* 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.
Step b: 4,6-Dichloro-2-methylsulfanyl-pyrimidine (19b) ; 2-Methylsulfanyl-pyrimidine-4,6-diol (30.0 g, 189 mmol) was added slowly to phosphorus oxychloride (350 ml ) while cooling on ice then N,N-diethylaniline (52.5 ml) was added slowly while cooling. The mixture was slowly warmed till reflux and refluxed for 2.5 hours. The mixture was evaporated and added to crushed ice. The mixture was extracted three times with ethyl acetate and the combined organic layers were washed three times with water, once with brine and concentrated. Purification by column chromatography on silica gel eluted with hexane - ethyl acetate gave the title compound (36 g, 97percent).
65%
at 105 - 110℃; for 6 h;
A solution of 2-methylthiopyrimidine-4,6-diol (12.5 g, 79.11 mmol) in phosphorous oxychloride (60 ml) was heated to 105-110° C. for 6 hours. The phosphorous oxychloride was removed under reduced pressure to give a residue which was partitioned between dichloromethane and water. The organic layer was separated, dried and concentrated to give a residue. Purification was done by silica gel flash column chromatography (3percent ethyl acetate in hexane) to afford the desired product as a white solid (10 g, 65percent yield). 1H NMR (CDCl3, 400 MHz): δ 7.03(s, 1H), 2.58 (s, 3H).
Reference：
[1] Patent: WO2008/95999, 2008, A1, . Location in patent: Page/Page column 96
[2] European Journal of Organic Chemistry, 2015, vol. 2015, # 29, p. 6547 - 6556
[3] Organic and Biomolecular Chemistry, 2003, vol. 1, # 19, p. 3353 - 3361
[4] ACS Combinatorial Science, 2014, vol. 16, # 4, p. 168 - 175
[5] Journal of Medicinal Chemistry, 1984, vol. 27, # 12, p. 1621 - 1629
[6] Patent: US2010/249110, 2010, A1, . Location in patent: Page/Page column 35-36
[7] Journal of Medicinal Chemistry, 2015, vol. 58, # 11, p. 4590 - 4609
[8] Pest Management Science, 2001, vol. 57, # 3, p. 205 - 224
[9] Patent: US5599770, 1997, A,
[10] Patent: WO2012/97478, 2012, A1, . Location in patent: Page/Page column 59
[11] Patent: WO2014/128719, 2014, A2, . Location in patent: Page/Page column 16
[12] Synthetic Communications, 2018, vol. 48, # 6, p. 714 - 720
2
[ 504-17-6 ]
[ 74-88-4 ]
[ 1979-98-2 ]
Yield
Reaction Conditions
Operation in experiment
95%
With sodium hydroxide In ethanol; water at 20 - 60℃;
Example 19; Step a: 2-Methylsulfanyl-pyrimidine-4,6-diol (19a) ; Methyl iodide (32,64g, 220 mmol) was added dropwise to a suspension of thiobarbituric acid (29g, 200 mmol) in EtOH (300ml) and 2M NaOH solution in water (110ml) at room temperature. The mixture was stirred at room temperature overnight and then stirred for two hours at 600C. The ethanol was removed, water was added and the mixture was allowed to stay for 2 hours on an ice bath. The solid title compound was filtered of, washed with ice cold water and dried (3Og, 95percent).
Reference：
[1] Journal of Medicinal Chemistry, 1984, vol. 27, # 12, p. 1621 - 1629
[2] ACS Combinatorial Science, 2014, vol. 16, # 4, p. 168 - 175
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 11, p. 4590 - 4609
4
[ 74-87-3 ]
[ 54028-41-0 ]
[ 1979-98-2 ]
Yield
Reaction Conditions
Operation in experiment
85 %Chromat.
With sodium hydroxide In methanol at 25 - 30℃; Autoclave
Example 7: Preparation of 2-Methylthio-4, 6-dihydroxypyrimidine 1.0m thiobarbituric acid sodium salt was dissolved in 1.5m 1 N aqueous sodium hydroxide solution and 50 ml methanol in a SS autoclave to obtain a mixture. To this 0.5m methyl chloride was fed in 1 to 2 hours. The obtained reaction mass was stirred for 2 to 6 hours at 25-30°C, a second lot of 0.5m methyl chloride was fed in 1 to 2 hours and mass was stirred at 25-30°C for 6-8 hours. To this, 0.05m methyl chloride was fed and reaction mass was stirred for 2 to 6 hours. After the end of reaction HPLC indicated 85percent 2-methylthio- 4, 6- dihydroxypyrimidine and 5percent 2-methylthio-4-methoxy-6-hydroxypyrimidine. Yield of product was 75-80 mole percent.
Reference：
[1] Pest Management Science, 2001, vol. 57, # 3, p. 205 - 224
9
[ 1979-98-2 ]
[ 33097-11-9 ]
Yield
Reaction Conditions
Operation in experiment
61%
Stage #1: With trichlorophosphate In Trichloroethylene at 5 - 20℃; Stage #2: at 80℃;
Example 1; 3-[2-r4-Amino-l-piperidinylV8-r2.6-difluorophenyl)-7-oxo-5,6.7,8- tetrahvdropyrimido[4,5-0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2-(methylthio)-4(lH)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for about 2 hours then filtered to afford the crude product. EPO <DP n="115"/>The crude product was further purified by recrystalization with hexane to afford 4,6- dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61percent). 1H-NMR (CDCl3) δ 2.66 (s, 3 H), 10.4 (s, 1 H).
