* 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 potassium acetate In 1,4-dioxane at 115℃; for 16 h;
Method 12; Synthesis of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine-2,4-diamine; [0252] To a dry 1 L flask was added 5-bromopyrimidine-2,4-diamine (30.0 g, 158.7 mmol), potassium acetate (45.8 g, 466.7 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (51.16g g, 202.2 mmol) and dioxane (50O mL). Argon was bubbled through the solution for 15 minutes, at which time l,l'-bis(diphenylphosphino)ferrocene palladium(II) chloride (2.53 g, 3.11 mmol) was added. The reaction was refluxed in a 115 0C oil bath for 16 hours under argon. After cooling to room temperature, the solid inorganic material was filtered, rinsed with EtOAc (1 L). The organic filtrate was concentrated in vacuo and to the resulting solid was added dichloromethane (1 L). After sonication the solid was filtered. The solid was the debrominated 2,4-diaminopyrimidine. The filtrate containing desired boronate ester was concentrated in vacuo. To this residue was added diethyl ether (10O mL). After <n="66"/>sonication, the solution was filtered, rinsed with additional diethyl ether (50 mL) and the solid obtained was dried under high vacuum to yield the desired 2,4-diaminopyrimidyl-5- boronate ester (10.13 g, 27percent). By 1H NMR the material was a 4:1 mixture of 2,4- diaminopyrimidyl-5-boronate ester and 2,4-diaminopyrimidine byproduct. The material was used as is in subsequent Suzuki reactions LCMS (m/z): 155 (MH+ of boronic acid, deriving from in situ product hydrolysis on LC); 1H NMR (CDCI3+CD3OD): δ 8.16 (s, IH), 1.34 (s, 12H).
With manganese(II) chloride tetrahydrate In water at 80℃; for 24 h;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
Reference：
[1] Patent: US2416617, 1944, ,
[2] Journal of the American Chemical Society, 1951, vol. 73, p. 3758,3760
5
[ 77287-34-4 ]
[ 156-81-0 ]
[ 849585-22-4 ]
[ 617-48-1 ]
[ 2491-15-8 ]
[ 110-15-6 ]
[ 108-53-2 ]
[ 71-30-7 ]
[ 113-00-8 ]
[ 127-17-3 ]
[ 66-22-8 ]
[ 66224-66-6 ]
[ 56-40-6 ]
[ 302-72-7 ]
[ 18514-52-8 ]
Yield
Reaction Conditions
Operation in experiment
0.18 mg
With ferric sulfate nonahydrate In water at 80℃; for 24 h;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
With copper(II) choride dihydrate In water at 80℃; for 24 h;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
Reference：
[1] Journal of the American Chemical Society, 1950, vol. 72, p. 2587,2593
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 1, p. 240 - 253
9
[ 3934-20-1 ]
[ 156-81-0 ]
Reference：
[1] Journal of the Chemical Society, 1948, p. 2240,2246
[2] Journal of the Society of Chemical Industry, London, 1950, vol. 69, p. 353
10
[ 156-83-2 ]
[ 156-81-0 ]
Reference：
[1] Chemische Berichte, 1903, vol. 36, p. 2234
[2] Chemische Berichte, 1903, vol. 36, p. 2234
11
[ 98198-74-4 ]
[ 156-81-0 ]
Reference：
[1] American Chemical Journal, 1905, vol. 34, p. 190
Reference：
[1] Chemische Berichte, 1903, vol. 36, p. 2234
14
[ 67-56-1 ]
[ 155-90-8 ]
[ 7664-41-7 ]
[ 156-81-0 ]
Reference：
[1] Journal of the American Chemical Society, 1946, vol. 68, p. 99
15
[ 98198-74-4 ]
[ 156-81-0 ]
Reference：
[1] American Chemical Journal, 1905, vol. 34, p. 190
16
[ 3934-20-1 ]
[ 7664-41-7 ]
[ 7758-99-8 ]
[ 108-95-2 ]
[ 156-81-0 ]
Reference：
[1] Journal of the Society of Chemical Industry, London, 1950, vol. 69, p. 353
17
[ 7647-01-0 ]
[ 156-83-2 ]
[ 156-81-0 ]
Reference：
[1] Chemische Berichte, 1903, vol. 36, p. 2234
18
[ 156-81-0 ]
[ 68-12-2 ]
[ 20781-06-0 ]
Yield
Reaction Conditions
Operation in experiment
59%
Stage #1: at 25℃; for 0.25 h; Cooling with ice Stage #2: at 0 - 25℃; for 24 h;
General procedure: Vilsmeier reagent was prepared by mixing ice-cold dry DMF (50 ml) and POCl3 (30.0 mmol, 2.8 ml). The mixture was stirred for 15 min at 25 °C. To the previous mixture, aminopyrimidines (10.0 mmol) in dry DMF (5.0 ml) were added over a period of 15 min at 0-5 °C. The reaction mixturewas stirred for 24 h at 25 °C.The mixture was then added to cold, saturated aq. K2CO3 andextracted with diethyl ether. The organic layer was washed withwater, dried over anhydrous Na2SO4, and evaporated underreduced pressure to afford the crude product, whichwas purified ina silica gel column chromatography using hexane/ethyl acetate(9:1) as an eluent to give the title compounds 2 and 8. 4.3.1. 2,4-Diaminopyrimidine-5-carbaldehyde (2) Brown powder, yield 59percent; 1H-NMR [DMSO-d6, 400 MHz]: (δ,ppm) 7.10 (d, 2H, NH2, exchange with D2O), 7.52 (d, 2H, NH2, exchangewith D2O), 8.32 (s, 1H, H6-pyrimidine), 9.45 (CHO); 13C NMR[DMSO-d6, 100 MHz]: (δ, ppm) 106.2 (C5-pyrimidine), 162.7(C4-pyrimidine), 164.4 (C6-pyrimidine), 167.0 (C2-pyrimidine),189.5 (CHO).
