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CAS No. : | 147118-36-3 | MDL No. : | MFCD08063917 |
Formula : | C16H20FN3O3S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MSDYDUNHTAYBHV-UHFFFAOYSA-N |
M.W : | 353.41 | Pubchem ID : | 9819937 |
Synonyms : |
|
Num. heavy atoms : | 24 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.38 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 91.3 |
TPSA : | 91.77 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -7.23 cm/s |
Log Po/w (iLOGP) : | 2.52 |
Log Po/w (XLOGP3) : | 1.72 |
Log Po/w (WLOGP) : | 3.64 |
Log Po/w (MLOGP) : | 0.87 |
Log Po/w (SILICOS-IT) : | 2.26 |
Consensus Log Po/w : | 2.2 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.15 |
Solubility : | 0.247 mg/ml ; 0.0007 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.26 |
Solubility : | 0.193 mg/ml ; 0.000545 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -5.1 |
Solubility : | 0.00283 mg/ml ; 0.00000802 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.97 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.1 % | With sodium iodide; sodium hydrogensulfite In trans-Decalin; ethyl acetate; mineral oil | EXAMPLE 1 N-[5-(Diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide 1.00 g (2.83 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol was initially charged in 5 ml of cis/trans-decalin and admixed with 204 mg (4.68 mmol) of sodium hydride (55 percent dispersion in mineral oil). After 30 min at room temperature, 680 mg (2.93 mmol) of chlorodiphenylphosphine was added with vigorous stirring over a period of 6 min. The mixture was admixed with 52.2 mg (0.35 mmol) of sodium iodide and heated at 184° to 186° C. for 2 h, 15 min. After cooling to room temperature, 50 ml of 38 to 40 percent strength sodium bisulfite solution and 50 ml of ethyl acetate were added. The organic phase was separated off and the aqueous phase was extracted with 50 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. This gave 1.74 g of crude product which was purified by silica gel chromatography (mobile phase: n-hexane/ethyl acetate 1:2). This gave 382.4 mg (25.1 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide in the form of a colorless solid. The melting point was 180° to 185° C. Other data concerning the product was: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With phosphorus tribromide In toluene; acetonitrile at 10 - 20℃; for 1 h; Inert atmosphere | Reference Example 1: 5-Bromomethyl-4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine [Show Image] To the mixed solution of 5-hydroxymethyl-4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidine (15 g, 42.42 mmol) dissolved in anhydrous toluene (120 ml) and anhydrous acetonitrile (60 ml), phosphorus tribromide (5.4 g, 19.44 mmol) was slowly added dropwise at 10 to 20°C under nitrogen stream. After the reaction for 1 hour, saturated brine (100 ml) and distilled water (10 ml) were added to the reaction mixture, and the mixture was stirred for 10 minutes. After the aqueous layer was separated and discarded, the organic layer was sequentially washed with a saturated sodium hydrogencarbonate aqueous solution (50 ml) and distilled water (50 ml). The organic layer was dried with anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The obtained crude product was dispersed in hexane (100 ml), and the title compound (17.5 g, yield: 99percent) was obtained as a white solid by filtration. 1H-NMR(CDCl3): δ1.36H, d, J=6.6Hz), 3.48(1H, m), 3.51(3H, s), 3.56 (3H, s), 4.48(2H, s), 7.20 (2H, m), 7.80(2H, m) |
90.6% | With phosphorus tribromide In dichloromethane at 0 - 10℃; for 1 h; | To a 1000 ml three-mouth bottle by adding 4 - (4 - fluorophenyl) -6 - isopropyl -2 - [(N - methyl - N - methanesulfonyl) amino] pyrimidine -5 - methanol (3) (70 g, 0.2 µM) and 420 ml dichloromethane, stirring under ice bath cooling to 0 - 10 °C, to the reaction system drop [...] phosphorus (59.0 g, 0 . 22 µM), stirring the reaction 1 h, TLC detection reaction is over. Add 250 ml water to stir liquid, organic layer respectively uses 200 ml 8percent sodium bicarbonate solution and 200 ml each wash once with purified water, collecting the organic phase and concentrated under reduced pressure to dry, the residue is added to 200 ml of petroleum ether beating at room temperature 2 h, filtering, the filter cake is dried to obtain the compound (4) a total of 75.4 g, yield 90.6percent. HPLC detection 98.9percent. |
82% | With phosphorus tribromide In dichloromethane at 20℃; for 1 h; | Phosphorus tribromide (6.2 g, 0.023 mol) is added to a solution of the compound of formula (36) (16.2 g, 0.046 mol) in dichloromethane (180 ml). Stirring is carried out at room temperature for 1 hour and 150 ML of water are then added. The organic phase is separated off and dried (using NA2SO4). The salt mixture is filtered off and the filtrate is concentrated by evaporation. By that means, 15.7 G (82 percent) of the bromide (37) can be obtained in the form of a yellow powder. H NMR (300 MHz, CDCI3) : 1.36 (d, J = 6. 6 Hz, 6H); 3.40-3. 36 (m, 1H); 3.48 (s, 3H); 3.54 (s, 3H); 4.47 (s, 2H); 7.18 (dd, J = 8.8, 8.8 Hz, 2H); 7.78 (dd, J = 8.8, 5.3 Hz, 2H). 13C NMR (75 MHz, CDCI3) : 22.3, 28.0, 32.0, 33.5, 42. 8, 115. 9 (JF = 21.9 Hz), 119.6, 131.0 (JCF = 8.4 HZ), 133.8 (JCF = 3.5 Hz), 158.2, 163.8 (JCF = 250 Hz), 165.8, 177.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.5% | Step-E: PREPARATION OF 4-(4-FLUOROPHENYL)-6-ISOPROPYL-2- (N- METHYL-N-METHYL SULFONYLAMINO)-5-PYRIMIDINE CARBOXALDEHYDE, COMPOUND OF FORMULA I [4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonylamino) pyridine- 5- yl] methanol (100.0 gm, 0.282 moles) was dissolved in dimethyl sulfoxide (110.0 gm, 1.41 moles) and dichloromethane (1000 ml). The reaction mass was cooled to 0 to -5 0C and stirred for 15 min at 0 to -5 0C. This was followed by addition of Diisopropylethyl amine ( 127.56 gm ,0.987 moles) at 0 to -5 0C and stirring continued for 15 min at 0 to -5 0C. In another flask, pyridine-sulfur trioxide complex (90.0 g, 0.44 moles), pyridine (44.6 g, 0.44 moles) and dimethyl sulfoxide (110.0 g, 1.41 moles) were charged at room temperature and stirred for 10 min at room temperature. The resulting suspension was added to the above alcohol solution in dichloromethane at 0 to -5 0C and stirring was continued for 1 hr at 0 to -5 0C. After the completion of reaction, water (400.0 ml) was added and under stirring for 10 min. This was followed by layer separation. The aqueous layer was extracted with dichloromethane (2 x 200 ml). Dichloromethane layers washed with water (3 x 600.0 ml) followed by drying over sodium sulfate. Dichloromethane was <n="19"/>distilled under vacuum at 40 to 45.0 0C and followed by degassed mass for 30 min at 40 to 45.0 0C. Isopropyl alcohol (100.0 ml) was added to the reaction mass and distilled out under reduced pressure at 50 to 55 0C. Isopropyl alcohol (250.0 ml) was again added to the reaction mass and heated the reaction mass at 60 to 650C to get clear solution. The solution was cooled to 25 to 300C and stirred for 4 hrs at 25 to 300C. The reaction mixture was further cooled to 0 to 5 0C and stirred for 2 hrs at 0 to 5 0C. The solid mass and washed with chilled (0 0C) isopropyl alcohol (50.0 ml). The wet product was dried at 40 to 450C under reduced pressure to obtain. The wet product was dried at 40 to 450C under reduced pressure to obtain 4-(4-fluorophenyl)-6-isopropyl-2- (N-methyl-N-methyl sulfonylamino)-5-pyrimidine carboxaldehyde, compound of formula I (90.0 gm, 90.5%).; Step-E: PREPARATION OF 4-(4-FLUOROPHENYL)-6-ISOPROPYL-2- (N- METHYL-N-METHYL SULFONYLAMINO)-5-PYRIMIDgammaNECARBOXALDEHYDE (FORMULA I)[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonylamino) pyridine- 5- yl] methanol (150.0 gm, 0.4244 moles) was dissolved in dimethyl sulfoxide (165.0 ml, and dichloromethane (1500 ml). The reaction mass was cooled to 0 to -5 0C and stirred for 15 min at 0 to -5 0C. This was followed by addition of Diisopropylethyl amine ( 190.8 gm ,1.477 moles) at 0 to -5 0C and stirring continued for 15 min at 0 to -5 0C. In another flask, pyridine-sulfur trioxide complex (148.6 g, 0.9337 moles), pyridine (73.7 g, 0.9337 moles) and dimethyl sulfoxide (165ml) were charged at room temperature and stirred for 10 min at room temperature. The resulting suspension was added to the above alcohol solution in dichloromethane at 0 to -5 0C and stirring was continued for 1 hr at 0 to -5 0C. After the completion of reaction, water (600.0 ml) was added and under stirring for 10 min. This was followed by layer separation. The aqueous layer was extracted with dichloromethane (2 x 300 ml). Dichloromethane layers washed with water (3 x 850.0 ml) followed by drying over sodium sulfate. Dichloromethane was distilled under vacuum at <n="24"/>40 to 45.0 0C and followed by degassed mass for 30 min at 40 to 45.0 0C. Isopropyl alcohol (150.0 ml) was added to the reaction mass and distilled out under reduced pressure at 50 to 55 0C. Isopropyl alcohol (750.0 ml) was again added to the reaction mass and heated the reaction mass at 60 to 650C. The reaction mass was cooled to 25 to 300C and stirred for 4 hrs at 25 to 300C. The reaction mixture was further cooled to 0 to 5 0C and stirred for 2 hrs at 0 to 5 0C. The solid mass and washed with chilled (0 0C) isopropyl alcohol (150.0 ml). The wet product was dried at 40 to 450C under reduced pressure to obtain. The wet product was dried at 40 to 450C under reduced pressure to obtain 134.0 gm 4-(4-fluorophenyl)-6-isopropyl-2- (N-methyl-N-methyl sulfonylamino)- 5-pyrimidine carboxaldehyde, compound of formula I .Purity by HPLC : 97.77%Melting point : 176.3C to 178.7C | |