61%
Stage #1: With trichlorophosphate In N,N-dimethyl-formamide at 5 - 20℃; Stage #2: at 80℃;
To the solution of phosphorus oxy chloride (65 mL, 0.70 mol) in trichloroethylene (46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2-(methylthio)-4(lH)- pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbaldehyde (21.3 g , 61percent). 1H-NMR (CDCl3) δ 2.66 (s, 3 η), 10.4 (s, 1 η).To a solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (10.0 g, 44.8 mmol) in TηF (250 mL) was added 2,6-difluoroaniline (5.35 mL, 49.3 mmol, 1.1 eq) followed by Et3N (12.6 mL, 89.6 mmol, 2 eq). The reaction mixture was heated to 550C for about 22 h before <n="109"/>concentrated. The slurry was re-dissolved in DCM (250 mL) and washed with H2O (2 x 100 mL), then concentrated and further washed with acetone (2 x 10 mL) to give 9.87 g (70 percent) of pure 4- chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbaldehyde. LC-MS m/z 316 (M+H)+.A solution of 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5- pyrimidinecarbaldehyde (200 mg, 0.63 mmol) in DMF (4.0 mL) and acetic anhydride (2.0 mL) was heated with a microwave (16O0C) for about 30 minutes. The resultant mixture was then concentrated. Flash chromatography (EtOAc / Hexane, 1 : 5) provided the title compound (109 mg, 51percent): LC-MS m/z 340 (M+H)+.
With trichlorophosphate In Trichloroethylene at 5 - 80℃;
To the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene(46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2- (methylthio)-4(lH)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum.The resulting slurry like residue was poured into ice, stirred for about 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61percent). 1H- NMR (CDCl3) δ 2.66 (s, 3 H), 10.4 (s, 1 H). To the mixture of hydroxylamine hydrochloride (139 mg, 2.0 mmol), HOAc (0.113 mL, 2.0 mmol) and EtOH (5 mL) was added 4,6-dichloro-2-(methylthio)-5- <n="80"/>pyrimidinecarbaldehyde (223 mg, 1.0 mol) to room temperature. The solution was then heated at 50 0C for about 1 hour, 60 0C for about 30 minutes and 70 0C for about 30 minutes before it was concentrated under vacuum and washed with H2O (10-20 mL) to afford 4,6- dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (190 mg, 80percent). LC-MS m/z 238 (M + H)+ 1.57 minute, 1.65 minute; 1H-NMR (CDCl3) δ 2.62, 2.65 (3 H), 7.53, 8.30 (1 H). To 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (2.38 g, 10 mmol) was added SOCl2 (21.8 mL, 0.30 mol) slowly at room temperature. The solution was then heated at 75 0C for about 3 hours before it was concentrated under vacuum. The residue SOCl2 was removed by evaporation with toluene (5 mL) under vacuum. The resulting solid was washed with EtOH/H2O (1OmL, 1 : 1) to afford 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbonitrile (2.04 g, 93percent). LC-MS m/z 220 (M + H)+1.99 minute; 1H-NMR (CDCl3) δ 2.64(3 H).To the solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile (2.20 g, 10.0 mmol) in DMF (10 mL) was added 2,6-difluoroaniline (2.17 mL, 20.0 mmol). The solution was stirred at 50 0C for about 60 minutes. The mixture was slowly added into a solution of MeOH (20 mL) and water (30 mL). The resultant solid was filtered and washed with MeOH / H2O (20 mL, 1 :1) to give 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5- pyrimidinecarbonitrile as a white solid (2.82 g, 90 percent). LC-MS m/z 313 (M + H)+; 1H-NMR (CDCl3) δ 2.33 (s, 3 H), 6.94 (s, 1 H), 7.04 (m, 2 H), 7.35 (m, 1 H).
61%
With trichlorophosphate In Trichloroethylene at 5 - 80℃;
To the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene(46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2- (methylthio)-4(lH)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for about 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4, 6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61percent). 1H- NMR (CDCl3) δ 2.66 (s, 3 H), 10.4 (s, 1 H).To the mixture of hydroxylamine hydrochloride (139 mg, 2.0 mmol), HOAc (0.113 rnL, 2.0 mmol) and EtOH (5 mL) was added 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbaldehyde (223 mg, 1.0 mol) to room temperature. The solution was then heated at 50 0C for about 1 hour, 60 0C for about 30 minutes and 70 0C for about 30 minutes before it was concentrated under vacuum and washed with H2O (10-20 mL) to afford 4,6- dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (190 mg, 80percent). LC-MS m/z 238 (M + H)+ 1.57 minute, 1.65 minute; 1H-NMR (CDCl3) δ 2.62, 2.65 (3 H), 7.53, 8.30 (1 H). To 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (2.38 g, 10 mmol) was added SOCl2 (21.8 mL, 0.30 mol) slowly at room temperature. The solution was then heated at 75 0C for about 3 hours before it was concentrated under vacuum. The residueSOCl2 was removed by evaporation with toluene (5 mL) under vacuum. The resulting solid was washed with EtOH/H2O (1OmL, 1 : 1) to afford 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbonitrile (2.04 g, 93percent). LC-MS m/z 220 (M + H)+1.99 minute; 1H-NMR (CDCl3) δ 2.64(3 H). To the solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile (2.20 g, 10.0 mmol) in DMF (10 mL) was added 2,6-difluoroaniline (2.17 mL, 20.0 mmol). The solution was stirred at 50 0C for about 60 minutes. The mixture was slowly added into a solution of MeOH (20 mL) and water (30 mL). The resultant solid was filtered and washed with MeOH / H2O (20 mL, 1 :1) to give 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5- pyrimidinecarbonitrile as a white solid (2.82 g, 90 percent). LC-MS m/z 313 (M + H)+; 1H-NMR (CDCl3) δ 2.33 (s, 3 H), 6.94 (s, 1 H), 7.04 (m, 2 H), 7.35 (m, 1 H).