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 136, p. 270 - 282
19
[ 77287-34-4 ]
[ 51953-18-5 ]
[ 156-81-0 ]
[ 113-00-8 ]
[ 66-22-8 ]
[ 56-06-4 ]
[ 57-13-6 ]
Yield
Reaction Conditions
Operation in experiment
0.1 mg
With manganese(II) chloride tetrahydrate In water at 80℃; for 24 h;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
With copper(II) choride dihydrate In water at 80℃; for 24 h;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
With ferric sulfate nonahydrate In water at 80℃; for 24 h;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
Stage #1: With Iodine monochloride In methanol at 25℃; for 15 h; Stage #2: With sodium hydroxide In water at 25℃; for 2 h;
To a flame-dried 100 mL round-bottom flask was added 2,4-diaminopyrimidine (1.0 g, 9.08 mmol) in MeOH (30 mL) followed by dropwise addition of ICl (30 mL, 29.06 mmol). The solution was stirred at 25° C. for 15 h and then the solvent removed under reduced pressure. The resulting viscous oil was stirred in Et2O (40 mL) for 45 min. The resulting solid was filtered off and washed with Et2O (3.x.10 mL) to afford the HCl salt as a yellow solid (3.14 g). The crude salt was suspended in 1.0 N NaOH (100 mL) and stirred at 25° C. for 2 h. The solids were filtered, washed with water (2.x.10 mL), and dried to afford 2,4-Diamino-5-iodopyrimidine as a brown powder (1.71 g, 80percent). An analytical sample was prepared by recrystallization from MeCN to give 2,4-Diamino-5-iodopyrimidine as colorless crystals: Rf=0.25 (9:1, CHCl3:MeOH); mp=212-214° C.; 1H NMR (DMSO-d6) δ 7.92 (s, 1H), 6.40 (s, 2H), 6.10 (s, 2H); 13C NMR (DMSO-d6) δ 162.8, 162.7, 162.0, 61.2; HREI[M+]235.9559 (calculated C4H5IN4: 235.9559); Anal. (C4H5IN4) C, H, N.
Reference：
[1] Nucleosides, Nucleotides and Nucleic Acids, 2009, vol. 28, # 4, p. 275 - 291
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 5, p. 940 - 950
[3] Patent: US2009/105287, 2009, A1, . Location in patent: Page/Page column 26
[4] Chemical Communications, 2015, vol. 51, # 32, p. 7043 - 7046
Second amine displacement was typically conducted at a higher temperature in NMP, for example for 48 hours at 120-130 C. The resin was again washed and treated with 100% TFA for 0.5-1 hours to obtain the 2,4-diaminopyrimidine, which was frequently obtained as a solid after lyophilization from a mixture of acetonitrile and water.
Method C Nitropyrimethamine (0.01 mol. equiv.), the substituted benzylamine hydrochloride salt (0.04 mol. equiv), triethylamine (0.04 mol. equiv) and 2-ethoxyethanol (30 ml) were refluxed for 10 h. The mixture was poured into ether (50 ml) and the product collected and washed with ether, followed by water. Crystallization from aqueous 2-ethoxyethanol afforded the diaminopyrimidine.
... 2, characterized by the fact that the respective persilylated pyrimidine derivatives are converted with metallo-organic compounds such as butyl lithium or sodium amide, converting compound III formed in the reaction mixture directly with halogenosis II. 6-methylene substituted nucleosides of 4-hydroxypyrimidine, 4-aminopyrimidine, 2-amino-4-hydroxypyrimidine and 2,4-diaminopyrimidine
Part C: The product from Part B (1.23 g) was dissolved in a mixture of methanol (30 mL) and acetic acid (1.5 mL). To this solution at 0 was added iron powder (0.78 g), the mixture was first allowed to come to room temperature, and then was refluxed for 2.5 hr. Additional iron powder (0.78 g) and acetic acid (1.5 mL) was added and reflux was continued for another 1.5 hr. The cooled reaction mixture was filtered through a pad of filter-aid, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated in vacuo, and partitioned between ethyl acetate and water, the aqueous layer was extracted three times with ethyl acetate and the combined extracts were dried over sodium sulfate and concentrated in vacuo to a brown solid. Chromatography on silica gel (ethyl acetate/hexanes 1:1) afforded the intermediate diaminopyrimidine (0.56 g).
To a flame-dried 100 mL round-bottom flask was added <strong>[156-81-0]2,4-diaminopyrimidine</strong> (1.0 g, 9.08 mmol) in MeOH (30 mL) followed by dropwise addition of ICl (30 mL, 29.06 mmol). The solution was stirred at 25 C. for 15 h and then the solvent removed under reduced pressure. The resulting viscous oil was stirred in Et2O (40 mL) for 45 min. The resulting solid was filtered off and washed with Et2O (3×10 mL) to afford the HCl salt as a yellow solid (3.14 g). The crude salt was suspended in 1.0 N NaOH (100 mL) and stirred at 25 C. for 2 h. The solids were filtered, washed with water (2×10 mL), and dried to afford 2,4-Diamino-5-iodopyrimidine as a brown powder (1.71 g, 80%). An analytical sample was prepared by recrystallization from MeCN to give 2,4-Diamino-5-iodopyrimidine as colorless crystals: Rf=0.25 (9:1, CHCl3:MeOH); mp=212-214 C.; 1H NMR (DMSO-d6) delta 7.92 (s, 1H), 6.40 (s, 2H), 6.10 (s, 2H); 13C NMR (DMSO-d6) delta 162.8, 162.7, 162.0, 61.2; HREI[M+]235.9559 (calculated C4H5IN4: 235.9559); Anal. (C4H5IN4) C, H, N.
