2,4,6-Trichloropyrimidine-5-carboxaldehyde (CAS: 50270-27-4) is an aniline derivative. It has been shown to inhibit nucleophilic substitutions involving flavin and metal ions.
Application In Synthesis of [ 50270-27-4 ]
* 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.
With triethylamine; hydrazine In methanol at -10℃; for 2 h;
(2) To a solution of the compound obtained in the above step (1) (40 g) in methanol (950 mL) was added dropwise a solution of hydrazine monohydrate (9.45 mL) in methanol (240 mL) at -10 °C and thereto was added dropwise a solution of triethylamine (26.8 mL) in methanol (240 mL) at -10 °C. The mixture was stirred at the same temperature for 2 hours and evaporated in vacuo. The residue was suspended in hot isopropyl alcohol and the insoluble materials were removed by filtration. The combined filtrate was concentrated in vacuo to give 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (23.49 g, yield: 67 percent) as a yellow amorphous solid. MS(APCI)m/z; Not detectable.
66.8%
With hydrazine hydrate; triethylamine In methanol at -10℃;
Step 2: To a solution of 1f (38.0g, 0.18mol, 1eq) in methanol (700mL) was added drop-wise a solution of hydrazine monohydrate (9.2mL) in methanol (180mL) at -100C and thereto was added drop-wise a solution of triethylamine (25.5mL) in methanol (180mL) at -100C. The mixture was stirred at the same temperature for 30min, the solvent was removed and the residue was purified by column chromatography to afford 7b (22.7g, yield: 66.8percent) as a light yellow solid. 1H NMR(CDCl3, 300MHz, ppm): δ=11.25(s, 1H), 8.23(s, 1H).
62%
With hydrazine hydrate; triethylamine In methanol at 0℃; for 0.5 h;
To a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (19.0 g, 990 mmol) in methanol (300 mL) was added drop-wise a solution of hydrazine monohydrate (4.8 mL) in methanol (80 mL) at 0 °C followed by drop-wise addition of triethylamine (13 mL) in methanol (80 mL) at 0 °C. The mixture was stirred at the same temperature for 30 mm. The solvent was removed and the residue was purified by flash chromatography to afford the title compound (10.3 g, 62percent yield) as a yellow solid. ‘H NMR (CDC13, 400IVIHz): 11.56 (br, 1H), 8.43 (s, 1H). MS m/z 190.68 [M+1].
56.3%
With hydrazine hydrate; triethylamine In methanol at -10℃; for 0.5 h;
At -10 willCompound 3 (100 mg, 0.47 mmol)In methanol was slowly added dropwise to a methanolic solution of hydrazine hydrate (0.024 ml)A solution of triethylamine (0.067 ml) in methanol was then added dropwiseTo the above mixture,Continue at -10 Reaction time 30 min.TLC detection (PE: EA = 2: 1),Raw material reaction is complete,Spin drying solvent,Column chromatography (PE: EA = 10: 1) gaveWhite solid 4 (50 mg), yield 56.3percent
40%
With hydrazine hydrate; triethylamine In tetrahydrofuran at -10℃; for 0.5 h;
To a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (3.50 g, 16.6 mmol) in THF (50 mL)was added N2H4.H20 (830 mg, 16.6 mmol) slowly at-lO °C. Then, Et3N (2.51 g, 24.9 mmol)was added to the mixture at -10 00. The mixture was stirred at -10 °C for 30 mm. The mixture was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the title compound (1.25 g, yield 40percent) as a yellow solid. 1H NMR (300 MHz, CDCI3): 611.61 (brs, 1H), 8.25 (s, IH).LCMS [mobile phase: 5-95percent CH3CNJ: Rt = 2.005 mm;MS Calcd: 188; MS Found: 189 [M+H].
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 24, p. 6830 - 6835
3
[ 60-34-4 ]
[ 50270-27-4 ]
[ 98141-42-5 ]
Yield
Reaction Conditions
Operation in experiment
78%
With triethylamine In ethanol; water at -78 - 0℃; for 2.5 h;
To a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (8 g, 37.84 mmol, 1.00 equiv) in ethanol (120 mL) was added a 40percent water solution of methylhydrazine (4 mL, 37.98 mmol, 1.00 equiv) and triethylamine (16 mL) at -78° C. The resulting mixture was stirred for 30 min at -78° C. and then 2 h at 0° C. After completion the reaction was concentrated under vacuum without heating. Then ethyl acetate was added and the solution was washed with saturated ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum without heating. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:1) to afford 6 g (78percent) of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine as a white solid. LC-MS (ES, m/z): 203 [M+H]+.
78%
With triethylamine In ethanol; water at -78 - 0℃; for 2.5 h;
To a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (8 g, 37.84 mmol, 1.00 equiv) in ethanol (120 mL) was added a 40percent water solution of methylhydrazine (4 mL, 37.98 mmol, 1.00equiv) and triethylamine (16 mL) at -78 °C. The resulting mixture was stuffed for 30 mm at -78 °C and then 2h at 0 °C. After completion the reaction was concentrated under vacuum without heating. Then ethyl acetate was added and the solution was washed with saturated ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum without heating. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:1) to afford 6 g (78percent) of4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine as a white solid. LC-MS (ES, m/z): 203 [M+H] .