Stage #1: at -5 - 20℃; for 1 h; Stage #2: at 20℃; for 3.5 h; Heating / reflux
POCI3 (7OmL, 0.75mol) was cooled to -5°C and DMF (23mL, 0.3mol) was added slowly. The resultant mixture was allowed to stand at 2O0C for 1 hour. 4,6-dihydroxy-2-methyl- mercaptopyrimidine (15.8 g., 0.1 mol) was added using a solid addition funnel. The reaction mixture was first stirred at room temperature for 30 minutes and then heated at reflux for 3 hours. Following removal of excess POCI3 and DMF in vacuo, the residue was poured into <n="107"/>ice. The solid obtained was filtered and washed with cold water. After treating the solid with hexanes (sonication). the desired product was obtained as a white solid (9.3g, 42percent). 1H NMR (CDCl3, 300 MHz) δ 10.34 (s, IH), 2.64 (s, 3H); CHN Calc'd for C6H4Cl2N2OS: C, 32.30; H, 1.81; N, 12.56. Found: C, 32.44; H, 1.69; N, 12.51.
13%
at 10 - 100℃;
Reference Example 69 Production of 4,6-dichloro-2-(methylsulfanyl)pyrimidine-5-carbaldehyde To ice-cooled phosphorus oxychloride (77.62 g, 506 mmol) was added dropwise DMF (9.29 mL, 120 mmol), and the mixture was stirred at room temperature for 1 hr. 2-(Methylsulfanyl)pyrimidine-4,6-diol (15.8 g, 100 mmol) was added thereto by small portions, and the mixture was stirred at room temperature for 1 hr, at 40-50°C for 1 hr, and then at 100°C overnight. After cooling, the reaction mixture was poured into ice, and the mixture was extracted twice with ethyl acetate. The extract was washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate, hexane:ethyl acetate=95:5-->85:15) to give the title compound (2.97 g, 13percent) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ:2.64 (3 H, s), 10.38 (1 H, s).
Stage #1: With trichlorophosphate In Trichloroethylene at 5 - 20℃; Stage #2: at 20 - 80℃; Stage #3: With water In Trichloroethylene at 0℃; for 2 h;
57a) 4-chloro-6-[(2,6-difluorophenyDamino]-2-(methylthio')-5- pyrimidinecarbonitrile; To the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene (46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2-(methylthio)-4(l/i)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for about 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4,6- dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61percent). 1H-NMR (CDCl3) δ 2.66 (s, 3 H), 10.4 (s, I H).
61%
Stage #1: With trichlorophosphate In Trichloroethylene at 5 - 10℃; Stage #2: at 20 - 80℃;
Example 1; N-CcvclopropylmethylV3-r8-r2,6-difluoroρhenylV2-(r2-hvdroxy-l- rhvdroxymethvπethyl"|amino)-7-oxo-718-dihvdropyridor2,3-dlpyrimidin-4-yl)-4- methylbenzamidela) 4-chloro-8-(2.6-difluorophenyl)-2-('methylthio)pyridor2.3-^)pyrimidin-7r8Hr)- oneTo the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene (46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2- (methylthio)-4(lH)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61percent). 1H-NMR (CDCl3) δ 2.66 (s, 3 H), 10.4 (s, 1 H).
EXAMPLE 99; 4-hydroxy-4-[3-(trifluoromethy)phenyl]piperidine-1-carboxylic acid (7-methoxy-5-methylsulfanyl-thiazolo[5,4-d]pyrimidin-2-yl)-amide; Step 1: 4,6-Dihydroxy-2-methylthiopyrimidine (10.0 g, 63.22 mmol) was added over 1 hr to fuming nitric acid (30 mL) at 0° C. The red solution was stirred an additional 1 hr at 0° C. and then poured onto ice to give a light brown solid which was filtered off and washed with water and diethyl ether. The solid was dried under vacuo to give 4,6-Dihydroxy-2-methylthio-5-nitropyrimidine (9.30 g, 72percent) as a light brown solid. LRMS for C5H5N3O4S (M+H)+ at m/z=203. The NMR spectrum obtained on the sample is compatible with its structure.
65%
Stage #1: at 20℃; for 0.5 h; Stage #2: at 5 - 20℃;
A solution of 4,6-dihydroxy-2-methylthiopyrimidine (50 g, 316.09 mmol) in trifluoroacetic acid (210 mL) was stirred at RT for 30 min. The mixture was cooled to 5°C then HNO3 fuming (19.5 mL, 426.73 mmol) was added drop wise at 5°C. The temperature was maintained at 10-15°C during the addition. The ice bath was removed and when the temperature reached 20°C, a violent exothermic event occurred (from 20°C to 45°C in 5 seconds). The mixture was stirred at RT for 16h. The mixture was poured into a mixture of water and ice. The precipitate was filtered off and washed with water. The precipitate was dried under vacuum at 50°C to give 42 g (65percent yield) of intermediate S2. This intermediate was directly used in the next step without any further purification.
49%
at 50℃; for 3 h;
Step A: 2-Methylsulfanyl-5-nitro-pyrimidine-4,6-diol. 2-Methylsulfanyl-pyrimidine-4,6-diol (10 g, 63 mmol) was added portion-wise to a stirring solution of glacial acetic acid (25 mL) and concentrated nitric acid (10 mL) at 50° C. After 3 h, the reaction mixture was poured onto crushed ice and the product was isolated by filtration as a yellow solid (6 g, 49percent). MS (ESI): mass calcd. for C5H5N3O4S, 203.0; m/z found, 202.4 [M-H].
49%
With nitric acid; acetic acid In water at 50℃; for 3 h;
Intermediate 1: 2-Methylsulfanyl-5-nitro-pyrimidine-4,6-diol 2-Methylsulfanyl-pyrimidine-4,6-diol (10 g, 63 mmol) was added portion wise to a stirring solution of glacial acetic acid (25 mL) and concentrated nitric acid (10 mL) at 50° C. After 3 h, the reaction mixture was poured onto crushed ice and the product was isolated by filtration as a yellow solid (6 g, 49percent). MS (ESI, negative mode): mass calcd. for C5H5N3O4S, 203.0; m/z found, 202.4 [M-H].