1.85 g
With N-iodo-succinimide; acetic acid; In methanol; at 0 - 35℃; for 2h;
a) 5-iodo<strong>[156-81-0]pyrimidine-2,4-diamine</strong> NIS (2.30 g) was added to a mixture of <strong>[156-81-0]pyrimidine-2,4-diamine</strong> (1.12 g), acetic acid (20 mL) and methanol (20 mL) at 0 C. The mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with a saturated aqueous sodium thiosulfate solution at 0 C., and neutralized with 8N aqueous sodium hydroxide solution. The precipitate was collected by filtration and washed with water to give the title compound (1.85 g). 1H NMR (300 MHz, DMSO-d6) delta 6.07 (2H, s), 6.35 (2H, brs), 7.92 (1H, s).
Synthesis of 3-Methyl-8-thiouric Acid (25) Intermediate The <strong>[156-81-0]pyrimidinediamine</strong> 33 (100 mg, 0.63 mmol) was combined with potassium ethyl xanthate (810 mg, 5 mmol) and DMF (10 mL) and heated at 100 C. The suspension became green almost immediately and reaction was complete after 30 min. by TLC. After a total reaction time of 1 h, the mixture was cooled, filtered and washed with Et2O, dried to yield an off-white solid (310 mg) which presumably contained the unreacted potassium ethyl xanthate and the potassium salt of the desired product. The solid was suspended in water (5 mL) and heated to dissolve. Glacial acetic acid was added to pH 5 and a vigorous effervescence was noted. A white solid formed which was filtered warm and washed with water, then ethanol and dried to yield 99 mg (79%) of the title compound. 1H NMR (DMSO-d6) delta13.40, 12.92 and 11.80 (3br s, 3H, NHs), 3.28 (s, 3H, CH3). Analysis: C6H6N4O2S (C, H, N; Table 2).
99 mg (79%)
In water; acetic acid; N,N-dimethyl-formamide;
Synthesis of 3-Methyl-8-thiouric acid (25) intermediate The <strong>[156-81-0]pyrimidinediamine</strong> 33 (100 mg, 0.63 mmol) was combined with potassium ethyl xanthate (810 mg, 5 mmol) and DMF (10 mL) and heated at 100 C. The suspension became green almost immediately and reaction was complete after 30 min. by TLC. After a total reaction time of 1 h, the mixture was cooled, filtered and washed with Et2O, dried to yield an off-white solid (310 mg) which presumably contained the unreacted potassium ethyl xanthate and the potassium salt of the desired product. The solid was suspended in water (5 mL) and heated to dissolve. Glacial acetic acid was added to pH 5 and a vigorous effervescence was noted. A white solid formed which was filtered warm and washed with water, then ethanol and dried to yield 99 mg (79%) of the title compound. 1 H NMR (DMSO-d6) delta13.40, 12.92 and 11.80 (3br s, 3H, NHs), 3.28 (s, 3H, CH3). Analysis: C6 H6 N4 O2 S (C, H, N; Table 2).
99 mg (79%)
In water; acetic acid; N,N-dimethyl-formamide;
Synthesis of 3-Methyl-8-thiouric acid (25) intermediate: The <strong>[156-81-0]pyrimidinediamine</strong> 33 (100 mg, 0.63 mmol) was combined with potassium ethyl xanthate (810 mg, 5 mmol) and DMF (10 mL) and heated at 100 C. The suspension became green almost immediately and reaction was complete after 30 min. by TLC. After a total reaction time of 1 h, the mixture was cooled, filtered and washed with Et2O, dried to yield an off-white solid (310 mg) which presumably contained the unreacted potassium ethyl xanthate and the potassium salt of the desired product. The solid was suspended in water (5 mL) and heated to dissolve. Glacial acetic acid was added to pH 5 and a vigorous effervescence was noted. A white solid formed which was filtered warm and washed with water, then ethanol and dried to yield 99 mg (79%) of the title compound. 1H NMR (DMSO-d6) delta 13.40, 12.92 and 11.80 (3br s, 3H, NHs), 3.28 (s, 3H, CH3). Analysis: C6H6N4O2S (C, H, N; Table 2).
2-[(2-aminopyrimidin-4-yl)amino]-1,3-thiazole-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; methanol; N,N-dimethyl-formamide; butan-1-ol;
2-[(2-aminopyrimidin-4-yl)amino]-1,3-thiazole-5-carbonitrile (2-3) 2,4-Diaminopyrimidine, 2-1, (0.1 g, 0.908 mmol) was dissolved in DMF and then sodium hydride (0.036 g of a 60% dispersion, 0.908 mmol) was added and stirred for 15 minutes at 25 C. and then <strong>[51640-36-9]2-chloro-1,3-thiazole-5-carbonitrile</strong>, 2-2, (0.131 g, 0.908 mmol) was added. This was heated at 100 C. for 2 hours. After this time the reaction was diluted with 4 mL of methanol and loaded onto a C18 prep lc column. The product, 2-3, was isolated via lyophilization from dioxane. 1H-NMR (DMSO): 8.42 ppm (s, 1H); 8.10 ppm (d, 1H); 6.45 ppm (d, 1H). 4,6-diaminopyrimidine hemisulfate, hemisulfate of 3-1, (0.10 g, 0.314 mmol) and diisopropylethylamine (0.122 g, 0.942 mmol) were suspended in n-butanol (1 mL) and then solid <strong>[51640-36-9]2-chloro-1,3-thiazole-5-carbonitrile</strong> 2-2 (0.091 g, 0.628 mmol) was added and heated at 125 C. for 18 hours. The product 3-2 was purified on C18 preparative hplc and the product was isolated upon evaporation. Hi-Res MS: calc: 219.0448 found: 219.0448. 1H-NMR (DMSO): 8.36 ppm (s, 1H); 8.26 ppm (s, 1H); 7.20 ppm (s, 1H); 6.12 pm (s, 1H).
