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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 6299-25-8 |
Formula : | C5H4Cl2N2S |
M.W : | 195.07 |
SMILES Code : | C1=C(N=C(N=C1Cl)SC)Cl |
MDL No. : | MFCD00006086 |
InChI Key : | FCMLONIWOAGZJX-UHFFFAOYSA-N |
Pubchem ID : | 80531 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H314-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338-P310 |
Class: | 8 |
UN#: | 3263 |
Packing Group: | Ⅱ |
* 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 |
---|---|---|
97.77% | With ammonia; In tetrahydrofuran; at 50 - 60℃; under 5149.01 - 5884.58 Torr;Autoclave; | [00230] Reagents[00231] Experimental procedure:.bul. ; Take ammonia in THF into a 2 L autoclave and add 4, 6-dichloro-2-(Methylthio) pyrimidine slowly..bul. Heat the reaction mixture to 50-60 ° C and maintain the reaction at 50-60 °C for 3-4 hours (Inbuilt pressure 7- 8 Kg/cm )..bul. Check the progress of the reaction by TLC. Upon completion, the reaction was brought to 25-35 ° C..bul. Concentrate the reaction mixture under vacuum..bul. Charge Hexane and stir for 30-45 minutes at 25-35 ° C..bul. Filter the solid and wash the solid with Hexane..bul. Wash the solid with water (2X400 mL)..bul. Dry the solid at 25-35 °C till M.C reaches to less than 2percent.Yield 352.0 gpercent of Yield: 97.77percent.Purity by HPLC: 99.07percent.Other suitable conditions such as ammonia in MeOH or dioxane could be used accordingly when different analogs are used. Example 1- 2. Preparation of 4-Amino-6-chloro-2- meth lthio)pyrimidine, 6.1 |
66% | With ammonia; In water; butan-1-ol; at 20 - 80℃; under 2172.08 Torr; for 0.5h; | 4,6-Dichloro-2-(methylthio)pyrimidine (10 g, 51 mmol) was dissolved in a mixtureButanol/NH4OH (100 ml/50 ml). It was stirred for V2 h in a sealed tube (internal pressure 42 PSI) heated to 8O0C. After cooling to RT, the organic layer was separated, dried over MgSO4 and concentrated. 6.0 g (66percent) of the desired intermediate was obtained as a colourless solid; mlz (ES+) 175, 177 (MH+). |
With ammonia; In water; isopropyl alcohol; at 100℃; for 15h; | Ammonium hydroxide (50 mL) was added to a solution of 4,6-dicloro-2-methylsulfanyl-pyrimidine (1.9 g, 9.7 mmol) in isopropanol (20 mL) in a sealed tube and the resulting mixture was heated to 100° C. for 15 h. The mixture was brought to RT, poured into water and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried and concentrated under vacuum to provide a white solid. MS m/z 176 (MH)+. |
With ammonium hydroxide; In ethanol; water; Petroleum ether; | Part C--4-Amino- 6-chloro-2-(methylthio)pyrimidine A reaction mixture consisting of 124.7 g. (0.64 mole) 4,6-dichloro-2-(methylthio)pyrimidine (prepared as in Part B, above), 500 ml. ethanol, and 250 ml. of substantially saturated aqueous ammonia was heated, with stirring, at 100° C. in an autoclave for 6 hrs. After cooling the reaction mixture, water was added, and a precipitate formed. The precipitate was collected on a filter, and recrystallized from a mixture of ether and petroleum ether to give 40 g. of the desired 4-amino-6-chloro-2-(methylthio)pyrimidine having a melting point at 130° to 131° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With N,N-diethylaniline; trichlorophosphate; at 0℃; for 2.5h;Heating / reflux; | 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, 97%). |
93% | With oxalyl dichloride; N,N-dimethyl-formamide; In toluene; for 6h;Reflux; | Take a 2L four-necked bottle, configure mechanical agitation, reflux condenser, exhaust gas absorption device, constant pressure dropping funnel and thermometer, and add 4,6-dihydroxy-2-methylthiopyrimidine (100g) to toluene (100g) 1000 mL), N,N-dimethylformamide (4.61 g), oxalyl chloride (241 g) was added dropwise at room temperature.After the dropwise addition is completed, the mixture is heated to reflux and kept for 6 hours. After the reaction is completed, the reaction liquid is cooled to 45 to 55 C, and the solvent is distilled off under reduced pressure. After substantially no solvent evaporation, toluene is added, and the product is cooled to room temperature. Filter through celite and concentrate the filtrate.Obtaining 115 g of 4,6-dichloro-2-methylthiopyrimidine product,The yield was 93% and the purity was 98.5%. |
65% | With trichlorophosphate; at 105 - 110℃; for 6h; | 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 (3% ethyl acetate in hexane) to afford the desired product as a white solid (10 g, 65% yield). 1H NMR (CDCl3, 400 MHz): delta 7.03(s, 1H), 2.58 (s, 3H). |