85 - 90% | With calcium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; potassium bromide; In dichloromethane; water; at 0℃; for 3h; | Example-9; Preparation of (4-fluorophenyl)-6-isopropyl-2(N-methyl-N-methylsulfonylamino)pyrimidine-5- carboxaldehyde; In 2-lit 3 -neck flask round bottom flask equipped with stirrer, hot plate, water bath, condenser , thermometer, charge 750 ml of dichloromethane. Add (10Og, 0.283 mol) [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl- N-methylsulfonylamino)pyrimidine-5-yl]methanol and stir it to dissolve at RT. Cool the reaction mixture to O0C Add TEMPO solution (450 mg TEMPO +50 ml dichloromethane ) in reaction mixture at O0C. Add KBr solution (3.4 gm KBr + 25 ml demineralized[DMjwater) in to reaction mixture between O0C. Add the slurry of calcium hypochlorite (60.05 gm calcium hypochlorite + 200 ml demineralized water) portion wise into reaction mixture at O0C within 15 min. Add <n="19"/>solution of sodium bicarbonate (sodium bicarbonate 46.8 gms + 468 ml DM water) drop wise in reaction mixture at O0C within 90 min. Maintain temperature of the reaction mass at O0C for 60 min. Check TLC for absence of starting material. Add calcium hypochlorite solution 2nd lot drop wise at O0C (2.9 gm Calcium Hypochlorite + 12 ml water) followed with sodium bicarbonate (2.25 gm Sodium bicarbonate + 22.5 ml water) solution at the same temperature. Stir reaction mixture at O0C for 15 min. Check TLC for absence of starting material. Raise the reaction mixture to RT. Separate dichloromethane [ DCM] layer and aqueous layer. Extract aqueous layer with 2 X 100 ml DCM. Wash DCM layer with 2 X 100 ml DM water. Separate DCM layer. Dry DCM layer over 50 gm anhydrous sodium sulphates. Distill DCM layer under vacuum at 40C.Remove traces of DCM with 100 ml hexane. Stir the reaction mixture with 320 ml hexane for 60 min at RT. Filter the slurry; give 2 X 100 ml hexane wash; suck dry for 15 min. Dry the solid at 500C in tray dryer. Weight of solid -85 gm; Yield - 85-90%Purity by HPLC= 96.79 - 98.9 %; Assay by HPLC= 99.05 - 99.63 % |
85.5% | With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical;potassium bromide; In tert-butyl methyl ether; water; at 25℃; for 2h;pH 8.6;Product distribution / selectivity; | Example 2; A 100 mL reactor was charged with 10 g of FPP-QH, 0.01 g of TEMPO, 0.34 g of KBr, and 70 mL of MTBE. The mixture was stirred at about 25C. NaC10(aq) (100 mL, 0.35M, pH = 8.6 (adjusted with solid NaHC03)) was added to the mixture, which was stirred for 2 hours to obtain a white precipitate of FPP-CHO.The white crystals of FPP-CHO were collected by filtration, washed with 20 mL MTBE, and then dried at 45C under reduced pressure (8.5 g, 85.5 %). |
80.5% | With manganese(IV) oxide; In dichloromethane; at 20℃; for 8 - 10h;Heating / reflux; | To the above obtained pyrimidine alcohol (lg), was added dichloromethane (10 ml) followed by the addition of y-active manganese dioxide (6 g). The reaction mixture was stirred at room temperature for few hours followed by refluxing for 8-10 hours. After the reaction was over, it was filtered through celite. The removal of solvent followed by crystallization in toluene-ethyl acetate mixture gave pyrimidine aldehyde (I). Yield: 80.5% (HPLC Quality >99%). |
72.0 - 88.5% | With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical;potassium bromide; In water; ethyl acetate; at 5 - 25℃; for 2h;pH 8.6;Product distribution / selectivity; | Example 4; A 100 mL reactor was charged with 5 g of FPP-OH, 5 mg of TEMPO, 0.17 g of KBr, and 35 mL of ethyl acetate. The mixture was stirred at 25C. NaClO(aq)(50 mL, 0.35M, pH = 8.6 (adjusted with solid NaHCOs)) was added to the mixture, which was stirred for 2 hours to obtain a white precipitate of FPP-CHO.The white crystals of FPP-CHO were collected by filtration, washed with 20 mL ethyl acetate, and dried at 45C under reduced pressure (yield = 3.6g, 72.0 %); Example 6A 100 mL reactor was charged with 5 g of FPP-OH, 5 mg of TEMPO, 0.17 g of KBr, and 35 mL of ethyl acetate. The mixture was stirred at about 5C. NaC10(aq) (50 mL, 0.35M, pH = 8.6 (adjusted with solid NaHCOs)) was added to the mixture, which was stirred for 2 hours to obtain a white precipitate of FPP-CHO.The white crystals of FPP-CHO were collected by filtration, washed with 20 mL ethyl acetate, and dried at 45C under reduced pressure (4.4 g, 88.5 %). |
64.0% | With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical;potassium bromide; In water; toluene; at 25℃; for 2h;pH 8.6;Product distribution / selectivity; | Example 5; A 100 mL reactor was charged with 5 g of FPP-OH, 5 mg of TEMPO, 0.17 g of KBr, and 35 mL of toluene. The mixture was stirred at about 25C. NaC10(aq) (50 mL, 0.35M, pH = 8.6 (adjusted with solid NaHCOs)) were added to the mixture, which was stirred for 2 hours to obtain a white precipitate of FPP-CHO. The white crystals of FPP-CHO were collected by filtration, washed with 20 mL toluene, and dried at 45C under reduced pressure (3.2g, 64.0 %). |
59.0 - 100% | With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical;potassium bromide; In water; acetonitrile; at 5 - 25℃; for 2 - 6h;pH 8.6 - 9.2;Product distribution / selectivity; | Example 1: (a) AIL reactor equipped with a mechanical stirrer and a dropping funnel was charged with 4-(Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylammo)-5-hydroxymethyl-pyrimidine (FPP-OH, 100 g), 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO, O.lg) , KBr (3.4 g), and acetonitrile (700 mL). The mixture was stirred at 5C, and NaC10(aq) (500 mL, 0.7 M, pH = 8.8-9.2 (adjusted with solid NaHCOs)) was added. The mixture was stirred for about 6 hours to obtain a white precipitate.The white precipitate was collected by filtration, washed with acetonitrile (100 mL) and dried at 45C under reduced pressure (99.5 g, 100 %); Example 3; A 100 mL reactor was charged with 10 g of FPP-OH, 0.01 g of TEMPO, 0.34 g of KBr, and 70 mL of acetonitrile. The mixture was stirred at about 25C. NaC10(aq) (100 mL, 0.35M, pH = 8.6 (adjusted with solid NaHC03)) was added to the mixture, which was stirred for 2 hours to obtain a white precipitate of FPP-CHO.The white crystals of FPP-CHO were collected by filtration and washed with 20 mL acetonitrile. The FPP-CHO was triturated with 100 mL water for 1 hour, filtered, and dried at 45C under reduced pressure (8.0 g, 80.5 %); Example 7; A 100 mL reactor was charged with 5 g of FPP-OH, 5 mg of TEMPO, 0.17 g of KBr, and 35 mL of acetonitrile. The mixture was stirred at 5C. NaC10(aq) (25 mL, 0.7 M, pH = 8.8-8.9 (adjusted with solid NaHCOs)) was added to the mixture, which was stirred for 2 hours to obtain a white precipitate of FPP-CHO.The white crystals of FPP-CHO were collected by filtration and washed with 20 mL acetonitrile. The FPP-CHO was triturated with 20 mL water for 1 hour, filtered, and dried at 45C under reduced pressure (4.0g, 80.6 %); Example 8; A 100 mL reactor was charged with 5 g of FPP-OH, 5 mg of TEMPO, 0.17 g of KBr, and 35 mL of acetonitrile. The suspension was stirred at 5C. NaC10(aq) (25 mL, 0.7 M, pH = 8.8-8.9 (adjusted with solid NaHCOs)) was added to the mixture, which was stirred for 2 hours to obtain a white precipitate of FPP-CHO.The white crystals of FPP-CHO were collected by filtration and washed with 20 mL acetonitrile. The FPP-CHO was crystallized using 100 mL acetonitrile, filtered, and dried at 45C under reduced pressure (2.9g, 59.0 %). |
39% | With acetic anhydride; dimethyl sulfoxide; at 85℃; | Example 12: Preparation of /V-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-//-methylmethane- sulfonamide (PMDCHO); a) from PMDOH: PMDOH (2.0 g, 5.68 mmol, 1 equiv.) was dissolved in DMSO (10 mL) and reaction mixture was heated to 85 C. Ac20 (4 equiv.) was slowly added (150 plJh) and reaction was left to stir for 17 hours. Reaction mixture was diluted with H20 (15 mL) and solids were filtered off. Collected precipitate was re-disolved in EtOAc (20 mL), washed with H20 (5 mL) and brine (10 mL). Solvent was evaporated under reduced pressure to give crude solid. Product was further purified by crystallization from EtOAc to afford 0.78 g (39 % yield) of PMDCHO as colorless crystals. |
39% | With acetic anhydride; dimethyl sulfoxide; at 85℃; for 17h; | Example 12 : Preparation of N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (PMDCHO) [Show Image] PMDOH (2.0 g, 5.68 mmol, 1 equiv.) was dissolved in DMSO (10 mL) and reaction mixture was heated to 85 C. Ac2O (4 equiv.) was slowly added (150 muL/h) and reaction was left to stir for 17 hours. Reaction mixture was diluted with H2O (15 mL) and solids were filtered off. Collected precipitate was re-disolved in EtOAc (20 mL), washed with H2O (5 mL) and brine (10 mL). Solvent was evaporated under reduced pressure to give crude solid. Product was further purified by crystallization from EtOAc to afford 0.78 g (39 % yield) of PMDCHO as colorless crystals. 1H NMR (CDCl3): delta 1.30 (6H, d, J = 6.7 Hz), 3.53 (3H, s), 3.62 (3H, s), 3.99 (1H, h, J = 6.7 Hz), 7.21 (2H, m), 7.61 (2H, m), 9.95 (1H, s). 13C NMR (CDCl3): delta 21.6, 31.9, 33.0, 42.4, 115.8, 116.0, 119.5, 132.5, 132.6, 158.7, 163.1, 165.6, 169.7, 178.9, 190.4. |
