* 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 sodium hydroxide In butan-1-ol for 16 h; Reflux
3-(Dimethylamino)-1-(pyridine-3-yl) prop-2-en-1-one (15.4 g, 0.088 mol), guanidine nitrate (10.7 g, 0.088 mol), and sodium hydroxide (3.5 g, 0.088 mol) were dissolved in n-butanol (120 mL). The mixture was heated to reflux with stirring and maintained for 16 hours. The reaction mixture was then cooled to room temperature. The solid was collected and washed with water (400 mL). The desired product was dried under vacuum for three days and 12.7 g of yellow crystals of desired product was obtained (yield: 85percent); 1H NMR (500 MHz, CDCl3) δ 5.15 (br., 2H), 7.09 (d, 1H), 7.44 (in, 1H), 8.33 (d, 1H), 8.42 (d, 1H), 8.73 (d, 1H), 9.22 (s, 1H). LC-MS (m/z) calculated, 172.2, found 173.2 [M+H]+.
1.18 g
With sodium hydroxide In butan-1-ol at 90℃; for 0.333333 h; Microwave irradiation
The obtained compound 3 followed by 3-(dimethylamino)-1-(pyridin-3-yl) prop-2-en-1-one (0.1 mol), guanidine nitrate(0.1 mol), sodium hydroxide (0.1 mol), and n-butanol (12.5 mL) was irradiated in the microwave synthesizer at 90 C for 20 min. Aftercompletion of the reaction mixture poured into ice-cold water andthe resulting solid was filtered and washed with water. The obtainedsolid of compound 4 (1.18 g) was dried under vacuum.Melting point 190-192 °C, ES-MS (M1) found (m/z): 173.1.
Reference：
[1] Organic Process Research and Development, 2008, vol. 12, # 3, p. 490 - 495
[2] Patent: US9095622, 2015, B2, . Location in patent: Page/Page column 31
[3] Chemical Communications, 2010, vol. 46, # 14, p. 2450 - 2452
[4] Synlett, 2016, vol. 27, # 15, p. 2233 - 2236
[5] European Journal of Medicinal Chemistry, 2017, vol. 128, p. 1 - 12
[6] Journal of Molecular Structure, 2018, vol. 1171, p. 541 - 550
3
[ 593-85-1 ]
[ 55314-16-4 ]
[ 66521-66-2 ]
Yield
Reaction Conditions
Operation in experiment
66%
With sodium hydroxide In butan-1-ol at 120℃; for 2 h;
NaOH (0.78 g, 19.5 mmol) was added to a mixture of 3-(dimethylamino)-l-(pyridin-3- yl)prop-2-en-l-one (3.52 g, 20.0 mmol) and guanidine carbonate (1.80 g) in n-butanol (20 mL). The mixture was heated at 1200C for 2 h. After cooling, the precipitates formed was collected by filtration and dried under vacuum to afford the desired product (2.3g, 66percent). LCMS: (M+H)+= 173.2.
Reference：
[1] RSC Advances, 2016, vol. 6, # 66, p. 61458 - 61467
[2] MedChemComm, 2015, vol. 6, # 10, p. 1816 - 1825
[3] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 11, p. 3860 - 3874
[4] Organic and Biomolecular Chemistry, 2009, vol. 7, # 24, p. 5129 - 5136
[5] Chemical Communications, 2010, vol. 46, # 7, p. 1118 - 1120
[6] Journal of the American Chemical Society, 2012, vol. 134, # 1, p. 700 - 706
[7] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 5, p. 1296 - 1301
[8] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 15, p. 3714 - 3718
[9] Journal of Organic Chemistry, 2016, vol. 81, # 23, p. 11788 - 11801
[10] Archiv der Pharmazie, 2017, vol. 350, # 3-4,
5
[ 506-93-4 ]
[ 55314-16-4 ]
[ 66521-66-2 ]
Yield
Reaction Conditions
Operation in experiment
93%
for 12 h; Reflux
General procedure: A mixture of compound 5 (1 mmol), guanidine nitrate (2 mmol), anhydrous K2CO3 (5 mmol) in n-butanol (10 ml) was refluxed for 12 h. After cooling, the solution was poured into H2O (30 ml) and then extracted with ethyl acetate (3x20 ml). The combined organic layer was concentrated in vacuo and then purified by recrystallisation with diethyl ether.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 13, p. 3024 - 3028
[2] Angewandte Chemie, International Edition, 2015, vol. 54, # 1, p. 179 - 183[3] Angewandte Chemie, 2015, vol. 127, # 1, p. 181 - 185,5