42 g
at 5 - 45℃;
A solution of F-2 (50 g, 316.09 mmol) in TFA (210 mL) was stirred at RT for 30 min. The mixture was cooled to 5°C then HN03 fuming (19.5 mL, 426.73 mmol) was added drop wise at 5°C. The temperature was maintained at 10-15°C during the addition. The ice bath was removed and when the temperature reached 20°C, a violent exothermic event occurred (from 20°C to 45°C in 5 seconds). The mixture was stirred at RT for 16h. The mixture was poured into a mixture of water and ice. The precipitate was filtered off and washed with water. The precipitate was dried under vacuum at 50°C to give 42 g (65percent yield) of intermediate G-2. This intermediate was directly used in the next step without any further purification.
This embodiment is a method for synthesizing 2-methylthio-4,6-dichloro-5-nitropyrimidine. The synthetic steps are as follows:(1) Take 200g of 2-methylthio-4,6-dihydroxypyrimidine in batches and add it to 600ml of fuming nitric acid, and stir at room temperatureAfter 1h, heat to 50 C for 4h;(2) After the heating reaction is completed, drop to room temperature, slowly pour it into ice water, stir for 1 h, and filter. Wash the filter cake to neutrality. After digging out the filter cake, dry to obtain 240 g of compound B. The purity is greater than 95%. Rate 88.75%;(3) Disperse 100 g of compound B in 450 ml of phosphorous oxychloride, and dropwise add 60 ml of diisopropylethylamine at room temperature. After the addition of diisopropylethylamine is completed, raise the reflux temperature to chlorination reaction 2 -5h;(4) After the chlorination reaction is completed, the obtained mixture is cooled and decompressed, and concentrated to remove excess phosphorus oxychloride. The residue is slowly poured into 1 kg of crushed ice and stirred for 1 h, and extracted with 200 ml of ethyl acetate 2-3 times The organic phases were combined, washed with a saturated aqueous sodium bicarbonate solution to neutral pH, washed once with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated to obtain a crude product, which was obtained by recrystallization from n-hexane. 118g pure product, purity is greater than 98%, yield is 97.87%.
72%
With nitric acid; at 0℃; for 2h;
EXAMPLE 99; 4-hydroxy-4-[3-(trifluoromethy)phenyl]piperidine-1-carboxylic acid (7-methoxy-5-methylsulfanyl-thiazolo[5,4-d]pyrimidin-2-yl)-amide; Step 1: 4,6-Dihydroxy-2-methylthiopyrimidine (10.0 g, 63.22 mmol) was added over 1 hr to fuming nitric acid (30 mL) at 0 C. The red solution was stirred an additional 1 hr at 0 C. and then poured onto ice to give a light brown solid which was filtered off and washed with water and diethyl ether. The solid was dried under vacuo to give 4,6-Dihydroxy-2-methylthio-5-nitropyrimidine (9.30 g, 72%) as a light brown solid. LRMS for C5H5N3O4S (M+H)+ at m/z=203. The NMR spectrum obtained on the sample is compatible with its structure.
67%
With nitric acid; acetic acid; at 5 - 20℃; for 1h;
To 6 mL of acetic acid cooled at 5C on an ice bath were added fuming nitric acid (2.5 mL) and (22e) (2.0 g, 12.6 mmol). After 1 hour stirring at room temperature, the mixture was cooled at 5C on an ice bath, water (50 mL) was added and the resulting precipitate was filtered off. Yield: 67%.Melting point: 220-221C (decomposition).H NMR (DMSO-dg) d 2.56 (s, 3H, S CH3).13C NMR (DMSO-dg) d 13.2 (SCH3), 117.4 (C-5), 158.7 (C-4/C-6), 164.6 (C-2).
65%
A solution of 4,6-dihydroxy-2-methylthiopyrimidine (50 g, 316.09 mmol) in trifluoroacetic acid (210 mL) was stirred at RT for 30 min. The mixture was cooled to 5C then HNO3 fuming (19.5 mL, 426.73 mmol) was added drop wise at 5C. The temperature was maintained at 10-15C during the addition. The ice bath was removed and when the temperature reached 20C, a violent exothermic event occurred (from 20C to 45C in 5 seconds). The mixture was stirred at RT for 16h. The mixture was poured into a mixture of water and ice. The precipitate was filtered off and washed with water. The precipitate was dried under vacuum at 50C to give 42 g (65% yield) of intermediate S2. This intermediate was directly used in the next step without any further purification.
49%
With nitric acid; acetic acid; at 50℃; for 3h;
Step A: 2-Methylsulfanyl-5-nitro-pyrimidine-4,6-diol. 2-Methylsulfanyl-pyrimidine-4,6-diol (10 g, 63 mmol) was added portion-wise to a stirring solution of glacial acetic acid (25 mL) and concentrated nitric acid (10 mL) at 50 C. After 3 h, the reaction mixture was poured onto crushed ice and the product was isolated by filtration as a yellow solid (6 g, 49%). MS (ESI): mass calcd. for C5H5N3O4S, 203.0; m/z found, 202.4 [M-H].
49%
With nitric acid; acetic acid; In water; at 50℃; for 3h;
Intermediate 1: 2-Methylsulfanyl-5-nitro-pyrimidine-4,6-diol 2-Methylsulfanyl-pyrimidine-4,6-diol (10 g, 63 mmol) was added portion wise to a stirring solution of glacial acetic acid (25 mL) and concentrated nitric acid (10 mL) at 50 C. After 3 h, the reaction mixture was poured onto crushed ice and the product was isolated by filtration as a yellow solid (6 g, 49%). MS (ESI, negative mode): mass calcd. for C5H5N3O4S, 203.0; m/z found, 202.4 [M-H].