31% | With acetic anhydride; dimethyl sulfoxide; at 85℃; for 17h; | 4.7.1. From alcohol 2A solution of <strong>[147118-36-3]N-[4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide</strong> (2, 2.00 g, 5.66 mmol) in DMSO (20 mL) was heated to 85 C Ac2O (2.15 mL, 22.79 mmol, 4.0 equiv) was slowly added (flow rate 150 muL/h) and the reaction mixture was left to stir for 17 h at 85 C. Water (15 mL) was added and the resulting precipitate was collected by filtration. The precipitate was dissolved in hot EtOAc (20 mL), cooled to 4 C and the precipitated solid was collected by filtration and dried to give product 1 (0.62 g, 31%) as colorless crystals.4.7.2. From bromide 3A mixture of NaHCO3 (0.40 g, 4.80 mmol, 2 equiv) and NaI (36.0 mg, 0.24 mmol 0.1 equiv) in DMSO (10 mL) was flushed with nitrogen, sealed, and maintained at 20 C while a solution of N-[4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide (3, 1.00 g, 2.40 mmol) in DMSO (9 mL) was slowly added over 3 h time. The reaction mixture was stirred for 68 h at 20 C, then warmed to 70 C and Ac2O (1.5 mL, 16.4 mmol, 6.6 equiv) was added dropwise in 3 h. The stirring was continued for additional 4 h at 70 C. Then, the reaction mixture cooled on an ice bath, and the product was precipitated by slow addition of water (20 mL). The precipitate was collected by filtration, washed with water (10 mL) and MeOH (10 mL), and dried under reduced pressure to afford aldehyde 1 (0.79 g, 94%) as colorless solid. Mp=178.2 C (DSC onset) and 179.1 C (DSC peak) (lit.13 147-148 C). 1H NMR (CDCl3): delta 1.32 (6H, d, J=6.7 Hz, CH3 of iPr), 3.55 (3H, s, NCH3), 3.64 (3H, s, SCH3), 4.01 (1H, sep, J=6.7 Hz, CH), 7.20-7.27 (2H, m, ArH), 7.61-7.66 (2H, m, ArH), 9.97 (1H, s, CHO). 13C NMR (CDCl3): delta 21.6, 31.9, 33.0, 42.5, 115.9 (d, JCF=22.0 Hz), 119.5, 132.3 (d, JCF=2.5 Hz), 132.6 (d, JCF=8.8 Hz), 158.7, 164.4 (d, JCF=252.7 Hz), 169.7, 179.0, 190.4. 19F NMR (CDCl3): delta -108.6 (m). IR (KBr) nu 3444, 3081, 2977, 2943, 1687, 1600, 1545, 1509, 1445, 1376, 1341, 1230, 1158, 1127, 956, 855, 809, 780 cm-1. HRMS (ESI+) calcd for C16H17FN3O3S- ([M-H]-): 350.0980; found: 350.0981. |
With sodium hypochlorite; sodium hydrogencarbonate; potassium bromide;4-oxo-2,2,6,6-tetramethylpiperidin-oxyl; In dichloromethane; water; at 0 - 5℃; for 1 - 2h; | 2,2,6,6-tetramethyl piperidinyl oxy free radical (TEMPO) (5 mg), potassium bromide (0.385 g) and sodium bicarbonate (3.63 g) were dissolved in methylene chloride (150 ml) and stirred together at 0-5 C. A solution of 4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol (11 g) in methylene chloride (25 ml) was added to the above solution at 0-5 C. To this solution 10% sodium hypochlorite solution (24.2 g) was added at 0-5 C. Reaction mass was maintained for 1-2 hours at 0-5 C. and filtered through perlite. Organic layer was separated and washed with 10% sodium thiosulfate solution (200 ml), water (200 ml) followed by saturated sodium chloride solution (150 ml). Organic layer was distilled off under reduced pressure and the title compound was isolated from the residue with cyclohexane (75 ml). Yield: 9.5 g. |
Yield | Reaction Conditions | Operation in experiment |
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99% | With phosphorus tribromide; In toluene; acetonitrile; at 10 - 20℃; for 1h;Inert atmosphere; | Reference Example 1: 5-Bromomethyl-4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine [Show Image] To the mixed solution of 5-hydroxymethyl-4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidine (15 g, 42.42 mmol) dissolved in anhydrous toluene (120 ml) and anhydrous acetonitrile (60 ml), phosphorus tribromide (5.4 g, 19.44 mmol) was slowly added dropwise at 10 to 20C under nitrogen stream. After the reaction for 1 hour, saturated brine (100 ml) and distilled water (10 ml) were added to the reaction mixture, and the mixture was stirred for 10 minutes. After the aqueous layer was separated and discarded, the organic layer was sequentially washed with a saturated sodium hydrogencarbonate aqueous solution (50 ml) and distilled water (50 ml). The organic layer was dried with anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The obtained crude product was dispersed in hexane (100 ml), and the title compound (17.5 g, yield: 99%) was obtained as a white solid by filtration. 1H-NMR(CDCl3): delta1.36H, d, J=6.6Hz), 3.48(1H, m), 3.51(3H, s), 3.56 (3H, s), 4.48(2H, s), 7.20 (2H, m), 7.80(2H, m) |
90.6% | With phosphorus tribromide; In dichloromethane; at 0 - 10℃; for 1h; | To a 1000 ml three-mouth bottle by adding 4 - (4 - fluorophenyl) -6 - isopropyl -2 - [(N - methyl - N - methanesulfonyl) amino] pyrimidine -5 - methanol (3) (70 g, 0.2 muM) and 420 ml dichloromethane, stirring under ice bath cooling to 0 - 10 C, to the reaction system drop [...] phosphorus (59.0 g, 0 . 22 muM), stirring the reaction 1 h, TLC detection reaction is over. Add 250 ml water to stir liquid, organic layer respectively uses 200 ml 8% sodium bicarbonate solution and 200 ml each wash once with purified water, collecting the organic phase and concentrated under reduced pressure to dry, the residue is added to 200 ml of petroleum ether beating at room temperature 2 h, filtering, the filter cake is dried to obtain the compound (4) a total of 75.4 g, yield 90.6%. HPLC detection 98.9%. |
82% | With phosphorus tribromide; In dichloromethane; at 20℃; for 1h; | Phosphorus tribromide (6.2 g, 0.023 mol) is added to a solution of the compound of formula (36) (16.2 g, 0.046 mol) in dichloromethane (180 ml). Stirring is carried out at room temperature for 1 hour and 150 ML of water are then added. The organic phase is separated off and dried (using NA2SO4). The salt mixture is filtered off and the filtrate is concentrated by evaporation. By that means, 15.7 G (82 %) of the bromide (37) can be obtained in the form of a yellow powder. H NMR (300 MHz, CDCI3) : 1.36 (d, J = 6. 6 Hz, 6H); 3.40-3. 36 (m, 1H); 3.48 (s, 3H); 3.54 (s, 3H); 4.47 (s, 2H); 7.18 (dd, J = 8.8, 8.8 Hz, 2H); 7.78 (dd, J = 8.8, 5.3 Hz, 2H). 13C NMR (75 MHz, CDCI3) : 22.3, 28.0, 32.0, 33.5, 42. 8, 115. 9 (JF = 21.9 Hz), 119.6, 131.0 (JCF = 8.4 HZ), 133.8 (JCF = 3.5 Hz), 158.2, 163.8 (JCF = 250 Hz), 165.8, 177.6. |
With phosphorus tribromide; In toluene; acetonitrile; at 15 - 30℃; for 1h; | Into a 2 L 4-necked round bottom flask, [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methyl sulfonylamino)pyrimidin-5-yl]methanol (100 g), toluene (800 ml) and acetonitrile (400 ml) were added at a temperature in the range of from about 25 C. to about 30 C. under stirring. The reaction mixture was cooled to a temperature of about 15 C. Phosphorous tribromide (35 g) was slowly added over about 30 minutes at a temperature in the range of from about 15 C. to about 20 C. After about 30 minutes, the reaction mixture was added to water (1000 ml) while maintaining the temperature in the range of from about 15 C. to about 20 C. The reaction mixture was stirred for about 5 minutes and the organic layer was separated. | |
Example-2Preparation of N-[5-Bromomethyl-4-(4-fluoro-phenyI)-6-isopropyI-pyrimidin-2- yI]-N-methyI-methanesulfonamide (I)N-[4~(4-Fluoro-phenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl]-N-methyl- methanesulfonamide (1Og) was taken in 5OmL of toluene and dissolved at 30 C. Added 49% aqueous hydrogenbromide solution(7.5mL) and refluxed at HO0C azeotropically for 3-4 hours. Brought the reaction mixture to 25 C and quenched the reaction mixture with 5% sodium bicarbonate solution to pH 7-7.5. Separated the organic layer and given water wahes. Extracted the aqueous layer with toluene (20 mL). Combined organic layer was given a brine wash and dried over anhydrous sodium sulphate and concentrated to get solid N-[5-Bromomethyl-4-(4-fluoro-phenyl)-6- isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide.Yield: 11. Og | ||
Example 55-bromomethyl-4-(4-fluorophenyl)-6-isopropyl-2-fmethyl(methylsulfonyl)aminoipyrimidine (Compound of Formula II, where X = Br)5O g 5-hydroxymethyl-4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl) aminojpyrimidine (Compound of Formula I) and 100 ml 62% aq. HBr are stirred for 4 hours at 60 - 65C. The solution formed is cooled to room temperature and poured into the mixture of 500 ml toluene and the solution prepared from 100 g tribasic potassium phosphate monohydrate in 500 ml water. All that time, the mixture is vigorously stirred at 00C. After neutralization the stirring is continued for 15 minutes. Then the two layers is separated and aqueous phase is re-extracted with 150 ml of toluene and combined toluene phases are washed with 200 ml water. Toluene phase is evaporated under reduced pressure at 60C to dryness yielding 59,1 g of the yellowish solid product, which is used without purification in the next step. | ||
Example-6: Preparation of N-(5-(bromomethyl)-4-(4-fluorophneyl)-6-isopropyl pyrimidin -2-yl) -N-m ethyl methane sulfonamide compound of formula-5a:Aqueous hydro bromic acid (85 ml) was added to a mixture of N-(4-(4-fluorophenyl)-5- (hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide (100 grams) in toluene (500 ml) and tertiary butyl ammonium bromide (8 grams). Heated the reaction mixture to 90-95C and stirred for 90 minutes at same temperature. Cooled the reaction mixture to 40- 45C and separated the both aqueous and organic layers. Washed the organic layer with 10% aqueous sodium bicarbonate. The obtained organic layer was further utilized in the next stage with out isolated as a solid. | ||
With phosphorus tribromide; In dichloromethane; at 10 - 15℃; for 1h; | To a solution of 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]-pyrimidine-5-yl-methanol (100 g) in dichloromethane (400 mL) was slowly added phosphorus tribromide (45.89 g) at 10-15 C and stirred for 1 h at 10-15C. Reaction monitored by TLC, quench the reaction by adding water (200 mL) at 0-5 C and stirred at 20-25 C for 30 min, separated the organic layer. Wash the organic layer with sodium bicarbonate solution (30 mL) followed by water (100 mL). Distilled off solvent completely at 35-40 C under reduced pressure to obtain the solid. |