44.9%
With triethylamine In ethanol; water at -70 - 0℃; for 2.5 h;
To a stirred solution of 2 4 6-trichloropyrimidine-5-carbaldehyde (18.5 g 88.1 mmol) in EtOH (250 mL) was added methyl hydrazine (6.8 g 88.1 mmol 60in water) and Et3N (26.7 g 264.4 mmol) at-70 and stirred for 30 min before it was allowed to warm up to 0 and stirred for another 2 h. After TLC (petroleum etherEtOAc 51) showed that the reaction was completed the mixture solution was concentrated in vacuo at room temperature. EtOAc (200 mL) was added and the resulting solution was washed washed with saturated aqueous NaHCO3solution and brine. The organic layer was dried over anhydrous Na2SO4 filtered and concentrated in vaouoto give a crude product which was purified by silica gel flash chomatography (petroleum etherEtOAc 201) to afford title compound (8 g 44.9yield) as a white solid. MS 203.2 [M+H]+.
Stage #1: for 15 h; Reflux Stage #2: With sodium hydrogencarbonate In water; ethyl acetate
Intermediate M(l)A solution of pyrimidine-2,4,6-triol (10.0 g, 78.2 mmol), DMF (12 mL) in POCl3 (10 vol.) was heated at reflux for 15 h. The excess of POCI3 was evaporated under reduced pressure. The residue was poured in to crushed ice. The precipitated solid was filtered and washed with water to give 2,4,6-trichloropyrimidine-5-carbaldehyde (8.0 g, 47percent) as yellow solid. This compound was taken to the next step without further purification.
36%
Reflux
A mixture of pyrimidine-2,4,6-triol (20.0 g, 156 mmol) in DMF (20 mL) and POCI3 (200 mL)was refluxed overnight. The mixture was concentrated. The residue was poured into ice-water (1 L) and filtered. The solid was collected and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1)to give the title compound (12.0 g, yield 36percent) as a yellow solid.1H NMR (CDCI3, 300 MHz): 6 10.41 (s, 1H).
A mixture of barbituric acid (5 g, 78.1 mmol) in POCl3 (47 mL) and DMF (6 mL) was heated at 1200C for 15 h; and then evaporated in vacuo to give a thick oily residue. To the residue at 0 0C, was added icy water to give a yellow precipitate. The precipitate was collected by vacuum filtration and was rinsed with water to give Compound 7A (14.45 g, 88percent). 1H NMR (CD3Cl) δ 11.45 (s, IH).
77.2%
at 120℃; for 16 h;
Step 1: DMF (24mL) was added drop-wise to POCl3 (150mL, 1.61mol, 6.9eq) at a temperature below 00C and barbituric acid(30.0g, 234mmol, 1eq) was added portion- wise to the mixture. The mixture was stirred at 120 0C for 16h. Excess amount of POCl3 was removed in vacuo and the resulting residue was gradually poured to ice water. The mixture was extracted with DCM (100mL) three times, the organic layer was washed with sat. NaHCO3 solution, dried and concentrated to give 1f (38.0g, yield: 77.2percent) as a yellow solid. 1H NMR(CDCl3, 300MHz, ppm): δ=10.41 (s, 1H).
75%
at -2 - 120℃; for 22 h;
To a 25 ml dry two neck flask34.6 ml of POCl was added,Cooled in a low temperature cooling tank at -2 ° C,0.6 ml of dry DMF was added dropwise,Compound 2 (1 g, 7.8 mmol) was added portionwise,The reaction was carried out at 120 ° C for 22 h,TLC detection (DCM: MeOH = 10: 1), The basic reaction of raw materials completely,The reaction solution was slowly poured into ice water,A yellow solid precipitation,Filtration gave a tan solid,EA extract filtrate,concentrate,Combine the column chromatography (PE: EA = 200: 1) to give white solid 3 (1.2 mg)Yield 75percent.
74%
Stage #1: at 10 - 90℃; for 26 h;
2,4,6-Trichloropyrimidine-5-carbaldehydeDry DMF (33 ml) was added drop-wise to a cooled (10-15 0C) phosphorus oxychloride (315 ml). Then barbituric acid (45 g) was added at once upon effective stirring. The suspension was left overnight at room temperature after which it was heated at 50 0C for 6 h and at 90 0C for 20 h. Remainder OfPOCl3 was evaporated and the residue was poured on crushed ice (700 g) and water (400 ml). Light yellow precipitate was filtered, the solid washed with water, and dried. Crude product was dissolved in dichloromethane (500 ml) and an insoluble material was filtered off. Evaporation of solvent afforded 57.4 g (74percent) of 2,4,6-trichloropyrimidine-5- carbaldehyde , m.p. 129-130 0C.
70%
Stage #1: at 10℃; for 0.333333 h; Stage #2: at 10 - 90℃;
(1) N,N-Dimethylformamide (39.3 mL) was added dropwise to phosphorus oxychloride (250 mL) at a temperature bellow 10 °C and thereto was added portionwise barbituric acid (50 g) over a period of 20 minutes and the mixture was stirred at room temperature and then stirred at 90 °C overnight. The reaction mixture was evaporated to remove excess amount of phosphorus oxychloride. The resultant residue was gradually poured to water under stirring. The mixture was extracted with chloroform and the organic layer was dried over sodium sulfate and concentrated in vacuo. The resultant precipitates were triturated in isopropylether and collected by filtration to give 5-formyl-2,4,6-trichloropyrimidine (57.5 g, yield: 70 percent) as yellow crystals. MS(APCI)m/z; Not detectable.
