| 87% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 95℃; for 3.5h; |
1.1a
Example 1a 2-Chloro-5-fluoro-3H-pyrimidin-4-one The title compound was prepared in 56% yield from 2,4-dichloro-5-fluoro-pyrimidine as described in U.S. patent application Ser. No. 10/918,317. Specifically, 5-Fluoro-2,4-dichloro-pyrimidine was stirred in THF (10 mL) with 1N NaOH at r.t. for 3 h. The solution was made slightly acidic with 1N HCl and was extracted with CHCl3. Organics were dried (MgSO4) and concentrated in vacuo. Precipitation from 20% CHCl3/hexanes and collection by filtration gave the title compound. 1H NMR (400 MHz, DMSO-d6): δ 13.98 (br s, 1H), 8.14 (d, 1H, J=3.2 Hz). The title compound of Example 1a was also prepared as follows. Dimethylaniline (195 mL, 1.54 mol) was added to a slurry of 5-fluorouracil (99.73 g, 0.77 mol) in phosphorus oxychloride (215 mL, 2.31 mol) at 95° C. under a nitrogen atmosphere. The reaction mixture was stirred at this temperature for 3.5 h, cooled to room temperature and then slowly added to a stirred mixture of ice (200 g) and 6 M HCl (200 mL). The resulting slurry was extracted with dichloromethane (2×400 mL) and the combined organic extracts were washed with DI water (4×275 mL), dried over MgSO4 and concentrated under reduced pressure to afford 111.77 g (87%, 98.1% AUC by HPLC) of 5-fluoro-2,4-dichloro-pyrimidine as an amber oil. A molar solution of sodium hydroxide (1.34 L) was slowly added to a solution of the 5-fluoro-2,4-dichloro-pyrimidine (111.77 g, 0.67 mol) in THF (377 mL) at 0° C. After the reaction mixture was stirred for about 30 min at room temperature, the pH was adjusted to 6 by a slow addition of 1.0 M HCl. The aqueous solution was extracted with ethyl acetate (440 mL) to remove impurities following which the pH was adjusted to 1 with 1.0 M HCl. The acidic aqueous solution was extracted with ethyl acetate (4×555 mL) and the combined organic extracts were washed with brine (111 mL), dried over MgSO4 and concentrated under reduced pressure to produce 88.35 g (89%, 99.2% AUC by HPLC) of 2-chloro-5-fluoro-3H-pyrimidin-4-one as an off-white powder. |
| 85% |
With N,N-diethylaniline; trichlorophosphate for 1.66667h; Reflux; Inert atmosphere; |
3 Intermediate Example 3
Preparation of 2, 4-Dichloro-5-fluoropyrimidine
Intermediate Example 3 Preparation of 2, 4-Dichloro-5-fluoropyrimidine. To 5-fluorouracil (5.0 g, 0.04 mol) was added phosphorus oxychloride (25 mL, 0.27 mol) and N,N-diethylaniline (6 mL, 0.06 mol) while stirring at room temperature. After being heated under reflux for 100 min, the mixture was concentrated under reduced pressure. The residue was poured into ice water (100 mL) and extracted with ether. The organic layer was dried with sodium sulfate and evaporated at 0 °C under reduced pressure to give 5.35 g of the desired product (85%). Mp 37-38 °C. HNMR: δ 8.95 (s, 1H). |
| 84% |
With phosphorus pentachloride; trichlorophosphate at 20℃; Reflux; |
15.a
To a stirred mixture of 5-fluoropyrimidine-2,4(1 H,3H)-dione (3.0 g, 23 mmol) and phosphorous pentachloride (14.41 g, 69 mmol) was added phosphorous oxychloride (12.6 mL, 130 mmol). The reaction mixture was heated to reflux, stirred 5 hours and then cooled to ambient temperature and stirred overnight. The mixture was carefully poured onto ice/water (600 mL) and stirred for 1 hour. Sodium chloride was added and the product was extracted into dichloromethane. The combined organic layer was dried (MgS0 ), filtered and evaporated to give the title compound (84%) as a yellow solid.LRMS (m/z): 167 (M+1)+.1H-NMR δ (CDCI3): 8.49 (s, H) |
| 84% |
With phosphorus pentachloride; trichlorophosphate for 5h; Reflux; |
15.a a) 2,4-Dichloro-5-fluoropyrimidine