[4] Organic and Biomolecular Chemistry, 2013, vol. 11, # 11, p. 1822 - 1839
6
[ 55314-16-4 ]
[ 66521-66-2 ]
Reference：
[1] Russian Journal of Organic Chemistry, 2011, vol. 47, # 8, p. 1222 - 1226
[2] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8551 - 8556[3] Angew. Chem., 2013, vol. 125, # 33, p. 8713 - 8718,6
[4] Synthesis, 2007, # 14, p. 2121 - 2124
[5] Russian Journal of Organic Chemistry, 2011, vol. 47, # 8, p. 1222 - 1226
[6] Russian Journal of Organic Chemistry, 2011, vol. 47, # 8, p. 1222 - 1226
7
[ 420-04-2 ]
[ 55314-16-4 ]
[ 88-74-4 ]
[ 66521-66-2 ]
Reference：
[1] Russian Journal of Organic Chemistry, 2011, vol. 47, # 8, p. 1222 - 1226
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 1, p. 249 - 255
[2] Organic Process Research and Development, 2008, vol. 12, # 3, p. 490 - 495
[3] Patent: US9095622, 2015, B2,
12
[ 55314-16-4 ]
[ 404844-11-7 ]
Reference：
[1] Angewandte Chemie, International Edition, 2015, vol. 54, # 1, p. 179 - 183[2] Angewandte Chemie, 2015, vol. 127, # 1, p. 181 - 185,5
13
[ 1025716-99-7 ]
[ 55314-16-4 ]
[ 641569-94-0 ]
Yield
Reaction Conditions
Operation in experiment
8.7 g
Stage #1: With sodium hydroxide In butan-1-ol for 12 h; Inert atmosphere; Reflux Stage #2: With water; sodium hydroxide In butan-1-ol at 25 - 125℃; for 0.333333 h; Stage #3: With hydrogenchloride In water; butan-1-ol at 25 - 35℃; for 1 h;
3- [(Aminoiminomethyl)amino] -4-methyl-benzoic acid methylester mononitrate (10 g),3-(Dimethylamino)-1-(pyridine-3-yl)prop-2-en-1-one (7.3 g), sodium hydroxide (1.7 g) was added to 1-butanol (100 mL) in a round bottom flask under nitrogen atmosphere. The reaction mass was heated to reflux temperature and stirred for 12 his. Then the reaction mass was cooled to 25-35°C and iN sodium hydroxide solution (1.5 g in 37 mLof DM wter) was added to it over a period of 20 mm. The reaction mass was heated to reflux temperature (120-125°C) and then cooled to 25-35°C. iN hydrochloric acid. (3.3 mL in 37 mL of DM water) was added to the reaction mass at 25-35°C and stirred for an hour. The material formed was filtred, washed with DM water’ and then dried under vacuum at 50-55°C to provide the title compound (8.7 g).
2-methyl-5-nitrophenyl-guanidine nitrate[ No CAS ]
[ 55314-16-4 ]
[ 152460-09-8 ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In isopropyl alcohol; for 12h;Heating / reflux;
248.2 g (0.96 mol) of 2-methyl-5-nitrophenylguanidine nitrate are added to a solution of 170 g (0.96 mol) of 3-dimethylamino-l-(3-pyridyl)-2-propen-l- one in 2.0 liters of isopropanol. After the addition of 42.5 g of sodium hydroxide, the reddish suspension is boiled at reflux for 12 hours. After cooling to 00C, filtration, washing with 2.0 liters of isopropanol and 3 400 ml of methanol and drying, there is obtained N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine, m.p. 195C-198C, Rf =0.68 (methylene chloride:rnethanol==9.1).
4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]benzoic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In ethanol; for 68h;Heating / reflux;
A stirred mixture of the intermediate Example 1 a (164 g, 0.577 [MOL),] 3-(dimethylamino)-1-(3- pyridinyl)-2-propen-1-one (113. [8] g, 0.646 mol) and powdered [NAOH] (99%; Merck, Darmstadt, Germany; 26.6 g, 0.658 mol) in ethanol (2200 mL) is heated under reflux for 68 h. The reaction solvent is evaporated off under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer is separated and the aqueous phase extracted twice with ethyl acetate. The combined organic extracts are washed with water and brine, dried [(NA2SO4)] and the solvent is evaporated off under reduced pressure to give a residue, which is crystallised from diethyl ether to give the title compound as a crystalline solid, m. p. [95-96C.]
