Structure of 1722-12-9
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CAS No. : | 1722-12-9 |
Formula : | C4H3ClN2 |
M.W : | 114.53 |
SMILES Code : | ClC1=NC=CC=N1 |
MDL No. : | MFCD00006060 |
InChI Key : | UNCQVRBWJWWJBF-UHFFFAOYSA-N |
Pubchem ID : | 74404 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302+H312+H332-H315-H319 |
Precautionary Statements: | P261-P270-P271-P264-P280-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330-P302+P352+P312-P304+P340+P312-P501 |
Num. heavy atoms | 7 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 27.04 |
TPSA ? Topological Polar Surface Area: Calculated from |
25.78 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.41 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.36 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.13 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.16 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.74 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.96 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.41 |
Solubility | 4.44 mg/ml ; 0.0388 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.47 |
Solubility | 39.2 mg/ml ; 0.342 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.21 |
Solubility | 0.705 mg/ml ; 0.00615 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.74 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.19 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With 1-methyl-3-(2-pyridinyl)-3,4,5,6-tetrahydropyrimidin-3-ium hexafluorophosphate; potassium <i>tert</i>-butylate; palladium diacetate In 1,2-dimethoxyethane at 100℃; for 0.666667 h; Microwave irradiation | General procedure: The Buchwald–Hartwig amination reaction under microwave irradiation was conducted in a CEM Discover apparatus. A 10-mL Teflon vessel was charged with 1.0 mmol of hetero-aryl halide, 3.0 mmol of amine, 2.0 of mmol base, 0.05 mmol of Pd(OAc)2 , 0.10 mmol of LHX, and 2.0 mL of solvent. The mixture was irradiated at 150 W at 100 °C for the specified time and then allowed to cool. The reaction mixture was extracted 3 times with diethyl ether, and the combined organic extracts were washed with water, dried (MgSO4) , and evaporated to dryness. Purification of the residue by flash chromatography on silica gel afforded the pure products. |
79% | With potassium carbonate In N,N-dimethyl-formamide for 24 h; | To a solution of morpholine 5a (3.63 mL, 42 mmol) in DMF (50 mL), K2CO3 (5.8 g, 42 mmol) was added; after 20 min stirring, 2-chloropyrimidine (4.0 g,35 mmol) was added. The reaction mixture was stirred for 24 h, the solvent was removed in vacuo, the residue was purified by column chromatography (elution with ethyl acetate—hexane, 1 : 1). |
12% | With (2-mesityl-1H-inden-3-yl)dicyclohexyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In 1,2-dimethoxyethane at 120℃; for 24 h; Inert atmosphere | General procedure: Pd(dba)2/1-catalyzed amination of aryl halides: An oven-dried Schlenk tube equipped with a magnetic stirring bar was charged with Pd(dba)2 (5.8 mg, 0.010 mmol), ligand 1 (8.6 mg, 0.020 mmol) and tBuONa (134 mg, 1.4 mmol). The flask was capped with a rubber septum, evacuated, and then flushed with argon. This cycle was repeated three times. Amine (1.2 mmol), aryl halide (1.0 mmol) and DME (4 mL) were then successively added by syringe. The tube was stirred at room temperature for several minutes and then placed into a preheated oil bath (120 °C) for the time period as indicated in tables. After completion of reaction as judged by GC analysis, the reaction tube was allowed to cool to room temperature and the reaction mixture was adsorbed onto silica gel, and then purified by column chromatography (hexane/ethyl acetate as eluent) to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at -78℃; for 0.166667 h; Stage #2: at 20 - 120℃; for 90 h; |
