* 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.
Reference:
[1] Nature (London, United Kingdom), 1950, vol. 165, p. 1010
2
[ 109-12-6 ]
[ 5428-89-7 ]
Reference:
[1] Chemical Communications, 2017, vol. 53, # 44, p. 5997 - 6000
[2] European Journal of Organic Chemistry, 2016, vol. 2016, # 36, p. 5937 - 5940
[3] Chemical Communications, 2015, vol. 51, # 80, p. 14852 - 14855
[4] Journal of the American Chemical Society, 1946, vol. 68, p. 453,457
[5] Patent: US2609372, 1950, ,
With N-Bromosuccinimide In acetonitrile at 20℃; Cooling with ice; Darkness
The 2-aminopyrimidine (2.5g, 26.29mmol) was dissolved in acetonitrile (25mL) was added N- bromosuccinimide (4.6g, 27.9mmol) under ice-cooling, stirred in the dark overnight at room temperature. Recovery of the solvent under reduced pressure, washed with water (100 mL) was washed, filtered off with suction, and dried in vacuo to give a white solid. Yield: 97percent
92.4%
With N-Bromosuccinimide In dichloromethane; acetonitrile at 5 - 20℃; for 24 h;
A 1 L flask was charged with 40 g (0.42 mol) of 2-aminopyrimidine and 840 mL of acetonitrile / 84 mL of DCM was added, and 78.6 g (0.44 mol) of NBS (N-bromosuccinimide) was added thereto at a temperature of 5 ° C for 4 times. The temperature was gradually raised to room temperature and stirred for 24 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 1000 mL of water and 1000 mL of DCM were added, and the mixture was stirred for 2 hours. The separated organic layer was washed with 500 mL of brine, dried over anhydrous Na2SO4, and concentrated. The concentrate was recrystallized under DCM / Hexane conditions to give 67.5 g (yield: 92.4percent) of a compound as a white solid (Intermediate (19)).
91%
With N-Bromosuccinimide In dichloromethane; acetonitrile at 20℃; for 72 h;
5-Thiophen-3-yl-pyrimidin-2-ylamine (A1 ); 2-amino-pyrimidine (1.9 g, 20 mmol) was suspended in 40 mL of dichloromethane and 40 mL of acetonitrile. N-Bromosuccinimide (5.34 g, 30 mmol) was added with stirring. The mixture was stirred for 72 hours at room temperature. The mixture was washed with sodium bisulfite solution, water and chloroform. The precipitate was collected by vacuum filtration and washed with acetone. The solids were dried under vacuum to give 3.2 g (91 percent yield) of 2-amino-5-bromo-pyrimidine as a white solid. 'H-NMR (dimethylsulfoxide-d6) No. 8.28 (s, 2H, aromatic), 6.87 (s, 2H, NH2). MS (m/z) 174 [M+1].
90.48%
With N-Bromosuccinimide In methanol; acetonitrile at 70℃; for 6 h;
A 5 L three-necked round bottom flask was charged with 2-aminopyrimidine (285.30 g, 3 mol), N-bromosuccinimide (1.17 kg, 6.6 mol), acetonitrile 2 L and methanol 1 L. The mixture in the reaction flask was stirred at 70 ° C for 6 hours. TLC and HPLC confirmed the reaction was complete. After the reaction was completed, the solvent was removed by rotary evaporation to give the crude product. The crude product was concentrated by evaporation and recrystallized to give the pure product 2-amino-5-bromopyrimidine. After drying, the yield was 90.48percent and the purity was 99.05percent (HPLC).
90.2%
With N-Bromosuccinimide In acetonitrile at 20℃; for 4 h;
Preparation example 10: Preparation of 5-bromo-2-aminopyrimidine 2-aminopyrimidine (20.0 g, 0.21 mol) was dissolved in acetonitrile (500 mL), and N-bromobutanimide (37.0 g, 0.21 mol) was added. The mixture was stirred at 20 °C for 4 h, and filtrated under suction. The filter cake was dried to get the product (33.0 g, yield: 90.2percent).
Reference:
[1] Journal of Organic Chemistry, 2012, vol. 77, # 16, p. 6908 - 6916
[2] European Journal of Organic Chemistry, 2018, vol. 2018, # 43, p. 5921 - 5934
[3] Patent: CN106588884, 2017, A, . Location in patent: Paragraph 0210; 0214; 0215; 0216
[4] Synthesis, 2004, # 17, p. 2809 - 2812
[5] Chemical Communications, 2017, vol. 53, # 44, p. 5997 - 6000
[6] Patent: KR2017/103574, 2017, A, . Location in patent: Paragraph 0118; 0119; 0120; 0121
[7] Patent: WO2005/113548, 2005, A1, . Location in patent: Page/Page column 32
[8] Patent: CN106632079, 2017, A, . Location in patent: Paragraph 0011; 0012; 0013; 0014; 0015; 0016
[9] Patent: EP3091008, 2016, A1, . Location in patent: Paragraph 0183; 0184
[10] Organic Letters, 2002, vol. 4, # 14, p. 2321 - 2323
[11] RSC Advances, 2016, vol. 6, # 93, p. 90031 - 90034
[12] Journal of Organic Chemistry, 2008, vol. 73, # 23, p. 9326 - 9333
[13] Journal of Organic Chemistry, 1983, vol. 48, # 7, p. 1064 - 1069
[14] Tetrahedron Letters, 2003, vol. 44, # 52, p. 9371 - 9373
[15] Synthesis, 1981, # 12, p. 987 - 989
[16] Journal of Materials Chemistry, 2000, vol. 10, # 7, p. 1555 - 1563
[17] Journal of the American Chemical Society, 1946, vol. 68, p. 452,456
[18] Patent: US2609372, 1950, ,
[19] Archives of Pharmacal Research, 2014, vol. 37, # 5, p. 588 - 599
5
[ 109-12-6 ]
[ 1445-39-2 ]
Yield
Reaction Conditions
Operation in experiment
22.2%
With sulfuric acid; iodine; acetic acid; periodic acid In water at 80℃; for 24 h; Inert atmosphere
Mixture of 2-aminopyrimidine (2.4 g, 25 mmol, 1.0 eq.) and elemental iodine (2.7 g, 10.7 mmol, 0.43eq.) was added to 60 ml of glacial acetic acid, and then added periodic acid (0.86 g, 3.76 mmol, 0.15 eq.) and 0.5 ml concentrated sulfuric acid dissolved in sulfuric acid solution 3 ml of water. Place reactions in a nitrogen atmosphere , the reaction was heated to 80 °C for 24 hours. The reaction was then poured into a saturated aqueous solution of sodium thiosulfate in until a clear solution, (200 ml × 3) and extracted with dichloromethane, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, after column chromatography silica gel to give a white solid 2-amino-5-iodopyrimidine (1.4 g, yield 22.2percent).
0.4 g
With iodine In dimethyl sulfoxide at 120℃; for 1 h;
To a solution of pyrimidin-2-amine (1.0 g, 0.010 mol) in DMSO (10 mL) was added iodine (3.2 g, 0.012 mol). The reaction mixture was stirred at 120°C for 1 h. The reaction mass was quenched in water and excess of iodine was neutralised with sodium metabisulphate. The reaction mass was extracted with ethyl acetate and concentrated to afford 0.400 g of the desired product.
Reference:
[1] Heterocycles, 1984, vol. 22, # 5, p. 1195 - 1210
[2] Journal of Organic Chemistry, 2000, vol. 65, # 22, p. 7468 - 7474
[3] Journal of Organic Chemistry, 2008, vol. 73, # 23, p. 9326 - 9333
[4] Synthesis, 1984, # 3, p. 252 - 254
[5] Patent: CN105622638, 2016, A, . Location in patent: Paragraph 0362
[6] Journal of the American Chemical Society, 1948, vol. 70, p. 157,158
[7] Patent: WO2013/186692, 2013, A1, . Location in patent: Page/Page column 62
6
[ 109-12-6 ]
[ 1600-27-7 ]
[ 7732-18-5 ]
[ 1445-39-2 ]
Reference:
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 157,158
Reference:
[1] Journal of the Chemical Society, Chemical Communications, 1987, # 2, p. 114 - 115
[2] Yakugaku Zasshi, 1942, vol. 62, p. 315,333; dtsch. Ref. S. 95, 106[3] Chem.Abstr., 1951, p. 5150
[4] Journal of the American Chemical Society, 1954, vol. 76, p. 6200
[5] Journal of the Chemical Society, 1953, p. 331,336
Reference:
[1] European Journal of Pharmaceutical Sciences, 2016, vol. 88, p. 166 - 177
11
[ 109-12-6 ]
[ 334-22-5 ]
[ 20980-22-7 ]
Reference:
[1] Research on Chemical Intermediates, 2011, vol. 37, # 8, p. 1041 - 1045
12
[ 109-12-6 ]
[ 121-60-8 ]
[ 68-35-9 ]
Reference:
[1] European Journal of Medicinal Chemistry, 2017, vol. 136, p. 63 - 73
13
[ 109-12-6 ]
[ 101570-35-8 ]
[ 68-35-9 ]
Reference:
[1] DRP/DRBP Org.Chem.,
14
[ 109-12-6 ]
[ 68-35-9 ]
Reference:
[1] Patent: US2386852, 1942, ,
15
[ 109-12-6 ]
[ 4595-60-2 ]
Reference:
[1] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2676 - 2699
16
[ 109-12-6 ]
[ 2032-35-1 ]
[ 274-95-3 ]
Yield
Reaction Conditions
Operation in experiment
5 g
With hydrogen bromide In ethanol; water for 18 h; Reflux
In a 250 ml three-neck round bottom flask, 2-aminopyrimidine (5 g),Bromoacetaldehyde diethyl acetal (20.7 g), 48percent aqueous solution of bromic acid (5 ml)Ethanol (50 ml) was added and the mixture was refluxed with stirring for 18 hours. The reaction solution was cooled to room temperature Silica gel was adsorbed. Through column separation using dichloromethane and methanol5 g of the title compound was obtained.