With sodium hydroxide; In ethanol; water; ethyl acetate;
EXAMPLE 3 Imidazo[1,2-a]pyrimidin-7-amine, 2-Phenyl-3-(4-pyridinyl) A solution of 1.2 g (11 mmoles) of <strong>[156-81-0]2,4-diaminopyrimidine</strong> in 10 ml of ethanol was heated to 80 C. A solution of 1.0 g (2.8 mmol) of the bromide in 20 ml of ethanol was added drop-wise by addition funnel. The reaction was stirred at 80 C. for 3 hours then cooled to room temperature. Approximately one-half of the solvent was removed in vacuo. Upon cooling to room temperature the reaction was filtered. The filtrate was concentrated in vacuo, diluted with 250 ml ethyl acetate and washed with 2*100 ml 0.5M sodium hydroxide solution, dried over sodium sulfate, filtered, and concentrated in vacuo to give a red-brown oil. Trituration of the residue with EtOAc, followed by filtration gave 0.108 g of Compound 5 as an off-white solid. MH+=288. 13.23 g (93.2 mmoles) of lodomethane was added drop-wise by syringe to a solution of 13.38 g (84.73 mmoles) of 2-mercapto-4-methylpyrimidine hydrochloride and 7.46 g (186.4 mmoles) sodium hydroxide in 120 ml of water. After 2 hours the reaction was extracted with 2*125 ml dichloromethane. The organic layers were separated, combined, dried over Na2SO4, filtered, and concentrated in vacuo to give 11.14 g (79.45 mmoles) of 4-methyl-2-(methylthio)pyrimidine as a red oil. MH+=140.9.
With hydrogen bromide; bromine; In sodium hydroxide; ethanol; water; acetic acid;
9 ml (44.91 mmoles) of 30% hydrogen bromide in acetic acid was added to 1 0.45 g (42.77 mmoles) of the ketone in 80 ml glacial acetic acid. A solution of 2.40 ml (46.19 mmoles) of bromine in 2.60 ml glacial acetic acid was added drop-wise and the reaction heated to 60 C. for 45 minutes, cooled to room temperature, and diluted with ether. The resultant slurry was filtered and washed with ether and dried in vacuo to give 18.06 g (44.69 mmolese of the crude bromide. MH+=324.9. A solution of 18.83 g (171.08 mmoles) of <strong>[156-81-0]2,4-diaminopyrimidine</strong> in 150 ml ethanol was heated to 80 C. A solution of 18.06 g (42.77 mmoles) of the crude bromide in 350 ml ethanol was added drop-wise by addition funnel. The reaction was stirred at reflux for two hours. Upon cooling to room temperature the reaction was filtered. The precipitate was stirred in 150 ml of 0.5M sodium hydroxide solution. The precipitate was collected by filtration, washed with water, ether and hexane to give 6.72 g (21.1 mmoles) of the product as a light yellow solid. MH+=334.9. A mixture of 0.60 g (1.79 mmoles) of the thiomethylpyrimidine, approximately 4 ml of a 50% Raney Nickel in water solution, 40 ml ethanol and 20 ml water was refluxed for eighteen hours under a nitrogen atmosphere. The reaction was cooled to room temperature and filtered through celite. The celite was washed with ethanol. The combined filtrates were concentrated in vacuo. The residue was collected by trituration with ethanol, collected by filtration and washed with ether to give 0.2310 g of the pyrimidine as a yellow solid (Compound 16). MH+=289.0.
With potassium carbonate; In N,N-dimethyl-formamide;
Step A Synthesis of 2,4-diaminopyrimidine as an intermediate This compound was prepared in a manner analogous to that of Example 2, Step E, using 7.3 grams (0.075 mole) of 3-ethoxyacrylonitrile, 28.7 grams (0.300 mole) of guanidine hydrochloride and 55.3 grams (0.400 mole) of powdered potassium carbonate in 250 mL of N,N-dimethyl-formamide. The yield of 2,4-diaminopyrimidine was 7.0 grams; mp 146-147 C. The NMR spectrum was consistent with the proposed structure.
To a stirring mixture of <strong>[156-81-0]2,4-diaminopyrimidine</strong> (25 g, 0.23 mol, 1.0 eq) in acetic acid (375 ml) was added Br2 (36.3 g, 0.23 mol, 1.0 eq) at room temperature. The resulting mixture was stirred at room temperature (about 25 C.) for 2 hours and then filtered. The yellow solid was mixed with water (250 ml) and the pH of the resulting mixture was adjusted to 8-9 using 50% NaOH solution. Stirring was continued at room temperature for 30 min and the mixture was filtered, washed with water, and then dried under vacuum to give 38 g (87%) of 2,4-diamino-5-bromo-pyrimidine as a white solid. 1H NMR (400 MHz, d6-DMSO) delta 6.06 (s, 2H, ex. D2O), 6.50 (br, 2H, ex. D2O), 7.76 (s, 1H); MS (+)-ES [M+H]+ m/z 191.
87%
To a mixture of <strong>[156-81-0]2,4-diaminopyrimidine</strong> (5.5 g, 0.05 mol, 1.0 eq.) and THF (200 ml) was added pyridinium tribromide (17.5 g, 0.055 mol, 1.1 eq) at 0 C. in three portions. The resulting mixture was stirred at about 0 C. for two hours, filtered and washed with THF (20 ml). The yellow solid was mixed with water (100 ml) and the resulting mixture was neutralized with 10% NaOH solution to a pH of about 7. Stirring was continued at room temperature for 30 minutes, after which the mixture was filtered, washed with water (2×20 ml) and dried under vacuum at 50 C. to give 8.2 g (87%) of 2,4-diamino-5-bromo-pyrimidine as a white solid. 1H NMR, HPLC and LCMS analyses of this product are identical to the product described in Step 1 of Example 1.
74%
With N-Bromosuccinimide; In chloroform; for 12h;
Method 11; Synthesis of 5-bromo<strong>[156-81-0]pyrimidine-2,4-diamine</strong>; [0251] To a solution of <strong>[156-81-0]2,4-diaminopyrimidine</strong> (1.0 g, 9.1 mmol) in chloroform (30 mL) was added N-bromosuccinimide (1.62 g, 9.08 mmol). The solution was stirred in the dark for 12 hours, at which time it was added to CH2Cl2 (150 mL) and IN NaOH (50 mL). The solid that formed was filtered, rinsed with water and concentrated in vacuo, yielding 1.4 g (74%) of 5-bromo<strong>[156-81-0]pyrimidine-2,4-diamine</strong>: LCMS (m/z): 189/191 (MH+); 1H NMR (DMSO-J6): delta 7.78 (s, IH), 6.58 (bs, 2H), 6.08 (bs, 2H).
