* 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.
Stage #1: With triethylamine; trichlorophosphate In dichloromethane for 5.5 h; Heating / reflux Stage #2: With hydrogenchloride; water In dichloromethane at 20℃;
Preparation Example 1; Preparation of 4-(l-bromo-ethyl)-6-(4-chloro- phenylsulfanyl)~5-fluoropyrimidine<1-1> Preparation of 4-chloro-6-ethyl-5-fluoropyrimidine 78.24 ml of triethylamine was added to a solution prepared by dissolving 80 g of 6-ethyl~5-fluoro-4-hydroxypyrimidine in 240 m of dichloromethane, and 57.4 mNo. of phosphorus oxychloride was slowly added thereto over 30 min. The resulting solution was refluxed for 5 hours to complete the reaction, and cooled to room temperature. Then, 352 ml of 3N HCl was added thereto while maintaining the temperature at below 200C . The resulting aqueous mixture was extracted with 100 mNo. of dichloromethane. The organic layer was washed with 100 mi of water, was dried over magnesium sulfate, and concentrated under a reduced pressure to obtain the title compound as an oil (85.9 g, yield: 95percent).1H-NMR (30OMHz&3 CDCl3) δ (ppm): 8.70 (IH), 2.90 (2H), 1.34 (3H)
81%
at 60℃; for 3 h;
To the solid product obtained in step (2) was added 117 g of phosphorus oxychloride, Heated to 60 ° C, the reaction 3h. After completion of the reaction, the excess of phosphorus oxychloride was recovered by distillation under reduced pressure,The product was distilled to obtain 34.1 g of 6-ethyl-5-fluoro-4-chloropyrimidine,Colorless liquid, yield 81percent, gas chromatography purity of 97percent.
Reference：
[1] Patent: WO2009/20323, 2009, A2, . Location in patent: Page/Page column 7; 9
[2] Organic Process Research and Development, 2001, vol. 5, # 1, p. 28 - 36
[3] Patent: CN103896855, 2016, B, . Location in patent: Paragraph 0023; 0033; 0038; 0039
[4] Patent: WO2007/13096, 2007, A1, . Location in patent: Page/Page column 8
[5] Patent: WO2010/95145, 2010, A1, . Location in patent: Page/Page column 17-18
[6] Patent: US2011/312977, 2011, A1, . Location in patent: Page/Page column 8
2
[ 137234-87-8 ]
[ 137234-74-3 ]
Yield
Reaction Conditions
Operation in experiment
99%
With triethylamine; trichlorophosphate In dichloromethane at 48℃; for 6 h; Industry scale; Heating / reflux
A reactor was charged with dichloromethane (20 I) and 6-ethyl-5- fluoropyrimidin-4(1 H)-one (5.00 kg, 35.2 mol) at 25-30 0C. The reaction mixture was stirred for 15 min, and triethylamine (3.60 kg, 35.6 mol) was added. Phosphorus oxychloride (5.95 kg, 38.8 mol) was added over 3 h, while the reaction temperature was kept below 35 0C. The reaction mass was heated at reflux (40-48 0C) for 3 h. The mixture was cooled to 5 0C, and <n="10"/>hydrochloric acid (3.7 M, 20 I, 74 mol) was added over 1 h. The mixture was stirred for 30 min at 20 0C. The layers were separated, and the aqueous layer was extracted twice with dichloromethane (2 x 5.0 I). The combined organic layers were washed with water (5.0 I), and the solvents were removed at reduced pressure (550 mmHg) at 28-46 0C. 5.61 kg (99percent yield) of the title compound was obtained as a brown liquid. Purity, HPLC: 99.6percent.
90%
With triethylamine; trichlorophosphate In dichloromethane for 5 h; Heating / reflux
Phosphorus oxychloride (47.2 g, 0.31 mol) was added slowly over 3 h to a mixture of 6-ethyl-5-fluoropyrimidin-4(1H)-one (40.0 g, 0.28 mol), triethylamine (28.4 g, 0.28 mol) and dichloromethane (120 ml), maintaining the reaction temperature below 40 0C. The mixture was heated at reflux for 5 h and cooled to 25 0C. The mixture was slowly poured into aqueous hydrochloric acid (3 N, 176 ml), while the temperature was kept below 20 0C. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water (50 ml), and the organic layer was concentrated at reduced pressure. Yield: 40.7 g (90percent) of an oil. Purity, HPLC: 99.8percent (RT=4.98 min).