Reference:
[1] Patent: KR2017/126059, 2017, A, . Location in patent: Paragraph 0069; 0072; 0073; 0076; 0077
17
[ 109-12-6 ]
[ 107-20-0 ]
[ 274-95-3 ]
Reference:
[1] Bioorganic & Medicinal Chemistry Letters, 1999, vol. 9, # 1, p. 97 - 102
[2] European Journal of Medicinal Chemistry, 1991, vol. 26, # 1, p. 13 - 18
[3] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 5, p. 1170 - 1176
18
[ 109-12-6 ]
[ 31575-35-6 ]
Reference:
[1] Tetrahedron, 1996, vol. 52, # 1, p. 23 - 36
[2] Russian Journal of General Chemistry, 2010, vol. 80, # 12, p. 2572 - 2589
[3] Organic Letters, 2017, vol. 19, # 19, p. 5178 - 5181
19
[ 109-12-6 ]
[ 70-23-5 ]
[ 64951-07-1 ]
[ 64951-06-0 ]
Yield
Reaction Conditions
Operation in experiment
30%
at 75℃; for 16 h;
2-Aminopyrimidine (5 g, 52.6 mmol) and bromoethyl pyruvate (90percent, 7.35 mL, 52.6 mmol) were dissolved in ethanol (80 mL) and the reaction was heated to 75 °C for 16 h. The reaction was concentrated under reduced pressure and diluted with CH2Cl2 and sat aq NaHCO3. The organic layer was washed with sat aq NaHCO3 (2x) and the aq layers were extracted with CH2Cl2 (3x). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting brown oil was suspended in cold CH2Cl2 and filtered. The filter cake was washed with cold CH2Cl2 to obtain ethyl imidazo[1,2-a]pyrimidine-2-carboxylate (3 g, 30percent) as a light yellow oil. The mother liquor contains a mixture of ethyl imidazo[1,2-a]pyrimidine-2- carboxylate and ethyl imidazo[1,2-a]pyrimidine-3-carboxylate (6 g, 60percent) in the form of thick, black oil. This black oil was first purified by silica gel chromatography followed by recrystallization from EtOAc to obtain ethyl imidazo[1,2-a]pyrimidine-3- carboxylate (2 g, 20percent).[00236] For 2-isomer: 1H NMR (500 MHz, CDCl3) δ 8.69 (dd, J= 2.2, 6.6 Hz, 1H), 8.67 (dd, J= 2.2, 4.4 Hz, 1H), 8.22 (s, 1H), 7.01 (dd, J= 3.9, 6.6 Hz, 1H), 4.46 (q, J= 7.2 Hz, 2H), 1.43 (t, J= 7.2 Hz, 3H). [00237] 13C NMR (500 MHz, CDCl3) δ 162.8, 152.2, 147.8, 137.7, 134.4, 115.3, 110.0, 61.2, 14.2.[00238] HPLC-MS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100percent B over 4 minutes, 1 minutes hold time, A = 90percent water, 10percent methanol, 0.1percent TFA, B = 10percent water, 90percent methanol, 0.1percent TFA, RT = 0.99 min, 95percent homogeneity index. [00239] LCMS: Anal. Calcd. for C9H9N3O2 191.07 found: 192.13 (M+H)+.[00240] For 3-isomer: HPLC Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100percent B over 4 minutes, 1 minutes hold time, A = 90percent water, 10percent methanol, 0.1percent TFA, B = 10percent water, 90percent methanol, 0.1percent TFA, RT = 1.39 min, 100percent homogeneity index. [00241] LCMS: Anal. Calcd. for C9H9N3O2 191.07 found: 192.19 (M+H)+.
Reference:
[1] Patent: WO2006/71752, 2006, A1, . Location in patent: Page/Page column 83
[2] European Journal of Medicinal Chemistry, 1994, vol. 29, # 4, p. 279 - 286
[3] European Journal of Medicinal Chemistry, 1991, vol. 26, # 1, p. 13 - 18
[4] Journal of Medicinal Chemistry, 2010, vol. 53, # 15, p. 5620 - 5628
[5] Patent: WO2018/11628, 2018, A1, . Location in patent: Paragraph 00266
20
[ 109-12-6 ]
[ 70-23-5 ]
[ 64951-07-1 ]
[ 64951-06-0 ]
Yield
Reaction Conditions
Operation in experiment
30%
at 75℃; for 16 h;
2-Aminopyrimidine (5 g, 52.6 mmol) and bromoethyl pyruvate (90percent, 7.35 mL, 52.6 mmol) were dissolved in ethanol (80 mL) and the reaction was heated to 75 °C for 16 h. The reaction was concentrated under reduced pressure and diluted with CH2Cl2 and sat aq NaHCO3. The organic layer was washed with sat aq NaHCO3 (2x) and the aq layers were extracted with CH2Cl2 (3x). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting brown oil was suspended in cold CH2Cl2 and filtered. The filter cake was washed with cold CH2Cl2 to obtain ethyl imidazo[1,2-a]pyrimidine-2-carboxylate (3 g, 30percent) as a light yellow oil. The mother liquor contains a mixture of ethyl imidazo[1,2-a]pyrimidine-2- carboxylate and ethyl imidazo[1,2-a]pyrimidine-3-carboxylate (6 g, 60percent) in the form of thick, black oil. This black oil was first purified by silica gel chromatography followed by recrystallization from EtOAc to obtain ethyl imidazo[1,2-a]pyrimidine-3- carboxylate (2 g, 20percent).[00236] For 2-isomer: 1H NMR (500 MHz, CDCl3) δ 8.69 (dd, J= 2.2, 6.6 Hz, 1H), 8.67 (dd, J= 2.2, 4.4 Hz, 1H), 8.22 (s, 1H), 7.01 (dd, J= 3.9, 6.6 Hz, 1H), 4.46 (q, J= 7.2 Hz, 2H), 1.43 (t, J= 7.2 Hz, 3H). [00237] 13C NMR (500 MHz, CDCl3) δ 162.8, 152.2, 147.8, 137.7, 134.4, 115.3, 110.0, 61.2, 14.2.[00238] HPLC-MS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100percent B over 4 minutes, 1 minutes hold time, A = 90percent water, 10percent methanol, 0.1percent TFA, B = 10percent water, 90percent methanol, 0.1percent TFA, RT = 0.99 min, 95percent homogeneity index. [00239] LCMS: Anal. Calcd. for C9H9N3O2 191.07 found: 192.13 (M+H)+.[00240] For 3-isomer: HPLC Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100percent B over 4 minutes, 1 minutes hold time, A = 90percent water, 10percent methanol, 0.1percent TFA, B = 10percent water, 90percent methanol, 0.1percent TFA, RT = 1.39 min, 100percent homogeneity index. [00241] LCMS: Anal. Calcd. for C9H9N3O2 191.07 found: 192.19 (M+H)+.
Reference:
[1] Patent: WO2006/71752, 2006, A1, . Location in patent: Page/Page column 83
[2] European Journal of Medicinal Chemistry, 1994, vol. 29, # 4, p. 279 - 286
[3] European Journal of Medicinal Chemistry, 1991, vol. 26, # 1, p. 13 - 18
[4] Journal of Medicinal Chemistry, 2010, vol. 53, # 15, p. 5620 - 5628
[5] Patent: WO2018/11628, 2018, A1, . Location in patent: Paragraph 00266
21
[ 109-12-6 ]
[ 70-23-5 ]
[ 64951-06-0 ]
Reference:
[1] ACS Combinatorial Science, 2018, vol. 20, # 3, p. 164 - 171
[2] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 5, p. 1170 - 1176
22
[ 109-12-6 ]
[ 2314-97-8 ]
[ 69034-08-8 ]
Reference:
[1] Journal of Fluorine Chemistry, 2010, vol. 131, # 1, p. 98 - 105
[2] Patent: WO2012/54233, 2012, A1, . Location in patent: Page/Page column 39
23
[ 109-12-6 ]
[ 70-23-5 ]
[ 149520-94-5 ]
Yield
Reaction Conditions
Operation in experiment
54%
Stage #1: at 75℃; Stage #2: With hydrazine hydrate In ethanol at 75℃;
To a mixture of imidazo[l,2-a]pyrimidine-2-carboxylic acid ethyl ester and imidazo[l,2-a]pyrimidine-3-carboxylic acid ethyl ester (500 mg, 2.62 mmol, 1.0 eq) in EtOH ( 20 mL) was added hydrazine hydrate (180 mg, 2.88 mmol, 1.1 eq). The reaction mixture was heated at 75 °C overnight. The reaction mixture was concentrated and the resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 20/1, v/v) to give 2-amino-lH-imidazole-4-carboxylic acid ethyl ester (220 mg, 54percent) as a yellow solid.