Method V: 4,6-Dihydroxy-2-methylthio-5-nitropyrimidine: A solution of 4,6-dihydroxy-2-methylthiopyrimidine (42 g, 0.257 mol) in trifluoroacetic acid (91 ml, 1.186 mol) was stirred at 23 C. and warmed until all solid had gone into solution. The reaction was stirred for five hours at 23 C. Next, fuming HNO3 (15 ml, 350 mmol) was added portion wise to the reaction mixture over 25 minutes at 0 C. The reaction was stirred for twenty hours at 23 C., and treated with H2O (at 23 C.) at 80% conversion (according LC-MS). The solid precipitate was captured via filteration giving 4,6-dihydroxy-2-methylthio-5-nitropyrimidine as a tan-colored solid. The crude solid was azeotroped with toluene to give 35 g of pale tan powdery solid. 1H-NMR: 300 MHz, (CD3OD, 300 MHz) d (ppm) 2.63 (s, 3H). LCMS-ESI+: calc'd for C5H4N3O4S: 202.0 (M-H-); Found: 202.0 (M-H-).
With nitric acid; for 2h;Cooling with ice;
EXAMPLE 176; METHYL {4,6-DIAMINO-2-[5-CHLORO-3-(2,3,6-TMFLUOROBENZYL)-1H-INDAZOL- 1 -YL]PYRIMIDiN-5-YL} CARBAMATEH3; Step A; Solid 4}6-dihydroxy-2-(methylmio)pyrimidine (lOg, 63.mmol) was added in portions over 30min, to fuming nitric acid (30ml) cooled in an ice bath. After stirring for 90min in an ice bath the solution was poured over ice. The product was collected by filtration, washed with a small amount of ice water and air dried on the filter. NMR (400 MHz, CDC13): delta 7.02 (s, 2 H); 2.56 (s, 3 H). LC rt~= 0.49min (Method A, not ionized).
42 g
With nitric acid; trifluoroacetic acid; at 5 - 45℃;
A solution of F-2 (50 g, 316.09 mmol) in TFA (210 mL) was stirred at RT for 30 min. The mixture was cooled to 5C then HN03 fuming (19.5 mL, 426.73 mmol) was added drop wise at 5C. The temperature was maintained at 10-15C during the addition. The ice bath was removed and when the temperature reached 20C, a violent exothermic event occurred (from 20C to 45C in 5 seconds). The mixture was stirred at RT for 16h. The mixture was poured into a mixture of water and ice. The precipitate was filtered off and washed with water. The precipitate was dried under vacuum at 50C to give 42 g (65% yield) of intermediate G-2. This intermediate was directly used in the next step without any further purification.
POCI3 (3.2 mL) was cooled at 5C on an ice bath and supplemented dropwise by dimethylformamide (20 mL, 215 mmol). 2-(Methylthio)pyrimidine-4,6-diol (22e) (5 g, 31.6 mmol) was then added portion-wise and the mixture was stirred at 100C for 20 h. The mixture was poured on crushed ice and extracted with CH2CI2 (3 x 50 mL). The combined organic layers were dried and evaporated to dryness under vacuum.Yield: 52%.Melting point: 87-89C.H NMR (DMSO -d6) d 2.57 (s, 3H, S CH3), 10.07 (s, 1H, CO H).13C NMR (DMSO -d6) d 13.3 (SCH3), 112.9 (C-5), 159.3 (C-4/C-6), 168.2 (C-2), 186.6 (COH).
42%
POCI3 (7OmL, 0.75mol) was cooled to -5C and DMF (23mL, 0.3mol) was added slowly. The resultant mixture was allowed to stand at 2O0C for 1 hour. 4,6-dihydroxy-2-methyl- mercaptopyrimidine (15.8 g., 0.1 mol) was added using a solid addition funnel. The reaction mixture was first stirred at room temperature for 30 minutes and then heated at reflux for 3 hours. Following removal of excess POCI3 and DMF in vacuo, the residue was poured into <n="107"/>ice. The solid obtained was filtered and washed with cold water. After treating the solid with hexanes (sonication). the desired product was obtained as a white solid (9.3g, 42%). 1H NMR (CDCl3, 300 MHz) delta 10.34 (s, IH), 2.64 (s, 3H); CHN Calc'd for C6H4Cl2N2OS: C, 32.30; H, 1.81; N, 12.56. Found: C, 32.44; H, 1.69; N, 12.51.
13%
With trichlorophosphate; at 10 - 100℃;
Reference Example 69 Production of 4,6-dichloro-2-(methylsulfanyl)pyrimidine-5-carbaldehyde To ice-cooled phosphorus oxychloride (77.62 g, 506 mmol) was added dropwise DMF (9.29 mL, 120 mmol), and the mixture was stirred at room temperature for 1 hr. 2-(Methylsulfanyl)pyrimidine-4,6-diol (15.8 g, 100 mmol) was added thereto by small portions, and the mixture was stirred at room temperature for 1 hr, at 40-50C for 1 hr, and then at 100C overnight. After cooling, the reaction mixture was poured into ice, and the mixture was extracted twice with ethyl acetate. The extract was washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate, hexane:ethyl acetate=95:5?85:15) to give the title compound (2.97 g, 13%) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) delta:2.64 (3 H, s), 10.38 (1 H, s).
Step 1. Preparation of 4,6-Dichloro-2-methylsulfsanyl-pyrimidine-5-carbaldehyde Phosphorous oxychloride (213 mL, 2.3 mol) was cooled in a sodium chloride-water ice bath to 1.8 C. under nitrogen. Dimethyl formamide (71.4 mL, 0.92 mol) was added dropwise over 45 minutes with stirring. The reaction mixture was allowed to warm up to room temperature and was stirred at room temperature for 30 minutes, and followed by stirring at 40 C. for 20 minutes. The reaction mixture was then heated to 57 C., and 2-Methylsulfanyl-pyrimidine-4,6-diol (50.0 g, 0.307 mol) was added in 5.0 g portions over 90 minutes. The reaction mixture was stirred for one hour at 55 C., and then heated to 110 C. with stirring for 17.5 hours. The reaction mixture was cooled and volatiles were removed under reduced pressure. The residue was poured into one lire of ice water. The resulting precipitate was isolated by filtration, washed with water, then with heptanes, and was dried to provide 25.2 g of crude 4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde. Mass Spec. M+H=224.
