG-SM-2 were sequentially added to the reactor, and then 3 mol of a catalyst and 6 mol of N,N-diisopropylethylamine were sequentially added thereto, and nitrogen gas was introduced thereto to raise the temperature by 100. C reflux, stirring for 10h, concentrated under reduced pressure to remove 1,4-dioxane, after cooling to room temperature, add dichloromethane and water, liquid, organic layer washed with water and saturated sodium chloride solution, washed organic The layer was concentrated under reduced pressure to give a crude material. EtOAc was evaporated. EtOAc EtOAc EtOAc. Filtration, vacuum drying to give a white solid TG-1; Wherein the molar ratio of TG-SM-3, TG-SM-2, 1,4-dioxane, catalyst, N,N-diisopropylethylamine is 1.5:1:25:3:6, catalyst It is 2 mol of sodium iodide and 1 mol of sodium p-toluenesulfonate. Among them, the mass ratio of TG-SM-2, dichloromethane and water was 1:6:10. Among them, n-hexane contained squalane in a mass fraction of 0.5%. |
18.6 g |
With triethylamine; In 1,2-dimethoxyethane; at 90 - 100℃; for 9.0h;Inert atmosphere; |
Add to the reaction flask 2-[[(3aR, 4S, 6R, 6aS) -6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl ] Oxy] -ethanol (2R, 3R) -2,3-dihydroxysuccinate (Compound 1) 20g, 4,6-dichloro-2- (propylthio) -5-aminopyrimidine (Compound 2 ) 15.5g, 30ml of ethylene glycol and 38ml of triethylamine, heated to 90-100 under the protection of nitrogen, and kept under reflux for 9 hours. After the reaction was completed, the reaction liquid was cooled to 30 C to 35 C, 200 ml of methylene chloride and 100 ml of purified water were added for extraction, liquid separation, the organic layer was washed with 100 ml of purified water × 2, dried over anhydrous sodium sulfate, and sodium sulfate was filtered out The filtrate was concentrated under reduced pressure to give 2-[((3aR, 4S, 6R, 6aS) -6-[5-amino-6-chloro-2- (propylthio) pyrimidin-4-yl] amino} -2,2 -Dimethyltetrahydro-3aH-cyclopenta [d] [1,3] -dioxol-4-yl) oxy] ethanol) (II) crude product;Add 50 ml of methanol and 0.5 ml of triethylamine to the reaction bottle, warm to reflux, and keep degassing at reflux for 30 minutes. Under nitrogen protection, the temperature was reduced to 50 C to 55 C, the crude product (II) above was added with stirring, and kept at 50 C to 55 C for 30 minutes, and 1 g of activated carbon was added and kept at 55 C to 60 C for 1 hour. While hot filtering, the filtrate was heated to 55 60, 220g of n-heptane was added dropwise, the temperature of the system was 50 60 during the addition of n-heptane, and the temperature was kept at 55 60 and stirred for 30 minutes. 40 45 , hold for 1 hour; then cool down to 30 35 , hold for 1 hour; then cool down to 20 25 , hold for 1 hour; finally cool down to 5 10 , crystallize 2 After filtering and drying for 1 hour, 18.6g of ticagrelor intermediate product (II) was obtained, HPLC purity was 99.59%, and impurity 3 was not detected. |