Reference:
[1] Journal of Medicinal Chemistry, 2010, vol. 53, # 15, p. 5620 - 5628
[2] Patent: WO2018/11628, 2018, A1, . Location in patent: Paragraph 00267
With potassium tert-butylate; copper diacetate; In 1,4-dioxane; at 130℃; for 48h;Inert atmosphere;
General procedure: To a solution of Cu(OAc)2 (0.025 mmol, 0.0046 g) and potassium tert-butoxide (0.175 g, 2.5 mmol) in anhydrous dioxane (3 mL), the corresponding amine 1 (2.5 mmol) or the triphenylphosphoranylidenaniline 18 (2.5 mmol) and the correspondent alcohol 2 or 4 (3.75 mmol) were added successively under inert argon atmosphere. After 2 or 5 days of reaction at 130 C (see Table 2 and Scheme 2), the resulting mixture was hydrolyzed with a saturated solution of ammonium chloride (10 mL). The mixture was extracted with AcOEt (3×10 mL) and washed with brine (10 mL), after drying with anhydrous MgSO4, was filtered on Celite and the solvents were removed under low pressure(15-18 Torr). The resulting mixture was purified by column chromatography (if needed).
98%
With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; 2-(2-(diphenylphosphanyl)phenyl)benzo[d]oxazole; potassium hydroxide; In toluene; at 110℃; for 24h;Schlenk technique; Inert atmosphere;
General procedure: [Cp*IrCl2]2 (1 mol %, 0.01 mmol, 8.0 mg), 4a (2 mol %, 0.02 mmol,7.6 mg), KOH (10 mol %, 0.1 mmol, 5.6 mg), and toluene (5 mL) wereadded to a 25mL Schlenk tube with stirring under N2 at roomtemperature. Then ketones/secondary alcohols/amines (1 mmol),primary alcohols (1.1 mmol) were added by syringe. The reactionmixture was heated to 110 C under reflux in an oil bath for 24 h. Itwas cooled to ambient temperature. Then it was concentrated invacuo, and purified by flash column chromatography with petroleumether/ethyl acetate to afford the corresponding alkylatedproduct.
97%
With trifuran-2-yl-phosphane; palladacycle; lithium hydroxide; In neat (no solvent); at 100℃; for 24h;Molecular sieve; Inert atmosphere;
General procedure: A similar protocol as mentioned for N-alkylation of amines using benzyl alcohol was used. The quantities involved are as follows: Amine (3.0 mmol), alcohol (6.0 mmol), LiOH (1.5 mmol), precatalyst (1.5*10-2 mmol, 0.50 mol %), P(2-Fur)3 (1.5*10-2 mmol, 1.00 mol%) and activated 4 A MS (100 mg). The reaction mixture was stirred at 120-130 C for 24-48 h.
95%
With C51H40Cl2N2O3P2Ru; potassium hydroxide; In toluene; at 120℃; for 14h;
General procedure: 0.5 mol% ruthenium(II) catalyst was stirred with 4 mmol ofKOH in toluene. To this mixture, 2 mmol of alcohol and 2 mmolof amine were added and the temperature was raised up to120 C. The progress of the reactions was monitored using TLC.As soon as the reaction was completed, the mixture was cooledto room temperature and added 3 mL of distilled water. The combinedmixture was extracted with CH2Cl2 and dried by addingmagnesium sulfate. The crude product was purified by columnchromatography (n-hexane/EtOAc) and characterized by 1H NMRspectral analyses. The 1H NMR data obtained for the catalytic productswere compared with literature [19].
92%
With C41H36AsClN3OPRuS; potassium hydroxide; In toluene; at 100℃; for 12h;
General procedure: Amine/sulfonamide (1mmol), alcohol (1mmol), catalyst (0.5mol %), KOH (50mol %) and toluene (2mL) were placed in a 25mL round bottomed flask and stirred on a preheated oil bath (100C) for 12h. Upon completion (as monitored by TLC), the reaction mixture was cooled at ambient temperature, H2O (3mL) was added and the organic layer was extracted with CH2Cl2. The organic extract was separated, dried, and concentrated. The desired product was purified by column chromatography with n-hexane/EtOAc as eluent.
80%
With C26H29ClIrN4O(1+)*F6P(1-); potassium tert-butylate; In toluene; at 110℃; for 48h;Inert atmosphere; Schlenk technique; Molecular sieve;
General procedure: Alcohol (1.00 mmol)and amine (1.10 mmol) were weighed into an oven-dried Schlenkflask containing 4A molecular sieves (60 mg). tBuOK (0.50 mmol)was added, followed by dry toluene (0.50 mL). The mixture wasput under an atmosphere of nitrogen, and catalyst (0.01 mmol)was added before stoppering the flask and immersing it in a pre-heated oil bath (110C) for 48 h. Then, the solvent was evaporatedand the crude solid was purified by column chromatography using petroleum ether and triethylamine. The analytical data of all products are consistent with the data reported in literature [6j,8,11e].
76%
With bis(mu-chloro)-bis[1,3-di(2-pyridyl)-4,6-dimethylbenzene-N,C(2'),N-iridium chloride]; caesium carbonate; In tert-Amyl alcohol; for 12h;Reflux;
Aminopyrazine (47.5 mg, 0.5 mmol),Cat.[Ir] (5.4 mg, 0.005 mmol, 1 mol%),Barium carbonate (49 mg, 0.15 mmol, 0.3 equiv.),Benzyl alcohol (64 mg, 0.6 mmol) and t-amyl alcohol (1 ml) were added to 5 mL of round bottom In the bottle.The reaction mixture was refluxed in air for 12 hours and then cooled to room temperature.The solvent was removed by rotary evaporation and then purified by column chromatography (developer: petroleum ether/ethyl acetate) to give the desired target compound. Yield: 76%
59%
With iron(III)phthalocyanine chloride; potassium tert-butylate; In neat (no solvent); at 110℃; for 12h;Inert atmosphere; Microwave irradiation;
General procedure: To a microwave vial (0.5-2.0 mL) was added iron(III) phthalocyanine chloride (10mol%), tBuOK (2.0 mmol), under an atmosphere. The vial was sealed using vial capsinclude reseal septa and then purged with nitrogen To the vial was added amine (1.0mmol) and alcohol (4.0 mmol) via syringe. The mixture was stirred and heated undermicrowave irradiation for 12 h at 130 C. After the reaction, the resulting mixture wasfiltered through celite with diethyl ether. The solution was evaporated and theresulting residue was purified by flash column chromatography (EtOAc:Hexane = 1:10)to yield the corresponding N-alkylated amine.
With N-Bromosuccinimide; In acetonitrile; at 20℃;Cooling with ice; Darkness;
The 2-aminopyrimidine (2.5g, 26.29mmol) was dissolved in acetonitrile (25mL) was added N- bromosuccinimide (4.6g, 27.9mmol) under ice-cooling, stirred in the dark overnight at room temperature. Recovery of the solvent under reduced pressure, washed with water (100 mL) was washed, filtered off with suction, and dried in vacuo to give a white solid. Yield: 97%
92.4%
With N-Bromosuccinimide; In dichloromethane; acetonitrile; at 5 - 20℃; for 24h;
A 1 L flask was charged with 40 g (0.42 mol) of 2-aminopyrimidine and 840 mL of acetonitrile / 84 mL of DCM was added, and 78.6 g (0.44 mol) of NBS (N-bromosuccinimide) was added thereto at a temperature of 5 C for 4 times. The temperature was gradually raised to room temperature and stirred for 24 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 1000 mL of water and 1000 mL of DCM were added, and the mixture was stirred for 2 hours. The separated organic layer was washed with 500 mL of brine, dried over anhydrous Na2SO4, and concentrated. The concentrate was recrystallized under DCM / Hexane conditions to give 67.5 g (yield: 92.4%) of a compound as a white solid (Intermediate (19)).
91%
With N-Bromosuccinimide; In dichloromethane; acetonitrile; at 20℃; for 72h;
5-Thiophen-3-yl-pyrimidin-2-ylamine (A1 ); 2-amino-pyrimidine (1.9 g, 20 mmol) was suspended in 40 mL of dichloromethane and 40 mL of acetonitrile. N-Bromosuccinimide (5.34 g, 30 mmol) was added with stirring. The mixture was stirred for 72 hours at room temperature. The mixture was washed with sodium bisulfite solution, water and chloroform. The precipitate was collected by vacuum filtration and washed with acetone. The solids were dried under vacuum to give 3.2 g (91 % yield) of 2-amino-5-bromo-pyrimidine as a white solid. 'H-NMR (dimethylsulfoxide-d6) No. 8.28 (s, 2H, aromatic), 6.87 (s, 2H, NH2). MS (m/z) 174 [M+1].
90.48%
With N-Bromosuccinimide; In methanol; acetonitrile; at 70℃; for 6h;
A 5 L three-necked round bottom flask was charged with 2-aminopyrimidine (285.30 g, 3 mol), N-bromosuccinimide (1.17 kg, 6.6 mol), acetonitrile 2 L and methanol 1 L. The mixture in the reaction flask was stirred at 70 C for 6 hours. TLC and HPLC confirmed the reaction was complete. After the reaction was completed, the solvent was removed by rotary evaporation to give the crude product. The crude product was concentrated by evaporation and recrystallized to give the pure product 2-amino-5-bromopyrimidine. After drying, the yield was 90.48% and the purity was 99.05% (HPLC).
90.2%
With N-Bromosuccinimide; In acetonitrile; at 20℃; for 4h;
Preparation example 10: Preparation of 5-bromo-2-aminopyrimidine 2-aminopyrimidine (20.0 g, 0.21 mol) was dissolved in acetonitrile (500 mL), and N-bromobutanimide (37.0 g, 0.21 mol) was added. The mixture was stirred at 20 C for 4 h, and filtrated under suction. The filter cake was dried to get the product (33.0 g, yield: 90.2%).