To a solution of diethylmalonate (6.65 mL, 43.65 mmol) in DMF (30 mL) at -78 °C,was added NaH (1.76 g, 52.38 mmol, 60percent dispersion in mineral oil). The reaction was stirredfor 10 min at -78 °C, warmed to room temperature and 2-chloropyrimidine (1.0 g, 8.73 mmol)in DMF (3 mL) was added. The reaction mixture was heated to 80 °C for 72 hours, then to120 °C for 18 hours, and upon completion was cooled to room temperature. The solution was15 quenched by addition of IN HCl, neutralized with saturated aqueous NaHC03 and extractedwith EtOAc (3X). The combined organics were dried over Na2S04, filtered, concentrated andpurified by flash chromatography on silica gel (0-1 00percent EtOAc in hexanes) to give the titlecompound as a yellow-orange oil (1.34 g, 92percent). MS 167 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | for 18 h; Reflux; Inert atmosphere | Method ACompound 1: l-Pyrimidin-2-yl-piperidine-4-carboxylic acid ethyl esterA mixture of 2-chloropyrimidine (2.28g, 20mmol) and ethyl isonipecotate (4.72g, 30mmol) in toluene (10ml) was heated at reflux for 18 h. then cooled to RT. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3. The organics were separated, dried, and the solvents removed in vacuo. The residue was purified by flash chromatography on silica (eluant: EtOAc/pet. ether 40/60 v/v) to yield the title compound as a colourless oil.Yield = 4.0Og, 81percent. (ESI+): [M+H]+ = 236.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | Stage #1: With N,N,N,N,-tetramethylethylenediamine; zinc(II) chloride In tetrahydrofuran at 0℃; for 2 h; Inert atmosphere Stage #2: With iodine In tetrahydrofuranInert atmosphere |
To a stirred, cooled (0 °C) solution of 2,2,6,6-tetramethylpiperidine (0.50 mL, 3.0 mmol) in THF (6 mL) were successively added BuLi(about 1.6 M hexanes solution, 3.0 mmol) and, 5 min later, ZnCl2·TMEDA7 (0.26 g, 1.0mmol). The mixture was stirred for 15 min at 0 °C before introduction of 2-chloropyrimidine(2, 0.11 g, 1.0 mmol). After 2 h at this temperature, a solution of I2 (0.76 g, 3.0 mmol) in THF(10 mL) was added. The mixture was stirred overnight before addition of an aqueoussaturated solution of Na2S2O3 (10 mL) and extraction with AcOEt (3 x 20 mL). The combinedorganic layers were dried over MgSO4, filtered and concentrated under reduced pressure.Purification was performed by chromatography on silica gel (eluent: heptane/AcOEt 95/5) toafford 4a in 18percent yield as a beige powder |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.8% | With potassium carbonate; hydrazine hydrate; at 100℃; for 0.5h; | [1484] a mixture of 2-chloropyrimidine (15 g, 131 mmol), NH2NH2.H2O (30 ml), K2CO3 (15 g, 109 mmol) was stirred at 100 C for 30 min. The mixture was ice cooled and the resulting crude crystals were collected by filtration. The crystals were washed with cold water, air dried, and recrystallized from petroleum ether (150 ml) to give compound 350a (14.4 g, 131 mmol, yield: 99.8%) as a yellow solid. 1H NMR (400mhz, DMSO-d6) delta 8.30 (d, = 4.8 hz, 2h), 8.12 (br s, ih), 6.59 (t, j = 4.7 hz, ih), 4.13 (s, 2h). |