Yield | Reaction Conditions | Operation in experiment |
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100% | DIBAL solution (1M in hexane, 270 MI, 0.27 mol) is added dropwise, AT-10C, to a solution of the compound of formula (35) (29 g, 0.076 mol) in toluene (250 ML). The mixture is subsequently stirred AT-10C for a further 1 hour. After adding 2 ml of methanol, the mixture is warmed to room temperature and is added dropwise to a warm (40C) solution of HCI (37 %, 50 ml) and water (90 ml). Stirring is carried out at 40C for 20 minutes, followed by cooling to room temperature, separating off the organic phase and drying (using NA2SO4). The salt mixture is filtered off and the filtrate is concentrated by evaporation. The residue is concentrated by evaporation. In that manner, 27 G (100 %) of the alcohol (36) are obtained in the form of a yellow oil which crystallises at room temperature. H NMR (300 MHz, DMSO-D6) : 1.26 (d, J = 6. 3 Hz, 6H); 3.44 (s, 3H); 3.50-3. 60 (m, 1H); 3.54 (s, 3H); 4.43 (d, J = 4.2 Hz, 2H); 5.41 (t, J = 4. 4 Hz, 1 H) ; 7.33 (dd, J = 8.8, 8.8 Hz, 2H); 7. 84 (DD, J = 8.8, 5.6 Hz, 2H). 13C NMR (75 MHz, DMSO-D6) : 22.8, 31.6, 34. 0,42. 4,56. 6,115. 9 (JCF = 21.6 Hz), 122.6, 132.2 (JCF = 8.7 Hz), 134. 8 (JCF = 3.2 Hz), 157. 9, 163.6 (JCF = 247 Hz), 165.6, 177. 8. | |
93.0% | Step-D: PREPARATION OF [4-(4-FLOUROPHENYL)-6-ISOPROPYL-2-(N- METHYL-N-METHYLSULPHONYLAMINO) PYRIMIDIN-5-YL] METHANOL (FORMULA V)Dissolved Methyl-4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methyl sulphonylamino) pyrimidine-5-carboxylate (130.0 g, 0.340 moles) in toluene (1300.0 ml) under nitrogen at 25 to 30 0C. The reaction mass was cooled to -10 to -15 0C followed by the addition of diisobutyl aluminum hydride (730.0 ml, 20% wt in toluene, 1.0266 moles) over period of 1 to 1.5 hrs at -10 to -15.0 0C under stirring for 1 hrs at -5 to -100C. After the completion of reaction, diluted HCl (137.0 ml in 1370.0 ml water) was <n="18"/>added over a period of 30 to 40 minutes, maintaining temperature below -10 0C and followed by stirring at 35 to 40 0C for 30 to 40 min. This was followed by addition of ethyl acetate (1000.0ml) and purified water (1000.0 ml) under stirring to the reaction mass and continued stirring for 10 minutes. This was followed by layer separation. Aqueous layer was extracted with ethyl acetate (2 x 500.0 ml). Ethyl acetate layer was washed with 5% sodium bicarbonate solution (1000.0 ml) and 25% sodium chloride solution (1000.0 ml) followed by the distillation of solvents under reduced pressure at 50 to 55 0C after drying over sodium sulfate followed by degassing mass for 30 min at 50 to 55 0C under vacuum. This was followed by addition of cyclohexane (650.0 ml), heating the reaction mass at 60 to 650C to get uniform slurry. The reaction mass was cooled at 25 to 300C and stirred for 2 hrs at 25 to 300C. The resulted mass was filtered and washed with cyclohexane (200.0 ml). The wet product was dried at 40 to 450C under reduced pressure to afford [4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N- methylsulphonylamino) pyrimidin-5-yl] methanol (112.0 gm, 93.0%); Step-D: PREPARATION OF [4-(4-FLOUROPHENYL)-6-ISOPROPYL-2-(N- METHYL-N-METHYLSULPHONYLAMINO) PYRIMIDIN-S-YL] METHANOL (FORMULA V)Dissolved Methyl-4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methyl sulphonylamino) pyrimidine-5-carboxylate (185.0 g, 0.485 moles) in toluene (1800.0 ml) under nitrogen at 25 to 30 0C. The reaction mass was cooled to -10 to -15 0C followed by the addition of diisobutyl aluminum hydride (1034.0 ml, 20% wt in toluene, 1.455 moles) over period of 1 to 1.5 hrs at -10 to -15.0 0C under stirring for 1 hrs at -5 to -10 0C. After the completion of reaction, diluted HCl (200.0 ml in 2000.0ml water) was added over a period of 30 to 40 minutes, maintaining temperature below -10 0C and <n="23"/>followed by stirring at 35 to 40 0C for 30 to 40 min. This was followed by addition of ethyl acetate (660.0ml) under stirring to the reaction mass and continued stirring for 10 minutes. This was followed by layer separation. Aqueous layer was extracted with ethyl acetate (374.0 ml). Ethyl acetate layer was washed with 5% sodium bicarbonate solution (1000.0 ml) and 25% sodium chloride solution (1000.0 ml) followed by the distillation of solvents under reduced pressure at 50 to 55 0C after drying over sodium sulfate followed by degassing mass for 30 min at 50 to 55 0C under vacuum. This was followed by addition of isopropyl alcohol (185.0 ml) and distilled out completely, followed by addition of isopropyl alcohol (555.00ml) heating the reaction mass at 60 to 650C to get clear solution. The reaction mass was cooled at 25 to 300C and stirred for 2 hrs at 25 to 300C then to 0c-5c for3hrs. The resulted mass was filtered and washed with isopropyl alcohol (185.0 ml). The wet product was dried at 40 to 450C under reduced pressure to obtain 165.0 gm [4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonylamino) pyrimidin-5-yl] methanol. Purity by HPLC : 99.87%Melting point : 138.90C to 142C | |
91.79 - 95.28% | Example-8; Preparation of [4-(4-fiuorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-yl] methanol; In a round bottom flask equipped with stirrer, hot plate, water bath, condenser , thermometer, charge 7.50 lit hexane and (1.00 kg, 2.625 mol) of Methyl 4-(4-Fluorophenyl)-6-isopropyl-2-(N-Methyl-N-Methyl Sulphonyl Amino) Pyrimidine-5- Carboxylate under stirring under N2 atmosphere at 25- 300C . Add (6.81 lit, 6.708 mol) DIBAL-H (20 % in hexane) drop wise at 25-300C into the flask. Stir at 25-300C for 1 hr; check TLC for absence of starting material. Add 1.7 lit. acetic acid drop wise below 2O0C. Add 10.0 lit of ethyl acetate. Stir well for 30.min. Add 7.0 lit water and 2.0 lit HCl into the flask & stir well for 15 min. Separate ethyl acetate layer. Extract the aqueous layer with 5.0-liter ethyl acetate. Add 5.0 liter 6% sodium bicarbonate solution into the flask & stir well for 15 min. (pH 8-9) Separate layer; Give 5.0 lit water wash (twice) to ethyl acetate layer. (pH neutral) Dry ethyl acetate layer over 0.5 kg anhydrous sodium sulphate. Distill ethyl acetate under vacuum at 450C. Remove traces of ethyl acetate with hexane stripping 5.0 lit (twice). Cool to 25-300C and add 5.0 lit hexane stir well for 30 min. and filter the solid. Give 1.0 lit hexane wash to the solid. Dry the material in oven at 550C. Approx weight of solid = 0.8 kg, Actual yield: - 0.85-0.88 kg; Yield- 91.79-95.28%; Purity by HPLC= 99.66 - 99.8 % |
81% | With sodium sulfide; sodium bis(2-methoxyethoxy)aluminium dihydride; In toluene; at 35 - 45℃; for 4h;Inert atmosphere; | 1) Under the protection of nitrogen, takeMethyl 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine-5-carboxylate10g, as a starting material, add 50mL of toluene to obtain a starting material solution, and set aside;2) Under the protection of nitrogen, add 5 g of sodium disulfide to the initial solution obtained in step 1), and add 15 mL (1.5 eq) of a red aluminum toluene solution having a mass concentration of 70% at room temperature, and raise the temperature to 35 C. , the reaction was 1.5h, and the temperature was further raised to 45 C.Reaction 2.5h, cooling, cooling to normal temperature, gotPrimary product3) To the initial product obtained in the step 2), 50 mL of a 30% by mass sodium hydroxide solution was added dropwise, quenched, stirred for 15 min, separated, separated, and the aqueous phase was extracted once with 30 mL of toluene and combined into an organic solvent phase. The mixture was washed twice with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness.4) The above crude product was added to 28.2 mL of toluene, and the temperature was raised at about 80 C. After stirring for 10 minutes, it was naturally cooled to normal temperature, and crystallization was carried out for 1 hour, and recrystallization was carried out to obtain 8.5 g of a white powdery solid.4-(4-Fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine-5-methanol.After measurement, the purity was 99.5%, and the yield was 81% |
80% | With diisobutylaluminium hydride; In toluene; at -75 - -70℃; | To a solution of the above obtained compound (7.0 g, 0. 0183 mole) in toluene (70 ml), was added drop wise DIBAL (20% solution in toluene; 47.6 ml) at-70 C to-75 C and stirred the solution for few hours. After the reaction was over, it was quenched with saturated ammonium chloride solution followed by filtration of the reaction mixture through celite. The filtrate was treated with charcoal and the solvent was removed to yield pyrimidine alcohol (XVI). Yield: 80% (HPLC Quality >99%). |
Yield | Reaction Conditions | Operation in experiment |
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382.4 mg (25.1%) | With sodium iodide; sodium hydrogensulfite; In trans-Decalin; ethyl acetate; mineral oil; | EXAMPLE 1 N-[5-(Diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide 1.00 g (2.83 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol was initially charged in 5 ml of cis/trans-decalin and admixed with 204 mg (4.68 mmol) of sodium hydride (55 percent dispersion in mineral oil). After 30 min at room temperature, 680 mg (2.93 mmol) of chlorodiphenylphosphine was added with vigorous stirring over a period of 6 min. The mixture was admixed with 52.2 mg (0.35 mmol) of sodium iodide and heated at 184 to 186 C. for 2 h, 15 min. After cooling to room temperature, 50 ml of 38 to 40 percent strength sodium bisulfite solution and 50 ml of ethyl acetate were added. The organic phase was separated off and the aqueous phase was extracted with 50 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. This gave 1.74 g of crude product which was purified by silica gel chromatography (mobile phase: n-hexane/ethyl acetate 1:2). This gave 382.4 mg (25.1 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide in the form of a colorless solid. The melting point was 180 to 185 C. Other data concerning the product was: |