74%
0258] To a solution of <strong>[156-81-0]2,4-diaminopyrimidine</strong> (1.0 g, 9.1 mmol) in chloroform(30 mL) was added N-bromosuccinimide (1.62 g, 9.08 mmol). The solution was stirred in the dark for 12 hours, at which time it was added to CH2Cl2 (150 mL) and IN NaOH (50 mL). The solid that formed was filtered, rinsed with water and concentrated in vacuo, yielding 1.4 g (74%) of 5-bromo<strong>[156-81-0]pyrimidine-2,4-diamine</strong>. LCMS (m/z): 189/191 (MH+). 1H NMR (DMSO-): delta 7.78 (s, IH), 6.58 (bs, 2H), 6.08 (bs, 2H).
74%
Synthesi -bromo<strong>[156-81-0]pyrimidine-2,4-diamine</strong>[00103] To a solution of <strong>[156-81-0]2,4-diaminopyrimidine</strong> (1.0 g, 9.1 mmol) in chloroform (30 mL) was added N-bromosuccinimide (1.62 g, 9.08 mmol). The solution was stirred in the dark for 12 hours, at which time it was added to CH2C12 (150 mL) and IN NaOH (50 mL). The solid that formed was filtered, rinsed with water and concentrated in vacuo, yielding 1.4 g (74%) of 5-bromo<strong>[156-81-0]pyrimidine-2,4-diamine</strong>. LCMS (m/z): 189/191 (MH ). ¾ NMR (DMSO-^): 5 7.78 (s, 1H), 6.58 (bs, 2H), 6.08 (bs, 2H).
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 115℃; for 16h;
Method 12; Synthesis of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine-2,4-diamine; [0252] To a dry 1 L flask was added 5-bromopyrimidine-2,4-diamine (30.0 g, 158.7 mmol), potassium acetate (45.8 g, 466.7 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (51.16g g, 202.2 mmol) and dioxane (50O mL). Argon was bubbled through the solution for 15 minutes, at which time l,l'-bis(diphenylphosphino)ferrocene palladium(II) chloride (2.53 g, 3.11 mmol) was added. The reaction was refluxed in a 115 0C oil bath for 16 hours under argon. After cooling to room temperature, the solid inorganic material was filtered, rinsed with EtOAc (1 L). The organic filtrate was concentrated in vacuo and to the resulting solid was added dichloromethane (1 L). After sonication the solid was filtered. The solid was the debrominated 2,4-diaminopyrimidine. The filtrate containing desired boronate ester was concentrated in vacuo. To this residue was added diethyl ether (10O mL). After <n="66"/>sonication, the solution was filtered, rinsed with additional diethyl ether (50 mL) and the solid obtained was dried under high vacuum to yield the desired 2,4-diaminopyrimidyl-5- boronate ester (10.13 g, 27%). By 1H NMR the material was a 4:1 mixture of 2,4- diaminopyrimidyl-5-boronate ester and 2,4-diaminopyrimidine byproduct. The material was used as is in subsequent Suzuki reactions LCMS (m/z): 155 (MH+ of boronic acid, deriving from in situ product hydrolysis on LC); 1H NMR (CDCI3+CD3OD): delta 8.16 (s, IH), 1.34 (s, 12H).
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 115℃; for 16.25h;Heating / reflux;
[0260] To a dry 1 L flask was added 5-bromopyrimidine-2,4-diamine (30.0 g,158.7 mmol), potassivim acetate (45.8 g, 466.7 rnmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (51.2 g, 202.2 mmol) and dioxane (50O mL). Argon was bubbled through the solution for 15 minutes, at which time l,r-bis(diphenylphosphino)ferrocene palladium(II) chloride (2.5 g, 3.11 mmol) was added. The reaction was refluxed in a 115 0C oil bath for 16 hours under argon. After cooling to room temperature, the solid inorganic material was filtered, rinsed with EtOAc (1 L). The organic filtrate was concentrated in vacuo and to the resulting solid was added dichloromethane (1 L). After sonication the solid was filtered. The solid was the debrominated 2,4-diaminopyrimidine. The filtrate containing desired boronate ester was concentrated in vacuo. To this residue was added diethyl ether (10O mL). After sonication, the solution was filtered, rinsed with additional diethyl ether (50 mL) and the solid obtained was dried under high vacuum to yield the desired 2,4-diaminopyrimidyl-5- boronate ester (10.13 g, 27%). By 1H NMR the material was a 4:1 mixture of 2,4- diaminopyrimidyl-5-boronate ester and 2,4-diaminopyrimidine byproduct. The material was used as is in subsequent Suzuki reactions. LCMS (m/z): 155 (MH+ of boronic acid, deriving from in situ product hydrolysis on LC). 1H lSIMR (CDCI3+CD3OD): delta 8.16 (s, IH), 1.34 (s, 12H).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 115℃; for 16h;Inert atmosphere;
Synthesis of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine-2,4- diamine[00105] To a dry 1 L flask was added 5-bromopyrimidine-2,4-diamine (30.0 g,158.7 mmol), potassium acetate (45.8 g, 466.7 mmol), 4,4,5,5 -tetramethyl-2-(4,4,5, 5- tetramethyl-l ,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (51.2 g, 202.2 mmol) and dioxane (500 mL). Argon was bubbled through the solution for 15 minutes, at which time l,l'-bis(diphenylphosphino)ferrocene palladium(II) chloride (2.5 g, 3.11 mmol) was added. The reaction was refiuxed in a 115 C oil bath for 16 hours under argon. After cooling to room temperature, the solid inorganic material was filtered, rinsed with EtOAc (1 L). The organic filtrate was concentrated in vacuo and to the resulting solid was addeddichloromethane (1 L). After sonication the solid was filtered. The solid was the debrominated 2,4-diaminopyrimidine. The filtrate containing desired boronate ester was concentrated in vacuo. To this residue was added diethyl ether (100 mL). After sonication, the solution was filtered, rinsed with additional diethyl ether (50 mL) and the solid obtained was dried under high vacuum to yield the desired 2,4-diaminopyrimidyl-5 -boronate ester (10.13 g, 27%). By XH NMR the material was a 4: 1 mixture of 2,4-diaminopyrimidyl-5- boronate ester and 2,4-diaminopyrimidine byproduct. The material was used as is in subsequent Suzuki reactions. LCMS (m/z): 155 (MH+ of boronic acid, deriving from in situ product hydrolysis on LC). l NMR (CDC13+CD30D): delta 8.16 (s, 1H), 1.34 (s, 12H).