With trichlorophosphate; | (1) Synthesis of an intermediate, 4,6-dichloro-2-(methylthio)pyrimidine (Compound IV-5) Into a 500 ml eggplant type flask, 4,6-dihydroxy-2-(methylthio)pyrimidine (Compound IV-124) (75.0 g, 474 mmol) and phosphorus oxychloride (250 g, 474*3.44 mmol) were introduced. After stirred for 2 hours at 100 C., HPLC monitoring showed the presence of 96.8% of the end product (Rt=4.5 min, acetonitrile/water=70/30 (v/v), 1 ml/min, 250 nm). After allowed to cool to room temperature, the reaction solution was carefully poured into iced water, extracted with ethyl acetate (500 ml). The organic phase was washed successively with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate, and thereafter, the solvent was distilled off to obtain the compound (IV-5). Yield: 92.3 g (99.8%). Purity 96.8%. (Rt=4.5 min: ODS411A, acetonitrile/water=70/30 (v/v), 1 ml/min, 250 nm). | |
With trichlorophosphate; at 120℃; for 4h; | Example 2B4,6-dichloro-2-(methyIthio)pyrimidine; A mixture of the product of Example 2 A (30 g, 190 mmol) and phosphorus oxychloride (1 17 g, 760 mmol) was heated at 120ftC for 4 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was poured into ice-water and the resulting solid was filtered to give the title compound. MS: 195 (M+H+). | |
With triethylamine; trichlorophosphate; In chlorobenzene; at 40 - 80℃; | Example 8: Preparation of 2-methylthio-4, 6-dichloropyrimidine To 4m monochlorobenzene, 1.0 m 2-methylthio-4,6-dihydoxypyrimidine was added. To this, 2.2m POCl3 was added in 1 to 2 hours and 2.2 m triethylamine was added over 2 to 4 hours at 40-50C.The obtained mixture was heated to 80C which resulted in a clear solution and stirred for 4-8 hours to obtain a mass. The obtained mass was cooled to 60C. To this 2.0m phosphorus trichloride was added. Then 2.0m chlorine was fed in 6-10 hours at 60C and stirred at 60C for 8 to 10 hours. Cl2 feeding was carried out in absence of light to avoid side chain chlorination. POCl3 was vacuum distilled and 200ml monochlorobenzene was added and continued the distillation to ensure complete removal of POCl3. 4.0m to 4.3m POCl3 was recovered; the residual mass was drowned in 200ml ice water and extracted with monochlorobenzene. To the monochlorobenzene layer, 100 ml water was added and neutralized with NaHC03. The layers were separated and monochlorobenzene layer was concentrated under vacuum. Yield of product was 85-87%. Product was vacuum distilled and then crystallized using methanol to get 85 mole % with 99% purity. | |
With triethylamine; trichlorophosphate; for 3h;Reflux; | General procedure: To a stirred solution of 2-methyl-2-thiopseudourea sulfate (8.35 g, 60 mmol) in ethanol 120 mL was added 1,3-dicarbonyl derivatives (50 mmol) and sodium hydroxide (2.4 g, 60mmol) at room temperature, and then heated at refluxed for 4 h. After this time, the reaction mixture was cooled to room temperature, the residue was precipitated and filtered, yielding compounds 3 as white solid. The solid was dried in vacuum and used directly to react with POCl3 (40 mL) in the presence of NEt3 (5.05 g, 50 mmol) heated at reflux for 3 h. The solvent was evaporated under reduced pressure, the residue was dissolved in 100 mL ethyl acetate and washed with saturated sodium bicarbonate, saturated sodium chloride, dried (MgSO4), filtered, and concentrated under reduced pressure. The desired products 4-chloro-2-(methylthio)pyrimidines 4a-4f were obtained by recrystallization from the mixed solvent of EtOAc-petroleum ether. Yields, melting points and spectroscopic data for selected 2-(methylsulfonyl)pyrimidines are listed as follows. 4,6-dichloro-2-(methylthio)pyrimidine (4a) White crystals, yield 72%, m.p. 38-39 C; IR (KBr, cm-1): 3104, 3003, 1539, 1501, 1266, 1092, 815; 1H NMR (400 MHz, CDCl3): delta 2.57 (s, 3H, SCH3), 7.03 (s, 1H, pyrimidine-H). 13C NMR (100 MHz, CDCl3): delta 14.43, 115.75, 161.33, 174.50; LC-MS (m/z): 193.9. Anal. Calcd for C5H4Cl2N2S: C, 30.79; H, 2.07; N, 14.36; Found: C, 30.85; H, 2.12; N, 14.16. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | To a solution of Compound 1 ( 5.00 g, 25.6 mmol ) and methyl 1-hydroxy-l- cyclopropane carboxylate ( 3.97 g, 30.8 mmol ) in THF ( 100 mL ) was added sodium hydride ( 60 %, 1.23 g, 30.8 mol ) at -78 C and the mixture was stirred at room temperature for 3hours. The reaction mixture was quenched with 1 M aqueous citric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( hexane : ethyl acetate = 15 : 1 ) to give Compound 2 ( 6.91 g, 98 % ) as a solid. MS: 275/277 [M+H]+, APCI |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h; | To a slurry of 4,6-dicUoro-2-(methyltMo)pyrimidine (1-1) (1.00 g, 5.13 mmol, 1.0 eq.) and cesium carbonate (2.70 g, 7.67 mmol, 1.5 eq.) in DMF (40 mL) at 0 °C under nitrogen was added a solution of 3,5-dimethyl-lH-l,2,4-triazole (498 mg, 5.13 mmol, 1.0 eq.) in DMF (20 mL) via a dropping funnel over 1 hour. The reaction was then warmed to room temperature. The reaction was monitored by TLC and was complete after 1 hour. The reaction was quenched by addition of water (100 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (0-50percent ethyl acetate in hexanes) to afford 4-cMoro-6-(3,5-dimemyl-lH-l,2,4-triazol-l-yl)-2-(m (1-2) as a white solid. 1HNMR (300 MHz, CDC13) delta 7.58 (s, 1H), 2.90 (s, 3H), 2.60 (s, 3H), 2.41 (s, 3H). LRMS mlz (M+H) 256 found, 256 required. |