3-nitro-7-pyridin-3-yl-pyrazolo[1,5-a]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
A mixture of 0.100 g (0.78 mmol) of 4-nitro-2H-pyrazol- 3-ylamine and 0.138 g (0.78 mmol) of 3-dimethylamino-1- pyridin-3-yl-propenone in 6 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 10 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 99 mg of 3-nitro-7-pyridin-3-yl- pyrazolo [1, 5-a] pyrimidine as a yellow solid (yield 47% ; m. p. 302-303C). 1H NMR (400 MHz, CDC) : 8 7.65-7. 69 (1H, m), 7.78 (1H, d, J= 4.4 Hz), 8.45-8. 48 (1H, m), 8. 81 (1H, dd, J= 4.8 and 1.6 Hz), 9.01 (1H, d, J= 4.8 Hz), 9.11 (1H, s), 9.16 (1H, dd, J= 2.4 and 0.8 Hz). HPLC = 94. 1%
With hydrazine; In 2-methoxy-ethanol; for 3h;Heating / reflux;
A mixture of 3-dimethylamino-l-pyridin-3-yl-propenone (1.0 g, 5.7 mmol) and hydrazine monohydrate (0.3 g) in 2-methoxyethanol (15 mL) was heated at reflux under an atmosphere of nitrogen for 3 h, then reduced in vacuo to give the title compound (806 mg) as an orange gum.
With sodium; acetic acid; dimethyl amine; In methanol; hexane; toluene;
Step 1.2 8 g (0.35 mol) of sodium are placed in 260 ml of toluene and at 100 made into a suspension using a vibromixer. After cooling to 0, 17 ml (0.42 mol) of methanol are added dropwise, with cooling, and the mixture is then stirred for 45 minutes at 75. At 25 and with ice-cooling, a solution of 38.5 ml (0.35 mol) of 3-acetylpyridine and 28 ml (0.35 mol) of ethyl formate in 300 ml of toluene are added dropwise in the course of 45 minutes. The yellow suspension is stirred for 16 hours at 25 and then 23.7 g (0.52 mol) of dimethylamine are added. After the addition of 100 ml of toluene, the mixture is stirred for 45 minutes at 25, and then at 0 a solution of 20 ml of acetic acid in 150 ml of toluene is added dropwise in the course of 30 minutes and the mixture is then boiled at reflux for 1 hour. After cooling to 25, the mixture is filtered and washed with 500 ml of toluene/hexane (1:1) and the filtrate is concentrated until crystallisation begins. Cooling to 0, filtration and drying at 80 under HV yield 3-dimethylamino-1-(3-pyridyl)-2-propen-1one; m.p. 81-82.
N-{3-[(trifluoromethyl)oxy]phenyl}guanidine nitrate[ No CAS ]
N-(3-trifluoromethoxy-phenyl)-4-(pyridin-3-yl)-2-pyrimidine-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 26 Analogously to Example 1, N-(3-trifluoromethoxy-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine is obtained from 1.0 g (5.68 mmol) of 3-dimethylamino-1-(3; -pyridyl)-2-propen-1-one and 1.53 g (5.68 mmol) of 3-trifluoromethoxyphenyl-guanidine nitrate; Rf =0.7 (chloroform:methanol=9:1). The starting material is obtained as follows:
7-(3-pyridyl)-1,2,4-triazolo[1,5-a]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In hexane; acetic acid;
EXAMPLE 1 7-(3-Pyridyl)[1,2,4]triazolo[1,5-a]pyrimidine A mixture of 2.54 g of 3-amino-1,2,4-triazole, 5.29 g of 3-dimethylamino-1-(3-pyridyl)-2-propene-1-one and 25 ml of glacial acetic acid was heated under reflux for 6 hours. The solvent was removed in vacuo and the solid residue was partitioned between a saturated aqueous sodium bicarbonate solution and dichloromethane. The organic layer was separated and dried over powdered anhydrous sodium sulfate. This solution was passed through a short column of a hydrous magnesium silicate and the effluent was refluxed on a steam bath with the gradual addition of hexane until crystallization was noted. On cooling the desired compound was separated and collection by filtration gave 1.95 g. of colorless crystals mp. 209-210 C. The following Examples for the preparation of 7-(heteroaryl and substituted heteroaryl)[1,2,4]triazolo-[1,5-a]pyrimidines which are listed in Table I were prepared by the procedure described in Example 1.
2-Methyl-7-(pyridin-3-yl)[1,2,4]triazolo[1,5-a]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetic acid;
EXAMPLE 5 2-Methyl-7-(3-pyridyl)[1,2,4]triazolo[1,5-a]pyrimidine A reaction mixture of 0.98 g of 3-amino-5-methyl-1,2,4-triazole and 1.76 g of 3-dimethylamino-1-(3-pyridyl)-2-propene-1-one in 25 ml of glacial acetic acid was refluxed for six hours. The procedure was continued as for Example 1 to give 0.85 g of the product of the Example as colorless crystals, mp 244-245 C.