Reference：
[1] Chemical Communications, 2010, vol. 46, # 35, p. 6527 - 6529
[2] Journal of the American Chemical Society, 2010, vol. 132, # 43, p. 15136 - 15139
[3] Patent: WO2008/39359, 2008, A2, . Location in patent: Page/Page column 38
[4] Patent: WO2010/56320, 2010, A2, . Location in patent: Page/Page column 59; 60
[5] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 5, p. 584 - 589
[6] Patent: , 2016, , . Location in patent: Paragraph 0019
[7] Patent: WO2006/128954, 2006, A1, . Location in patent: Page/Page column 8
[8] Journal of Labelled Compounds and Radiopharmaceuticals, 2014, vol. 57, # 13, p. 705 - 709
[9] Patent: EP1772454, 2007, A1, . Location in patent: Page/Page column 58
[10] MedChemComm, 2017, vol. 8, # 3, p. 640 - 646
[11] Journal of the American Chemical Society, 2001, vol. 123, # 16, p. 3854 - 3855
[12] Organic and Biomolecular Chemistry, 2015, vol. 13, # 18, p. 5082 - 5085
[13] Journal of Organic Chemistry, 2008, vol. 73, # 11, p. 4248 - 4251
[14] Journal of Medicinal Chemistry, 2009, vol. 52, # 22, p. 7081 - 7089
[15] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 2, p. 636 - 639
[16] Helvetica Chimica Acta, 2006, vol. 89, # 12, p. 2987 - 3001
[17] Journal of Organic Chemistry, 2013, vol. 78, # 21, p. 10666 - 10677
[18] Patent: US2008/234262, 2008, A1, . Location in patent: Page/Page column 50; 83
[19] Patent: US2009/98086, 2009, A1, . Location in patent: Page/Page column 58-59
[20] Patent: US2009/162319, 2009, A1, . Location in patent: Page/Page column 139
[21] Patent: US2010/15141, 2010, A1, . Location in patent: Page/Page column 17
[22] Journal of Medicinal Chemistry, 2009, vol. 52, # 24, p. 8010 - 8024
[23] Patent: US2012/208808, 2012, A1, . Location in patent: Page/Page column 17
[24] Patent: WO2016/130920, 2016, A2, . Location in patent: Page/Page column 118; 119
[25] ACS Chemical Neuroscience, 2017, vol. 8, # 11, p. 2522 - 2534
With sulfur trioxide; In diethyl ether; sulfuric acid;
EXAMPLE 5 Production of 2,4,6-trichloropyrimidine-5-carboxylic acid (intermediate) To a solution of 63.3 g (0.3 mol) of 2,4,6-trichloro-5-formylpyrimidine in 300 ml of fuming sulfuric acid (SO3 content 25%) are added in flake form 24 g (0.24 mol) of chromium trioxide, and the mixture is stirred for 20 hours. The temperature rises within about one hour to 45-50 C., and then falls again to room temperature (20-25 C.). The reaction solution is poured into ice water, and the precipitate is filtered off and washed with a small amount of ice-water. The reaction product is dissolved in diethyl ether; the solution is then dried over sodium sulfate and subsequently evaporated to dryness. The yield is 55.4 g (81.2%) of 2,4,6-trichloropyrimidine-5-carboxylic acid, m.p. about 150 C. The melting point can be raised to 155-157 C. by recrystallisation of the product from chloroform.
With triethylamine; hydrazine; In methanol; at -10℃; for 2h;
(2) To a solution of the compound obtained in the above step (1) (40 g) in methanol (950 mL) was added dropwise a solution of hydrazine monohydrate (9.45 mL) in methanol (240 mL) at -10 °C and thereto was added dropwise a solution of triethylamine (26.8 mL) in methanol (240 mL) at -10 °C. The mixture was stirred at the same temperature for 2 hours and evaporated in vacuo. The residue was suspended in hot isopropyl alcohol and the insoluble materials were removed by filtration. The combined filtrate was concentrated in vacuo to give 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (23.49 g, yield: 67 percent) as a yellow amorphous solid. MS(APCI)m/z; Not detectable.
66.8%
With hydrazine hydrate; triethylamine; In methanol; at -10℃;
Step 2: To a solution of 1f (38.0g, 0.18mol, 1eq) in methanol (700mL) was added drop-wise a solution of hydrazine monohydrate (9.2mL) in methanol (180mL) at -100C and thereto was added drop-wise a solution of triethylamine (25.5mL) in methanol (180mL) at -100C. The mixture was stirred at the same temperature for 30min, the solvent was removed and the residue was purified by column chromatography to afford 7b (22.7g, yield: 66.8percent) as a light yellow solid. 1H NMR(CDCl3, 300MHz, ppm): delta=11.25(s, 1H), 8.23(s, 1H).
62%
With hydrazine hydrate; triethylamine; In methanol; at 0℃; for 0.5h;
To a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (19.0 g, 990 mmol) in methanol (300 mL) was added drop-wise a solution of hydrazine monohydrate (4.8 mL) in methanol (80 mL) at 0 °C followed by drop-wise addition of triethylamine (13 mL) in methanol (80 mL) at 0 °C. The mixture was stirred at the same temperature for 30 mm. The solvent was removed and the residue was purified by flash chromatography to afford the title compound (10.3 g, 62percent yield) as a yellow solid. ?H NMR (CDC13, 400IVIHz): 11.56 (br, 1H), 8.43 (s, 1H). MS m/z 190.68 [M+1].