With sodium iodide; sodium hydrogensulfite; In toluene; mineral oil; | EXAMPLE 3 N-[5-(Diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide 512 mg (1.45 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol was initially charged in 8 ml of toluene and admixed with 96 mg (2.20 mmol) of sodium hydride (55 percent dispersion in mineral oil). After 1 h, 333.5 mg (1.44 mmol) of chlorodiphenylphosphine in 2.5 ml of toluene was added at room temperature with vigorous stirring over a period of 5 min. The mixture was admixed with 28.7 mg (0.19 mmol) of sodium iodide and heated at 108 C. for 22 h. After 6 h, a further 28.7 mg (0.19 mmol) of sodium iodide were added. After cooling to room temperature, the mixture was admixed with 30 ml of 38 to 40percent strength sodium bisulfite solution and extracted with 50 ml of ethyl acetate. The organic phase was separated off and the aqueous phase was extracted with 50 ml of ethyl acetate. The combined organic phases were subsequently concentrated under reduced pressure. This gave 740 mg of crude product which was purified by silica gel chromatography (mobile phase:ethyl acetate), and 212.7 mg (27.3 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide was isolated in the form of a colorless solid. | |
With sodium iodide; sodium hydrogensulfite; In 5,5-dimethyl-1,3-cyclohexadiene; mineral oil; | EXAMPLE 4 N-[5-(Diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide 502.6 mg (1.42 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol was initially charged in 8 ml of xylene (isomer mixture) and admixed with 96.6 mg (2.21 mmol) of sodium hydride (55 percent dispersion in mineral oil). After 1 hour, 340.8 mg (1.47 mmol) of chlorodiphenylphosphine in 2.5 ml of xylene was added at room temperature with vigorous stirring over a period of 5 min. The mixture was admixed with 34.6 mg (0.23 mmol) of sodium iodide and heated at 136 C. for 19 h. After 3 h, a further 25.1 mg of sodium iodide were added. After cooling to room temperature, the mixture was admixed with 30 ml of dilute sodium bisulfite solution and extracted with 50 ml of ethyl acetate. The organic phase was separated off and the aqueous phase was extracted with 50 ml of ethyl acetate. The combined organic phases were subsequently concentrated under reduced pressure. This gave 906 mg of crude product which was purified by silica gel chromatography (mobile phase: ethyl acetate), and 315.9 mg (41.3 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide was isolated in the form of a colorless solid. |
With potassium hydroxide; tetrabutyl-ammonium chloride; In water; toluene; | EXAMPLE 6 (DIRECT REACTION) N-[5-(Diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulphonamide 2.03 g (5.69 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol was initially charged in 13 g of toluene and, with ice-bath cooling, admixed with 1.67 g (7.51 mmol) of chlorodiphenylphosphine in 2 g of toluene. The mixture was heated at 111 C. for 2.5 h. After cooling to room temperature, 1.08 g (8.66 mmol) of a 45 percent strength potassium hydroxide solution and 175 mg (0.574 mmol) of tetrabutylammonium chloride was added, and the mixture was stirred vigorously at 60 C. for 2 h. 30 ml of water was added to the warm reaction mixture. The mixture was briefly stirred at 60 C. and slowly cooled to 4 C., and the precipitated solid was filtered off. The product was washed with cold water (10 ml) and cold toluene (10 ml) and dried under reduced pressure at 40 C. 2.66 g (84.1 percent; content: 96.6 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide was isolated in the form of a colorless solid. | |
With sodium hydroxide; tetrabutyl-ammonium chloride; In water; toluene; | EXAMPLE 8 (DIRECT REACTION) N-[5-(Diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulphonamide 2.02 g (5.69 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol was initially charged in 13.1 g of toluene and, with ice-bath cooling, admixed with 1.71 g (7.69 mmol) of chlorodiphenylphosphine in 1.9 g of toluene. The mixture was heated at 111 C. for 2.5 h. After cooling to room temperature, 1.17 g (8.78 mmol) of 30 percent strength sodium hydroxide solution and 182 mg (0.597 mmol) of tetrabutylammonium chloride were added, and the mixture was stirred vigorously at 60 C. for 3.5 h. 30 ml of water was added to the warm reaction mixture. The mixture was briefly stirred at 60 C. and slowly cooled to 4 C., and the precipitated solid was filtered off. The product was washed with cold water (10 ml) and cold toluene (10 ml) and dried under reduced pressure at 40 C. 2.18 g (71.3 percent; content: 97.3 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide were isolated in the form of a colorless solid. The melting point of the product was 184 to 185 C. | |
With potassium hydroxide; tetrabutylammomium bromide; In water; toluene; | EXAMPLE 9 (DIRECT REACTION) N-[5-(Diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulphonamide A suspension of 9.29 g (26.3 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol in 26 g of toluene was, with ice-bath cooling, admixed with 7.64 g (34.4 mmol) of chlorodiphenylphosphine. After rinsing with a little toluene, the mixture was heated at 111 C. for 2 h. After cooling to room temperature, 4.94 g of a 45 percent strength potassium hydroxide solution and 873 mg (2.71 mmol) of tetrabutylammonium bromide were added, and the mixture was stirred vigorously at 60 C. for 1 h. 100 ml of water was added to the warm reaction mixture. The mixture was briefly stirred at 60 C. and slowly cooled to 4 C., and the precipitated solid was filtered off. The product was washed with cold water (30 ml) and cold toluene (30 ml) and dried under reduced pressure at 40 C. 11.74 g (78.4 percent; content: 94.4 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide was isolated in the form of a colorless solid. | |
With potassium hydroxide; In water; toluene; | EXAMPLE 10 (DIRECT REACTION WITHOUT PHASE-TRANSFER CATALYST) N-[5-(Diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulphonamide 2.03 g (5.69 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol was initially charged in 13 g of toluene and, with ice-bath cooling, admixed with 1.69 g (7.60 mmol) of chlorodiphenylphosphine in 1.9 g of toluene. The mixture was heated at 109 C. for 2.5 h. After cooling to room temperature, the mixture was admixed with 1.09 g (8.74 mmol) of a 45 percent strength potassium hydroxide solution and stirred vigorously at 60 C. for 2 h, 45 min. 30 ml of water was added to the warm reaction mixture. The mixture was briefly stirred at 60 C. and slowly cooled to 4 C., and the precipitated solid was filtered off. The product was washed with cold water (10 ml) and cold toluene (10 ml) and dried under reduced pressure at 40 C. 2.44 g (76.8 percent; content: 99.1 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide was isolated in the form of a colorless solid. | |
With potassium hydroxide; In water; toluene; | EXAMPLE 7 (DIRECT REACTION) N-[5-(Diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide 2.02 g (5.69 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol was initially charged in 13.1 g of toluene and, with ice-bath cooling, admixed with 1.67 g (7.51 mmol) of chlorodiphenylphosphine in 1.9 g of toluene. The mixture was heated at 109 C. for 3 h. After cooling to room temperature, 590 mg (8.94 mmol) of solid potassium hydroxide and 159 mg (0.582 mmol) of 18-crown-6 were added, and the mixture was stirred vigorously at 60 C. for 3.5 h. 30 ml of water was added to the warm reaction mixture. The mixture was briefly stirred at 60 C. and slowly cooled to 4 C., and the precipitated solid was filtered off. The product was washed with cold water (10 ml) and cold toluene (10 ml) and dried under reduced pressure at 40 C. 1.82 g (59.5 percent; content: 95.9 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulphonamide was isolated in the form of a colorless solid. | |
In 5,5-dimethyl-1,3-cyclohexadiene; water; ethyl acetate; mineral oil; | EXAMPLE 2 N-[5-(Diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide 282.8 mg (0.80 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonylamino)pyrimidin-5-yl]methanol was initially charged in 4.5 ml of xylene (isomer mixture) and admixed with 55 mg (1.30 mmol) of sodium hydride (55 percent dispersion in mineral oil). After 35 min, 185 mg (0.84 mmol) of chlorodiphenylphosphine in 1.5 ml of xylene was added at room temperature with vigorous stirring over a period of 5 min, and the mixture was subsequently heated at 135 C. for 20 h. After cooling to room temperature, the mixture was admixed with 15 ml of water and extracted with 10 ml of ethyl acetate. The organic phase was separated off and the aqueous phase was extracted with 2*10 ml of ethyl acetate. The combined organic phases were subsequently dried (MgSO4) and concentrated under reduced pressure. This gave 510 mg of crude product which was purified by silica gel chromatography (mobile phase: n-hexane/ethyl acetate 1:2, then ethyl acetate), and 230 mg (53.5 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulphonamide was isolated in the form of a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