2-Ethyl-7-(pyridin-3-yl)[1,2,4]triazolo[1,5-a]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetic acid;
EXAMPLE 7 2-Ethyl-7-(3-pyridyl)[1,2,4]triazolo[1,5-a]pyrimidine A mixture of 1.12 g of 3-amino-5-ethyl-1,2,4-triazole and 1.76 g of 3-dimethylamino-1-(3-pyridyl)-2-propene-1-one in 25 ml of glacial acetic acid was refluxed for six hours and the procedure of Example 1 was continued to give 1.51 g of the desired product as colorless needles, mp 147-149 C. The following additional Examples for the preparation of 2-ethyl-7-(heteroaryl and substituted heteroaryl)[1,2,4]triazolo[1,5-a]pyrimidines listed in Table II were prepared by the procedure described in Example 7.
In butan-1-ol; at 130℃; for 3.5h;Product distribution / selectivity;
Step 1.4: 4-methyl-N*3*-(4-pyridin-3-yl-r2-14C1pyrimidin-2-yl)-benzene-1.3-diamine A solution of crude /V-(5-amino-2-methyl-phenyl)-[14C]guanidine (step 1.4, 476 mg, 2.89 mmo.) and 3-dirr.Sthy.arnino-1-py.r.dir.-3-y.-p.ropenone (509 mg, 2.89 mmo.) in n-bupsilontanol (30 ml) is heated at reflux (1300C) for 3.5 hours. Removal of the solvent and purification by flash EPO <DP n="19"/>chromatography eluting with 2:98 pentane:acetone gives the title product as a yellow foam. Radio TLC, 2:98 pentane:acetone, on silica gel F254 plates RF=0.5. Total activity, 2.3 GBq.
p-guanidino-benzoic acid ethyl ester nitrate[ No CAS ]
[ 55314-16-4 ]
[ 112722-57-3 ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In isopropyl alcohol; for 48h;Heating / reflux;
Preparation 8; [119] Preparation of 4-(4-PVrJdJn-S-Vl -pyrimidin-2-ylamino)benzoic acid ethyl ester[120] 3-dimethylamino-l-pyridin-3-yl-propenone (3.3g, 18.71mmol), 4-guadino-benzoic EPO <DP n="13"/>acid ethyl ester nitrate (5g, 18.71mmol) prepared in Preparation 6, sodium hydroxide (0.83g, 20.58mmol), and isopropanol (25ml) were added to a reaction vessel, and then mixed under reflux. After 48 hr, a reaction vessel was cool to RT, an organic layer was extracted with ethyl acetate and water, distilled under vacuum, and then washed with ether to give the titled compound as yellow solid.[121] 1H-NMR (CDCl = 1.34 (t,3H), 4.30 (q,2H), 7.63 (d,2H), 7.97 (m,4H), 8.70(d,lH), 8.80 (d,lH), 8.85 (m,lH), 9.38 (m,lH), 10.27 (s,lH)
With sodium hydroxide; In butan-1-ol; for 12h;Heating / reflux;
To 3-guanidino-4-methyl-benzoic acid methyl ester nitrate 2 (0.02 mol) in nBuOH (40 mL) is added 3 (0.02 mol) and sodium hydroxide flakes (0.02 mol). The resulting mixture is heated at reflux for 12 h to yield ester 4. 1 N aq. NaOH (20 mL) is added to the nBuOH solution of ester 4 and heated at reflux for 30 min. After cooling to rt, 1 N (aq) HCl (20 mL) is slowly added to the mixture with vigorous stirring. The product is collected by filtration and washed with water to afford acid 5. 1H NMR (400MHz, d6-DMSO) delta 9.28 (d, 7 =1.8 Hz, IH), 9.08 (s, IH), 8.7 (dd, 7 = 4.7, 1.5 Hz, IH), 8.55 (d, J = 5.1 Hz, IH), 8.46 (dt, J = 8, 1.8 Hz, IH), 8.31 (s, IH), 7.65 (dd, 7 = 7.8, 1.5 Hz, IH), 7.54 (dd, 7 = 7.7, 4.7 Hz, IH), 7.49 (dd, 7 = 5.2 Hz, IH), 7.37 (d, J = 7.9 Hz , IH), 3.08 (s, 3H). MS (m/z) (M+l)+: 307.2.