56.3%
With hydrazine hydrate; triethylamine; In methanol; at -10℃; for 0.5h;
At -10 willCompound 3 (100 mg, 0.47 mmol)In methanol was slowly added dropwise to a methanolic solution of hydrazine hydrate (0.024 ml)A solution of triethylamine (0.067 ml) in methanol was then added dropwiseTo the above mixture,Continue at -10 Reaction time 30 min.TLC detection (PE: EA = 2: 1),Raw material reaction is complete,Spin drying solvent,Column chromatography (PE: EA = 10: 1) gaveWhite solid 4 (50 mg), yield 56.3percent
40%
With hydrazine hydrate; triethylamine; In tetrahydrofuran; at -10℃; for 0.5h;
To a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (3.50 g, 16.6 mmol) in THF (50 mL)was added N2H4.H20 (830 mg, 16.6 mmol) slowly at-lO °C. Then, Et3N (2.51 g, 24.9 mmol)was added to the mixture at -10 00. The mixture was stirred at -10 °C for 30 mm. The mixture was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the title compound (1.25 g, yield 40percent) as a yellow solid. 1H NMR (300 MHz, CDCI3): 611.61 (brs, 1H), 8.25 (s, IH).LCMS [mobile phase: 5-95percent CH3CNJ: Rt = 2.005 mm;MS Calcd: 188; MS Found: 189 [M+H].
With triethylamine; hydrazine; In methanol;
Step A: 4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidine; 4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidine can be prepared according to previously described procedures (see Takamuro et al., EP 1 772 454 A1, filed Jul. 22, 2005) according to the scheme below:
With triethylamine; In ethanol; water; at -78 - 0℃; for 2.5h;
To a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (8 g, 37.84 mmol, 1.00 equiv) in ethanol (120 mL) was added a 40% water solution of methylhydrazine (4 mL, 37.98 mmol, 1.00 equiv) and triethylamine (16 mL) at -78 C. The resulting mixture was stirred for 30 min at -78 C. and then 2 h at 0 C. After completion the reaction was concentrated under vacuum without heating. Then ethyl acetate was added and the solution was washed with saturated ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum without heating. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:1) to afford 6 g (78%) of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine as a white solid. LC-MS (ES, m/z): 203 [M+H]+.
78%
With triethylamine; In ethanol; water; at -78 - 0℃; for 2.5h;
To a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (8 g, 37.84 mmol, 1.00 equiv) in ethanol (120 mL) was added a 40% water solution of methylhydrazine (4 mL, 37.98 mmol, 1.00equiv) and triethylamine (16 mL) at -78 C. The resulting mixture was stuffed for 30 mm at -78 C and then 2h at 0 C. After completion the reaction was concentrated under vacuum without heating. Then ethyl acetate was added and the solution was washed with saturated ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum without heating. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:1) to afford 6 g (78%) of4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine as a white solid. LC-MS (ES, m/z): 203 [M+H] .
44.9%
With triethylamine; In ethanol; water; at -70 - 0℃; for 2.5h;
To a stirred solution of 2 4 6-trichloropyrimidine-5-carbaldehyde (18.5 g 88.1 mmol) in EtOH (250 mL) was added methyl hydrazine (6.8 g 88.1 mmol 60in water) and Et3N (26.7 g 264.4 mmol) at-70 and stirred for 30 min before it was allowed to warm up to 0 and stirred for another 2 h. After TLC (petroleum etherEtOAc 51) showed that the reaction was completed the mixture solution was concentrated in vacuo at room temperature. EtOAc (200 mL) was added and the resulting solution was washed washed with saturated aqueous NaHCO3solution and brine. The organic layer was dried over anhydrous Na2SO4 filtered and concentrated in vaouoto give a crude product which was purified by silica gel flash chomatography (petroleum etherEtOAc 201) to afford title compound (8 g 44.9yield) as a white solid. MS 203.2 [M+H]+.
With triethylamine; In ethanol; at -78 - 0℃; for 2.5h;
Example 2; 4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (Scheme 1)To a solution of the chloroaldehyde (3.7 g, 17.5 mmol) dissolved in EtOH (50 mL) and cooled to 78 C. is added methyl hydrazine (0.93 mL, 17.5 mmol) and TEA (8 mL). The mixture is stirred for 30 min. at -78 C. then 2 hr at 0 C. The solution is then concentrated in vacuo without heating. To the reduced volume solution is added EtOAc and the solution washed with a sat. NaHCO3 solution and concentrated in vacuo without heating. Filtration over a small silica gel plug (2:1 EtOAc:Hex) and concentration affords the desired product as a yellow solid.
With triethylamine; In ethanol; at -78 - 0℃; for 2.5h;
To a solution of 2,4,6-trichloro-pyrimidine-5-carbaldehyde (3.7 g, 17.5 mmol) in EtOH (50 mL) cooled to -78 C. was added methyl hydrazine (0.93 mL, 17.5 mmol) and TEA (8 mL). The mixture was stirred for 30 minutes at -78 C then 2 hr at 0 C. The solution was concentrated in vacuo without heating. To the reduced volume solution was added EtOAc and the solution washed with a sat NaHCO3 solution and concentrated in vacuo without heating. Filtration over a small silica gel plug (2:1 EtOAc:Hex) and concentration afforded the desired product as a yellow solid. It should be noted that the reaction with aromatic hydrazine compounds can be conducted at 0 C.
With triethylamine; In ethanol; at -78 - 0℃; for 2.5h;
To a solution of the chloroaldehyde (3.7 g, 17.5 mmol) dissolved in EtOH (50 mL) cooled to -78 C. was added methyl hydrazine (0.93 mL, 17.5 mmol) and TEA (8 mL). The mixture was stirred for 30 minutes at -78 C. then 2 hr at 0 C. The solution was concentrated in vacuo without heating. To the reduced volume solution EtOAc was added and the solution washed with a sat NaHCO3 solution and concentrated in vacuo without heating. Filtration over a small silica gel plug (2:1 EtOAc:Hex) and concentration afforded the desired product as a yellow solid.