With trichlorophosphate; at 1.8 - 110℃; for 20.5h;
Phosphorous oxychloride (213 mL, 2.3 mol) was cooled in a sodium chloride-water ice bath to 1.8 C. under nitrogen. Dimethyl formamide (71.4 mL, 0.92 mol) was added dropwise over 45 minutes with stirring. The reaction mixture was allowed to warm up to room temperature and was stirred at room temperature for 30 minutes, and followed by stirring at 40 C. for 20 minutes. The reaction mixture was then heated to 57 C., and 2-Methylsulfanyl-pyrimidine-4,6-diol (50.0 g, 0.307 mol) was added in 5.0 g portions over 90 minutes. The reaction mixture was stirred for one hour at 55 C., and then heated to 110 C. with stirring for 17.5 hours. The reaction mixture was cooled and volatiles were removed under reduced pressure. The residue was poured into one litre of ice water. The resulting precipitate was isolated by filtration, washed with water, then with heptanes, and was dried to provide 25.2 g of crude 4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde. Mass Spec. M+H=224.
With trichlorophosphate; at 30℃; for 4h;Heating / reflux;
4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde. DMF (7 mL, 91 mmol) was slowly added to POCl3 (22 ml, 240 mmol) maintaining the temperature below 300C. To the resultant solution was added 2-methylsulfanyl-pyrimidine-4,6-diol (7.06 g, 44.6 mmol) maintaining the temperature below 300C. The resultant slurry was heated to reflux for 4 h. The solvent was removed and the residue was poured onto ice and extracted with EtOAc, dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (5% ethyl acetate in hexanes) gave the desired product. ESIMS calcd 224 (M+ + H), found 224 (M+ + H).
57a) 4-chloro-6-[(2,6-difluorophenyDamino]-2-(methylthio')-5- pyrimidinecarbonitrile; To the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene (46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2-(methylthio)-4(l/i)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for about 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4,6- dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61%). 1H-NMR (CDCl3) delta 2.66 (s, 3 H), 10.4 (s, I H).
61%
Example 1; N-CcvclopropylmethylV3-r8-r2,6-difluororhohenylV2-(r2-hvdroxy-l- rhvdroxymethv?ethyl"|amino)-7-oxo-718-dihvdropyridor2,3-dlpyrimidin-4-yl)-4- methylbenzamidela) 4-chloro-8-(2.6-difluorophenyl)-2-('methylthio)pyridor2.3-^)pyrimidin-7r8Hr)- oneTo the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene (46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2- (methylthio)-4(lH)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61%). 1H-NMR (CDCl3) delta 2.66 (s, 3 H), 10.4 (s, 1 H).
Example 11: Synthesis of 6-(2,4-Difluoro-phenoxy)-3-iodo-lH-pyrazolo[3,4-d]pyri- midine; Step 1. Preparation of4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde; Phosphorous oxychloride (213 mL, 2.3 mol) was cooled in a sodium chloride- water ice bath to 1.8 0C under nitrogen. Dimethyl formamide (71.4 mL, 0.92 mol) was added drop- wise over 45 min with stirring. The reaction mixture was allowed to warm up to RT and was stirred at RT for 30 min, and followed by stirring at 400C for 20 min. The reaction mixture was then heated to 570C, and 2-Methylsulfanyl-pyrimidine-4,6-diol ( 50.0 g, 0.307 mol) was added in 5.0 g portions over 90 min. The reaction mixture was stirred for one hour at 55 0C, and then heated to 1100C with stirring for 17.5 hours. The reaction mixture was cooled and volatiles were removed under reduced pressure. The residue was poured into one litre of ice water. The resulting precipitate was isolated by filtration, washed with water, then with heptanes, and was dried to provide 25.2 g of crude 4,6-Dichloro-2- methylsulfanyl-pyrimidine-5-carbaldehyde. Mass Spec. M+H = 224.Example 19: Synthesis of (i?)-l-[6-(2,4-Difluoro-phenoxy)-3-(2-ethoxy-5-fluoro- phenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-olStep 1.; Preparation of4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde; Phosphorous oxychloride (213 mL, 2.3 mol) was cooled in a sodium chloride- water ice bath to 1.8 0C under nitrogen. Dimethyl formamide (71.4 mL, 0.92 mol) was added drop- wise over 45 min with stirring. The reaction mixture was allowed to warm up to RT and was stirred at RT for 30 min, and followed by stirring at 400C for 20 min. The reaction mixture was then heated to 570C, and 2-Methylsulfanyl-pyrimidine-4,6-diol ( 50.0 g, 0.307 mol) was added in 5.0 g portions over 90 min. The reaction mixture was stirred for one hour at 55 0C, and then heated to 1100C with stirring for 17.5 hours. The reaction mixture was cooled and volatiles were removed under reduced pressure. The residue was poured into one litre of ice water. The resulting precipitate was isolated by filtration, washed with EPO <DP n="71"/>water, then with heptanes, and was dried to provide 25.2 g of crude 4,6-Dichloro-2- methylsulfanyl-pyrimidine-5-carbaldehyde. Mass Spec. M+H = 224.
4,6-Dihydroxy-2-methylthiopyrimidine (27 g; European Patent Application No. 0343752) was added portionwise to a mixture of phosphoryl bromide (196 g) and acetonitrile (500 ml). The mixture was stirred and heated to reflux for 3 hours. The mixture was evaporated and the residue was poured onto ice and extracted with diethyl ether. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 97:3 mixture of petroleum ether and ethyl acetate as eluent. There was thus obtained 4,6-dibromo-2-methylthiopyrimidine (35 g, 73%).