With sulfuric acid; iodine; acetic acid; periodic acid; In water; at 80℃; for 24h;Inert atmosphere;
Mixture of 2-aminopyrimidine (2.4 g, 25 mmol, 1.0 eq.) and elemental iodine (2.7 g, 10.7 mmol, 0.43eq.) was added to 60 ml of glacial acetic acid, and then added periodic acid (0.86 g, 3.76 mmol, 0.15 eq.) and 0.5 ml concentrated sulfuric acid dissolved in sulfuric acid solution 3 ml of water. Place reactions in a nitrogen atmosphere , the reaction was heated to 80 C for 24 hours. The reaction was then poured into a saturated aqueous solution of sodium thiosulfate in until a clear solution, (200 ml × 3) and extracted with dichloromethane, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, after column chromatography silica gel to give a white solid 2-amino-5-iodopyrimidine (1.4 g, yield 22.2%).
0.4 g
With iodine; In dimethyl sulfoxide; at 120℃; for 1h;
To a solution of pyrimidin-2-amine (1.0 g, 0.010 mol) in DMSO (10 mL) was added iodine (3.2 g, 0.012 mol). The reaction mixture was stirred at 120C for 1 h. The reaction mass was quenched in water and excess of iodine was neutralised with sodium metabisulphate. The reaction mass was extracted with ethyl acetate and concentrated to afford 0.400 g of the desired product.
2-Aminopyrimidine (5 g, 52.6 mmol) and bromoethyl pyruvate (90%, 7.35 mL, 52.6 mmol) were dissolved in ethanol (80 mL) and the reaction was heated to 75 C for 16 h. The reaction was concentrated under reduced pressure and diluted with CH2Cl2 and sat aq NaHCO3. The organic layer was washed with sat aq NaHCO3 (2x) and the aq layers were extracted with CH2Cl2 (3x). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting brown oil was suspended in cold CH2Cl2 and filtered. The filter cake was washed with cold CH2Cl2 to obtain ethyl imidazo[1,2-a]pyrimidine-2-carboxylate (3 g, 30%) as a light yellow oil. The mother liquor contains a mixture of ethyl imidazo[1,2-a]pyrimidine-2- carboxylate and ethyl imidazo[1,2-a]pyrimidine-3-carboxylate (6 g, 60%) in the form of thick, black oil. This black oil was first purified by silica gel chromatography followed by recrystallization from EtOAc to obtain ethyl imidazo[1,2-a]pyrimidine-3- carboxylate (2 g, 20%).[00236] For 2-isomer: 1H NMR (500 MHz, CDCl3) delta 8.69 (dd, J= 2.2, 6.6 Hz, 1H), 8.67 (dd, J= 2.2, 4.4 Hz, 1H), 8.22 (s, 1H), 7.01 (dd, J= 3.9, 6.6 Hz, 1H), 4.46 (q, J= 7.2 Hz, 2H), 1.43 (t, J= 7.2 Hz, 3H). [00237] 13C NMR (500 MHz, CDCl3) delta 162.8, 152.2, 147.8, 137.7, 134.4, 115.3, 110.0, 61.2, 14.2.[00238] HPLC-MS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 4 minutes, 1 minutes hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 0.99 min, 95% homogeneity index. [00239] LCMS: Anal. Calcd. for C9H9N3O2 191.07 found: 192.13 (M+H)+.[00240] For 3-isomer: HPLC Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 4 minutes, 1 minutes hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 1.39 min, 100% homogeneity index. [00241] LCMS: Anal. Calcd. for C9H9N3O2 191.07 found: 192.19 (M+H)+.
In ethanol; at 75.0℃;
A mixture of pyrimidin-2-ylamine (2.0 g, 21.1 mmol, 1.0 eq) and 3-bromo-2- oxo-propionic acid ethyl ester (5.13 g, 21.1 mmol, 1.0 eq ) in EtOH (30 mL ) was stirred at 75 C overnight. The reaction mixture was concentrated and the resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 20/1, v/v ) to give a mixture of imidazo[l,2-a]pyrimidine-2-carboxylic acid ethyl ester and imidazo[l,2- a]pyrimidine-3-carboxylic acid ethyl ester (3.05 g, 76% ) as a yellow solid.
With sodium hydrogencarbonate; In ethanol; at 80℃; for 5h;
Sodium bicarbonate (10.8 g, 128 mmol) was added to a solution of 2-bromo-1-(4-chlorophenyl)ethanone (20.0 g, 85.7 mmol) and <strong>[109-12-6]pyrimidin-2-amine</strong> (8.96 g, 94.2 mmol) in 200 ml of ethanol, and the mixture was stirred at 80 C. for 5 hours. The batch was then cooled to 0 C. (ice bath). The resulting precipitate was filtered off and washed twice with an ethanol/water mixture (1:1). The solid was then dried under reduced pressure at 40 C. overnight. This gave 15.9 g (69.23 mmol, 80.8% of theory) of the target product. (0476) LC-MS (Method 2): Rt=1.25 min; m/z=230 (M+H)+. (0477) 1H-NMR (400 MHz, DMSO-d6, delta/ppm): 7.07 (dd, 1H), 7.53 (d, 2H), 8.03 (d, 2H), 8.41 (s, 1H), 8.54 (dd, 1H), 8.97 (dd, 1H).
EXAMPLE 95; o [2-(4-Chlorophenyl)imidazo[l,2-a]pyrimidin-3-yl]methanol; 2-Aminopyrimidine (29 mg, 0.30 mmol) and 4-chlorophenacyl bromide (47 mg, 0.20 mmol) were mixed in ethanol (0.5 mL) and stirred at rt over the weekend. The mixture was then heated at 70 C for 4 h. 0.5 M NaOH (1.2 mL) was added slowly with stirring. Thes precipitate that formed was collected by centrifugation and washed with water (1.5 mL) to give the intermediate compound 2-(4-chlorophenyl)imidazo[l,2-a]pyrimidine. MS (ESI+) m/z 230, 232 [M+H]+.
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 95℃; for 18h;Schlenk technique; Inert atmosphere;
General procedure: To a Schlenk tube charged with Pd2(dba)3 (2 mol %) and Xantphos (3 mol %) was added <strong>[109-12-6]2-aminopyrimidine</strong> (1 mmol) and NaOtBu (1 mmol). The tube was evacuated and backfilled with Ar three times. Toluene (1 mL /mmol aryl halide) was then added via syringe followed by aryl bromide (0.5 mmol) by syringe.The mixture was heated to 95 C. Once deemed complete (TLC) the reaction mixture wascooled, filtered through a pad of Celite, washed with EtOAc (20 mL) and diluted with water (20ml), then extracted with EtOAc (3 x 20 mL). The organic layers were then combined, washedwith brine (50 mL), dried over MgSO4 and concentrated under reduced pressure. The product was then purified using column chromatography (hexanes: ethyl acetate, gradient from 20-70%ethyl acetate).
With potassium carbonate; In dichloromethane; at 0℃; for 3h;Inert atmosphere;
(1), weighing 1.008g 2-amino pyrimidine (10.6mmol), 1.480g chloro acetyl chloride (13.1mmol), 1.779g potassium carbonate (12.9mmol) and 13 ml dichloromethane;(2), will step one (1) weighed in 2-amino pyrimidine, potassium carbonate and two-thirds the volume of dichloromethane (about 9 ml) with nitrogen protection device is of the three-port flask, in 0 C under the condition of stirring to dissolve;(3), will step one (1) weighed chloroacetic chloride in and the remaining dichloromethane (about 4 ml) in the constant voltage dropping funnel, then with a constant acceleration of 0.25 ml/min into the three-port flask, 20 min the completion of the dropping, the continued after dropping 0 C stirring reaction under the conditions of 3h, obtaining a reaction product;(4), using vacuum filtration device, step a (3) in the obtained after filtering the reaction product is the reaction product of in addition to the solvent, each with 10 ml deionized water washing the product, washing a total of 5 times, at a temperature of 45 C the product under the conditions of drying, drying time is 5h, the lime-green powdery solid, lime-green powdery solid is acetyl-2-amino pyrimidine, weighing mass is 1.550g, yield 85.22%.
39%
With triethylamine; In chloroform; at 0 - 5℃; for 12h;Inert atmosphere;
General procedure: To a solution of theappropriate amine (31-44, 10 mmol) and triethylamine (10 mmol) in anhydrous chloroform was added dropwisechloroacetylcloride (30, 12 mmol) at0-5 C and the mixture was stirred for 12 h at the same temperature under N2.Then the solvent was removed under vacuum, and the residue dissolved in ethylacetate was once washed with water. The organic phase was stirred with 10%activated charcoal for 30 min and filtered through a neutral alumina bed.Finally, the solvent was distilled under vacuum. It is worth mentioning thatall the products obtained decompose rapidly, therefore they were used immediatelyin the next reaction.
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;
a) 2-Chloro-N-pyrimidin-2-yl-acetamide A solution of 2 amino-pyrimidine (2.0 g) in dry dichloromethane (17 mL) under nitrogen at 0 C. was treated with triethylamine (2.6 mL) followed by slow addition of chloroacetyl chloride (1.5 mL 18.4 mmol). The reaction mixture was allowed to warm up to room temperature. After 2h, the mixture was partitioned between dichioromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane (*2). The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated to give the crude product which was purified by silica gel chromatography eluting with 10% MeOH/dichloromethane. The relevant fractions were combined and evaporated to give the title compound (1.20 g) as a green solid. 1H NMR (400 MHz, CDCl3): delta 8.84 (s, 1H), 8.65 (d, 2H), 7.09 (t, 1H), 4.46 (s, 2H).