87% | With hydrazine hydrate; In ethanol;Reflux; | General procedure: To 2-chloropyridine (1.1 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (2 mL) dropwise at room temperature. The mixture was refluxed until completion as monitored by TLC. The reaction mixture was cooled, ethanol was removed by evaporation. Then, the residue was partitioned between ethyl acetate and water. The combined organic phase was dried over anhydrous sodium sulfate and concentrated to give the product, which was used for the following cyclization reaction without purification. |
82% | With potassium carbonate; hydrazine hydrate; | Reference Example 2-57 2-Hydrazinopyrimidine The title compound was prepared according to the method described in Yakugaku Zasshi, vol.73, p.598 (1953). A mixture of 2-chloropyrimidine (25.0 g, 218 mmol), potassium carbonate (25.0 g, 181 mmol), and hydrazine monohydrate (50 mL, 1.01 mol) was heated and stirred at 100 C. for 20 minutes. The mixture was ice cooled and the resulting crude crystals were collected by filtration. The crystals were washed with cold water, air dried, and recrystallized from benzene to give the title compound (19.7 g, 82% yield). NMR (DMSO-d6) delta: 4.12 (2H, br s), 6.60 (1H, t, J=4.8 Hz), 8.10 (1H, br s), 8.31 (2H, d, J=4.8 Hz). |
80% | With hydrazine hydrate; In ethanol; for 2h; | H2mphp was synthesized by the following procedure. 2-Chloropyrimidine (1.145 g, 20 mmol) was dissolvedin ethanol (30 mL). Then, excess hydrazine hydrate (85%, 6 mL) was added to the above solutionunder stirring. A bright yellow solution formed, from which white needle crystals appeared after 2 h. The crystals were collected by filtration and recrystallized in ethanol (yield 80%). 3-Methylsalicylaldehyde(1.36 g, 10 mmol) was added to an ethanolic solution (30 mL) of 2-hydrazinopyrimidine (1.10 g, 10 mmol)and light yellow precipitate formed immediately. After reflux for 3 h, the reaction mixture was filteredand the precipitate washed with ethanol to yield light yellow powder of H2mphp. Yield 95%. |
40% | With hydrazine; In ethanol; at 20℃; for 1.33333h; | [Referential Example 34] 2-Hydrazinopyrimidine; [Show Image] Hydrazine monohydrate (20 ml) was added to a suspension of 2-chloropyrimidine (6.00 g) in ethanol (60 ml) at room temperature, and the mixture was stirred for 80 minutes. The solvent was evaporated under reduced pressure, and water (34 ml) was added to the residue. The solid precipitate was collected by filtration to give the title compound (2.30 g, 40%). 1H-NMR (400 MHz, DMSO-d6)delta: 4.12 (2H, s), 6.57-6.60 (1H, m), 8.12 (1H, s), 8.30 (2H, d, J = 4.9 Hz). EI-MSm/z: 110 (M+). |
40% | With hydrazine; In ethanol; at 20℃; for 1.33333h; | [Referential Example 3] 2-Hydrazinopyrimidine [Show Image] Hydrazine monohydrate (20 mL) was added to a suspension of 2-chloropyrimidine (6.00 g) in ethanol (60 mL) at room temperature, followed by stirring for 80 minutes. The solvent of reaction mixture was evaporated under reduced pressure, and then water (34 mL) was added to the residue. The solid that precipitated was collected through filtration, to thereby give the title compound (2.30 g, 40%). 1H-NMR(400MHz,DMSO-d6)delta:4.12(2H,s), 6.57-6.60 (1H,m), 8.12(1H,s), 8.30(2H,d,J=4.9Hz). EI-MS m/z:110(M+). |
25% | With pyridine; hydrazine; at 20℃; for 1.6h; | PREPARATION 9Preparation of 2-hydrazinylpyrimidine; A solution of 2-chloropyrimidine (0.70 g, 6.11 mmol) in pyridine (15 mL) and anhydrous hydrazine (2.5 mL) was stirred for 5 minutes at ambient temperature, and further pyridine (8 mL) was added. The reaction mixture was stirred at ambient temperature for 1.5 h and concentrated in vacuo. The residue was suspended in water (4 mL) and the resultant solid was collected by suction filtration and air-dried to afford 2-hydrazinylpyrimidine as a colorless solid in 25% yield (0.171 g): 1H NMR (300 MHz, DMSO-d6) delta 8.29 (d, J = 4.8 Hz, 2H), 8.13 (br s, 1 H), 6.59 (t, J = 4.8 Hz, 1 H), 4.12 (br s, 2H). |