tert-butyl (4-aminopyrimidin-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Reference Example 18 4-Amino-2-(t-butoxycarbonylamino)pyrimidine A 5.52 g portion of <strong>[156-81-0]2,4-diaminopyrimidine</strong> was added to 150 ml of t-butanol and dissolved by heating to about 60 C., and the solution was cooled to room temperature, mixed with 12.38 g of DIBOC and then stirred at room temperature for about 3 days.. The reaction mixture was evaporated under reduced pressure and the thus formed crude product was purified by a silica gel column chromatography to obtain 7.02 g of the title compound from chloroform-methanol-28% aqueous ammonia (200:9:1, v/v/v) elude as white crystals.
With N-ethyl-N,N-diisopropylamine; tert-butyl alcohol; at 20℃; for 6h;
1 g of commercial 2,4-diamino pyrimidine was treated in 40 ml tert.-butanol with1.5 g BOC20 in the presence of 3.48 ml DIPEA at ambient temperature for 6 hrs. After evaporation, the product was extracted with ethyl acetate from water, dried with Na2S04, filtered and evaporated to dryness. After digestion with petrolether : ether 3:1 (vol) and drying 849 mg (4-amino-pyrimidin-2-yl)-carbamic acid tert-butyl ester was obtained as a white powder with Rt ~ 1.08 min and correct mass of M+H ~ 211
With N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; at 20℃; for 6h;
EXAMPLE 8a; Synthesis of {4-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-ylamino]-pyrimidin-2-yl}-carbamic acid tert-butyl ester (no. 51) 1 g of commercial 2,4-diamino pyrimidine was treated in 40 ml tert.-butanol with 1.5 g BOC2O in the presence of 3.48 ml DIPEA at ambient temperature for 6 hrs. After evaporation, the product was extracted with ethyl acetate from water, dried with Na2SO4, filtered and evaporated to dryness. After digestion with petrolether:ether 3:1 (vol) and drying 849 mg (4-amino-pyrimidin-2-yl)-carbamic acid tert-butyl ester was obtained as a white powder with Rt1.08 min and correct mass of M+H211
6-methyl-7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidin-4-ylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 117; Synthesis of nthesis of 2-(4-Amino-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl)-5-hydroxymethyl-tetrahydro-furan-3, 4-diol (219); Step 1; Synthesis of 6-Methyl-7H-pyrrolo [2, 3-dlpyrimidin-4-ylamine; N'N'-dimethylformamide dimethyl acetal (1 equiv. ) is added to 2, 6-diamino pyrimidine in DMF and heated to 80C. The resuting mono protected compound is purified and converted to the hydrazine with NaNO2, 6 N HC1, 0C, then SnCl2- 2H20. To the hydrazine in EtOH is added acetone and TEA and refluxed. The resulting hydrazone is heated in the presence of PPA to form the desired product.
Step 1: 2-Phenyl-imidazo[1,2-a]pyrimidin-7-ylamine Bromoacetophenone (2.71 g, 14 mmol) was added to a solution of <strong>[156-81-0]2,4-diaminopyrimidine</strong> (1.00 g, 9 mmol) in acetone (40 ml), and the mixture was heated to reflux for 5 h. The cooled suspension was filtered, the precipitate was washed (acetone), and then stirred for 15 min in a mixture of 10 ml water and 15 ml NH4OH (25%). The suspension was filtered, washed (water), and dried under vacuum. The crude product (1.9 g, quant.) was used in the next step without further purification. MS (m/e)=211.1 [M+H+].
Bromoacetophenone (2.71 g, 14 mrnol) was added to a solution of <strong>[156-81-0]2,4-diaminopyrimidine</strong> (1.00 g, 9 mrnol) in acetone (40 ml), and the mixture was heated to reflux for 5 h. The cooled suspension was filtered, the precipitate was washed (acetone), and then stirred for 15 min in a mixture of 10 ml water and 15 ml NH4OH (25%). The suspension was filtered, washed (water), and dried under vacuum. The crude product (1.9 g, quant.) was used in the next step without further purification.MS (m/e) = 211.1 [M+H+].
2-(3-Fluoro-phenyl)-imidazo[1,2-a]pyrimidin-7-ylamine 2-Bromo-1-(3-fluorophenyl)ethanone (10.9 g, 50 mmol) was added to a solution of <strong>[156-81-0]2,4-diaminopyrimidine</strong> (3.70 g, 34 mmol) in acetone (185 ml), and the mixture was heated to reflux for 6 h. The cooled suspension was filtered and the precipitate was washed with acetone (50 ml). The solid was re-suspended in water (35 ml) and NH4OHaq. (25%, 50 ml), then it was collected over a glass fiber paper and the filtrate was washed with H2O (75 ml). After drying under vacuum, the product was obtained (5.56 g, 72%) as a yellow solid. MS (m/z)=229.1 [M+H+].