In benzene; for 6h;Reflux;
General procedure: Compound 1 (1.0 equiv.) and chloroacetyl chloride (1.0 equiv.) were taken in benzene and the reaction mixture was refluxed for 6 h after completion of the reaction monitored by TLC, the reaction mixture was diluted with EtOAc and washed with sat NaHCO3, H2O and brine. The combined organic layer was dried over anhyd. Na2SO4, evaporated to get compound corresponding 2a-o.
With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
Example 50: (/?)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyrimidin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane chloridea) 2-Chloro-/V-pyrimidin-2-yl-acetamide A solution of 2 amino-pyrimidine (2.0 g) in dry dichloromethane (17 mL) under nitroj at O0C was treated with triethylamine (2.6 mL) followed by slow addition of chloroaalpha r-hlnriHp ( ^ ml 1 8 immnl^ Thp rpnrtinn migammatiirp WSQ nllnwpri tn warm ?n tn rnnrn <n="102"/>The phases were separated and the aqueous layer was extracted with dichloromethane The combined organic layers were washed with brine, dried over sodium sulphate, fill and concentrated to give the crude product which was purified by silica gel chromatography eluting with 10% MeOH/dichloromethane. The relevant fractions we 5 combined and evaporated to give the title compound (1.20 g) as a green solid.1H NMR (400 MHz, CDCl3): delta 8.84 (s, IH), 8.65 (d, 2H), 7.09 (t, IH), 4.46 (s, 2H).
With pyridine; In dichloromethane; at 0 - 5℃; for 3h;Inert atmosphere;
2-AP (1; 31.54 mmol) was dissolved in dry DCM in the presence ofpyridine (44.16 mmol). Following the addition of PCF (37.85 mmol)under a nitrogen blanket, the reaction mixture was stirred for 3 h at 0-5 C. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated in vacuo to obtain a solid. This solid was suspended in 60 ml of petroleum ether and 50 ml of distilled water. The resulting suspension was filtered and washed with water (500 ml) and petroleum ether (100 ml) to yield pure compound 2 as a yellow solid.Yield: 79%; FT-IR (ATR, nu cm-1): 3203 (-NH), 1720 (> C]O); 1HNMR (500 MHz, deltaH, DMSO-d6): 11.31 (s, 1H), 8.59 (d, 2H, J=5.0),7.45 (d, 2H, J=7.5), 7.33-7.24 (m, 3H), 7.15 (t, 1H, J=4.5 Hz); 13CNMR (125 MHz, deltaC, DMSO-d6): 158.7, 158.3, 156.3, 151.2, 149.2,128.8, 124.5, 122.1, 114.6. Anal. C11H9N3O2: C, 61.39; H, 4.22; N,19.53; Found: C, 61.46; H, 4.18; N, 19.50.
61.7%
With pyridine; In dichloromethane; at 20℃; for 0.5h;Inert atmosphere;
To a solution of phenyl carbonochloridate (2.140 g, 13.67 mmol), and pyridine (1.361 mL, 16.82 mmol) in dichloromethane (DCM) (10 mL) stirred under nitrogen at room temperature was added <strong>[109-12-6]pyrimidin-2-amine</strong> (1.0 g, 10.51 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with saturated sodium bicarbonate solution. Separated organic layer and the aqueous layer extracted with DCM (50 ml). Combined DCM layer washed with water and dried out with sodium sulfate, filtered and concentrated under high vacuum to get crude product. This was added to a silica gel column and was eluted with 20% EtOAc/Hexane. Collected fractions were evaporated to afford the desired product (1.6 g, 6.49 mmol, 61.7%), LCMS (m/z) 216.3 (M+H)+.
61.7%
With pyridine; In dichloromethane; at 20℃; for 0.5h;Inert atmosphere;
To a solution of phenyl carbonochloridate (2.140 g, 13.67 mmol), and pyridine (1.361 mL, 16.82 mmol) in dichloromethane (DCM) (10 mL) stirred under nitrogen at room temperature was added <strong>[109-12-6]pyrimidin-2-amine</strong> (1.0 g, 10.51 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with saturated sodium bicarbonate solution. Separated organic layer and the aqueous layer extracted with DCM (50 ml). Combined DCM layer washed with water and dried out with sodium sulfate, filtered and concentrated under high vacuum to get crude product. This was added to a silica gel column and was eluted with 20% EtOAc/Hexane. Collected fractions were evaporated to afford the desired product (1.6 g, 6.49 mmol, 61.7 %), LCMS (m/z) 216.3 (M+H)+.
N-2-pyrimidine-trichloromethylsulphenamide[ No CAS ]
[ 628-13-7 ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; In dichloromethane;
EXAMPLE 1 A solution of 0.5 mol of trichloromethylsulphenyl chloride in 300 ml of methylenchlorid was added dropwise to a suspension of 47.5 g (0.5 mol) of 2-pyrimidineamine and 44 g of pyridine in 300 ml of dry methylenchloride. The mixture was stirred for 6 hours at room temperature, and the mother liquor was filtered from the precipitated pyridine hydrochloride and extracted twice by shaking with ice-water. The organic phase was dried over sodium sulphate, the solvent was evaporated off in vacuo and the residue was recrystallized from toluene. 16 g of N-2-pyrimidine-trichloromethylsulphenamide were obtained as white crystals of melting point 178 to 179 C.
A library of compounds in which R4 was various groups having the formula [CONHR »] was prepared by the process described above using 4-fluoro-3-nitrobenzoic acid, as follows: [72] Aldehyde resin was mixed with a primary amine (R17-NH2) in [DICHLOROETHANE] (DCE), triethylorthoformate (TEOF), and DMF (containing [1%] acetic acid) in a 1: 1: 1 ratio. After shaken overnight, sodium triacetoxyborohydride (20 eq. ) dissolved in DMF was added (Abdel-Magid, A. F. , et al., Tetrahedron Lett, 3 1: 5595-5598 (1990) ). After the mixture was shaken at room temperature overnight, the resin was filtered and washed with DMF (3 x 5 mL), [MEOH] [(3 X 5] mL), DMF [(3 X 5] mL), [MEOH] [(3 X 5] mL), and [CH2CL2] [(3 X 5] mL). The resin was washed twice with 5 mL DMF containing [1%] Hunig's base. To the filtered resin was added a mixture of 4-fluoro-3-nitrobenzoic acid (FNBA, 10 eq. ) and diisopropylcarbodiimide (DIC, 5 eq. ) in 2: 1 DMF : DCM. After shaking at room temperature overnight, the resin was filtered and washed with DMF (3 x 5 mL) and [CH2C12] (3 x 5 mL). [73] The resin was shaken with a primary amine [(R2-NH2)] in DMF for 8 hrs, filtered, and washed with DMF (6 x 5 mL), [MEOH] [(3 X 5] mL), and CH2C12 (3 x 5 mL). The aryl nitro group was reduced by the addition of tin (II) chloride dihydrate (20 eq. , >2 M) and N-methyl morpholine (NMM, 20 eq. ) in N-methyl pyrrolidinone (NMP). After shaken at room temperature overnight, the resin was filtered and washed with NMP (3 x 5 mL), [MEOH] (3 x 5 mL), and [CH2CI2 (3 X 5] mL). The resulting resin was shaken at room temperature with cyanogen bromide (5 eq. ) overnight, filtered, and washed with CH2Cl2 (3 x 5 mL), [MEOH] (3 x 5 mL), and CH2CI2 (3 x 5 mL). To produce a free amine, the resin was shaken for 30 min. in CHCl2 with the addition of sodium methoxide in methanol, filtered, and washed with CH2Cl2 [(4 X 5] mL). [[74]] In the final diversification step, the resin was heated at 500 C in DMF with a mono- substituted epoxide [[RLCH (-CH2O-)].] After shaking for 2 to 4 days the resin was filtered and washed with DMF (5 x 5 mL), [MEOH] [(3 X 5] mL), and CH2Cl2 (3 x 5 mL). T he resin-bound benzimidazole was cleaved from the solid-support by treatment with TFA: [CH2C12] (2: 3) for 1 hour at room temperature.
Example 36A (42 mg, 0.287 mmol) and 2-aminopyrimidine (27 mg, 0.284 mmol) were combined with scandium trifiate (7 mg, 0.014 mmol) in anhydrous methanol (2 mL) in <n="71"/>a 4 mL vial. The vial was sealed and shaken at ambient temperature for 30 minutes. Isopropyl isocyanide (27 mL, 0.286 mmol) was added and the mixture was shaken at ambient temperature overnight, followed by 400C for 2 hours. The mixture was absorbed on silica gel and purified using silica gel chromatography eluting using a gradient of 0-5% methanol in dichloromethane to afford the title compound. 1H NMR (300 MHz, DMSOd5) delta ppm 13.08 (s, 1 H) 8.75 (d, J=6.95, 1.86 Hz, 1 H) 8.60 (s, 1 H) 8.31 (d, J=8.82, 1.36 Hz, 1 H) 8.20 (d, J=4.75 Hz, 1 H) 8.14 (s, 1 H) 7.60 (d, J=8.82 Hz, 1 H) 7.03 (d, J=6.78, 4.07 Hz, 1 H) 6.54 (d, J=4.75 Hz, 1 H) 4.86 (d, J=5.09 Hz, 1 H) 1.05 (d, J=6.10 Hz, 6 H). MS (ESI+) m/z 293.0 (M+H)+.