(i) 1-Benzyl-4-ethyl-5-fluoropyrimidin-6-one Sodium hydride (60% w/w dispersion in oil, 928 mg) was triturated with hexane then dimethylformamide (30 ml) added. To this mixture was added the compound of Preparation 1(iv) (3 g) and, following cessation of the effervescence, benzyl bromide (2.51 ml). The mixture was stirred for 1 hour then quenched with water. The mixture was partitioned between diethyl ether and water, the ether layer separated and washed successively with dilute sodium hydroxide solution, brine and water, then concentrated under reduced pressure to provide the required product as white crystals (4.04 g). LRMS m/z=232.9(m)+. 1H-NMR (300 MHz, CDCl3): delta=1.22 (t,3H), 2.63 (dq,2H), 5.14 (s,2H), 7.32-7.40 (m,5H), 7.93 (s,1H) ppm.
With hydrogenchloride; triethylamine; In dichloromethane;
(v) 4-Chloro-6-ethyl-5-fluoropyrimidine To a mixture of the compound of part (iv) (40 kg), dichloromethane (120 L) and triethylamine (28.4 g) was slowly added phosphor us oxychloride (47.2 kg) over 3 hours maintaining the reaction temperature below 40 C. during the addition. The mixture was heated under reflux for 5 hours, cooled to 25 C. and cautiously quenched into 3N aqueous hydrochloric acid solution (176 L), maintaining the temperature below 20 C. during this operation. The layers were separated, the aqueous phase extracted with dichloromethane (50 L) and the combined organic layers washed with water (50 L). The organic layer was concentrated under reduced pressure to provide the product as an oil (40.69 kg). 1H-NMR (300 MHz, CDCl3): delta=1.30 (t,3H), 2.87 (q,2H), 8.65 (s,1H) ppm.
(iv) 6-Ethyl-5-fluoro4-hydroxypyrimidine To a mixture of the compound of part (iii) (34 kg), ethanol (170 L) and water (5 kg) was added 5% w/w palladium-on-carbon (50% w/w water content) (3.4 kg) and the mixture hydrogenated at 50 C. and 345 kPa (50 psi) until completion of the reaction. Water (10.5 L) w as added and the catalyst removed by filtration. The filtrate was concentrated under reduced pressure to a small volume and extracted with dichloromethane (2*58 L). The combined organic extracts were concentrated under reduced pressure and toluene (150 L) added. The mixture was concentrated under reduced pressure to 50 L in volume, toluene (50 L) added and cooled to 4 C. for 4 hours. The precipitated product was collected by filtration, washed with toluene (10 L) and dried (Yield=20 kg), m.p. 112-4 C. 1H-NMR (300 MHz, CDCl3): delta=1.25 (m,3H), 2.73 (m,2H), 8.00 (s,1H) ppm.
Preparation Example 1; Preparation of 4-(l-bromo-ethyl)-6-(4-chloro- phenylsulfanyl)~5-fluoropyrimidine<1-1> Preparation of 4-chloro-6-ethyl-5-fluoropyrimidine 78.24 ml of triethylamine was added to a solution prepared by dissolving 80 g of 6-ethyl~5-fluoro-4-hydroxypyrimidine in 240 m& of dichloromethane, and 57.4 mNo. of phosphorus oxychloride was slowly added thereto over 30 min. The resulting solution was refluxed for 5 hours to complete the reaction, and cooled to room temperature. Then, 352 ml of 3N HCl was added thereto while maintaining the temperature at below 200C . The resulting aqueous mixture was extracted with 100 mNo. of dichloromethane. The organic layer was washed with 100 mi of water, was dried over magnesium sulfate, and concentrated under a reduced pressure to obtain the title compound as an oil (85.9 g, yield: 95%).1H-NMR (30OMHz3 CDCl3) delta (ppm): 8.70 (IH), 2.90 (2H), 1.34 (3H)
81%
With trichlorophosphate; at 60℃; for 3h;
To the solid product obtained in step (2) was added 117 g of phosphorus oxychloride, Heated to 60 C, the reaction 3h. After completion of the reaction, the excess of phosphorus oxychloride was recovered by distillation under reduced pressure,The product was distilled to obtain 34.1 g of 6-ethyl-5-fluoro-4-chloropyrimidine,Colorless liquid, yield 81%, gas chromatography purity of 97%.