With triethylamine; In 1,4-dioxane; at 110℃; for 1h;
76.23 mul of methylhydrazine, 196.7 ml of triethylamine are added to a solution of 300 mg of ?1? in 12.5 ml of 1,4-dioxane, and the mixture is stirred for one hour at 110. The mixture is subjected to conventional work-up, giving 210.9 mg of ?2?.
4.1.12 General procedure for the synthesis of compounds 22a-h
General procedure: The suspension of 8 (13.50g, 64.31mmol) in EtOH (200mL) was stirred at -78°C for 10min, followed by dropwise addition of corresponding hydrazines (77.17mmol) and Et3N (13.5mL, 97.12mmol) in EtOH (200mL). After 1h, the reaction mixture was warmed up to room temperature for 1h. The mixture was concentrated and purified by silica gel flash column chromatography to afford compounds 22a-h in moderate yield.
With triethylamine at -78℃;
4.1.12 General procedure for the synthesis of compounds 22a-h
General procedure: The suspension of 8 (13.50g, 64.31mmol) in EtOH (200mL) was stirred at -78°C for 10min, followed by dropwise addition of corresponding hydrazines (77.17mmol) and Et3N (13.5mL, 97.12mmol) in EtOH (200mL). After 1h, the reaction mixture was warmed up to room temperature for 1h. The mixture was concentrated and purified by silica gel flash column chromatography to afford compounds 22a-h in moderate yield.
With triethylamine; In ethanol; at -78 - 20℃; for 3h;
Step 1: Synthesis of l-tert-butyl-4,6-dichloro-lH-pyrazolo[3,4-d]pyrimidine (0742) [00268] To a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (5.0 g, 23.8 mmol) in EtOH (100 mL), stirred at -78°C was added Et3N (7.18 g, 71.1 mmol) followed by tert- butylhydrazine hydrochloride (2.97 g, 23.8 mmol) and the mixture was further stirred at the same temperature for lh.; the cooling bath was then removed and the mixture allowed to warm to room temperature for over 2h. The reaction mixture was concentrated and the resulting residue was purified by chromatographic column on silicagel eluted with 15percent EtOAc in petroleum ether to give l-tert-butyl-4,6-dichloro-lH-pyrazolo[3,4-d]pyrimidine (5 g, 86 percent yield) as white solid. ESI-LCMS (m/z): 245.1 found for [M+H]+.
73%
With triethylamine; In ethanol; at -78 - 0℃; for 5h;Inert atmosphere;
To 2,4,6-trichloropyrimidine-5-carbaldehyde (2 g, 9.46 mmol) in EtOH (25 mL) at -78 °C under argon were added tert-butylhydrazine hydrochloride (1.18 g, 9.46 mmol) and TEA (6 mL, 42.57 mmol) dropwise. The mixture was stirred at -78 °C for 2 h, then at 0 °C for 3 h. The mixture was then concentrated under reduced pressure onto Celite and purified by silica gel chromatography eluting with 0- 1percent) MeOH in DCM to afford l-tert-butyl-4,6-dichloro-lH-pyrazolo[3,4-d]pyrimidine (1.7 g, 73percent) as an oil that solidified upon standing. LCMS (ESI) m/z 245 (M + H)+.
With triethylamine In ethanol at -78 - 0℃; for 4h; Inert atmosphere;
29.A
To 2,4,6-trichloropyrimidine-5-carbaldehyde (582 mg, 2.75 mmol) in EtOH (7 mL) at -78 °C under argon was added 4-(2- hydrazinylethyl)morpholine hydrochloride (0.5 g, 2.75 mmol) followed by dropwise addition of TEA (1.72 mL, 12.37 mmol). The mixture was stirred at -78 °C for 2 h, then at 0 °C for 2 h. The mixture was concentrated under reduced pressure onto Celite and purified by silica gel chromatography eluting with 0-12% MeOH in DCM to afford 4-(2-(4,6-dichloro-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)morpholine (242 mg, 29%) as a solid. LCMS (ESI) m/z 302 (M + H)+.
With N-ethyl-N,N-diisopropylamine In ethanol at -78 - 20℃; for 3h; Inert atmosphere;
90%
With triethylamine In isopropyl alcohol at -10℃; for 1h;
4 Example 4 Synthesis of Compound A2
Dissolve 2,4,6-trichloropyrimidine-5-carbaldehyde(100g, 473mmol) in 750mL of isopropanol, lower the temperature to about -10 ° C, stir, and dissolve isopropylhydrazine hydrochloride (55g, 497mmol) in 250mL of isopropyl In alcohol, add dropwise to the above solution, dissolve triethylamine (98.1 g, 970 mmol) in 50 mL of isopropanol, slowly add dropwise to the reaction solution, stir for about 1 hour at about -10 ° C, suction filter,Compound A1 (99 g, 90%) was obtained.
87%
With triethylamine In ethanol at -78 - 20℃;
17 Example 17. Preparation of 4,6-dichloro-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidine
[00180] A solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (1.0 g, 4.7 mmol) and isopropylhydrazine hydrochloride (522 mg, 4.7 mmol) in ethanol (10 mL) stirred at -78 °C was treated with slow addition of triethylamine (1.42 g, 14.0 mmol). Then the mixture was warmed up to room temperature and stirred for 5 h., concentrated under vacuum at room temperature, diluted with water (10 mL) and extracted with EtOAc (20 ml mL X 2). The combined organic layers were washed with brine (20 mL), dried over Na2S04, filtered and concentrated to give 4,6-dichloro-l-isopropyl-lH- pyrazolo[3,4-d]pyrimidine (946 mg, 87 % yield) which was used directly without further purification. ESI-LCMS (m/z): 231.1 [M+l]+.