With sodium hydroxide; In butan-1-ol; for 12h;Heating / reflux;
To a solution of 3-amino-4-methyl-benzoic acid methyl ester (0.6 mol) in nBuOH (50 mL) is added 70% nitric acid (2.7 mL) to form the nitrate salt followed by condensation with aqueous cyanamide solution (50%wt., 7 mL, 0.09 mol). The resulting mixture is heated at reflux for 16 h and cooled to ambient temperature followed by addition of diethyl ether (100 mL). After cooling at OC for 30 min, filtration and washing with 1 :1 = methanol : diethyl ether (120 mL) affords 3-guanidino-4-methyl-benzoic acid methyl ester nitrate 2.[00105] To 3-guanidino-4-methyl-benzoic acid methyl ester nitrate 2 (0.02 mol) in nBuOH (40 mL) is added 3 (0.02 mol) and sodium hydroxide flakes (0.02 mol). The resulting mixture is heated at reflux for 12 h to yield ester 4. 1 N aq. NaOH (20 mL) is added to the nBuOH solution of ester 4 and heated at reflux for 30 min. After cooling to it, 1 N (aq) HCl (20 mL) is slowly added to the mixture with vigorous stirring. The product is collected by filtration and washed with water to afford acid S. 1H NMR (400MHz, d6-DMSO) delta 9.28 (d, J =1.8 Hz, IH), 9.08 (s, IH), 8.7 (dd, 7= 4.7, 1.5 Hz, IH), 8.55 (d,J = 5.1 Hz, IH), 8.46 (dt,J= 8, 1.8 Hz, IH), 8.31 (s, IH), 7.65 (dd, J= 7.8, 1.5 Hz, IH), 7.54 (dd,J= 7.7, 4.7 Hz, IH), 7.49 (dd,J= 5.2 Hz, IH), 7.37 (d, J = 7.9 Hz , IH), 3.08 (s, 3H). MS (m/z) (M+l)+: 307.2. [00106] Reactant 3 can be obtained by the following procedures. A mixture of 3- acetylpyridine (2.47 mol) and N,N-dimethylformamide dimethylacetal (240 mL) is heated at reflux for 16 h. The solvent is removed in vacuo and hexanes (100 mL) is added to the residue to crystallize a solid. The solid is recrystallized from methylene chloride-hexanes to give 3- dimethylamino-l-(3-pyridyl)-2-propen-l-one. 1H NMR (400MHz, d-chloroform) delta 9.08 (d, J = 2.4 Hz, IH), 8.66 (m, IH), 8.20 (m, IH), 7.87 (m, IH), 7.37 (m, IH), 5.68 (d,J = 16.4 Hz, IH), 3.18 (s, 3H), 2.97 (s, 3H).
With sodium hydroxide; In butan-1-ol; at 120℃; for 2h;
NaOH (0.78 g, 19.5 mmol) was added to a mixture of 3-(dimethylamino)-l-(pyridin-3- yl)prop-2-en-l-one (3.52 g, 20.0 mmol) and guanidine carbonate (1.80 g) in n-butanol (20 mL). The mixture was heated at 1200C for 2 h. After cooling, the precipitates formed was collected by filtration and dried under vacuum to afford the desired product (2.3g, 66percent). LCMS: (M+H)+= 173.2.
In iso-butanol; for 24h;Heating / reflux;
4-Pyridin-3 - yl-pyrimidin-2- ylamine (7)[0042] A mixture of 3-acetylpyridine (20.72 g, 171.0 mmol) and N, N-dimethylformamide dimethyl acetal (60 mL, 450 mmol) is heated at 110 0C. After reaction overnight, the reaction mixture is cooled to room temperature and concentrated. Ethyl ether (20 mL) and hexanes (60 <n="17"/>P A T E N TGNF Docket No.: P1286PC10mL) are added to the residue. The resulting solid is collected by filtration, washed with hexanes, and dried to afford 3-dimethylamino-l-pyridin-3-yl-propenone which is used for next reaction without further purification. A mixture of 3-dimethylamino-l-pyridin-3-yl-propenone (17.6 g, 100 mmol) and guanidine carbonate (10.8 g, 60.0 mmol) in 2-butanol (100 mL) is heated at reflux. After 24 hours, the reaction mixture is cooled to room temperature and concentrated. The residue is triturated in water (50 mL). The solid is collected by filtration, washed with water and dried to afford the desired product 4-pyridin-3-yl-pyrimidin-2-ylamine as a white solid. C29H31N7O Exact MS: 172.07. Found MS m/z 173.1 (M+l). 1H NMR (DMSO-J6): delta 9.23 (s, IH), 8.69 (m, IH), 8.37 (m, 2H), 7.54 (d, IH), 7.20 (d, IH), 6.80 (s, 2H).
3,5-bis(trifluoromethyl)-N-(4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)phenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step (IV): Preparation of (3,5-bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)phenyl]-benzamide(I)A suspension of (3,5-bis-trifluoromethyl)-N-(3-guanidino-4-methylphenyl)-benzamide nitrate (70 g, 0.15 mol) in n-butanol (470 ml) under an atmosphere of nitrogen was treated successively with sodium hydroxide flakes (7.0 g, 0.18 mol) and 3-dimethylamino-1-pyridin-3-yl-propenone (28.0 g, 0.16 mol). The resulting suspension was heated to reflux temperature for 2 hrs. The reaction mixtures became a homogeneous deep orange solution and dimethylamine was removed by the distillation of n-butanol. Reaction mass was cooled down to RT and a mixture of water and chloroform (300 ml +300 ml) was added and chloroform layer was separated out. The chloroform layer was washed with water and distilled to a residual volume of 70 ml. Ethyl acetate (350 ml) was added to the reaction mass and filtered off with suction, the isolated solid was washed with ethyl acetate (2×50 ml) and water (2×50 ml) and dried in vacuum at 60 C.Yield: 48.0 g of (3,5-bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)phenyl]-benzamide of the formula I.The compound of formula-I obtained by Step-IV process was suspended in 480 ml Chloroform and heated to 50-55 C. The reaction mass was cooled to room temperature and then cooled further to -5-0 C. The product was filtered and washed with Chloroform (250 ml). The wet cake was dried for 6 hours at 60 C. The yield was 40 gms.Melting range -230-237 C. (DSC).