5-fluoropyrimidine-2,4(1H,3H)-dione (3.0 g, 23 mmol) and phosphorous pentachloride (14.41 g, 69 mmol) was added phosphorous oxychloride (12.6 mL, 130 mmol). The reaction mixture was heated to reflux, stirred 5 hours and then cooled to ambient temperature and stirred overnight. The mixture was carefully poured onto ice/ water (600 mL) and stirred for 1 hour. Sodium chloride was added and the product was extracted into dichloromethane. The combined organic layer was dried (MgSO4), filtered and evaporated to give the title compound (84%) as a yellow solid.LRMS (m/z): 167 (M+1)+.1H-NMR δ (CDCl3): 8.49 (s, 1 H) |
| 84% |
With phosphorus pentachloride; trichlorophosphate at 20℃; Reflux; |
21 PREPARATION 21 2,4-Dichloro-5-fluoropyrimidine
PREPARATION 212,4-Dichloro-5-fluoropyrimidineTo a stirred mixture of 5-fluoropyrimidine-2,4(1 /-/,3/-/)-dione (3.0 g, 23 mmol) and phosphorous pentachloride (14.41 g, 69 mmol) was added phosphorous oxychloride (12.6 mL, 130 mmol). The reaction mixture was stirred and heated to reflux for 5 hours and then cooled to ambient temperature and stirred overnight. The mixture was carefully poured onto ice/water (600 mL) and then stirred for 1 hour. Sodium chloride was added and the product was extracted into dichloromethane. The combined organic layer was dried (MgS04), filtered and evaporated to give the title compound (84%) as a yellow solid.LRMS (m/z): 167 (M+1 )+.1H-NMR δ (CDCIs): 8.49 (s, 1 H). |
| 84% |
With phosphorus pentachloride; trichlorophosphate for 5h; Reflux; |
8 2,4-Dichloro-5-fluoropyrimidine
To a stirred mixture of 5-fluoropyrimidine-2,4(1H,3H)-dione (3.0 g, 23 mmol) and phosphorous pentachloride (14.41 g, 69 mmol) was added phosphorous oxychloride (12.6 mL, 130 mmol). The reaction mixture was heated to reflux, stirred 5 hours and then cooled to ambient temperature and stirred overnight. The mixture was carefully poured onto ice/water (600 mL) and stirred for 1 hour. Sodium chloride was added and the product was extracted into dichloromethane. The combined organic layer was dried (MgSO4), filtered and evaporated to give the title compound (84%) as a yellow solid. LRMS(m/z): 167(M+1)+. 1H-NMR δ (CDCl3): 8.49 (s, 1H). |
| 56% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 90 - 95℃; for 15.5h; |
1 Preparation of 4-tert-butyl-N-(5-fluoro-2-chloropyrimidin-4-yl)thiazol-2-amine (II-1)
Add 5-fluorouracil (3.9g, 0.03mol), phosphorus oxychloride (27g, 0.18mol) to a 100ml three-necked bottle, stir, and after warming to 90°C, start dropping N,N-dimethylaniline ( 7.27g, 0.06mol), about 0.5h after the completion of the drop, and then continue to heat up to 95 , heat preservation reaction for 15h. After the reaction, under ice bath conditions, slowly add 30ml of ice water dropwise, control the temperature of the system not to exceed 30°C, stir for 1h, then extract with dichloromethane, wash the organic layer with water, dry over anhydrous sodium sulfate, and remove under reduced pressure As a solvent, a yellow liquid was obtained. After refrigerated storage, the compound of formula (IV-1) (2.79g, yield 56.0%) was gradually formed, mp38-39°C. |
| 56% |
With trichlorophosphate at 90 - 95℃; for 15.5h; |
1 Preparation of N-propargyl-5-fluoro-2-chloropyrimidine-4-amine (IV-1)
Add 5-fluorouracil (3.9g, 0.03mol), phosphorus oxychloride (27g, 0.18mol) to a 100ml three-necked bottle, stir, and after warming to 90°C, start dropping xylidine (7.27g, 0.06mol) ), about 0.5h after the drop, and then continue to heat up to 95 , heat preservation reaction for 15h. After the reaction, under ice bath conditions, slowly add 30ml of ice water dropwise, control the system temperature not to exceed 30°C, stir for 1h, and then extract with dichloromethane, the organic layer was washed with water, dried over anhydrous sodium sulfate, and distilled off under reduced pressure As a solvent, a yellow liquid was obtained. After refrigerated storage, a compound of formula (VI-1) (2.79 g, yield 56.0%) was gradually formed, mp38-39°C. |