87%
With triethylamine In ethanol at 20℃; for 5h;
17.1 Example 17. Preparation of 4,6-dichloro-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine
A solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (1.0 g, 4.7 mmol) and isopropylhydrazine hydrochloride (522 mg, 4.7 mmol) in ethanol (10 mL) stirred at -78 °C was treated with slow addition of triethylamine (1.42 g, 14.0 mmol). Then the mixture was warmed up to room temperature and stirred for 5 h., concentrated under vacuum at room temperature, diluted with water (10 mL) and extracted with EtOAc (20 ml mL X 2). The combined organic layers were washed with brine (20 mL), dried over Na2S04, filtered and concentrated to give 4,6-dichloro-l-isopropyl-lH- pyrazolo[3,4-d]pyrimidine (946 mg, 87 % yield) which was used directly without further purification. ESI-LCMS (m/z): 231.1 [M+l]+.
87%
With N-ethyl-N,N-diisopropylamine In ethanol at -78℃; for 3h;
22.1 Step 1: Preparation of 4,6-dichloro-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine
2.22 g of 2,4,6-trichloropyrimidine-5-carbaldehyde (10.49 mmol) was dissolved in 30 ml of ethanol, and 1.16 g of isopropyl hydrazine hydrogen chloride (10.49 mmol) and 5.5 ml of N,N-diisopropylethylamine (31.47 mmol) was added at -78°C and stirred for 3 hours. After completion of the reaction, the resultant was extracted with 200 ml of ethyl acetate, washed with 200 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate = 10:1, v/v) to give 2.1 g of the title compound (9.08 mmol) in 87% yield.Rf= 0.48 (hexane:ethyl acetate = 10:1, v/v) 1H NMR (500 MHz, CDCl3 δ 8.16 (s, 1H), 5.16-5.22 (m, 1H), 1.60 (d, J = 6.7 Hz, 6H)
70%
With triethylamine In ethanol at -78 - 20℃; for 10h;
1 Example 1Synthesis of Compound M- 1 of Formula (M-1)
10035] 2,4,6-trichloro-5-pyrimidinecarbaldehyde (424 mg, 2 mmol), isopropylhydrazine hydrochloride (221 mg, 2 mmol), triethylamine (505 mg, 5 mmol) were reacted in ethanol (40 ml) at temperature -78° C. for 2 hours; the temperature was raised to room temperature, and the mixture was further reacted for 8 hours; the solvent was removed by rotatary evaporation, and the reaction product was extracted using ethyl acetate and dried by anhydrous sodium sulfate; the solvent was evaporated by reducing the pressure and the reaction product was separated and purified through rapid colunm chromatography; finally 323 mg white solids were obtained, and the yield was 70%.10036] MS (ESIj: mlz: 231 ([M+H]j; ‘H NMR (400MHz, CDC13) ö 8.13 (s, 1H), 5.16 (hept, J=6.8 Hz, 1H), 1.57(d, J=6.7 Hz, 6H).
70%
With triethylamine In ethanol at -78 - 20℃; for 10h;
1 Synthesis of compound M-1 having the structural formula represented by the formula (M-1)
A mixture of 2,4,6-trichloropyrimidine formaldehyde (424 mg, 2 mmol)Isopropylhydrazine hydrochloride (221 mg, 2 mmol),Triethylamine (505 mg, 5 mmol) at -78 & lt; 0 & gt; C,In ethanol (40 mL) for 2 hours,The reaction was carried out at room temperature for 8 hours. The solvent was dried, extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and purified by flash column chromatography to give 323 mg of white solid in 70%
36%
With triethylamine In ethanol at -78 - 20℃;
1.2 Preparation of compound (1b)
Dissolve compound 1a (15g, 71mmol) and isopropylhydrazine hydrochloride (8.6g, 78mmol) in ethanol (100150mL), and slowly add triethylamine dropwise at -78 (20mL), after reacting for 2 hours, move to room temperature and react overnight.After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, ethyl acetate was added, and the insoluble matter was removed by suction filtration. The filtrate was rotary evaporated under reduced pressure to remove the solvent, and purified by column to obtain a brown-red solid (6 g, yield 36%) which is Compound (1b)
With triethylamine In ethanol at -78 - 0℃; for 2.5h;
2.1 Compound 4.121 : N6-[(2R)-2-amino-2-phenyl-ethyl]-N4-tert-butyl-1-cyclopropyl- pyrazolo[3,4-d]pyrimidine-4, 6-diamine
Step 1 : To a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (1.00 g, 4.73 mmol) in ethanol (10 ml_) at -78 °C was added triethylamine (1.6 ml_, 11.8 mmol) and cyclopropyl hydrazine hydrochloride (0.54 g, 4.97 mmol) and the resulting yellow mixture was allowed to stir at -78 °C for 30 minutes and warmed to 0 °C for a further 2 hours. The solvent was removed in vacuo (keeping the water bath at 20 °C). The resulting yellow solid was dissolved in ethyl acetate (10 ml_) and washed with saturated ammonium chloride solution (5 ml_). The layers were separated and the aqueous layer extracted twice more with ethyl acetate (2 x 10 ml_). The organic layers were combined and washed with brine (5 ml_), dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow solid which was purified by silica gel chromatography eluting with 0-100% ethyl acetate: heptane to yield 4,6-dichloro- 1-cyclopropyl-pyrazolo[3,4-d]pyrimidine (670 mg, 62%) as a white solid. LCMS (Analytical Method A) tR= 1.18 min, [M+H]+= 228.8/230.85; 1 H NMR (500 MHz, DMSO-d6) d 8.48 (s, 1 H), 3.93 - 3.88 (m, 1 H), 1.23 - 1.14 (m, 4H).