(1) Synthesis of an intermediate, 4,6-dibromo-2-(methylthio)pyrimidine (Compound IV-3) Into a 300 ml eggplant type flask, 4,6-dihydroxy-2-(methylthio)pyrimidine (Compound IV-124) (12.5 g, 0.079 mol) and phosphoryl tribromide (49.8 g, 0.079*2.1 mol) were introduced, and the flask was immersed in 80 C. oil bath and the solution was stirred for 30 minutes. The reaction mixture was cooled to room temperature, then ethyl acetate was added thereto and dissolved. The resulting solution was poured onto ice and an organic phase was separated. The separated organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and thereafter, the solvent was distilled off. The residue was purified on silica gel column chromatography (Wakogel C300, 300 ml, ethyl acetate/hexane=35 ml/700 ml) to obtain the compound (IV-3) as a white crystalline product from the fraction of 20 ml to 480 ml. Yield: 14.6 g. m.p. 90 to 92 C.
In ethyl acetate;
(1) Synthesis of an intermediate, 4,6-dibromo-2-(methylthio)pyrimidine (Compound No. VII-22) Into a 300 ml eggplant type flask, 4,6-dihydroxy-2-(methylthio)pyrimidine (12.5 g, 0.079 mol) and phosphoryl tribromide (49.8 g, 0.079*2.1 mol) were introduced and the flask was immersed in an 80 C. oil bath, and the mixture was then stirred for 30 minutes. The reaction mixture was allowed to cool to room temperature and dissolved in ethyl acetate, and then poured onto ice to separate an organic phase. The organic phase was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and filtered, and thereafter the solvent was distilled off. The residue was purified on silica gel column chromatography (Wakogel C300, 300 ml, ethyl acetate/hexane=35 ml/700 ml) to obtain a white crystal from the fraction of 120 ml to 480 ml. Yield: 14.6 g. Melting point: 90-92 C.
With hydrogenchloride; In sodium hydroxide; water;
EXAMPLE 12 2-Methylthio-4,6-dihydroxypyrimidine The following process is to be effected only with gas-mask and gloves. 600 g (4.15 mols) of thiobarbituric acid are dissolved in 8 l of 2N sodium hydroxide solution. 523 g (4.15 mols) of dimethyl sulphate are then added dropwise, while stirring, at room temperature, over the course of 15 minutes, whereupon the temperature rises to approximately 38. The solution is allowed to react for 3 hours without cooling; the reaction mixture is then boiled for approximately 10 minutes, treated with charcoal and after cooling, the pH value is adjusted to 1 with 900 cc of concentrated hydrochloric acid. The compound crystallizes as colorless needles while cooling with ice. Filtration is effected and the precipitate is washed with approximately 2 l of ice-cold water. Analysis: C5 H6 N2 O2 S. Molecular weight: 158.2. Calc.: C, 38.0 %; H, 3.8 %; N, 17.7 %; S, 20.3 %; O, 20.3 %. Found: C, 38.8 %; H, 3.8 %; N, 17.6 %; S, 20.2 %; O, 20.1 %.
EXAMPLE 10 2-Methylthio-4-methoxy-6-hydroxypyrimidine 15.8 g (0.2 mol) of 2-methylthio-4,6-dihydroxypyrimidine are added while stirring well, to 100 cc of 2N sodium hydroxide solution and the mixture is stirred at 50 for half an hour. The mixture is subsequently cooled to room temperature and 13.9 g (0.11 mol) of dimethyl sulphate are added dropwise, while stirring; by the addition of sodium hydroxide solution 2N the pH value is kept at between 8 and 8.2. After the dropwise addition a precipitate is obtained. The mixture is stirred at 50 for a further 21/2 hours, whereby the pH value is kept at between 8 and 8.3, then cooled to 0 and filtered. The obtained white powder has an M.P. of 193-195. Analysis: C6 H8 N2 O2 S. Molecular weight: 172.2. Calc.: C, 41.9 %; H, 4.7 %; N, 16.3 %; O, 18.6 %; S, 18.6 %. Found: C, 41.7 %; H, 4.6 %; N, 16.5 %; O, 18.8 %; S, 18.4 %.
With sodium hydroxide;
EXAMPLE 48 2-Methylthio-4-methoxy-6-hydroxypyrimidine 15.8 g (0.2 mol) of 2-methylthio-4,6-dihydroxypyrimidine are added while stirring well, to 100 cc of sodium hydroxide solution 2N and the mixture is stirred at 50 for half an hour. The mixture is subsequently cooled to room temperature and 13.9 g (0.11 mol) of dimethyl sulphate are added dropwise, while stirring; by the addition of sodium hydroxide solution 2N the pH value is kept at between 8 and 8.2. After the dropwise addition a precipitate is obtained. The mixture is stirred at 50 for a further 21/2 hours, whereby the pH value is kept at between 8 and 8.3, then cooled to 0 and filtered. The obtained white powder has a M.P. of 193-195.
EXAMPLE 9 2-Methylthio-4-ethoxy-6-hydroxypyrimidine 31.6 g (0.2 mol) of 2-methylthio-4,6-dihydroxypyrimidine are added, while stirring well, to 100 cc of 2N sodium hydroxide solution 2N and the mixture is stirred at 50 for half an hour. 34.0 g (0.22 mol) of diethyl sulphate are then added dropwise and with stirring, at 50; by the addition of 2N sodium sulphate the pH value is kept at between 8 and 8.2. Towards the end of the dropwise addition a precipitate is obtained. The mixture is subsequently stirred at 50 for 1 further hour, cooled to 0 and filtered. The precipitate is washed with cold ethanol, then with ether and dried in a high vacuum at 80. The obtained white powder has a M.P. of 185-187. Analysis: C7 H10 N2 O2 S. Molecular weight: 186.2. Calc.: C, 45.1 %; H, 5.4 %; N, 15.0 %; O, 17.2 %; S, 17.2 %. Found: C, 44.8 %; H, 5.4 %; N, 15.0 %; O, 17.6 %; S, 17.1 %.