With ionic liquid immobilized on gamma-Fe2O3(at)SiO2 nanoparticles; In water; at 100℃; for 1.33333h;
General procedure: To a solution of amine (1 mmol) in water (2 ml) was added tetrahydro-2,5-dimethoxyfuran (1.1 mmol) and gamma-Fe2O3(at)SiO2-Sb-IL (0.08 g). The reaction mixture was stirred at 100 C for a certain period of time as required to complete the reaction. During that time, the reaction was monitored constantly by TLC. After completion of the reaction, the catalyst was removed by using a magnet and washed with ethyl acetate. The aqueous solution was extracted by ethyl acetate (3 × 5 ml). The combined organic phase was dehydrated with anhydrous sodium sulfate. After the evaporation of the solvent, the residue was purified by silica gel flash chromatography using petroleum ether/ethyl acetate as the eluent to afford the pure product.
85%
With L-(+)-tartaric acid-choline chloride based deep eutectic solvent; at 90℃; for 1.33333h;Green chemistry;
General procedure: Amine (1 mmol), 2,5-dimethoxytetrahydrofuran (1.1 mmol)and L-(+)-tartaric acid-choline chloride based DES (1.5 g) were added to a 50 mL round bottom flask and the reaction mixturewas stirred at 90 C. The progress of the reaction was monitoredby TLC. After completion of the reaction, the mixture was cooled to room temperature and the product was extracted with ethyl acetate.After the evaporation of the solvent, the residue was purified by columnchromatography on silica gel to afford the pure product. The DES wasdried under vacuumand reused for the next cycle.
With water; potassium carbonate;palladium diacetate; dicyclohexyl-(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; In tert-butyl alcohol; at 110℃; for 1h;Inert atmosphere;
EXAMPLE FIVE: General Procedure for Cross-Coupling Reactions of Heteroarylamines; An oven-dried test tube, which was equipped with a magnetic stir bar and fitted with a Teflon screw cap septum, was charged with Pd(OAc)2 (0.01 mmol) and 1 (0.03 mmol). The vessel was evacuated and backfilled with argon (this process was repeated a total of 3 times) and then t-BuOH (2 mL) and degassed H2O (0.04 mmol) were added via syringe. After addition of the water the solution was heated to 80 0C for 1 minute.A second oven-dried reaction vessel, which was equipped with a magnetic stir bar and fitted with a Teflon screw cap septum, was charged with K2Ctheta3 (1.4 mmol). The vessel was evacuated and backfilled with argon (this process was repeated a total of 3 times) and then the aryl chloride (1.0 mmol) and amine (1.2 mmol) were added via syringe (aryl chlorides or amines that were solids at room temperature were added with the base) and the activated catalyst solution was transferred from the first reaction vessel via cannula. The solution was heated to 110 0C until the starting material had been completely consumed as monitored by GC. The reaction was then cooled to room temperature, diluted with EtOAc, washed with water, concentrated in vacuo, and purified via the Biotage SP4 (silica-packed 25+M cartridge).
SYNTHESIS EXAMPLE 2Preparation of N-[[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl]-6- (trifluoromethyl)imidazo[ 1 ,2-a]pyrimidine-2-carboxamide (compound 6) Step A: Preparation of 2-amino-5-(trifluoromethyl)pyrimidineA 2-L flask fitted with a dry ice condenser and addition funnel was charged with dimethylsulfoxide (500 mL) and a 0.5 M solution of sulfuric acid in dimethylsulfoxide (400 mL), followed by the addition of 2-aminopyrimidine (20.0 g, 21 1 mmol). The reaction mixture was stirred vigorously for 5 minutes, and then a 1 M solution of iron(II) sulfate in water (60 mL) was added. Trifluoromethyl iodide (200 g, 1.02 moles) was added below the surface of the reaction mixture at room temperature. The reaction mixture was then cooled to 0 C, and 50% aqueous hydrogen peroxide (20 mL, 294 mmol) was added dropwise over one hour. The ice bath was then removed, and the reaction mixture was allowed to warm to room temperature over three hours. The reaction mixture was then carefully neutralized to pH 6.5 with aqueous sodium carbonate. The reaction mixture was then extracted with ethyl acetate (3 x 300 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was purified by chromatography on silica gel eluting with a hexane/ethyl acetate gradient to afford 4.51 g of the title compound as an off white solid. 1H NMR (CDCI3) delta 8.51 (s, 2H), 5.55 (br s, 2H).
To a mixture of imidazo[l,2-a]pyrimidine-2-carboxylic acid ethyl ester and imidazo[l,2-a]pyrimidine-3-carboxylic acid ethyl ester (500 mg, 2.62 mmol, 1.0 eq) in EtOH ( 20 mL) was added hydrazine hydrate (180 mg, 2.88 mmol, 1.1 eq). The reaction mixture was heated at 75 C overnight. The reaction mixture was concentrated and the resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 20/1, v/v) to give 2-amino-lH-imidazole-4-carboxylic acid ethyl ester (220 mg, 54%) as a yellow solid.
With C41H36AsClN3OPRuS; potassium hydroxide; In toluene; at 100℃; for 12h;
General procedure: Amine/sulfonamide (1mmol), alcohol (1mmol), catalyst (0.5mol %), KOH (50mol %) and toluene (2mL) were placed in a 25mL round bottomed flask and stirred on a preheated oil bath (100C) for 12h. Upon completion (as monitored by TLC), the reaction mixture was cooled at ambient temperature, H2O (3mL) was added and the organic layer was extracted with CH2Cl2. The organic extract was separated, dried, and concentrated. The desired product was purified by column chromatography with n-hexane/EtOAc as eluent.
95%
With C51H40Cl2N2O3P2Ru; potassium hydroxide; In toluene; at 120℃; for 14h;
General procedure: 0.5 mol% ruthenium(II) catalyst was stirred with 4 mmol ofKOH in toluene. To this mixture, 2 mmol of alcohol and 2 mmolof amine were added and the temperature was raised up to120 C. The progress of the reactions was monitored using TLC.As soon as the reaction was completed, the mixture was cooledto room temperature and added 3 mL of distilled water. The combinedmixture was extracted with CH2Cl2 and dried by addingmagnesium sulfate. The crude product was purified by columnchromatography (n-hexane/EtOAc) and characterized by 1H NMRspectral analyses. The 1H NMR data obtained for the catalytic productswere compared with literature [19].
Example 1075-Bromo- l-methyl-3-(pyrimidin-4-ylamino)pyridin-2(lH)-one 107aA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 3,5-dibromo- l-methylpyridin-2(lH)-one (2.00 g, 21.0 mmol), 2-aminopyrimidine (5.61 g, 21.0 mmol), cesium carbonate (13.7 g, 42.1 mmol), DMF (5 mL) and 1,4-dioxane (70 mL). After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (1.10 g, 1.89 mmol) and tris(dibenzyl-ideneacetone)dipalladium(0) (963 mg, 1.05 mmol) were added. A reflux condenser was attached to the flask, and the reaction mixture was heated at 100 C for 4 h. After this time, the mixture was cooled to room temperature and diluted with 90: 10 methylene chloride/methanol (150 mL) and water (100 mL), and the layers were separated. The aqueous layer was extracted with 90: 10 methylene chloride/methanol (50 mL), and the combined organic layers were washed with brine and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica, 90: 10 methylene chloride/methanol) to afford 107a in 58% yield (3.42 g) as an amorphous light green solid: mp 217-219 C; ]H NMR (500 MHz, CDC13) delta 9.29 (s, 1H), 8.77 (s, 1H), 8.72 (d, J = 2.5 Hz, 1H), 8.36 (d, J = 6.0 Hz, 1H), 7.69 (d, J = 2.5 Hz, 1H), 7.37 (dd, J = 5.5, 1.0 Hz, 1H), 3.53 (s, 3H); MS (ESI+) m/z 281.0 (M+H).
58%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; N,N-dimethyl-formamide; at 100℃; for 4h;Inert atmosphere;
Example 113a 5-Bromo-1-methyl-3-(pyrimidin-4-ylamino)pyridin-2(1H)-one 113a A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with <strong>[14529-54-5]3,5-dibromo-1-methylpyridin-2(1H)-one</strong> (2.00 g, 21.0 mmol), 2-aminopyrimidine (5.61 g, 21.0 mmol), cesium carbonate (13.7 g, 42.1 mmol), DMF (5 mL) and 1,4-dioxane (70 mL). After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (1.10 g, 1.89 mmol) and tris(dibenzylideneacetone)dipalladium(0) (963 mg, 1.05 mmol) were added. A reflux condenser was attached to the flask, and the reaction mixture was heated at 100 C. for 4 h. After this time, the mixture was cooled to room temperature and diluted with 90:10 methylene chloride/methanol (150 mL) and water (100 mL), and the layers were separated. The aqueous layer was extracted with 90:10 methylene chloride/methanol (50 mL), and the combined organic layers were washed with brine and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flush column chromatography (silica, 90:10 methylene chloride/methanol) to afford 113a in 58% yield (3.42 g) as an amorphous light green solid: mp 217-219 C.; 1H NMR (500 MHz, CDCl3) delta 9.29 (s, 1H), 8.77 (s, 1H), 8.72 (d, J=2.5 Hz, 1H), 8.36 (d, J=6.0 Hz, 1H), 7.69 (d, J=2.5 Hz, 1H), 7.37 (dd, J=5.5, 1.0 Hz, 1H), 3.53 (s, 3H); MS (ESI+) m/z 281.0 (M+H).
With C41H36AsClN3OPRuS; potassium hydroxide; In toluene; at 100℃; for 12h;
General procedure: Amine/sulfonamide (1mmol), alcohol (1mmol), catalyst (0.5mol %), KOH (50mol %) and toluene (2mL) were placed in a 25mL round bottomed flask and stirred on a preheated oil bath (100C) for 12h. Upon completion (as monitored by TLC), the reaction mixture was cooled at ambient temperature, H2O (3mL) was added and the organic layer was extracted with CH2Cl2. The organic extract was separated, dried, and concentrated. The desired product was purified by column chromatography with n-hexane/EtOAc as eluent.