With hydrazine hydrate; In ethanol; | Preparation Example 2 of Intermediate Compound Hydrazine monohydrate (43.5 g) was added to a solution of 2-chloropyrimidine (33 g) in ethanol, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the crystalline product thus obtained was recrystallized from ethyl acetate (50 ml) to give 2-hydrazinopyrimidine (20 g). Melting point 109.5C. 1H-NMR (CDCl3/DMSO-d6/TMS) delta (ppm): 8.34 (d, 2H), 6.38 (brs, 1H), 6.62 (t, 1H), 3.98 (brs, 2H). | |
With hydrazine hydrate; In methanol; at 10 - 40℃; for 1.5h; | 1) Synthesis of compound B: A solution of 26.2 g of a hydrazine monohydrate (manufactured by Wako Pure Chemical Industries, Ltd.) and 30 mL of methanol was adjusted to an internal temperature of 10C, and 15 g of Compound (A) (manufactured by Wako Pure Chemical Industries, Ltd.) is gradually added thereto, followed by stirring for 0.5 hours at the same temperature. Then, an internal temperature was elevated to 40C, and the mixture was stirred for 1.0 hour. Subsequently, the reaction liquid was allowed to cool to room temperature, and 30 mL of water was added thereto, followed by filtration and washing with 30 mL of each of water and isopropyl alcohol. The resulting crystals were dried at room temperature for 8 hours to obtain 12.4 g of Compound (B). (1H-NMR(DMSO-d6), delta value TMS standard: 4.08 to 4.20(2H, brs), 6.55 to 6.72(2H, d), 8.10 to 8.15(1H, s), 8.27 to 8.35(2H, d)) | |
With hydrazine hydrate; at 100℃; | General procedure: A mixture of 2-chloro-5-methyl-benzimidazole (10.2 g, 61.2 mmol) and hydrazine monohydrate (59 mL, 1.22 mol) was stirred at 100 C overnight. After being cooled to ambient temperature, to the reaction mixture was added to water (60 mL). After stirring under ice cooling, the resulting precipitates were collected by filtration. The precipitates were washed with water 3 times, and then dried in vacuo to give 2-hydrazino-5-methyl-benzimidazole (8.4 g, 84.6%). | |
With hydrazine hydrate; In ethanol; at 60℃; | General procedure: Hydrazine hydrate (5 mL) and 14a (10 mmol)was added to EtOH, and the mixture was heated to 60C overnight. After cooling, the solvent was evaporated, and the residue was diluted with 50 mL water, and extracted with DCM (50 mL×3). The combined organic extract was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to get the crude product 15a which was used in the next step without further purification. A solution of 2-hydroxybenzaldehyde (122 mg, 1 mmol) in 5 mL MeOH was added slowly to a solution of 15a (1 mmol), and the mixture was heated at 40C overnight. The residue was filtered, and washed with water, brine and petrol ether to give the product 16b. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | for 2h;Reflux; | A mixture of 2-chloropyrimidine (1.02 g, 8.9 mmol) and ethylendiamine (15 mL) was refluxedfor 2 h. The mixture was diluted with brine and extracted with DCM. The solvent was removedunder reduced pressure. The crude product was purified by flash chromatography (DCM: CH3OH=7: 1) to give a yellow oil ( 700 mg, yield 57%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Preparation of 2-chloro-4-pyridin-3-yl-pyrimidine lll-a To a solution of n-butyllithium (2.5 molar in hexane, 13.5 mL, 34 mmol) in anhydrous diethylether (50 mL) under argon at -78 ' was added 3-bromo pyridine (3 mL, 31 mmol). The mixture was stirred for 1 h, then a suspension of 2-chloro pyrimidine (3.6 g, 31 mmol) in anhydrous diethylether (30 mL) was added portionwise over 10 min. The resulting mixture was stirred at -30 C for 30 min, and then allowed to warm to 0 C for 1 h, at which point the reaction was successively quenched by addition of water (1 mL) in THF (10 mL) and DDQ (7.6 g, 34 mmol) in THF (25 mL). The resulting brown suspension was stirred at room temperature for 15 min, then cooled to 0 ', and treated with hexane (25 mL) and aqueous NaOH (3N, 25 mL). The mixture was stirred at 0 ' for 5 min, diluted with water (100 mL) and then extracted with ethyl acetate. The combined organic layers were washed with water, dried on MgS04, and concentrated to a minimum volume to afford after filtration lll-a as a pale brown solid (3.14 g, 53 %). H NMR (400 MHz, DMSO- de) delta 9.35 (dd, J = 2.3, 0.8 Hz, 1 H), 8.90 (d, J = 5.3 Hz, 1 H), 8.79 (dd, J = 4.8, 1 .6 Hz, 1 H), 8.54 (ddd, J = 8.0, 2.3, 1 .7 Hz, 1 H), 8.26 (d, J = 5.3 Hz, 1 H), 7.62 (ddd, J = 8.0, 4.8, 0.8 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of butyllithium (1.6M in hexanes, 9.7 ml, 16 mmol) in 25 ml of anhydrous ether at -78C was added 3-bromopyridine (1.5 ml, 16 mmol) over 5 min. The resulting mixture was stirred at -75C for 1 h. A suspension of 2- chloropyrimidine (1.8 g, 16 mmol) in 15 ml of ether was then added in portions <n="36"/>over 8 min. The resulting suspension was stirred for 30 min at -30C and allowed to warm to O'C for 1 h. The reaction was quenched with water (0.5 ml, 1.5 eq.) in THF (5 ml) and then 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.8 g, 17 mmol) in THF (12 ml) was added. The resulting suspension was stirred at RT for 15 min, then cooled to 0C. Hexane (13 nriL) was added followed by 0*C solution of NaOH (12 ml, 3N). The suspension was stirred at 0C for 5 min, 50 ml of water was added and the layers were separated. The organic layer was dried (Na2SO4) and concentrated in vacuo. The crude product was dissolved in DCM and chromatographed through a Redi-Sep pre-packed silica gel column (120 g), eluting with a gradient of 20% to 65% EtOAc in hexane, to provide 2-chloro-4- (pyridin-3-yl)pyrimidine as off-white solid. Found M+H* = 192, 194 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | EXAMPLE 9 This Example illustrates the preparation of (E)-methyl 2-[2-(4-phenylpyrimidin-2-yloxy)phenyl]-3-methoxypropenoate (Compound No.180 of Table III). To a stirred suspension of sodium methanethiolate (0.35 g) in DMF (5 ml) at 0 C. was added dropwise a solution of 2-chloro-4-phenylpyrimidine (0.86 g, prepared from 2-chloropyrimidine according to the method of D B Harden et al., J.Org.Chem., 1988, 53, 4137) in DMF (5 ml). Stirring was continued at 0 C. for 15 minutes and then the temperature was allowed to rise to room temperature. After a further 2 hours, the reaction mixture was diluted with water and then extracted with ether (*3). The combined ether extracts were washed with water, dried, filtered and evaporated to give 2-methylthio-4-phenylpyrimidine (0.76 g) as a brown solid which was used directly in the next stage. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; water; | 2-t-Butyl-4-(1-piperazinyl)-6-trifluoromethylpyrimidine (3) A solution of 60 g (0.25 mol) of the chloropyrimidine described above in 200 ml of ethanol was added dropwise to a boiling solution of 129 g (1.5 mol) of piperazine in 500 ml of ethanol over the course of 2 h, and then the mixture was boiled for a further 6 h. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was mixed with 2 l of water. The product crystallized on cooling and was then filtered off with suction. 1H-NMR (250 MHz, CDCl3): delta=1.3 (s, 9H); 1.8 (s, 1H); 3.0 (m, 4H); 4.7 (m, 4H); 6.6 (s, 1H) ppm. | |