| 50% |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 3h; Reflux; |
3a
A mixture of 15.6 g of 5-FU [1] in 80 mL of POCl3 was stirred in a three neck-flask equipped with condenser, thermometer and dropping funnel at 40° C. After addition of 25 mL of N,N-dimethylaniline drop wise, the resulting mixture was heated to reflux for 3 hours. The excess of POCl3 was evaporated under reduced pressure. The mixture was cooled to room temperature and poured into 75 g of crushed ice. It was then extracted with chloroform (50 mL three times). The combined extracts were washed with water, dried with MgSO4, and concentrated to give a yellowish solid of compound [7] in about 50% yield. |
|
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate Heating; |
|
|
With trichlorophosphate |
|
|
With phosphorus pentachloride; trichlorophosphate Heating; |
|
|
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 3h; Heating / reflux; |
Preparation of N2,N4-Bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, HCl salt
Preparation of N2,N4-Bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, HCl salt As shown in Scheme 2, a mixture of 5-fluorouracil (2000 g) (XI), N,N-dimethylaniline (3720 g) and phosphorus oxychloride (12 L) was refluxed under nitrogen for 3 hours. The resulting mixture was cooled to room temperature. Intermediate (XII) was not isolated but was used as follows. Dichloromethane, hydrochloric acid and water were added over approximately 3 hours between 10 to 30° C. The mixture was stirred for approximately 1 hour at 10 to 30° C. and then allowed to settle for approximately 30 minutes and separated. The aqueous layer was extracted with dichloromethane and combined with the organic layer. The combined organic layer was washed with water and the dicloromethane exchanged for isopropanol. 3-Aminophenol (4853 g) (XIII) was added and the mixture refluxed at 80 to 85° C. for approximately 7 hours. After cooling to 0 to 5° C., solid (XIV) was collected by filtration and washed with chilled isopropanol. The wet powder was dried under vacuum until a constant weight was obtained. The final product (XIV) was obtained as a solid (1657 g). |
|
With hydrogenchloride; trichlorophosphate In 1,2-dimethoxyethane; <i>N</i>,<i>N</i>-dimethyl-aniline |
1.i (i)
(i) 2,4-Dichloro-5-fluoropyrimidine A stirred mixture of 5-fluorouracil (111.5 kg) and phosphorus oxychloride (394.6 kg) was heated to 95° C. and N,N-dimethylaniline (207 kg) added over 1 hour during which time an exotherm was noted. The mixture was maintained at 95° C. for 15 hours then cooled to room temperature and cautiously quenched into ice-cooled 3N aqueous hydrochloric acid solution (450 L) over 4 hours, maintaining the temperature below 30° C. during this operation. The mixture was extracted with dichloromethane (2*390 L), the combined extracts washed with water (280 L) until the aqueous washings reached pH7 and concentrated under reduced pressure. The residue taken up in dimethoxyethane (190 L) and the solution of the product used directly in the next step. 1H-NMR (300 MHz, CDCl3): δ=8.5 (s, 1H) ppm. |
|
With sodium carbonate In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; chloroform |
R.19 Synthesis of 2,4-dichloro-5-fluoropyrimidine
REFERENCE EXAMPLE 19 Synthesis of 2,4-dichloro-5-fluoropyrimidine 25.3 g of 5-fluorouracil was fully mixed with 72.9 of phosphor pentachloride, and the mixture was gradually heated to 130° C. and reacted for 4 hours. (The reaction mixture became liquid in about 1 hour, and the reaction proceeded at a high rate.) After adding 300 ml of ice water and 200 ml of chloroform, the mixture was stirred for 20 minutes. The insoluble content was separated by filtration with celite, and the filtrate was separated. The chloroform layer was washed with 5% aqueous solution of sodium carbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 30.6 g of the title compound as a brown oil (which crystallized at a lower temperature). 1 H-NMR (CDCl3) δ; 8.49 (s, 1H) |