72%
In acetone; for 6h;Reflux;
2-Bromo-l-(3-fluorophenyl)ethanone (10.9 g, 50 mmol) was added to a solution of 2,4- diaminopyrimidine (3.70 g, 34 mmol) in acetone (185 ml), and the mixture was heated to reflux for 6 h. The cooled suspension was filtered and the precipitate was washed with acetone (50 ml). The solid was re-suspended in water (35 ml) and NH40Haq. (25%, 50 ml), then it was collected over a glass fiber paper and the filtrate was washed with Iota¾0 (75 ml). After drying under vacuum, the product was obtained (5.56 g, 72%) as a yellow solid.MS (m/z) = 229.1 [M+H+].
With hydrogenchloride; In 1,4-dioxane; methanol; at 140℃; for 0.0833333h;Microwave irradiation;
Example No. 139Preparation of N2- (8-methoxy-2H-pyrazolo [3 , 4-c] quinolin-4- y1 ) pyrimidine-2,4 -diamine4-chloro-8-methoxy-2- (4 -methoxybenzyl) -2H-pyrazolo [3,4- clquinoline (0.16 mmol) and pyrimidine-2 , 4 -diamine (2 eq.,0.3 mmol) were suspended in MeOH (dry, 3mL) in a microwave vial (2-5mL) , HC1 in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140C. The reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3mL) . The reaction mixture was irradiated in a microwave reactor for 5 min at 140C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried from water/t-BuOH 4/1. exact mass: 307.1344 g/mol HPLC-MS: analytical method Brt: 1.695 min - found mass: 308.1 (m/z+H)
The title compound was prepared according to reported procedure1. A mixture of 2-bromo-1-(4-fluorophenyl)-2-(2-(methylthio)pyrimidin-4-yl)ethanone 9 (8.53 g, 25 mmol) and <strong>[156-81-0]2,4-diaminopyrimidine</strong> 10 (1.85 g, 16.8 mmol) in EtOH (100 mL) was heated at reflux for 760 minutesand then cooled to room temperature. The formed yellow precipitate was filtered off and washed witha solution of NaOH (0.5 N, 50 ml) water (50 mL), diethyl ether (50 ml) and heptane (20 mL) leadingto 2-(4-fluorophenyl)-3-(2-(methylthio)pyrimidin-4-yl)imidazo[1,2-a]pyrimidin-7-amine 11 (2.5 g,7.10 mmol) in 42% yield as an off-white solid.
With sodium hydrogencarbonate; In ethanol; water; at 70℃;
Example 199a Imidazo[1,2-a]pyrimidin-7-amine 199a To the solution of <strong>[156-81-0]pyrimidine-2,4-diamine</strong> (3.0 g, 0.027 mol) in ethanol (90 mL) and aqueous NaHCO3 (2M, 20 mL) was added 2-chloroacetaldehyde (4.3 g, 0.055 mol). The mixture was stirred at 70C overnight. TLC showed the starting material disappeared. The solvent was removed under reduced pressure and the residue was extracted with ethyl acetate (3 X 30 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 1:5 petroleum ether/ethyl acetate to afford 199a as a white solid (2.2 g, 60%). MS: [M+H]+ 135.1.
With ferric sulfate nonahydrate; In water; at 80℃; for 24h;pH 7.57;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 muL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0% w/w) at 80 C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 muL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0% w/w ofthe corresponding salt?s pellet) at 80 C for 24 h. For the innerenvironment, NH2CHO (200 muL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0% w/w) at80 C for 24 h. The reaction of NH2CHO (10% v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 muL) at 60C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 C, detector temperature 280 C, gradient 100 C for 2min, and 10 C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98% compared to that of the reference standards.The analysis was limited to products of ?1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
With magnesium sulfate; In water; at 80℃; for 24h;pH 7.57;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 muL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0% w/w) at 80 C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 muL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0% w/w ofthe corresponding salt?s pellet) at 80 C for 24 h. For the innerenvironment, NH2CHO (200 muL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0% w/w) at80 C for 24 h. The reaction of NH2CHO (10% v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 muL) at 60C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 C, detector temperature 280 C, gradient 100 C for 2min, and 10 C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98% compared to that of the reference standards.The analysis was limited to products of ?1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
With copper(II) choride dihydrate; In water; at 80℃; for 24h;pH 7.57;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 muL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0% w/w) at 80 C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 muL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0% w/w ofthe corresponding salt?s pellet) at 80 C for 24 h. For the innerenvironment, NH2CHO (200 muL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0% w/w) at80 C for 24 h. The reaction of NH2CHO (10% v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 muL) at 60C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 C, detector temperature 280 C, gradient 100 C for 2min, and 10 C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98% compared to that of the reference standards.The analysis was limited to products of ?1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
With manganese(II) chloride tetrahydrate; In water; at 80℃; for 24h;pH 7.57;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 muL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0% w/w) at 80 C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 muL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0% w/w ofthe corresponding salt?s pellet) at 80 C for 24 h. For the innerenvironment, NH2CHO (200 muL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0% w/w) at80 C for 24 h. The reaction of NH2CHO (10% v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 muL) at 60C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 C, detector temperature 280 C, gradient 100 C for 2min, and 10 C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98% compared to that of the reference standards.The analysis was limited to products of ?1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
With potassium carbonate; In chloroform; water; at 5 - 20℃; for 6.5h;
First, 20 g of chloroacetyl chloride was dissolved in 240 mL of chloroform, 55.2 g of potassium carbonate was dissolved in 240 mL of water, 8.8 g of 2,4-bisAminopyrimidine dissolved in 200 mL of chloroform;The <strong>[156-81-0]2,4-diaminopyrimidine</strong> solution was then added to a three-necked flask,Adjust the water bath temperature of 5 ,Then chloroacetyl chloride solution and potassium carbonate solution at the same time slowly dropping to 2. 4-diaminopyrimidine solution,Dropping time of about 1.5h.After completion of the dropwise addition, the reaction was carried out at room temperature for 5 h.Filtration followed by washing with water twice and recrystallization from absolute ethanol yielded 2,4-bis (bromoacetamide) aminopyrimidine in 40% yield.