(2-methyl-5-nitrophenyl)guanidine nitrate[ No CAS ]
[ 55314-16-4 ]
[ 152460-09-8 ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In isopropyl alcohol; for 12h;Reflux;
248.2 g (0.96 mol) of 2-methyl-5-nitrophenylguanidine nitrate are added to a solution of 170 g (0.96 mol) of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one in 2.0 liters of isopropanol. After the addition of 42.5 g of sodium hydroxide, the reddish suspension is boiled at reflux for 12 hours. After cooling to 0 C., filtration, washing with 2.0 liters of isopropanol and 3 400 ml of methanol and drying, there is obtained N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine, m.p. 195 C.-1 98 C., Rf=0.68 (methylene chloride:methanol=9.1).
N-(2-methylphenyl)-4-(pyridin-3-yl)pyrimidin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In ISOPROPYLAMIDE; at 111℃; for 12h;
A mixture of JV-2-tolyl guanidi?e (16.Og, 0.075mol), 3-dimethylamino-l-(pyridin-3-yl)-propenone (13.2g, 0.075mol) and potassium carbonate (12.5g, 0.090mol) in ./VyV-dimethylacetamide (40ml) was heated to 111C for 12hrs. Water was added to the reaction mixture and stirred at room temperature for 15min. The solid product obtained was filtered, washed with water and dried to give 10.8g of (4-(3-pyridinyl)-2- pyrimidinyl-2-tolylamine which was used as such in the next step.
With sodium hydrogencarbonate; In butan-1-ol; at 120℃; for 16h;Reflux; Inert atmosphere;
Example 2.Preparation of N-(5-bromo-2-methylphenyl)-4-(pyridin-3-yl)-pyrimidin-2-ylamine of the Formula 5; Preparation of N-(5-bromo-2-methylphenyl)-4-(pyridin-3-yl)-pyrimidin-2-ylamineA 1 L-reactor is charged with 52.5 g of 5-bromo-2-methylphenylguanidine nitrate (171.7 mmol, 1.0 eq), 30.2 g of 3-dimethylamino-l-(pyridin-3-yl)prop-2-en-l-one (171.3 mmol, 1.0 mmol), 28.0 g of sodium hydrogen carbonate (333.3 mmol, 1.9 mmol) and 300 g of M-butanol. The reaction mixture was heated to reflux (temperature of 120C) and stirred at reflux under nitrogen for 16 h. After that time, the reaction mixture was cooled down to 80C and 150 g of TBME ether was added. When temperature reached 60C, cooling was started until reaching -10C, and then the reaction mixture was stirred at that temperature for 2 h. The product was filtered off under reduced pressure. The crude product was stirred in the reactor with 180 g of water for 30 minutes. The product was filtered off again, and the precipitate was washed with 80 g of water on a filter funnel. The product was dried at 60C for 15 h to yield 47.98 g (82.0%) of (5-bromo-2-methylphenyl)-4-(pyridin-3-yl)-pyrimidin-2-ylamine having an HPLC purity of 99.0%.
With sodium hydroxide; In tert-butyl alcohol; at 85℃;
The starting material was added 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (Compound 4) (1.76 g, 0.01 mol) in a three-neck flask.Guanidine hydrochloride (2.87 g, 0.03 mol)And sodium hydroxide (1.2g, 0.03mol), add 25ml of solvent t-butanol, stir, heated in a constant temperature oil bath to 85 C reflux reaction, 6-8h. After the reaction is completed, the solvent is spin-dried, an appropriate amount of water and ethyl acetate are added, the insoluble solid is filtered, and the filter cake is washed with water and dried to obtain a yellow solid; the filtrate is further subjected to extraction, the organic phase is collected, dried, and the solvent is dried and dried. The solid was subjected to column chromatography to give a pale yellow solid, Compound 5 (1.55 g, yield: 90%).