To a mixture of 6-ethyl-5-fluoro-4-hydroxy pyrimidine (100gr), dichloromethane (300ml) and triethylamine (70 gr) was slowly added phosphorous oxychloride (118 gr) over three hours stirring the reaction mixture temperature below 40C during the addition. The mixture was heated under reflux for 5 hours, cooled to 25 C and cautiously quenched into 3N aqueous hydrochloric acid solution (440 ml) maintaining the temperature below 20 C during this operation layers were separated, the aqueous layer extracted with 100 ml of dichloromethane, the obtained organic layer was washed with water (250 ml) and then with 10% sodium bicarbonate solution till to get the aqueous layer pH above 7.0. stripped of the solvent under reduced pressure at below 60 C. the residue is distilled under reduced pressure (at 70-80 C, Vac 750mm/Hg) to get highly pure 4-chloro-6-ethyl-5-fluoropyrimidine. Yield : 84 gr (Purity by HPLC : >99.0%, pH of the product 6.8)
With triethylamine; trichlorophosphate; In dichloromethane; at 5 - 55℃;
EXAMPLE 1The preparation of 4-chloro-6- ethyl-5-fluoropyrimidine of formula IV. 100 gm of 6-ethyl-5-fluoro-4-hydroxy pyrimidine was charged under stirring into a reactor containing 250 ml of methylene dichloride (MDC). 99 ml of triethylamine was added to the reaction mass and the reaction mass was cooled to about 5C to about 100C. 73 ml of phosphorous oxychloride was added to the reaction mass at below about 100C in about 2 hours. The reaction mass was heated to about 45C to about 55C and stirred at reflux temperature for about 6 hours. The reaction mass was cooled to room temperature and was quenched into 438 ml of 3N HCl at below about 150C and stirred for about 30 minutes. MDC layer was separated and the aqueous layer was extracted with MDC. Combined the MDC layers and washed with water and dried over sodium sulphate and treated with 5gm of charcoal and filtered through hyflo bed. Distilled-off MDC under vacuum below about 35C to obtain an oily mass. 25 ml of tetrahydrofuran (THF) is added to the oily mass and then distilled off THF under vacuum below about 45C to obtain 1 lOgm of pure 4-chloro-6- ethyl-5-fluoropyrimidine as an oily mass.
Example 1 The preparation of 4-chloro-6-ethyl-5-fluoropyrimidine of formula IV 100 gm of 6-ethyl-5-fluoro-4-hydroxy pyrimidine was charged under stiffing into a reactor containing 250 ml of methylene dichloride (MDC). 99 ml of triethylamine was added to the reaction mass and the reaction mass was cooled to about 5 C. to about 10 C. 73 ml of phosphorous oxychloride was added to the reaction mass at below about 10 C. in about 2 hours. The reaction mass was heated to about 45 C. to about 55 C. and stirred at reflux temperature for about 6 hours. The reaction mass was cooled to room temperature and was quenched into 438 ml of 3N HCl at below about 15 C. and stirred for about 30 minutes. MDC layer was separated and the aqueous layer was extracted with MDC. Combined the MDC layers and washed with water and dried over sodium sulphate and treated with 5 gm of charcoal and filtered through hyflo bed. Distilled-off MDC under vacuum below about 35 C. to obtain an oily mass. 25 ml of tetrahydrofuran (THF) is added to the oily mass and then distilled off THF under vacuum below about 45 C. to obtain 110 gm of pure 4-chloro-6-ethyl-5-fluoropyrimidine as an oily mass.
With triethylamine; trichlorophosphate; In dichloromethane; at 48℃; for 6h;Industry scale; Heating / reflux;Product distribution / selectivity;
A reactor was charged with dichloromethane (20 I) and 6-ethyl-5- fluoropyrimidin-4(1 H)-one (5.00 kg, 35.2 mol) at 25-30 0C. The reaction mixture was stirred for 15 min, and triethylamine (3.60 kg, 35.6 mol) was added. Phosphorus oxychloride (5.95 kg, 38.8 mol) was added over 3 h, while the reaction temperature was kept below 35 0C. The reaction mass was heated at reflux (40-48 0C) for 3 h. The mixture was cooled to 5 0C, and <n="10"/>hydrochloric acid (3.7 M, 20 I, 74 mol) was added over 1 h. The mixture was stirred for 30 min at 20 0C. The layers were separated, and the aqueous layer was extracted twice with dichloromethane (2 x 5.0 I). The combined organic layers were washed with water (5.0 I), and the solvents were removed at reduced pressure (550 mmHg) at 28-46 0C. 5.61 kg (99% yield) of the title compound was obtained as a brown liquid. Purity, HPLC: 99.6%.
90%
With triethylamine; trichlorophosphate; In dichloromethane; for 5h;Heating / reflux;Product distribution / selectivity;
Phosphorus oxychloride (47.2 g, 0.31 mol) was added slowly over 3 h to a mixture of 6-ethyl-5-fluoropyrimidin-4(1H)-one (40.0 g, 0.28 mol), triethylamine (28.4 g, 0.28 mol) and dichloromethane (120 ml), maintaining the reaction temperature below 40 0C. The mixture was heated at reflux for 5 h and cooled to 25 0C. The mixture was slowly poured into aqueous hydrochloric acid (3 N, 176 ml), while the temperature was kept below 20 0C. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water (50 ml), and the organic layer was concentrated at reduced pressure. Yield: 40.7 g (90%) of an oil. Purity, HPLC: 99.8% (RT=4.98 min).