|
With hydrogenchloride; trichlorophosphate In dichloromethane; <i>N</i>,<i>N</i>-dimethyl-aniline |
7.i (i)
(i) 2,4-Dichloro-5-fluoropyrimidine To phosphorus oxychloride (141.1 g) at 25° C. was added powdered 5-fluorouracil (20 g). The resulting slurry was heated to 90° C. and N,N-dimethylaniline (37.7 g) was added over 1 hour. The reaction was then heated at a reflux for 5 hours and 70 g of the phosphorus oxychloride was removed by distillation. The mixture was then cooled to 25° C. and quenched into 3N HCl (200 ml) at 0° C., portionwise over 1 hour. The title compound was then extracted from the mixture using dichloromethane (2*70 ml). The combined dichloromethane layers were washed with water (50 ml) and concentrated under vacuum to give an oil (24 g), which was characterised by 1 H-NMR and mass spectrometry. 1 H-NMR (CDCl3): δ=8.5 (s, 1H), ppm. Mass Spec.: m/e=166. |
|
Stage #1: 5-fluorouracil With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 2 - 5h; Heating / reflux;
Stage #2: With water at 0℃; for 1h; |
4; 26-1
[0299] Experimental Details: The mixture of compound 1 (25 g) and N, N- dimethylaniline (24.2 g) in POCl3 (110 niL) was reflux ed for 5 h. POCl3 was removed by evaporation at reduced pressure and the residue was poured into ice-water (500 g) cautiously and stirred for Ih. The mixture was then filtered and the solid was washed with water to give compound 2 as a yellow solid.; EXAMPLE 26.[0510] 1. Reaction Scheme: 1 2[0511] Experimental Details: A solution of 5-fluoro-lH-pyrimidine-2,4-dione (113 g, 0.5 mol) in N,N-dimethylaniline (70 mL) was treated with POCb (500 mL), then was reflux for 2 h. After cooling to room temperature, the reaction mixture was poured onto ice- water. The resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous OfNaHCO3, then brine. The solvent was removed under reduced pressure to give compound 2. |
|
With sodium chloride; phosphorus pentachloride; trichlorophosphate In water |
1.1 Step 1:
Step 1: 2,4-Dichloro-5-fluoro-pyrimidine Phosphorus oxychloride (2 ml) was added to 5-fluorouracil (1 g, 7.688 mmol) followed by phosphorus pentachloride (3.28 g, 15.76 mmol), the mixture was heated and stirred at 110° C. for 5 hours and then allowed to cool. The excess phosphorus oxychloride was slowly hydrolised in a bath of ice/water mixture (10 ml). The aqueous mixture was extracted with diethyl ether (3*10 ml). The organic layers were combined, washed with saturated sodium bicarbonate (10 ml) followed by saturated sodium chloride (10 ml), dried with anhydrous magnesium sulfate and then filtered. The solvent was removed by evaporation at 350 mmHg to leave a viscous oil which slowly crystallized to afford the title compound (1.22 g-95%). The compound was used without further analysis on the next step. |
|
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 5h; Reflux; |
2.1
Example 21. Synthesis of Compound 2: Experimental Details:The mixture of compound 1 (25 g) and N,N-dimethylaniline (24.2 g) in POCl3 (110 mL) was refluxed for 5 h. POCl3 was removed by evaporation at reduced pressure and the residue was poured into ice-water (500 g) cautiously and stirred for 1 h. The mixture was then filtered and the solid was washed with water to give compound 2 as a yellow solid. |
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With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate Reflux; |
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With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 95℃; for 15h; |
General Procedure for Preparation of Compounds 2-4.