With sodium hydroxide; In butan-1-ol; at 120℃;
To aflask 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one(1.76 g, 10.0 mmol), guanidine hydrochloride (1.15 g, 12.0 mmol), NaOH (480 mg,12.0 mmol) and n-BuOH (20 mL) were added. The mixturewas heated to 120 oC.The resulting solid was collected, rinsed with water (50 mL) and dried overhigh vacuum to get the product as light yellow crystalline (1.51 g, 88% yield).1H NMR(400 MHz, DMSO) delta 9.23 (d, J = 2.0 Hz, 1H), 8.67 (dd, J = 4.7,1.3 Hz, 1H), 8.38 (dt, J = 8.0, 1.8 Hz, 1H), 8.36 (d, J = 5.1 Hz,1H), 7.52 (dd, J = 8.0, 4.8 Hz, 1H), 7.20 (d, J = 5.1 Hz, 1H),6.81 (s, 2H).13C NMR (101 MHz, DMSO) delta163.78, 161.53, 159.36, 151.11, 147.93, 134.11, 132.44, 123.72, 105.99
With sodium hydroxide; In butan-1-ol; at 120℃;
3-dimethylamino-1-(3-pyridyl)-2-propenyl-1-one (1.76 g, 10.0 mmol) was suspended in n-butanol (20 mL), followed by the addition of guanidine hydrochloride (1.15 g, 12.0 mmol) and NaOH (480 mg, 12.0 mmol). The mixture was heated to 120 C for reacting overnight. The precipitated solid was collected and washed with water (50 mL), followed by vacuum drying to give a light yellow crystal (1.51g, 88% yield). 1H NMR (400 MHz, DMSO) delta 9.23 (d, J = 2.0 Hz, 1H), 8.67 (dd, J = 4.7, 1.3 Hz, 1H), 8.38 (dt, J = 8.0, 1.8 Hz, 1H),8.36 (d, J = 5.1 Hz, 1H), 7.52 (dd, J = 8.0, 4.8 Hz, 1H), 7.20 (d, J = 5.1 Hz, 1H), 6.81 (s, 2H). 13C NMR (101 MHz, DMSO) delta 163.78, 161.53, 159.36, 151.11, 147.93, 134.11, 132.44, 123.72, 105.99
With sodium hydroxide; In butan-1-ol; for 16h;Reflux;
3-(Dimethylamino)-1-(pyridine-3-yl) prop-2-en-1-one (15.4 g, 0.088 mol), guanidine nitrate (10.7 g, 0.088 mol), and sodium hydroxide (3.5 g, 0.088 mol) were dissolved in n-butanol (120 mL). The mixture was heated to reflux with stirring and maintained for 16 hours. The reaction mixture was then cooled to room temperature. The solid was collected and washed with water (400 mL). The desired product was dried under vacuum for three days and 12.7 g of yellow crystals of desired product was obtained (yield: 85percent); 1H NMR (500 MHz, CDCl3) delta 5.15 (br., 2H), 7.09 (d, 1H), 7.44 (in, 1H), 8.33 (d, 1H), 8.42 (d, 1H), 8.73 (d, 1H), 9.22 (s, 1H). LC-MS (m/z) calculated, 172.2, found 173.2 [M+H]+.
1.18 g
With sodium hydroxide; In butan-1-ol; at 90℃; for 0.333333h;Microwave irradiation;
The obtained compound 3 followed by 3-(dimethylamino)-1-(pyridin-3-yl) prop-2-en-1-one (0.1 mol), guanidine nitrate(0.1 mol), sodium hydroxide (0.1 mol), and n-butanol (12.5 mL) was irradiated in the microwave synthesizer at 90 C for 20 min. Aftercompletion of the reaction mixture poured into ice-cold water andthe resulting solid was filtered and washed with water. The obtainedsolid of compound 4 (1.18 g) was dried under vacuum.Melting point 190-192 °C, ES-MS (M1) found (m/z): 173.1.
l-(2-methyl-5-nitrophenyl)guanidine (63g, 0.324moles) obtained from step-A, 3- dimethylamino-l-(3-pyridyl)-2-propen-l-one(62.5g, 0.357) and n-butanol (560ml) were placed in reaction flask. The reaction mixture was heated to 120C for nine hours. Reaction mass was brought to room temperature, water (450ml) was added and stirred at room temperature for 3-4 hours. The precipitated solid was isolated by filtration and dried to afford 2-(2-methyl-5-nitroanilino)-4-(3-pyridinyl)pyrimidine. (73.7g, yield 81.9%%, purity by HPLC: 99.9%), Melting point: 195.6-195.9G;
70%
In 4-methyl-2-pentanone; for 12h;Reflux;
Example-3: Preparation of (2-methyl-5-nitrophenyl)-(4-pyridin-3-ylpyrimidin-2-yl)amineMethod A: A solution of N-(2-methyl-5-nitrophenyl) guanidine (88g, 0.45mol) and 3-dimethyl pyridin-3- yl-propenone (68.6g, 0.39mol as prepared above) in methyl isobutylketone (880 ml) was refluxed for 12 hours. After completion of reaction, the reaction mass was cooled and filtered. The resulting solid was washed and purified with methyl isobutylketone to give 96.8g (70%) of the title compound as yellow solid having purity 98.3% by HPLC.