48%
With triethylamine In ethanol at -78 - 20℃; for 5h;
20 Example 20. Preparation of 4,6-dichloro-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidine
A solution of cyclopropylhydrazine hydrochloride (1.2 g, 7.5 mmol) in EtOH (20 ml) was slowly added to a solution of 2, 4, 6-trichloropyrimidine-5-carbaldehyde (1.43 g, 6.8 mmol) and Et3N (2.8 ml, 20.4 mmol) in EtOH (20 ml) stired at -78 °C. The resulting mixture was then warmed to room temperature and further stirred at the same temperature for 10 min. EtOAc (150 ml) was added, and the organic layer was washed with water (100 mL X 2) and brine (100 ml); dried over Na2S04, filtered and concentrated. The residue was purified by chromatographic column on silica gel (petroleum ether/EtOAc = 15/1) to give 4,6-dichloro-l- cyclopropyl -lH-pyrazolo[3,4-d]pyrimidine (1.1 g, 48 % yield). ESI-LCMS (m/z): 229.1 [M+l] +.
48%
With triethylamine In ethanol at -78 - 20℃;
20 Example 20. Preparation of 4,6-dichloro-l-cyclopropyl-lH-pyrazolo[3,4-d]pyrimidine
Example 20. Preparation of 4,6-dichloro-l-cyclopropyl-lH-pyrazolo[3,4-d]pyrimidine [00189] A solution of cyclopropylhydrazine hydrochloride (1.2 g, 7.5 mmol) in EtOH (20 ml) was slowly added to a solution of 2, 4, 6-trichloropyrimidine-5-carbaldehyde (1.43 g, 6.8 mmol) and Et3N (2.8 ml, 20.4 mmol) in EtOH (20 ml) stired at -78 °C. The resulting mixture was then warmed to room temperature and further stirred at the same temperature for 10 min. EtOAc (150 ml) was added, and the organic layer was washed with water (100 mL X 2) and brine (100 ml); dried over Na2S04, filtered and concentrated. The residue was purified by chromatographic column on silica gel (petroleum ether/EtOAc = 15/1) to give 4,6-dichloro-l- cyclopropyl -lH-pyrazolo[3,4-d]pyrimidine (1.1 g, 48 % yield). ESI-LCMS (m/z): 229.1 [M+l] +.
45%
With N-ethyl-N,N-diisopropylamine In ethanol at -78℃; for 3h;
23.1 Step 1: Preparation of 4,6-dichloro-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidine
1.95 g of 2,4,6-trichloropyrimidine-5-carbaldehyde (9.21 mmol) was dissolved in 30 ml of ethanol, and 1 g of cyclopropyl hydrazine hydrogen chloride (9.21 mmol) and 4.8 ml of N,N-diisopropylethylamine (27.63 mmol) were added at -78°C and stirred for 3 hours. After completion of the reaction, the resultant was extracted with 200 ml of ethyl acetate, washed with 200 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate = 10:1, v/v) to give 950 mg of the title compound (4.15 mmol) in 45% yield. Rf= 0.45 (hexane:ethyl acetate = 10:1, v/v) 1H NMR (500 MHz, CDCl3 δ 8.10 (s, 1H), 3.88-3.92 (m, 1H), 1.35-1.38 (m, 2H), 1.21-1.25 (m, 2H)
With N-ethyl-N,N-diisopropylamine In ethanol at -78 - 20℃; for 3h; Inert atmosphere;
1 4,6-Dichloro-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine
4,6-Dichloro-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine To a solution of 7,4,6-trichloro-5-pyrimidinecarboxaldehyde (6.00 g, 28.38 mmol) in EtOH (120 mL) was cooled to -78° C. and added isopropylhydrazine hydrochloric (3.14 g, 28.38 mmol) under a N2 atmosphere. To a solution was added DIPEA (14.83 mL, 85.14 mmol) dropwise. The mixture was stirred at -78° C. for 2 h and then warmed up to rt and stirred at this temperature for 1 h. Water (60 mL) was added to the reaction solution and concentrated under reduced pressure. The mixture was extracted with EtOAc, washed with brine and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give title compound (6.15 g, 94%) as white solids. 1H NMR (400 MHz, CDCl3): δ 8.14 (s, 1H), 5.18 (sept, J=6.8 Hz, 1H), 1.58 (d, J=6.8 Hz, 6H). LCMS: m/z=231 [M+H]+.