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With tetrabutylammomium bromide; In water; toluene; | EXAMPLE 5 (DIRECT REACTION) N-[5-(Diphenylphosphinoylmethyl)-4(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide With ice-bath cooling, 1.05 g (2.95 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol was initially charged in 7 g of toluene and admixed with stirring with 820 mg (3.69 mmol) of chlorodiphenylphosphine. The mixture was heated at 108 C. for 3 h. After cooling to room temperature, 553 mg (4.43 mmol) of aqueous potassium hydroxide solution (45 percent strength) and 97.5 mg (0.29 mmol) of tetrabutylammonium bromide was added, and the mixture was stirred vigorously at 60 C. for 1 h. The heat source was removed and the reaction mixture, which was still warm, was admixed with 20 ml of water. The mixture was slowly cooled to 4 C., and the precipitated solid was filtered off. The product was washed with cold water and toluene and dried under reduced pressure at 40 C. 1.04 g (64.1 percent; content: 97.6 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide was isolated in the form of a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
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With tetrabutyl-ammonium chloride; In water; toluene; | EXAMPLE 11 (DIRECT REACTION) N-[(5-Diphenylphosphinoylmethyl)-4-(4-fluorphenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide A solution of 60.08 g (0.170 mol) [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol in ca. 485 ml of toluene was admixed at 60 C. with 42.55 g (0.192 mol; content 99,7 percent) chlorodiphenylphosphine. The mixture was stirred for 2.5 h and then added to a mixture of 70.66 g of a 20 percent strength potassium hydroxide solution and 5.04 g (0.017 mol) tetrabutylammonium chloride at 60 C. The resulting reaction mixture was stirred for another 2 h at 60 C. Then 215 ml of water and 108 ml of toluene were added. The aqueous phase was separated off at 80 C. The organic phase was extracted twice with 2*215 ml of hot water. Residual water of the organic phase was removed azeotropicly. The mixture was slowly (2 h) cooled to 0 C. and the precipitated solid was filtered off. The product was washed twice with 2*160 ml of toluene and dried under reduced pressure at 40 C. 81.94 g (89.7 percent) of N-[(5-diphenylphosphinoylmethyl)-4-(4-fluorphenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide was isolated in the form of a colorless solid [content (HPLC): 100 percent]. |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 2h; | Example 165-(methanesulfonyl) methyl-4-(4-fluorophenyl)-6-isopropyl-2- fmethvKmethylsulfonvDaminoipyrimidine (Compound of Formula II, where X = OSO7CH3)3,5 g 5-hydroxymethyl-4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine (Compound of Formula I) and 2,2 ml of N-ethyl- diisopropylamine in 20 ml dichloromethane are stirred on ice bath, and while stirring thereto 2,0 g of methansulfonyl anhydride are added. Reaction mixture is stirred for another 2 h at room temperature whereupon the reaction mixture is washed by 20 ml 1 % phosphoric acid and 20 ml of water, and after evaporation of organic phase under reduced pressure at 50 0C, 4.3 mg of product are obtained, which is crystallized from mixture of isopropyl acetate and hexane. |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 1.08333h; | Example 15; 5-(trifluoroacetyloxy) methyl-4-(4-fluorophenyl)-6-isopropyl-2- fmethvKmethylsulfonyDaminolpyrimidine (Compound of Formula II, where X = OCOCF3) EPO <DP n="33"/>21 g 5-hydroxymethyl-4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidine (Compound of Formula I) and 13,2 ml of N-ethyl-diisopropylamine in 120 ml dichloromethane are stirred on ice bath, and thereto 10,2 ml of trifluoroacetyl anhydride are added during 5 minutes. Reaction mixture is stirred for another hour at room temperature whereupon the reaction mixture is washed twice by 120 ml of water, and after evaporation of organic phase under reduced pressure at 50 0C, 27 mg of product are obtained. |
Yield | Reaction Conditions | Operation in experiment |
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98% | With methanol; sodium tetrahydroborate; In tetrahydrofuran; at 5 - 25℃; for 2h; | Compound IV (10 g) was added to a reaction flask, which was dissolved in tetrahydrofuran (60 mL) and methanol (20 mL), and the mixture was cooled to 5 to 10 C, and sodium borohydride (0.91 g) was added. Stir at 5 C for 2 hours and slowly warm to 25 C. The reaction was quenched by the addition of a saturated ammonium chloride solution and the pH was adjusted to 7-8. 50 mL of ethyl acetate was added, allowed to stand, and the layers were separated. The organic layer and the aqueous layer were separated, and then aqueous layer was extracted with ethyl acetate (60mL). The ethyl acetate extracts and organic layers were combined and washed sequentially with water (40 mL) and brine (aq. The organic layer was dried over anhydrous sodium sulfate.Concentration gave Compound V (9.8 g) in a yield of 98%. |
With methanol; sodium tetrahydroborate; In tetrahydrofuran; at 5 - 10℃; | Preparation of N~[4-(4-Fluoro-phenyl)-5~hydroxymethyl-6-isopropyl-pyrimidin-2- yl]-N-methyI-methanesuIfonamideN-[4-(4-Fluoro-phenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-N-methyl- methanesulfonamide 1Og was taken in tetrahydrofuran (6OmL) and methanol (2OmL) and chilled the reaction mixture to 5 to 1O0C. Added sodiumborohydride (0.9Ig) in 4 lots. Stirred for 2 h at 5C and slowly raised the temperature to 25C. Quenched the reaction mixture with saturated ammonium chloride solution to pH 7 - 8. Added 5OmL ethylacetate and separated the layers. Extracted the aqueous layer with ethyl acetate (6OmL). Combined the organic layers and given water wash (4OmL) followed by a brine wash (2OmL). Organic layer was dried over anhydrous sodium sulphate and concentrated to get N-[4-(4-Fluoro-phenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2- yl]-N-methyl-methane sulfonamide as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
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100% | With water; In tetrahydrofuran; for 6h;Reflux; | A solution of N-[4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide (3, 0.50 g, 1.20 mmol) in THF (10 mL) and water (10 mL) was stirred and heated under reflux for 6 h. The reaction mixture was cooled to room temperature and THF was evaporated under reduced pressure. The product was extracted from the residue with MeTHF (3×6 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, and the solvent was evaporated under reduced pressure to give alcohol 2 in quantitative yield as colorless oil, which crystallized upon standing. Mp=131.5 C (DSC onset) and 133.6 C (DSC peak). 1H NMR (CDCl3): delta 1.32 (6H, d, J=6.7 Hz, CH3 of iPr), 2.27 (1H, br s, OH), 3.47-3.54 (4H, m, CH3N, CH), 3.55 (3H, s, CH3SO2), 4.61 (2H, s, CH2), 7.12-7.17 (2H, m, ArH), 7.79-7.83 (2H, m, ArH). 13C NMR (CDCl3): delta 22.2, 31.5, 33.0, 42.3, 57.4, 115.3 (d, JCF=21.6 Hz), 120.7, 131.4 (d, JCF=8.4 Hz), 133.9 (d, JCF=2.5 Hz), 157.8, 163.7 (d, JCF=250.0 Hz), 166.1, 175.4. 19F NMR (CDCl3): delta -111.3 (m). IR (KBr) nu 3308, 2979, 2934, 2909, 2875, 1606, 1557, 1513, 1457, 1397, 1379, 1340, 1318, 1234, 1168, 1158, 955, 859, 823, 775, 523 cm-1. HRMS (ESI+) calcd for C16H21FN3O3S+ ([M+H]+): 354.1282; found: 354.1284. |
With water; sodium hydrogencarbonate; In acetonitrile; for 4h;Reflux; | Example 3 /V-(4-(4-fluorophenyl)-5-methyl-6-isopropylpyrimidin-2-yl)-Lambda/-methylmethanesulfonamide (1 12.5 mg, 0.33 mmol, 1 equiv.) and /V-bromosuccinimide (NBS) (1 18.7 mg, 0.66 mmol, 2 equiv.) were dissolved in 2 mL of acetonitrile. The mixture was irradiated with light of a wavelength lambda = 310 nm for 4 hours at ambient temperature (about 200C). The obtained yellow solution was diluted with 1 mL of acetonitrile. After 2 mL of saturated NaHCO3 solution was added, the obtained mixture was further stirred under reflux for 4 hours. Then the mixture was cooled to room temperature, water (10 mL) was added and the mixture was extracted with CH2C^ (3 * 10 mL). The combined organic phases were washed with 10 mL of brine, and the obtained solution was dried with Na2SO4. Solvent was removed under the reduced pressure to give 1 10.8 mg (95%) of crude Lambda/-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-/V- methylmethanesulfonamide (III) which contained 77% of Lambda/-(4-(4-fluorophenyl)-5- (hydroxymethyl)-6-isopropylpyrimidin-2-yl)-Lambda/-methylmethanesulfonamide (III) as determined by 1H-NMR integral. This product can be further purified by crystallization from MTBE/hexane mixture to afford pure material (HPLC area% = 99.6) with Tm =140-1410C. | |
With water; sodium hydrogencarbonate; In acetonitrile; for 4h;Reflux; | c) One-pot synthesis of PMDOH; (PMDME) (113. mg, 0.33 mmol, 1 equiv.) and /V-bromosuccinimide (NBS) (119 mg, 0.66 mmol, 2 equiv.) were dissolved in 2 mL of acetonitrile. The mixture was irradiated with light of a wavelength lambda = 254 nm for 4 hours at ambient temperature (about 20 C). The obtained yellow solution of PMDBR was diluted with 1 mL of acetonitrile. After 2 mL of saturated NaHC03 solution was added, the obtained mixture was further stirred under reflux for 4 hours. Then the mixture was cooled to room temperature, water (10 mL) was added and the mixture was extracted with CH2CI2 (3 chi 10 mL). The combined organic phases were washed with 10 mL of brine, and the obtained solution was dried with Na2S0 . Solvent was removed under the reduced pressure to give 110.8 mg (95 %) of crude V-(4-(4- fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-/V-methylmethanesulfonamide (PMDOH), which contained 77 % of /V-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-/V- methylmethanesulfonamide (PMDOH) as determined by H-NMR integral. This product was further purified by crystallization from MTBE/hexane mixture to afford pure material (HPLC area% = 99.6) with Tm =140-141 C.1H NMR (CDCI3): delta 1.30 (6H, d, J = 6.6 Hz), 2.51 (1 H, s), 3.44 - 3.50 (4H, m), 3.54 (3H, s) 4.58 (2H, d, J = 2.5 Hz), 7.1 1 (2H, m), 7.79 (2H, m) ppm. |