90%
With C51H40Cl2N2O3P2Ru; potassium hydroxide; In toluene; at 120℃; for 14h;
General procedure: 0.5 mol% ruthenium(II) catalyst was stirred with 4 mmol ofKOH in toluene. To this mixture, 2 mmol of alcohol and 2 mmolof amine were added and the temperature was raised up to120 C. The progress of the reactions was monitored using TLC.As soon as the reaction was completed, the mixture was cooledto room temperature and added 3 mL of distilled water. The combinedmixture was extracted with CH2Cl2 and dried by addingmagnesium sulfate. The crude product was purified by columnchromatography (n-hexane/EtOAc) and characterized by 1H NMRspectral analyses. The 1H NMR data obtained for the catalytic productswere compared with literature [19].
Example 1 Preparation and Characterization of the Co-Crystal <strong>[287714-41-4]Rosuvastatin</strong> 2-Aminopyrimidine Hemihydrate of Formula (III) [0072] Preparation [0073] Note: RSVNa may be prepared according EP0521471A1 and RSV may be prepared from RSVNa with acidic treatment and extraction with organic solvent. (See example 4) [0074] To an assay tube equipped with magnetic stirrer containing <strong>[287714-41-4]Rosuvastatin</strong> (as acid form) (RSV) (62 mg, 0.13 mmol) and 2-aminopyrimidine (13 mg, 0.13 mmol) was added toluene (0.75 mL, 10 vol.) before heating to 110 C. The resulting solution was allowed to cool to room temperature (24-28 C.) resulting in the precipitation of a white solid. The crude was filtered through a sintered glass funnel (n 4) to provide 38 mg of the co-crystal <strong>[287714-41-4]Rosuvastatin</strong> 2-aminopyrimidine hemihydrate with a molar yield of 49%. 1H-NMR Characterization [0075] Proton nuclear magnetic resonance analyses were recorded in deuterated dimethyl sulfoxide (DMSO-d6) in a Varian Mercury 400 spectrometer, equipped with a broadband probe ATB 1H/19F/X of 5 mm. Spectra were acquired dissolving 5-10 mg of sample in 0.6 mL of deuterated solvent. [0076] 1H-NMR (DMSO, 400 MHz): delta=8.20 (d, J=4.7 Hz, 2H); 7.76-7.69 (m, 2H); 7.32-7.24 (m, 2H); 6.58-6.47 (m, 4H); 5.54 (dd, J=5.9 Hz, J=16.0 Hz, 1H); 4.20 (q, J=6.6 Hz, 1H); 3.89-3.78 (m, 1H); 3.55 (s, 3H); 3.49-3.39 (m, 4H); 2.30 (dd, J=4.7 Hz, J=14.5 Hz, 1H); 2.20 (dd, J=8.2 Hz, J=14.5 Hz, 1H); 1.60-1.48 (m, 1H); 1.45-1.35 (m, 1H); 1.22 (d, J=6.6 Hz, 6H). (See FIG. 1-1H-NMR) X-Ray Powder Diffraction (XRPD) Characterization [0077] XRPD analysis was performed using a Philips X?Pert diffractometer with Cu Kalpha radiation in Bragg-Brentano geometry. The system is equipped with a mono-dimensional, real time multiple strip detector. The diffractogram was recorded from 3 to 40 (20) at a scan rate of 17.6 per minute (see FIG. 2). [0078] List of selected peaks (only peaks with relative intensity greater than or equal to 1% are indicated): [TABLE-US-00003] Pos. d-spac. Rel. Int. [2Th.] [] [%] 9.40 9.41 100 10.49 8.43 2 11.81 7.49 6 12.65 7.00 7 13.50 6.56 55 14.08 6.29 29 15.15 5.85 24 16.84 5.26 7 17.92 4.95 7 18.32 4.84 16 18.59 4.77 29 18.82 4.71 9 19.03 4.66 8 19.53 4.55 3 20.10 4.42 11 20.40 4.35 15 20.94 4.24 2 21.67 4.10 33 22.16 4.01 34 22.21 4.00 36 22.66 3.92 32 23.67 3.76 14 24.21 3.68 4 25.24 3.53 4 25.63 3.48 8 25.92 3.44 14 26.32 3.39 4 27.14 3.29 4 27.75 3.22 8 28.68 3.11 4 29.16 3.06 5 29.52 3.03 4 30.12 2.97 6 30.59 2.92 4 32.25 2.78 1 33.12 2.71 1 33.52 2.67 2 34.02 2.64 4 35.99 2.50 2 36.55 2.46 1 37.26 2.41 1 38.58 2.33 2 (See FIG. 2-XRPD Diffractogram). DSC Characterization [0079] DSC analyses were recorded with a Mettler DSC822e. A sample of 1.7540 mg was weighed into a 40 muL aluminium crucible with a pinhole lid and was heated, under nitrogen (50 mL/min), at 10 C./min from 30 to 300 C. [0080] The co-crystal <strong>[287714-41-4]Rosuvastatin</strong> 2-aminopyrimidine hemihydrate shows an endothermic sharp peak corresponding to the melting point with an onset at 109.37 C. (fusion enthalpy -70.77 J/g). (See FIG. 3-DSC). TGA Characterization [0081] Thermogravimetric analyses were recorded in a thermogravimetric analyzer Mettler TGA/SDTA851e. A sample of 5.2206 mg was weighed into a 70 muL alumina crucible with a pinhole lid and was heated at 10 C./min from 30 to 300 C., under nitrogen (50 mL/min). [0082] The TG analysis of the co-crystal shows 1.26% weight loss before the melting point. (See FIG. 4-TGA). Single Crystal X-Ray Diffraction Characterization [0083] The crystal structure of the co-crystal <strong>[287714-41-4]Rosuvastatin</strong> 2-aminopyrimidine hemihydrate was determined from single crystal X-ray diffraction data. The colourless prism used (0.36×0.27×0.07 mm) was obtained from the crystallization from a solution of starting products in toluene. The single crystal structural data are shown in Table 4: [TABLE-US-00004] TABLE 4 Crystal system Monoclinic Space group C2 a () 18.7043(15) b () 8.2230(7) c () 18.8025(15) beta () 91.182(2) Volume (3) 2891.3(7) Z 4 D calc. (Mg/m3) 1.35 N. of refl. 9775 Refl. with I > 2sigma(I) 4059 R (I > 2sigma(I)) 4.71 [0084] Analysis was performed at room temperature using a Bruker Smart Apex diffractometer with graphite monochromated Mo Kalpha radiation equipped with a CCD detector. Data were collected using phi and omega scans (program used: SMART 5.6). No significant decay of standard intensities was observed. Data reduction (Lorentz and polarization corrections) and absorption correction were applied (program used: SAINT 5.0). [0085] The structure was solved with direct methods and least-squares refinement of Fo2 against all measured intensities was carried out (program used: SHELXTL-NT 6.1). All non-hydrogen atoms were refined with anisotropic displacement parameters. The O atom of the water molecule lies in a twofold axis. [0086] The asymmetric unit of the crystal structure is depicted in FIG. 5, viewed nearly down the b axis (i.e., the twofold axis passing through the 0 of the water molecule is al...
A solution of 2-chloro(5-methylboromo)pyridine (12.80 g, 62 mmol) and 2-aminopyrimidine (5.930 g, 62 mmol) in DMF (100 ml), was heated to 80 C for 18 hours. The reaction was then concentratedin vacuo, and THF (150 ml) was added to the residue. The slurry was stirred for 24 hoursat room temperature and a precipitate formed. The solid was then filtered through a frit, washed with THF, dried in a vacuum oven at 40C for 18 hours and carried on without further purification.To a portion of the above synthesized salt (0.500 g, 1.13 mmol) in dichloromethane (1 0 ml)5 was sequentially added DMAP (0.030 g, 0.23 mmol), triethylamine (0.340 mg, 3.38 mmol), andbenzoyl chloride (0.240 g, 1.69 mmol). The reaction was then stirred at room temperature for 18hours. The reaction was then diluted with ethyl acetate (150 ml), and washed with water (1 00ml) dried over Na2S04 and concentrated in vacuo to afford a residue. The residue was purifiedby flash chromatography over silica gel (MeOH/CH2CI2-gradient) to afford the product E-1 as an10 orange wax (0.400 g, 90%).LC-MS: [M+H]+ 325.3; tR = 0.85 min
For a 1:1 co-crystal of dicamba and 2-aminopyrimidine, 140 mg of dicamba, 60 mg of2-aminopyrimidine and 80 jtl of 50 v/v-% water-ethanol or nitromethane solution wasgrinded in a ball mill (Retsch Modell MM3OI) for 20 minutes. The residual solventswere left to dry in air. The crystalline product gave the PXRD presented in Figure 4.Figure 4. XRPD pattern of the co-crystal (Complex Ill) comprising dicamba and 2-aminopyrimidine
4-[4-(pyrimidin-2-ylcarbamoyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
STEP C: 4-[4-(Pyrimidin-2-ylcarbamoyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl esterIn a first round bottom flask, <strong>[149353-75-3]4-(4-carboxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester</strong> (1.0 g, 3.27 mmol) in THF (15 ml) was treated with 1-chloro-N,N,2-trimethylpropenylamine (0.65 ml, 4.91 mmol) and stirred for 1 hour. In a second flask, 2-aminopyrimidine was dissolved in 15 ml of THF and cooled to 0C under nitrogen atmosphere. 1 M lithium bis-(trimethylsilyl)amide (10 ml, 10 mmol) was added dropwise and the cold solution was stirred for 30 minutes before the content of the first flask was introduced via cannula . The mixture was then stirred for 2 hours. The reaction was quenched with water (50 ml) and organics extracted with ethyl acetate (100 ml). The organic layer was dried over MgSO4, filtered and concentrated to dryness. The residue was purified by column chromatography over silica gel eluting with gradient of MeOH in DCM from 0 to 2%. The product fractions were collected and concentrated to yield 4-[4-(pyrimidin-2-ylcarbamoyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester. MS m/z 383 (M+H)+
(2-fluoro-4-nitrophenyl)(pyrimidin-2-ylamino)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
In acetonitrile; at 20℃; for 2h;
General procedure: Equimolar amounts of 2-aminopyrimidine and a suitable nitrobenzaldehyde derivative weredissolved in acetonitrile and stirred on a magnetic stirrer for two hours at room temperature (or slightlyheated, up to 50 C). Crystals obtained upon slow evaporation of the solvent were afterwards filteredoff, washed with a small amount of acetonitrile and then diethyl ether and air-dried.