87%
With N-ethyl-N,N-diisopropylamine In ethanol at -78℃; for 3h;
12.1 Step 1:Preparation of 4,6-dichloro-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine
2.22 g of 2,4,6-trichloropyrimidine-5-carbaldehyde (10.49 mmol) was dissolved in 30 ml of ethanol, and 1.16 g of isopropyl hydrazine hydrogen chloride (10.49 mmol) and 5.5 ml of N,N-diisopropylethylamine (31.47 mmol) were added at -78°C, followed by stirring for 3 hours. After completion of the reaction, the resultant was extracted with 200 ml of ethyl acetate, washed with 200 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate = 10:1, v/v) to give 2.1 g of the title compound (9.08 mmol) in 87% yield. Rf = 0.48 (hexane:ethyl acetate = 10:1, v/v) 1H NMR (500 MHz, CDCl3)δ 8.16 (s, 1H), 5.16-5.22 (m, 1H), 1.60 (d, J = 6.7 Hz, 6H)
Dissolve 2,4,6-trichloropyrimidine-5-carbaldehyde (100 g, 473 mmol) in 750 mL of methanol, lower the temperature to about -10 C, stir, and dissolve c<strong>[24214-72-0]cyclopentylhydrazine hydrochloride</strong>(67.8 g, 497 mmol) in 200 mL of water and 50 mL of methanol In a mixed solvent, the solution was added dropwise, diethylamine (70.9 g, 970 mmol) was dissolved in 150 mL of methanol, and slowly added to the reaction solution. The temperature was controlled at about -10 C and stirred for about 1 hour. Compound A3 (100 g, 82.1%) was obtained.
73%
With triethylamine; In ethanol; at -78 - 20℃; for 10h;
A mixture of 2,4,6-trichloropyridine formaldehyde(424 mg, 2.0 mmol),Isopentylhydrazine hydrochloride (300 mg, 2.2 mmol),Triethylamine (404 mg, 4.0 mmol) was dissolved in ethanol (40 mL). The mixture was stirred at -78 C for 2 hours and then allowed to warm to room temperatureContinued reaction for 8 hours. Dried solvent, extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and purified to give a white solid (373 mg, 73%).
Step 2. 2,4,6-trichloropyrimidin-5-formonitrile 2,4,6-trichloropyrimidin-5-carboxaldehyde (10 g, 47.4 mmol), hydroxylamine hydrochloride (3.3 g, 47.5 mmol), glacial acetic acid (100 mL), and H2O (5 mL) were added to a 150-mL round-bottom flask, and heated to 60 C. to react for 1 hour. After the completion of the reaction, the reaction solution was poured into crushed ice, and was extracted with CH2Cl2. The resultant organic phases were combined, washed with a saturated NaCl solution, dried with anhydrous Na2SO4, and then filtered and concentrated. The obtained substance was dissolved in SOCl2 (60 mL), reacted at room temperature for 10 minutes, and then heated for a reflux reaction for 2 hours. After the completion of the reaction, the resultant mixture was subjected to reduced pressure distillation to remove SOCl2 to give a residue, which was then dissolved in EtOAc and washed with H2O. The resultant organic phase was dried with anhydrous Na2SO4, filtered, and concentrated to obtain an oily substance of 9 g. The yield was 92%.
ethyl 3-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In tetrahydrofuran; water; at -78 - -10℃; for 2.5h;Inert atmosphere;
To a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (3.9 g, 18.5 mmol) in tetrahydrofuran (100 mL) was added dropwise a solution of ethyl 3-hydrazinobenzoate hydrochloride (4.0 g, 18.5 mmol) in tetrahydrofuran/ water (50 mL, v: v = 9: 1) at -78 C under nitrogen atmosphere. Then triethylamine (7.7 mL, 55.4 mmol) was added dropwise and the mixture was stirred at -78 C for 30 minutes under nitrogen atmosphere. Then the mixture was warmed to -10 C and stirred for further 2 h. Upon completion of the reaction, the solvent was removed in vacuo. The residue was purified with silica gel column chromatography (ethyl acetate: petroleum ether = 1: 10) to give 1.01 g of the product (batch contained impurities) as a light yellow solid. MS (ESIpos): m/z = 337 (M+H)+
4,6-dichloro-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With N-ethyl-N,N-diisopropylamine In ethanol at -78℃; for 3h;
2.1 Step 1: Preparation of 4,6-dichloro-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine
340 mg of 2,4,6-trichloropyrimidine-5-carbaldehyde (1.61 mmol) was dissolved in 6 ml of ethanol, and 300 mg of (4,4-difluorocyclohexyl)hydrazine hydrogen chloride (1.61 mmol) obtained in Preparation Example 1 Step 3 and 0.86 ml of N,N-diisopropylethylamine (4.82 mmol) were added at -78°C and stirred for 3 hours. After completion of the reaction, the resultant was extracted with 100 ml of ethyl acetate, washed with 100 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 10:1, v/v) to give 360 mg of the title compound (1.17 mmol) in 73% yield.Rf= 0.35 (hexane:ethyl acetate = 10:1, v/v) 1H NMR (300 MHz, DMSO-d6) δ 8.57 (s, 1H), 4.97-5.04 (m, 1H), 2.13-2.23 (m, 6H), 2.03-2.07 (m, 2H)
With N-ethyl-N,N-diisopropylamine In ethanol at -78℃; for 3h;
20.1 Step 1: Preparation of 4,6-dichloro-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine
5.9 g of 2,4,6-trichloropyrimidine-5-carbaldehyde (27.97 mmol) obtained in Preparation Example 19 was dissolved in 60 ml of ethanol, and 4.7 g of (tetrahydro-2H-thiopyran-4-yl)hydrazine hydrogen chloride (27.97 mmol) obtained in Step 3 above and 15 ml of N,N-diisopropylethylamine (83.91 mmol) were added at -78°C and stirred for 3 hours. After completion of the reaction, the resultant was extracted with 200 ml of ethyl acetate, washed with 200 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na2SO4), and the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate = 5:1, v/v) to give 7 g of the title compound (24.20 mmol) in 86% yield. Rf=0.41 (hexane:ethyl acetate = 10:1, v/v)1H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H), 4.78-4.85 (m, 1H), 2.93-2.98 (m, 2H), 2.73-2.78 (m, 2H), 2.15-2.25 (m, 4H)
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