With sodium hydroxide;
EXAMPLE 47 2-Methylthio-4-ethoxy-6-hydroxypyrimidine 31.6 g (0.2 mol) of 2-methylthio-4,6-dihydroxypyrimidine are added, while stirring well, to 100 cc of sodium hydroxide solution 2N and the mixture is stirred at 50 for half an hour. 34.0 g (0.22 mol) of diethyl sulphate are then added dropwise and with stirring, at 50; by the addition of sodium sulphate 2N the pH value is kept at between 8 and 8.2. Towards the end of the dropwise addition a precipitate is obtained. The mixture is subsequently stirred at 50 for 1 further hour, cooled to 0 and filtered. The precipitate is washed with cold ethanol, then with ether and dried in a high vacuum at 80. The obtained white powder has a M.P. of 185-187.
With sodium hydrogencarbonate; dimethyl sulfate; In water;
25.2 g (0.2 mole) of dimethyl sulfate were added to a solution of 28.8 g (0.2 mole) of 2-mercapto-4,6-dihydroxypyrimidine and 16.8 g (0.2 mole) of sodium bicarbonate in 400 ml of water. The mixture was stirred for a further hour at room temperature and the product which had precipitiated was then filtered off. This gave 10.3 g (33% of theory) of 2-methylmercapto-4,6-dihydroxypyrimidine in the form of a pink-colored powder of melting point >250 C. STR264
With sodium hydroxide; In ethanol; water; at 20 - 60℃;
Example 19; Step a: 2-Methylsulfanyl-pyrimidine-4,6-diol (19a) ; Methyl iodide (32,64g, 220 mmol) was added dropwise to a suspension of thiobarbituric acid (29g, 200 mmol) in EtOH (300ml) and 2M NaOH solution in water (110ml) at room temperature. The mixture was stirred at room temperature overnight and then stirred for two hours at 600C. The ethanol was removed, water was added and the mixture was allowed to stay for 2 hours on an ice bath. The solid title compound was filtered of, washed with ice cold water and dried (3Og, 95%).
77%
With potassium hydroxide; at 80℃; for 1h;Sealed tube;
2-Thiobarbituric acid (2,5 g, 17.4 mmol) was dissolved in KOH 10% (25 mL) and supplemented with methyl iodide (1.25 mL, 20.0 mmol). The reaction mixture was introduced in a sealed vessel and heated at 80C for 1 h. After cooling on an ice bath to 5C, the mixture was acidified by addition of hydrochloric acid 6N and the resulting precipitate was filtered off and washed with diethyl ether.Yield: 77%.Melting point: >300C.H NMR (DMSO-c/g) d 2.46 (s, 3H, S CH3), 5.13 (s, 1H, CH), 11.71 (bs, 2H, OH).13C NMR (DMSO-c/g) d 12.7 (SCH3), 85.5 (CH), 158.9 (C-4/C-6), 163.5 (C-2).
With sodium hydroxide; In ethanol; water; at 20 - 60℃;
Example 25-(2,6-dichlorobenzyl)-7-{ [2-methoxy-4-(piperazin-l-yl)phenyl]amino} [ l ,2,4]triazolo[4,3- c]pyrimidine-8-carboxamideExample 2A2-(methylthio)pyrimidine-4,6-diol; To a suspension of 2-thioxo-dihydrop rimidine-4,6(lH,5H)-dione (57.9 g, 401.6 mmol) in ethanol (600 mL) and 2M aqueous sodium hydroxide (402 mL) was added methyl iodide (570 g, 4016 mmol) dropwise at ambient temperature and the mixture was stirred overnight at ambient temperature and at 60C for 2 hours. The solvent was removed in vacuo and water was added. The mixture was cooled on an ice bath for 2 hours, filtered and the filtrate was washed with ice cold water and concentrated to give the title compound which was used in the next step without further purification. MS. 159 (M+H+).
4,6-Dihydroxy-2-(methylsulfanyl)pyrimidine (6.00 g, 38.2 mmol) in DMSO (200 mL) was treated with NaH (60% dispersion in mineral oil, 1.42 g, 35.5 mmol) and the reaction mixture was heated at 60 C under argon atmosphere for 30 min. 2-[(Diisopropoxyphosphoryl)methoxy]ethyl chloride (9.6 g, 36.2 mmol) in DMSO (20 mL) was added dropwise (30 min) and the resulting mixture was heated at 120 C for 8 h. The mixture was cooled to room temperature, poured into ice cold water (250 mL) and the product was extracted with CHCl3 (3×100 mL) and dried over MgSO4. Flash chromatography afforded 4a as a colourless oil (5.00 g, 34%), Rf 0.35 (A). 1H NMR (DMSO-d6): 12.32 (br s, 1H, OH), 5.39 (br s, 1H, H-5), 4.59 (d, JCH,CH3=6.2, JCH,P=7.8, 2H, CHipr.), 4.33 (m, 2H, H-1'), 3.80 (m, 2H, H-2'), 3.79 (d, JCH2,P=8.3, 2H, CH2P), 2.47 (s, 3H, SCH3), 1.24 (d, JCH3,CH=6.0, 6H) and 1.22 (d, JCH3,CH=6.0, 6H, CH3ipr.). 13C NMR (DMSO-d6): 169.2 (C-4), 86.1 (C-5), 70.7 (d, J2,P=11.9, C-2'), 70.4 (d, JC,O,P=6.3, CHipr.), 65.8 (C-1'), 65.0 (d, JC,P=164.5, CH2P), 24.0 (d, JCH3,P=3.6) and 23.9 (d, JCH3,P=4.4, CH3ipr.), 13.1 (SCH3). MS (ESI): m/z (%)=403 (100) [M+Na]+. HRMS (FAB) for C14H26N2O6PS [MH]+ calcd: 381.1249, found 381.1265.
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