With triethylamine; trichlorophosphate; In dichloromethane; at 40℃; for 5.16667h;Reflux;
Phosphorus oxychloride (0.787 mL, 8.44 mmol) was added slowly over 10 min to a mixture of 6-ethyl-5-fluoropyrimidin-4(1 H)-one (1 g, 7.04 mmol) (Apollo Scientific) and triethylamine (0.981 mL, 7.04 mmol) in DCM (15 mL), keeping the reaction temperature below 40C. The mixture was then heated to reflux for 5hrs then cooled to room temperature. The reaction mixture was then slowly poured into aqueous HCI (4M, 20 mL), keeping the temp below 20C. The organic layer was collected and the aqueous layer was further extracted with DCM (20 mL). The organic layers were combined then washed with water (20 mL), dried (MgSC^) filtered and the solvent was removed to give the title compound as a colourless oil (1 g).1 H NMR (400 MHz, d6-DMSO): delta 8.81 (1 H, s), 2.91-2.83 (2H, m), 1.25 (2H, t).
With triethylamine; In dichloromethane; at 20℃; for 5h;
Example 2. Preparation of 6-ethyl-4-fluoropyrimidin-4-yl methanesulfonate [98] First, 100 g of <strong>[137234-87-8]6-ethyl-5-fluoropyrimidin-4-ol</strong> is introduced to 1000 mL of methylene chloride (MC), followed by agitation. Next, 196 mL of triethyl amine is introduced theretoat room temperature and 59.9 mL of methanesulfonyl chloride is added dropwise thereto. After the reaction mixture is agitated for 5 hours at room temperature, the reaction mixture is cooled to 5C and 126.75 g of acetic acid is introduced thereto. The reaction mixture is washed twice with 1000 mL of purified water, and then the organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 153.4 g of the title compound (yield 99%, purity 93.5%, HPLC, detected at a wavelength of 256 nm, 18C 4.6 X 250 mm, mobile phase 60% ACN, flow rate 1 mL/min).[99] 1H-NMR (200MHz, CDCl3) delta (ppm) : 8.67(1H), 3.60(3H), 2.97-2.89(2H), 1.35(3H).
With triethylamine; In dichloromethane; at 20℃; for 5h;
EXAMPLE 2Preparation of 6-ethyl-4-fluoropyrimidin-4-yl methanesulfonateFirst, 100 g of <strong>[137234-87-8]6-ethyl-5-fluoropyrimidin-4-ol</strong> is introduced to 1000 mL of methylene chloride (MC), followed by agitation. Next, 196 mL of triethyl amine is introduced thereto at room temperature and 59.9 mL of methanesulfonyl chloride is added dropwise thereto. After the reaction mixture is agitated for 5 hours at room temperature, the reaction mixture is cooled to 5 C. and 126.75 g of acetic acid is introduced thereto. The reaction mixture is washed twice with 1000 mL of purified water, and then the organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 153.4 g of the title compound (yield 99%, purity 93.5%, HPLC, detected at a wavelength of 256 nm, 18C 4.6×250 mm, mobile phase 60% ACN, flow rate 1 mL/min).1H-NMR (200 MHz, CDCl3) delta (ppm): 8.67(1H), 3.60(3H), 2.97-2.89(2H), 1.35(3H).
With sodium methylate; In methanol; at 15℃; for 20h;
In a 500 mL three-necked flask, 200 mL of methanol was added, 27.5 g of sodium methoxide was slowly added, the temperature was lowered to 10 C, 45.9 g of ethyl 2-fluoropropionoacetate prepared in the same manner as in the above step (1) was added dropwise, 27.8 g of formamidine acetate was added in one portion, and the reaction was stirred at 15 C for 20 h. After completion of the reaction, the solution was cooled to 0 C, and acetic acid was added dropwise thereto. After adjusting the pH value to 6,Heating, hot filter, get red filtrate, vacuum distillation recovery solvent methanol, 6-ethyl-5-fluoro-4-hydroxypyrimidine as a solid product.
((1R,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonyl chloride[ No CAS ]
[ 137234-87-8 ]
C16H21FN2O4S[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With pyridine; In dichloromethane; at 20℃;
Compound A 14.2 g (mw: 142.1) and D-camphor-10-sulfonyl chloride 20.9 g (mw: 250.7) were added to dry 200 mL of methylene chloride,Add 1 mL of pyridine,The reaction was stirred at room temperature until complete,The reaction was complete with saturated sodium carbonate solution 30mL × 3 dichloromethane,Washing was completed, washed with saturated saline 30mL × 3,Concentration under reduced pressure to remove methylene chloride gave 28.5 g of Compound B in a yield of 80.0%
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