A mixture of 43.6 g of 3-dimethylamino-l- (pyridin-3- yl ) -propenone, 28.9 g of N-acetylglycine and 300 ml of acetic anhydride was stirred with heating at 90C for 9 hours. After cooling down to room temperature, 200 ml of ethanol was added, and the deposited precipitate was filtrated. The filtrated product was washed with 100 ml of ethanol, and dried under reduced pressure to obtain 25.0 g of N- [2-OXO-6- (pyridin-3-yl) -2H-pyran-3-yl] - acetamide (hereinafter, referred to as the inventive com ound 1 ) .Inventive compound 11 H-NMR (DMSO-D6) delta: 9.80 (1H, s), 9.03-9.00 (1H, m) ,8.64-8.61 (1H, m) , 8.26 (1H, d) , 8.18-8.15 (1H, m) ,7.55-7.51 (1H, m) , 7.24 (1H, d) , 2.15 (3H, s).1 H-NMR (CDCI3) delta: 9.02-9.00 (1H, m) , 8.66-8.63 (1H, m) , 8.39 (1H, d) , 8.08-8.04 (1H, m) , 8.04 (1H, s), 7.39 (1H, dd) , 6.80 (1H, d) , 2.25 (3H, s).
General procedure: A mixture of compound 5 (1 mmol), guanidine nitrate (2 mmol), anhydrous K2CO3 (5 mmol) in n-butanol (10 ml) was refluxed for 12 h. After cooling, the solution was poured into H2O (30 ml) and then extracted with ethyl acetate (3x20 ml). The combined organic layer was concentrated in vacuo and then purified by recrystallisation with diethyl ether.
With sodium hydroxide; In butan-1-ol; for 48h;Reflux;
6.3.3 4-Methoxyl-3-[[4-(3-pyridyl)-2-pyrimidinyl] amino] benzoic acid ethyl ester (4) In a round-bottom flask, 3-guanidino-4-methoxyl nitrate ethyl benzoate (3) (3.00 g, 10 mmol), 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (1.76 g, 10 mmol), sodium hydroxide (0.48 g, 12 mmol) was dissolved in n-butanol (20 mL). The mixture was stirred and heated to reflux for 48 h. Then n-butanol was removed completely by reduced pressure distillation. EtOAc (50 mL) and water (30 mL) were added into the residue, and the mixture was stirred for 20 min. The organic phase was separated from the aqueous phase, and the aqueous phase was extracted by EtOAc (20 mL * 2). The combined organic phase was washed by water (15 mL), saturated sodium chloride (15 mL). The organic layer was dried over Na2SO4, filtered, and distilled under vacuum to give the crude product. The crude product was purified by recrystallization from ether and EtOAc, giving a white solid (2.57 g). The total yield was 73.4%, mp 99-100 C. EI-MS (m/z): 350.1 [M]+. 1H NMR (400 MHz, DMSO-d6): delta = 1.34 (t, J = 8.0 Hz, 3H), 3.96 (s, 3H), 4.34 (q, J = 8.0 Hz, 16.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 1H), 7.57-7.59 (m, 1H), 7.61 (d, J = 4.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 8.37 (s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.64 (d, J = 8.0 Hz, 1H), 8.75 (d, J = 8.0 Hz, 1H), 9.03 (s, 1H).
A mixture of 65 g (0.156 moles) of 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl-5-(trifluoromethyl)phenyl]-3-guanidino-benzamide from step (c), 30.0 g (0.171 moles) of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one of the formula (VIII) in 650 ml n-butanol was heated at 110-115 C. for 9 hours. Reaction mass was brought to room temperature and the separated solid (70 g) was filtered off. Wet solid was leached with hot water (700 ml) and hot methanol (700 ml) successively. The wet product was dried at 60-65 C. under vacuum to yield compound of formula (I). Yield: 52.1 g (63%) MR: 235-236 C. Purity: 99.0% (by HPLC)
63%
In butan-1-ol; at 110 - 115℃; for 9h;
A mixture of 65g (0.156moles) of 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl-5-(trifluoromethyl)phenyl]-3-guanidino-benzamide from step (c), 30.0g(0.171 moles) of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one of the formula (VIII) in 650 ml n-butanol was heated at 110-115C for 9 hours. Reaction mass was brought to room temperature and the separated solid (70g) was filtered off. Wet solid was leached with hot water (700ml) and hot methanol (700ml) successively. The wet product was dried at 60-65C under vacuum to yield compound of formula (I). Yield: 52.1g (63%). MR: 235-236C Purity: 99.0% (by HPLC) IR and NMR were consistent with the proposed structure
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