General procedure: 2,4-Dichloro-5-fluoropyrimidine (2) was synthesized from 5-FU by treating with phosphorus oxychloride and N,N-dimethylaniline in good yield. Compound 2 was hydrolyzed in tetrahydrofuran by adding 2 N sodium hydroxide to give 3, which was treated with sodium alkoxide to form 2-butoxy-5-fluoropyrimidine-4(3H)-one (4). The spectra data of compounds 2-4 are in good agreement with literature.22,26,27 |
| 95 %Chromat. |
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 95℃; for 15h; |
|
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Stage #1: 5-fluorouracil With trichlorophosphate at 110℃; for 8h; Inert atmosphere;
Stage #2: With phosphorus pentachloride at 110℃; for 12h; Inert atmosphere; |
7.1.1 7.1.1 2,4-Dichloro-5-fluoropyrimidine
To a dry reaction flask equipped with a stir bar and a reflux condenser was placed 5-fluorouracil (0.65 g, 5 mmol) followed by phosphorus oxychloride (POCl3) (1.53 g, 10 mmol). The resultant mixture was heated at 110° C. for 8 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, phosphorus pentachloride (PCl5) (3.12 g, 15 mmol) was added and heated to 110° C. for a period of 12 hours. After cooling to room temperature, the mixture was poured into ice-water, saturated with sodium chloride and left for 1 hour at 0° C. to complete the decomposition of POCl3 and PCl5. The solid of 2,4-dichloro-5-fluoropyrimidine was collected by rapid filtration, dried using blotting paper and stored at low temperature. 1H NMR (CDCl3): δ 8.47 (s, 1H); 13C NMR (CDCl3): δ 155.42, 151.87, 147.43 and 147.13; 19F NMR (CDCl3): -38149. |
|
With trichlorophosphate In N,N-dimethyl-formamide at 0.11 - 15℃; for 2h; |
1 (1) chlorination process
Fluorouracil and phosphorus oxychloride into the chlorinated pot,Stirring, controlling the temperature below 15 ,Low N, N- dimethylaniline;After the addition was completed, the reaction was heated to about 110 ° C for 2h;Cool to room temperature, put it in ice brine,Maintain the temperature of 15 , stirring 1.5h;Filtered and washed with water to give 2,4-dichloro-fluoropyrimidine; |
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In <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate |
142.1 2,4-dichloro-5-fluoropyrimidine
Step 1 2,4-dichloro-5-fluoropyrimidine A stirred solution of 5-fluorouracil (15.0 g, 0.115 mol), N,N-dimethylaniline (7.31 mL, 0.058 mol) in POCl3 (107 mL) was heated to reflux for 1 h. The reaction mixture was concentrated in vacuo and the residue quenched with ice (100 g) at 0° C. The solution was then extracted with ethyl ether (3*200 mL). The combined ether layer was washed with aqueous saturated NaHCO3 (100 mL), water (100 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to give the title compound. 1H NMR (400 MHz, CDCl3): δ8.49 (s, 1 H, Ar). |
|
In <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate |
69.1 2,4-Dichloro-5-fluoro-pyrimidine
Step 1 2,4-Dichloro-5-fluoro-pyrimidine A solution of 5-fluoro-uracil (5.00 g, 38.44 mmol) and N,N-dimethylaniline (5 mL) in POCl3 (20 mL) was refluxed for 1 h. The solution was then concentrated in vacuo. The resulting residue was quenched with water (20 mL) at 0° C., and extracted with ether (3*150 mL). The combined ether layers were washed with water (2*50 mL), sat. aq. NaHCO3, water (5 mL), dried over Na2SO4, filtered and concentrated to give 2,4-dichloro-5-fluoro-pyrimidine compound. |
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