With sodium hydrogencarbonate; In acetonitrile; for 4h;Reflux; | b) One-pot synthesis of PMDOH (PMDME) (113. mg, 0.33 mmol, 1 equiv.) and N-bromosuccinimide (NBS) (119 mg, 0.66 mmol, 2 equiv.) were dissolved in 2 mL of acetonitrile. The mixture was irradiated with light of a wavelength lambda = 254 nm for 4 hours at ambient temperature (about 20 C). The obtained yellow solution of PMDBR was diluted with 1 mL of acetonitrile. After 2 mL of saturated NaHCO3 solution was added, the obtained mixture was further stirred under reflux for 4 hours. Then the mixture was cooled to room temperature, water (10 mL) was added and the mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic phases were washed with 10 mL of brine, and the obtained solution was dried with Na2SO4- Solvent was removed under the reduced pressure to give 110.8 mg (95 %) of crude N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (PMDOH), which contained 77 % of N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (PMDOH) as determined by 1H-NMR integral. This product was further purified by crystallization from MTBE/hexane mixture to afford pure material (HPLC area% = 99.6) with Tm =140-141 C. 1H NMR (CDCl3): delta 1.30 (6H, d, J = 6.6 Hz), 2.51 (1H, s), 3.44 - 3.50 (4H, m), 3.54 (3H, s) 4.58 (2H, d, J = 2.5 Hz), 7.11 (2H, m), 7.79 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
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90% | Example 20({4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)aminol-5- pyrimidinvDmethylphosphonium trifluoroacetate (Compound of Formula III, where A = CF3COO)56,55 g 5-(4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5- yl)methanol (160 mmol), 26,8 ml triethylamine (192 mmol) is mixed with 200 ml of n-butyl acetate and 23,4 ml trifluoroacetanhydride (168 mmol) is added dropwise to the reaction mixture at room temperature. After finishing of the addition the reaction mixture is warmed to 60 0C and all components are dissolved, then tri-n-butylphosphine (44,8 ml, 176 mmol) is added. The mixture is heated under reflux for 2 h, then cooled and washed twice with 400 ml of water. The second aqueous crop is rewashed with 100 ml of n-butyl acetate. Collected organic phases are concentrated by evaporation to 150 ml, cooled to 200C and while stirring EPO <DP n="35"/>400 ml of methyl t-butyl ether is added. After 8 h of stirring the product is collected by filtration, washed twice with 400 ml of methyl t-butyl ether and dried 4 h at 70 0C and 50 mBar. Yield 94,0 g (90 %). |
Yield | Reaction Conditions | Operation in experiment |
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With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 5℃; for 0.5h; | Example 1 : N-r4-(4-Fluorophenvn-5- (r(5-Methyl-l,3,4-Thiadiazol-2- Yl)SulfanyllMethyl|-6-(Propan-2-Yl)Pyrimidin-2-Yll-N-MethylmethanesulfonamideDiisopropyl ethyl amine (84.12 g) was slowly added to a mixture of N-[4-(4- fluorophenyl)-5-(hydroxymethyl)-6-(propan-2-yl)pyrimidin-2-yl]-N- methylmethanesulfonamide (commercially available; 100 g) and dimethyl aminopyridine (5 g) and diphenyl chlorophosphate (123.2 g) in dichloromethane (500 mL) at 0C to 5C. The reaction mixture was stirred for 30 minutes at the same temperature to give [4-(4- fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]methyl diphenyl phosphate. To this mixture was added 2-mercapto-5-methyl-l,3,4-thiadiazole (41 g) at 0C to 5C followed by slow addition of diisopropyl ethyl amine (36.5 g). The resultant mixture was stirred for 2 hours at 0C to 5C. After completion of the reaction, the mixture was quenched with de-ionized water (500 mL) and acidified to pH 3.5 using hydrochloric acid (6N). The organic layer was separated and washed with sodium bicarbonate (5%) at room temperature. The organic layer was separated anddichloromethane was recovered at 45C to give oily residue. Methanol (300 mL) was added to resulting oily residue and the mixture was stirred at room temperature for one hour to give N-[4-(4-fluorophenyl)-5-[(5-methyl-l,3,4-thiadiazol-2-yl)sulfanyl]methyl}- 6-(propan-2-yl)pyrimidin-2-yl]-N-methylmethanesulfonamide, which was filtered, washed with methanol (100 mL) and dried at 45C for 2 hours.Dry Weight: 115 g | |
With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 5℃; for 0.5h; | Example 1 N-[4-(4-Fluorophenyl)-5-[(5-Methyl-1,3,4-Thiadiazol-2-Yl)Sulfanyl]Methyl}-6-(Propan-2-Y1)Pyrimidin-2-Yl]-N-Methylmethanesulfonamide Diisopropyl ethyl amine (84.12 g) was slowly added to a mixture of <strong>[147118-36-3]N-[4-(4-fluorophenyl)-5-(hydroxymethyl)-6-(propan-2-yl)pyrimidin-2-yl]-N-methylmethanesulfonamide</strong> (commercially available; 100 g) and dimethyl aminopyridine (5 g) and diphenyl chlorophosphate (123.2 g) in dichloromethane (500 mL) at 0 C. to 5 C. The reaction mixture was stirred for 30 minutes at the same temperature to give [4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]methyl diphenyl phosphate. |
Yield | Reaction Conditions | Operation in experiment |
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N-(4-(4-fluorophenyl)-5-methyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (112.5 mg, 0.33 mmol, 1 equiv.) and N-bromosuccinimide (NBS) (118.7 mg, 0.66 mmol, 2 equiv.) were dissolved in 2 mL of acetonitrile. The mixture was irradiated with light of a wavelength lambda=310 nm for 4 hours at ambient temperature (about 20 C.). The obtained yellow solution was diluted with 1 mL of acetonitrile. After 2 mL of saturated NaHCO3 solution was added, the obtained mixture was further stirred under reflux for 4 hours. Then the mixture was cooled to room temperature, water (10 mL) was added and the mixture was extracted with CH2Cl2 (3×10 mL). The combined organic phases were washed with 10 mL of brine, and the obtained solution was dried with Na2SO4. Solvent was removed under the reduced pressure to give 110.8 mg (95%) of crude N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (III) which contained 77% of N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (III) as determined by 1H-NMR integral. This product can be further purified by crystallization from MTBE/hexane mixture to afford pure material (HPLC area %=99.6) with Tm=140-141 C. |
Yield | Reaction Conditions | Operation in experiment |
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88% | With methanesulfonyl chloride; triethylamine; In dichloromethane; at 0 - 25℃; for 5h; | Preparation 2. [175] N-[5-chloromethyl-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide [176] N-[4-(4-fluorophenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (50.0 g), dichloromethane (250.0 mL), and triethylamine (47.3 mL) were added to a reactor and then the reaction mixture was cooled to 0?5 C. Methanesulfonyl chloride (13.2 mL) was slowly added to the reaction mixture, which was then stirred at 20?25C for 5 hours. Water (100.0 mL) was added to the reaction mixture. The separated organic layer was sequentially washed with 0.5N hydrochloric acid solution (100.0 mL) and then water (100.0 mL). The organic layer was concentrated under reduced pressure to remove the solvent. n-Hexane (150.0 mL) was added to the resulting residue under stirring. The resulting suspension was filtered under reduced pressure. The resulting white solid was dried to obtain N-[5-chloromethyl-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (45.5 g, yield 88%).[177] 1H-NMR, 400 MHz, CDCl3, ppm : 1.35(d, 6H), 3.48(m, 1H), 3.50(s, 3H), 3.57(s, 3H), 4.58(q, 2H), 7.22(t, 2H), 7.80(q, 2H) |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydrogencarbonate; dimethyl sulfoxide; sodium iodide; at 20℃; for 71h;Inert atmosphere; | 4.7.1. From alcohol 2A solution of N-[4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide (2, 2.00 g, 5.66 mmol) in DMSO (20 mL) was heated to 85 C Ac2O (2.15 mL, 22.79 mmol, 4.0 equiv) was slowly added (flow rate 150 muL/h) and the reaction mixture was left to stir for 17 h at 85 C. Water (15 mL) was added and the resulting precipitate was collected by filtration. The precipitate was dissolved in hot EtOAc (20 mL), cooled to 4 C and the precipitated solid was collected by filtration and dried to give product 1 (0.62 g, 31%) as colorless crystals.4.7.2. From bromide 3A mixture of NaHCO3 (0.40 g, 4.80 mmol, 2 equiv) and NaI (36.0 mg, 0.24 mmol 0.1 equiv) in DMSO (10 mL) was flushed with nitrogen, sealed, and maintained at 20 C while a solution of N-[4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide (3, 1.00 g, 2.40 mmol) in DMSO (9 mL) was slowly added over 3 h time. The reaction mixture was stirred for 68 h at 20 C, then warmed to 70 C and Ac2O (1.5 mL, 16.4 mmol, 6.6 equiv) was added dropwise in 3 h. The stirring was continued for additional 4 h at 70 C. Then, the reaction mixture cooled on an ice bath, and the product was precipitated by slow addition of water (20 mL). The precipitate was collected by filtration, washed with water (10 mL) and MeOH (10 mL), and dried under reduced pressure to afford aldehyde 1 (0.79 g, 94%) as colorless solid. Mp=178.2 C (DSC onset) and 179.1 C (DSC peak) (lit.13 147-148 C). 1H NMR (CDCl3): delta 1.32 (6H, d, J=6.7 Hz, CH3 of iPr), 3.55 (3H, s, NCH3), 3.64 (3H, s, SCH3), 4.01 (1H, sep, J=6.7 Hz, CH), 7.20-7.27 (2H, m, ArH), 7.61-7.66 (2H, m, ArH), 9.97 (1H, s, CHO). 13C NMR (CDCl3): delta 21.6, 31.9, 33.0, 42.5, 115.9 (d, JCF=22.0 Hz), 119.5, 132.3 (d, JCF=2.5 Hz), 132.6 (d, JCF=8.8 Hz), 158.7, 164.4 (d, JCF=252.7 Hz), 169.7, 179.0, 190.4. 19F NMR (CDCl3): delta -108.6 (m). IR (KBr) nu 3444, 3081, 2977, 2943, 1687, 1600, 1545, 1509, 1445, 1376, 1341, 1230, 1158, 1127, 956, 855, 809, 780 cm-1. HRMS (ESI+) calcd for C16H17FN3O3S- ([M-H]-): 350.0980; found: 350.0981. |