General procedure: Vilsmeier reagent was prepared by mixing ice-cold dry DMF (50 ml) and POCl3 (30.0 mmol, 2.8 ml). The mixture was stirred for 15 min at 25 C. To the previous mixture, aminopyrimidines (10.0 mmol) in dry DMF (5.0 ml) were added over a period of 15 min at 0-5 C. The reaction mixturewas stirred for 24 h at 25 C.The mixture was then added to cold, saturated aq. K2CO3 andextracted with diethyl ether. The organic layer was washed withwater, dried over anhydrous Na2SO4, and evaporated underreduced pressure to afford the crude product, whichwas purified ina silica gel column chromatography using hexane/ethyl acetate(9:1) as an eluent to give the title compounds 2 and 8. 4.3.1. 2,4-Diaminopyrimidine-5-carbaldehyde (2) Brown powder, yield 59%; 1H-NMR [DMSO-d6, 400 MHz]: (delta,ppm) 7.10 (d, 2H, NH2, exchange with D2O), 7.52 (d, 2H, NH2, exchangewith D2O), 8.32 (s, 1H, H6-pyrimidine), 9.45 (CHO); 13C NMR[DMSO-d6, 100 MHz]: (delta, ppm) 106.2 (C5-pyrimidine), 162.7(C4-pyrimidine), 164.4 (C6-pyrimidine), 167.0 (C2-pyrimidine),189.5 (CHO).
2-bromo-1-(5-chloro-2,4-dimethoxyphenyl)ethanone[ No CAS ]
2-(5-chloro-2,4-dimethoxyphenyl)imidazo[1,2-a]pyrimidin-7-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
In acetone; for 16h;Reflux;
A solution of 2-bromo-1-(5-chloro-2,4-dimethoxyphenyl)ethanone 3 (140 mg, 0.47 mmol) and <strong>[156-81-0]pyrimidine-2,4-diamine</strong> (50 mg, 0.45 mmol) in acetone (5 mL) was heated to reflux for 16 h. The reaction mixture was cooled to room temperature. The precipitate was filtered and treated with dilute ammonia. Precipitate was filtered, washed with water, and dried under reduced pressure to yield 2-(5-chloro-2,4- dimethoxyphenyl)imidazo[l,2-a]pyrimidin-7-amine 158b ( 95 mg, 36%) as a white solid. 1H NMR (300 MHz, DMSO-d6) delta 8.36 (d, 1H J = 7.2Hz), 8.09 (s, 1H). 7.76 (s, IH), 6.84 (s, IH), 6.76 (s, 2H), 6.22 (d, 1H, J = 7.2Hz), 3.98 (s, 3H), 3.92 (s, 3H); ESI MS m/z 305 [M+H]+
2-(5-bromo-2,4-dimethoxyphenyl)imidazo[1,2-a]pyrimidin-7-amine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
A solution of 2-bromo-1-(5-bromo-2,4-dimethoxyphenyl)ethanone 7 (62 mg, 0.0.21 mmol) and <strong>[156-81-0]pyrimidine-2,4-diamine</strong> 164a (20 mg, 0.18 mmol) in acetone (5 ml) was heated to reflux for 3h. The reaction mixture was cooled to room temperature: the white precipitate was filtered and washed with acetone. The precipitate was suspended in aqueous ammonia (10 mL) and stirred for 30 mins. The precipitate was filtered, washed with water. The solid was converted to HCl salt by treating it to dilute HCl. The precipitate obtained dried under reduced pressure to yield 2-(5-bromo-2,4-dimethoxyphenyl)imidazo[l,2-a]pyrimidin-7-amine hydrochloride 164a (18 mg, 44%) as an off-white solid. 1H NMR (300 MHz, DMSO-ifc): delta 8.54- 8.52(d, ./ 7.6 Hz, 1H), 8.22 (br s, 2H), 8.11 (s, 1H), 8,07 (s, 1H), 6.92(s, 3H), 6,71-6.68(d, J= 7,6 Hz, 1H), 4.03 (s, 3H), 3 ,97 (s, 3H). HPLC (Method 3} 97.8% (AUC), = 16.84 min; APCI MS m/z 351 [M +2+ i l l .
N-[(2'-aminopyrimidin-4'-yl)carbamoyl]-4-methylbenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
In acetonitrile; at 20℃; for 12h;
General procedure: To a solution of <strong>[156-81-0]2,4-diaminopyrimidine</strong> 9 (10 mmol, 1.10 g) in acetonitrile (15 ml), isocynate derivatives (10 mmol) was added. The reaction mixture was stirred at room temperature for 12 hr. The progress of the reaction was monitored by TLC and after completion; the precipitate formed was filtered, washed with ethanol, and dried to give the final products 10a,b.
1-(2'-aminopyrimidin-4'-yl)-3-phenylurea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
In acetonitrile; at 20℃; for 12h;
General procedure: To a solution of <strong>[156-81-0]2,4-diaminopyrimidine</strong> 9 (10 mmol, 1.10 g) in acetonitrile (15 ml), isocynate derivatives (10 mmol) was added. The reaction mixture was stirred at room temperature for 12 hr. The progress of the reaction was monitored by TLC and after completion; the precipitate formed was filtered, washed with ethanol, and dried to give the final products 10a,b.
At 0 C,To i-105 (5g, 45.4mmol, 1.00 eq.) in DMF (100mL)NaH (5.45 g, 136 mmol, 60% purity, 3.00 eq.) was added portionwise from mixture.The mixture was stirred at 25 C for 1 hour.The mixture was cooled to 0 C and p-methoxybenzyl chloride was added at 0 C.(17.8 g, 113 mmol, 2.50 eq.) was added to the mixture.The mixture was stirred at 0 C for 13 hours.The mixture was poured into ice water (500 mL) and ethyl acetate (3×500 mL)Extract the mixture.The combined organic phases were washed with brine (400 mL).Dry over anhydrous Na 2SO 4, filtered and concentrated in vacuo.By silica gel column chromatographyPurify the residue to give an oilyI-106 (10.5 g, 30 mmol).
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