4-chloro-2-(Methylthio)-5,6,7,8-tetrahydroquinazoline synthesis
- Product Name:4-chloro-2-(Methylthio)-5,6,7,8-tetrahydroquinazoline
- CAS Number:51660-11-8
- Molecular formula:C9H11ClN2S
- Molecular Weight:214.71
34170-21-3
51660-11-8
GENERAL STEPS: To a mixture of ethyl 2-cyclohexanone carboxylate (3.00 g, 17.6 mmol) and 2-methyl-2-thiopseudourea sulfate (3.68 g, 13.2 mmol) was added a solution of potassium carbonate (7.31 g, 52.9 mmol) in water (60 mL). The reaction mixture was stirred at room temperature for 16 h to form a suspension. The white solid product was collected by vacuum filtration, washed with water and dried under vacuum. The dried solid was dissolved in phosphoryl chloride (20 mL) and heated at 110 °C in a sealed tube until completely dissolved. After cooling to room temperature, the reaction solution was slowly poured into a mixture of crushed ice and water (300 mL). It was stirred vigorously at 0 °C for 1 h. The precipitate was collected by vacuum filtration, washed with water and dried under vacuum to give 1.61 g of 2-methylthio-4-chloro-5,6,7,8-tetrahydroquinazoline (43% yield) as an off-white solid. 2-Methylthio-4-chloro-5,6,7,8-tetrahydroquinazoline (0.5121 g, 2.39 mmol) was dissolved in a 10:1 solvent mixture of methanol-acetic acid (30 mL), and activated zinc powder (500 mg, 7.65 mmol) was added. The mixture was heated at 70 °C for 1 h and then cooled to room temperature and filtered. The filtrate was concentrated in vacuum and residual water was removed by azeotropy with toluene (50 mL). The residue was partitioned between ethyl acetate (150 mL) and 1N aqueous hydrochloric acid (50 mL), and the organic phase was washed sequentially with saturated aqueous sodium bicarbonate and brine. The organic phase was dried with anhydrous magnesium sulfate and concentrated in vacuum to give 0.1461 g of 2-methylthio-5,6,7,8-tetrahydroquinazoline (34% yield) as a purple oil. 2-Methylthio-5,6,7,8-tetrahydroquinazoline (0.1461 g, 0.81 mmol) was dissolved in dichloromethane (5 mL) and m-chloroperbenzoic acid (0.462 g, 2.68 mmol) was added. The suspension was stirred for 3 h at room temperature. After removing the solvent under vacuum, methanol (5 mL) and hydrazine monohydrate (1 mL, 20.6 mmol) were added. The mixture was heated and stirred at 50 °C for 16 hours. After cooling to room temperature, it was purified by reversed-phase HPLC to give 0.1126 g of 4-chloro-5,6,7,8-tetrahydro-2-(methylthio)quinazoline (85% yield) as a colorless oil. Mass spectrometry analysis showed [M+H]+ peak at m/z 165.
34170-21-3
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$58.00/100mg
51660-11-8
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$28.00/100mg
Yield:51660-11-8 43%
Reaction Conditions:
with trichlorophosphate at 110;
Steps:
14 Preparation 14; 2-Hydrazino-5,6, 7, 8-tetrahydroquinazoline
To a mixture of ethyl 2-cyclohexanonecarboxylate (3.00 g, 17.6 mmol) and 2-methyl-2- thiopseudourea sulfate (3.68 g, 13.2 mmol) was added a solution of potassium carbonate (7.31 g, 52.9 mmol) in water (60 mL). The reaction solution was stirred at room temperature for 16 h, at which time it was observed to be a suspension. The white solid was collected by vacuum filtration, washed with water, and dried in vacuo. A mixture of the solid in phosphorus oxychloride (20 mL) was heated at [110°C] in a sealed tube, at which time it was observed to be a solution. The solution was cooled to room temperature and was then poured over cracked ice and water (300 [ML).] The mixture was vigorously stirred at 0°C for 1 h, and the resulting precipitate was collected by vacuum filtration, washed with water, and dried in vacuo to afford 1.61 g of 2-thiomethyl-4-chloro-5, 6,7, 8-tetrahydroquinazoline (43%) as an off-white solid. To a solution [OF 2-THIOMETHYL-4-CHLORO-5,] 6,7, 8-tetrahydroquinazoline (0.5121 g, 2.39 mmol) in a 10: [1] mixture of MeOH-HOAc (30 mL) was added activated zinc dust (500 mg, 7.65 mmol). The mixture was heated at [70°C] for 1 h, and was then cooled to room temperature and filtered. The resulting solution was concentrated in vacuo, and azeotropically dried with toluene (50 mL). The residue was partitioned between EtOAc (150 mL) and 1 N aq. [HC1] (50 mL), and the organic phase was then washed with saturated aq. [NAHCO3] and brine. The organic phase was then dried over anhydrous [MGSO4] and concentrated in vacuo to provide 0.1461 g of 2- thiomethyl-5,6, 7,8-tetrahydroquinazoline (34%) as a purple oil. To a solution of 2-thiomethyl-5, 6,7, 8-tetrahydroquinazoline (0.1461 g, 0.81 mmol) in [CH2CL2] (5 mL) was added m-chloroperbenzoic acid (0.462 g, 2.68 [MMOL).] The solution was stirred at room temperature for 3 h at which time it was observed to be a suspension. The solvent was then removed in vacuo, and [MEOH] (5 [ML)] was added followed by hydrazine monohydrate (1 mL, 20.6 mmol). The solution was then heated at [50°C] and stirred for 16 h. The solution was cooled to room temperature and purified by reverse phase HPLC to give 0.1126 g of the title compound [(85%)] as a colorless oil. MH+ 165.
References:
WO2003/101442,2003,A1 Location in patent:Page 55