(4-fluoro-2-nitrophenyl)(pyrimidin-2-ylamino)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
In acetonitrile; at 20℃; for 2h;
General procedure: Equimolar amounts of 2-aminopyrimidine and a suitable nitrobenzaldehyde derivative weredissolved in acetonitrile and stirred on a magnetic stirrer for two hours at room temperature (or slightlyheated, up to 50 °C). Crystals obtained upon slow evaporation of the solvent were afterwards filteredoff, washed with a small amount of acetonitrile and then diethyl ether and air-dried.
[2-nitro-4-(trifluoromethyl)phenyl](pyrimidin-2-ylamino)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
In acetonitrile; at 20℃; for 2h;
General procedure: Equimolar amounts of 2-aminopyrimidine and a suitable nitrobenzaldehyde derivative weredissolved in acetonitrile and stirred on a magnetic stirrer for two hours at room temperature (or slightlyheated, up to 50 C). Crystals obtained upon slow evaporation of the solvent were afterwards filteredoff, washed with a small amount of acetonitrile and then diethyl ether and air-dried.
With hydrogen bromide; In ethanol; water; for 18.0h;Reflux;
In a 250 ml three-neck round bottom flask, 2-aminopyrimidine (5 g),Bromoacetaldehyde diethyl acetal (20.7 g), 48percent aqueous solution of bromic acid (5 ml)Ethanol (50 ml) was added and the mixture was refluxed with stirring for 18 hours. The reaction solution was cooled to room temperature Silica gel was adsorbed. Through column separation using dichloromethane and methanol5 g of the title compound was obtained.
4-amino-N-(pyrimidine-2-yl)-3-(pyrimidine-2-yldiazenyl)benzene sulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89.5%
2-amino Pyrimidine (0.01 mole)( 0.95 g) was dissolved in (4 ml) of concentrated hydrochloric acid and (15 ml) of distilled water The mixture was cooled at (0-5 C) in ice-water bath , Then a solutionof sodium nitrite ( 0.01 mole) (0.69 g ) was dissolved in (10 ml) of distilled water then it will be cooled at (0-5 C). This solution was added a drop wise to the mixture with stirring at the same temperature. The diazonum salt solution was added portion wise to solution of (0.01 mol, 2.5 g) <strong>[68-35-9]sulfadiazine</strong> in distilled water with sodium hydroxide (5 g) dissolved in (100 ml) distilled water. The basicity was nutralise by adding drops of (HCl ) until the pH become (7) and temperature was maintained at (0-5 C). Themixture was stirred for 30 min. and was left overnight. The product was precipitated and filtered, washed well with distilled water and re-crystallized from absolute ethanol, yield ( 89.5%) m.p. (248-249 C). I.R spectra ( NH2 )str. (3427-3358)cm-1, Azo (1440-1492) cm-1,(C=C) str.Aromatic (1585) cm-1, (N-H)str. Sulfone (3257)cm-1, (C=N) str. Pyrimidine(1666-1635) cm-1,(C-H) str. Aromatic (3039)cm-1,SO2(1325) cm-1. 1HNMR spectrum (delta ppm), (DMSO-d6 MHz), (NH2) (6.015)((Ar-H) (6.559-7.033), (HC=N) pyrimidine (7.612-8.498), (N-H) Sulfone ( 11.294), DMSO(2.5). 13C-NMR-spectrum (delta ppm), (DMSO-d6, MHz), 110.56, 112.59, 115.99, 125.33, 130.28, 153.50, 157.69 , 158.47, 158.71.
N,N-dimethyl-N'-(pyrimidin-2-yl)propanimidamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23.4%
With trichlorophosphate; In toluene; at 110℃; for 2h;
Step A: 2-aminopyrimidine (570 mg, 6.0 mmol), phosphorus oxychloride (4.6 g, 30.0 mmol), N,N-dimethylpropanoyl (910 mg, 9.0 mmol) and toluene (15 mL) The mixture was stirred at 110 C for 2 hours. After cooling to room temperature, the reaction mixture was poured into ice water (60 mL). The pH was then adjusted to 8-9 with 2M aqueous sodium hydroxide. It was extracted with ethyl acetate (40 mL × 5) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, Ethyl acetate: petroleum ether = 1:1 to 20:1 eluted to give N,N-dimethyl-N'-(pyrimidin-2-yl)propanthone (1) (250 mg). The yield was 23.4%.
N-(pyrimidin-2-yl)-2,8-bis(trifluoromethyl)quinolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
General procedure: To a suspension of sodium hydride in mineral oil (80%, 3.33 mmol)in dry DMSO (2 ml) at 0 C, the appropriate amine (3.33 mmol) wasslowly added. The mixture was stirred for 15 min at 0 C and then atroom temperature for 1 h. After this time, <strong>[83012-13-9]4-chloro-2,8-bis(trifluoromethyl)quinoline</strong> or 4,7-dichloroquinoline (1 mmol) in dry DMSO(2 ml) was added to the reaction mixture, and it was stirred at room temperature for an additional 24 h. The reaction was monitored by TLC. After it was complete, the reaction was poured into iced distilled water to form a precipitate, which was isolated by filtration and dried. When no precipitation occurred, the reaction mixture was extracted with ethyl acetate (3×20 ml), washed with water (3×15 ml), and dried over anhydrous Na2SO4. The solvent was evaporated under vacuum andsolid 1-17 precipitated in 56-87% yields.
Analar grade <strong>[603-11-2]3-nitrophthalic acid</strong> and 2-aminopyrimidine were used for the synthesis of the title adduct. 2-Amino pyrimidine(0.95 g, 0.01 mol) was dissolved in 15 ml of Millipore water and <strong>[603-11-2]3-nitrophthalic acid</strong> (2.11 g, 0.01 mol) in 30 ml of methanol. Both the solutions were mixed together and stirred well for about an hour on a magnetic stirrer. The solution was filtered through a quantitative Whatmann No.41 grade filter paper to remove suspended impurities. Then the solution was kept aside undisturbedand allowed to evaporate at room temperature. Good optical quality crystals were harvested from the mother solution within 15days. The reaction involved is given in the scheme.
tert-butyl 8,9-dihydropyrido[4',3':4,5]imidazo[1,2-a]pyrimidine-7-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; at 80℃; for 6h;
Pyrimidin-2-amine (3600 mg, 37.9 mmol) and tert-butyl 3-bromo-4- oxopiperidine-1-carboxylate (5000 mg, 17.98 mmol) were heated in EtOH (18 mL) at 80 C for 6 h. The reaction mixture was concentrated in vacuo, and purified by silica gel column chromatography twice (gradient elution 100% EtOAc to 25% MeOH/EtOAc) to give the title product. LC/MS [M+H]+: 275.24
N-((1H-pyrazol-1-yl) methyl)pyrimidin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.3%
In dichloromethane; at 20℃; for 96h;
The three compounds were prepared by the same procedure analogue for L1. L1 was prepared by a similar procedure asdescribed in the literature [21]. The CH2Cl2 solution (10.0 mL) ofpyrimidinamine (1.15 g, 12.09 mmol) was added to the CH2Cl2 solution(10.0 mL) of <strong>[1120-82-7]1H-1-pyrazolyl-1-methanol</strong> (1.86 g,12.09 mmol). The reaction solution was dried over MgSO4 afterstirring at room temperature for 4 days. The filtrate solvent, underreduced pressure, produced a transparent oil andwas recrystallizedusing a mixture of methanol with a few drops of ether. The whitecrystals obtained after 3 days were filtered and washed withmethanol (2 50 mL), followed by washing with Et2O (2 50 mL)to yield the final product (L1). 2.2.1.1. The N-((1H-pyrazol-1-yl) methyl) pyrimidin-2-amine (L1).White cristal. Yield (1.8 g, 85.3%). mp 418 K. FT-IR, cm1: 1077(CeN), 3080 (CeH, HeC]CeH), 1333 (C]N), 1380 (N]N), 1582(C]C), 3234 (NeH). UVevis (l 298 nm). 1H NMR(300 MHz,DMSO): dH 5.37 (d, 2H, CH2), 6.27 (t, 1H, CHPyr), 6.54 (t,1H, CHAr), 6.71 (t, 1H, NH), 7.47 (d, 1H, CHPy), 7.78 (d, 1H, CHPyr), 8.20(d, 1H, CHAr), 8.21 (d, 1H, CHAr). 13C NMR (75 MHz, CDCl3):dC 73.70 (CH2), 106.15 (CHPy), 110.55 (CHAr), 112.30 (CHPy), 129.85(CHPy), 139.74 (CHAr), 158.45 (CHAr), 164.02 (C).