Yield | Reaction Conditions | Operation in experiment |
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97.8% | With lithium borohydride; boron trifluoride diethyl etherate; In tetrahydrofuran; at -5 - 20℃; for 4h; | 70 mL of tetrahydrofuran and 1.3 g of lithium borohydride were added into a 500 mL three mouth flask, a temperature was lowered to between -5 and 5C. 18 g of boron trifluoride diethyl etherate was slowly dripped into the flask while stirring. After stirring for 30 min-1 h, 7.2 g of a compound represented by formula III (HPLC: 99.2%) was added at the temperature of between -5 and 5C. The temperature was kept at between -5 and 5C for 2-4 h for reaction, then, the temperature was increased to 10-20C for reaction. After a complete reaction of the compound represented by formula III, methanol was slowly dripped for quenching the reaction. Thereafter, vacuum distillation was carried out at a temperature of 30-35C and a vacuum degree of 250-350 Pa to remove a dissolvent; then, a remaining solid was added with 40 mL of water and stirred, PH value was adjusted to 2-3. After that, extraction was carried out three times with 200 mL of methyl tert-butyl ether. A vacuum concentration was carried out at the temperature of 30-35C and the vacuum degree of 250-350 Pa to obtain a white solid, i. e., a crude product of a compound represented by formula I. The crude product was recrystallized by a mixture of methyl tert-butyl ether and n-hexane (1: 10 of a volume ratio) to obtain 6.8 g of a product, its purity was 99.0%, and its yield was 97.8%. |
97% | With chloro-trimethyl-silane; potassium borohydride; In tetrahydrofuran; at 65℃; for 30h;Inert atmosphere; | Example 2 Synthesis of 4-p-fluorophenyl-5-hydroxymethyl-6-isopropyl-2-(N-methylmethylsulfonylamino)pyrimidine (VIII) Under the protection of nitrogen, potassium borohydride (0.54 g), dry tetrahydrofuran (40 mL) and steel beads (10 mL) are placed in a dry reaction flask, trimethylchlorosilane (1.1 g) is dropwise added under stirring at room temperature, after the completion of the addition, heating is performed to 65 C., reflux stirring is performed for 3 h, then a suspension of 4-p-fluorophenyl-6-isopropyl-2-(N-methylmethylsulfonylamino)pyrimidine-5-carboxylic acid VII (1.83 g) in tetrahydrofuran (5 mL) is added, and after the completion of the addition, the temperature is maintained under stirring for 30 h. After the completion of the addition, the reaction solution is cooled to 0-5 C., a saturated ammonium chloride solution is dropwise added slowly, and after the completion of the addition, the solution is stirred for 15 min, extracted using dichloromethane, washed with a 10% sodium carbonate solution, dried with anhydrous sodium sulphate, and subjected to solvent recovery under a reduced pressure to dryness to precipitate a solid, such that a white crystalline powder 4-p-fluorophenyl-5-hydroxymethyl-6-isopropyl-2-(N-methylmethylsulfonylamino) pyrimidine is obtained (1.71 g, 97%). |
97.9% | In a 50 mL round bottom flask, 10 mL of anhydrous THF, 2 g of Intermediate 1 (5.4 mmol)0.78 g (16.3 mmol) of potassium borohydride was added and the mixture was stirred for 5 min in an ice bath. 0.72 g (5.4 mmol) of anhydrous aluminum trichloride was added and the mixture was stirred for 5 min. The mixture was slowly heated to 74 C. and refluxed for 4 h.The mixture was cooled to room temperature, the reaction mixture was quenched by dropwise addition of dilute hydrochloric acid under ice bath, the THF was removed by concentration under reduced pressure, and extracted with ethyl acetate (10 mL × 3). The organic layers were combined,Washed twice with 0.1mol / L sodium hydroxide solution and twice with saturated saline. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give 1.87g of a white solid with a yield of 97.9% |
96.4% | With sodium tetrahydroborate; boron trifluoride diethyl etherate; In tetrahydrofuran; at -5 - 30℃; | 70 mL of tetrahydrofuran and 2.2 g of sodium borohydride were added into a 500 mL three mouth flask, a temperature was lowered to between -5 and 5 C.18 g of boron trifluoride diethyl etherate was slowly dripped into the flask while stirring. After stirring for 30 min-1 h, 7.2 g of a compound represented by formula III (HPLC: 99.5%) was added at the temperature of between -5 and 5 C. The temperature was kept at between -5 and 5 C. for 2-4 h for reaction, then, the temperature was increased to 20-30 C. for reaction. After a complete reaction of the compound represented by formula III, methanol was slowly dripped for quenching the reaction. Thereafter, vacuum distillation was carried out at a temperature of 30-35 C. and a vacuum degree of 250-350 Pa to remove a dissolvent; then, a remaining solid was added with 40 mL of water and stirred, PH value was adjusted to 2-3. After that, extraction was carried out three times with 200 mL of methyl tert-butyl ether. A vacuum concentration was carried out at the temperature of 30-35 C. and the vacuum degree of 250-350 Pa to obtain a white solid, i.e., a crude product of a compound represented by formula I. The crude product was recrystallized by a mixture of methyl tert-butyl ether and n-hexane (1:10 of a volume ratio) to obtain 6.7 g of a product, its purity was 99.0%, and its yield was 96.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With tetrabutylammomium bromide; potassium hydroxide; In tetrahydrofuran; at 20℃; | General procedure: ethyl 5-(bromomethyl)-1,3-diphenyl-1H-pyrazole-4-carboxylate (5, 0.38 g, 1.00 mmol) is taken in THF (20 ml) and stirred at room temperature for 10 min. N-(4-(4-fluorophenyl)-5-(-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide, a component of Rosuvastatin (obtained from Lee Pharma, Hyderabad) which is used as dislypidemia (6a, 0.35 g, 1.00 mmol) was added followed by the potassium hydroxide (0.06 g, 1.00 mmol) and tetrabutylammonium bromide (TBAB) (0.03 g, 0.10 mmol). The above reaction mass is stirred at room temperature for about 4-6 hr. After the completion of the reaction the reaction mixture was concentrated under reduced pressure to evaporate THF and later extracted with diethyl ether (3 x 20 ml), washed with water (3 x 20 ml). The organic extract was dried with anhydrous sodium sulfate, concentrated under reduced pressure and crystallized to provide the desired compound (7a) in 95% yield (0.61 g). This is then recrystalised from saturated solution of methanol. MP 180-183 C (MeOH), in IR (Nujol): 1627 cm-1 (C=C), 1646 cm-1 1650 cm-1(C=N) and 1710 cm-1 (C=O); 1H NMR (400 MHz, CDCl3), delta ppm (J, Hz): 1.09-1.12 (t, 3H, J = 7.2), 1.20-1.22 (d, 6H, J = 9.2), 3.24-3.29 (m, 1H), 3.44 (s, 3H), 3.54 (s, 3H), 4.16-4.22 (q, 2H, J = 7.2), 4.42 (s, 2H), 4.83 (s, 2H), 7.25-7.29 (t, 2H, J = 8.8), 7.43-7.46 (m, 3H), 7.59-7.72 (m, 9H); 13C NMR (CDCl3-d6): 13.8, 22.2, 29.6, 31.4, 33.0, 42.4, 60.3, 60.8, 65.9, 112.3, 115.3, 115.6, 118.1, 125.4, 127.7, 128.4, 129.0, 129.2, 129.5, 131.5, 131.6, 132.8, 133.6, 133.7, 138.5, 142.8, 153.5, 158.1, 162.5, 163.6, 165.0, 166.4, 178.1; MS (relative intensity): m/z for C35H36FN5O5S; 658.3 [M+H]+ (100). Anal. % Calc: C, 63.91; H, 5.52; N, 10.65; Found: C, 63.87; H, 5.54; N, 10.67. The same procedure was followed in all the case. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In toluene; for 10h;Reflux; | Example 4 Synthesis of ((4-p-fluorophenyl-6-isopropyl-2-(N-methylmethylsulfonylamino)-5-pyridyl)methyl)triphenyl phosphonium hydrobromate (IX) (X=Br) A compound VIII (0.88 g) and triphenyl phosphonium hydrobromate (0.85 g) are placed in toluene (50 mL), heated to 81 C., and subjected to reflux stirring for 10 h, and after the completion of the reaction, cooling and leaving to stand are performed to precipitate a solid, and after filtration and drying, a white powdery solid IX is obtained (X=Br, 1.41 g, 83%), 1H NMR (400 MHz, DMSO-d6): delta 7.87 (m, 3H), 7.63 (m, 6H), 7.27 (m, 8H), 7.13 (t, J=8.4 Hz, 2H), 5.08 (d, J=13.6 Hz, 2H), 3.49 (s, 3H), 3.40 (s, 3H), 2.86 (m, 1H), 0.79 (d, J=4.4 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In acetonitrile; for 24h;Reflux; | Example 3 Synthesis of ((4-p-fluorophenyl-6-isopropyl-2-(N-methylmethylsulfonylamino)-5-pyridyl)methyl)triphenyl phosphonium fluoroborate (IX) (X=BF4) A compound VIII (0.88 g) and triphenyl phosphonium fluoroborate (0.88 g) are dissolved in acetonitrile (20 mL), heated to 81 C., and subjected to reflux stirring for 24 h, and after the completion of the reaction, concentration under a reduced pressure is performed to dryness to obtain a white foamy solid IX (X=BF4, 1.67 g, 97%), 1H NMR (400 MHz, CDCl3): delta 7.74 (t, J=7.8 Hz, 3H), 7.54 (td, J=8, 3.2 Hz, 6H), 7.26 (t, J=6.8 Hz, 2H), 7.17 (dd, J=12.8, 7.8 Hz, 6H), 6.98 (t, J=8.4 Hz, 2H), 5.17 (d, J=12.4 Hz, 2H), 3.48 (s, 3H), 3.43 (s, 3H), 2.73 (sept., J=6.4 Hz, 1H), 0.88 (br, 6H). |
Tags: 147118-36-3 synthesis path| 147118-36-3 SDS| 147118-36-3 COA| 147118-36-3 purity| 147118-36-3 application| 147118-36-3 NMR| 147118-36-3 COA| 147118-36-3 structure
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