In ethanol; water; | 2-t-Butyl-4-(1-piperazinyl)-6-trifluoromethylpyrimidine (3) A solution of 60 g (0.25 mol) of the chloropyrimidine described above in 200 ml of ethanol was added dropwise to a boiling solution of 129 g (1.5 mol) of piperazine in 500 ml of ethanol over the course of 2 h, and then the mixture was boiled for a further 6 h. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was mixed with 2 l of water. The product crystallized on cooling and was then filtered off with suction. Yield: 56 g (77% of theory) C13H19ClF3N4 (MW 288) m.p. 78-80 C. 1H-NMR (250 MHZ, CDCl3): d=1.3 (s, 9H); 1.8 (s, 1H); 3.0 (m, 4H); 4.7 (m, 4H); 6.6 (s, 1H) ppm. | |
In ethanol; water; | 2-t-Butyl-4-(l-piperazinyl)-6-trifluoromethylpyrimidine (3) A solution of 60 g (0.25 mol) of the chloropyrimidine described above in 200 ml of ethanol was added dropwise to a boiling solution of 129 g (1.5 mol) of piperazine in 500 ml of ethanol over the course of 2 h, and then the mixture was boiled for a further 6 h. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was mixed with 2 l of water. The product crystallized on cooling and was then filtered off with suction. Yield: 56 g (77% of theory); C13H19ClF3N4 (MW 288) m.p. 78-80 C.; 1H-NMR (250 MHZ, CDCl3): d=1.3 (s, 9H); 1.8 (s, 1H); 3.0 (m, 4H); 4.7 (m, 4H); 6.6 (s, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In propan-1-ol; | Preparation of N-(2-Pyrimidinyl)ethylenediamine a)N-Boc-N'-(2-Pyrimidinyl)ethylenediamine N-(Boc)ethylenediamine (0.80 g, 5.0 mmol) (Syn. Commun. 1990, 20, 255-264) was dissolved in 1-propanol (12 mL) and treated with K2 CO3 (1.2 g, 9.0 mmol), followed by 2-chloropyrimidine (0.91 g, 8.0 mmol), and the mixture was heated to reflux for 24 h. The reaction mixture was poured into H2 O (30 mL) and extracted with EtOAc (3*30 mL). The combined organic fractions were dried (MgSO4) and concentrated to give the title compound as a yellow solid (1.6 g): MS (ES) m/e 238.9 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; butanone; | 1.1 2-(5-Amino-2-chloro-4-fluorophenoxy)pyrimidine (Intermediate IIp). A mixture of <strong>[84478-72-8]5-amino-2-chloro-4-fluorophenol</strong> (3.57 g), potassium carbonate (3.04 g), and 2-chloropyrimidine (3.20 g) suspended in butan-2-one (100 ml) and dimethylsulfoxide (10 ml) was heated at reflux overnight. The solution was processed and chromatographed on silica gel eluding with ethyl acetate:hexane, 1:2, to yield yellow crystals (4.0 g). 1 H NMR (acetone-d6, TMS): 4.75(2H, br s), 6.78(1H, d, J=8.4 Hz), 7.09(1H, d, J=10.6 Hz), 7.15(1H, t, J=4.8 Hz), 8.56(2H, d, J=4.8 Hz). | |
With potassium carbonate; In dimethyl sulfoxide; butanone; | 1.1 2-(5-Amino-2-chloro-4-fluorophenoxy)pyrimidine (Intermediate IIp). A mixture of <strong>[84478-72-8]5-amino-2-chloro-4-fluorophenol</strong> (3.57 g), potassium carbonate (3.04 g), and 2-chloropyrimidine (3.20 g) suspended in butan-2-one (100 ml) and dimethylsulfoxide (10 ml) was heated at reflux overnight. The solution was processed and chromatographed on silica gel eluding with ethyl acetate:hexane, 1:2, to yield yellow crystals (4.0 g). 1H NMR (acetoned-d6, TMS): 4.75(2H, br s), 6.78(1H, d, J=8.4 Hz), 7.09(1H, d, J=10.6 Hz), 7.15(1H, t, J=4.8 Hz), 8.56(2H, d, J=4.8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With triethylamine; In ethanol;Heating / reflux;Product distribution / selectivity; | 5.1. Preparation of N-(3 '-chloro-3-methylbiphenyl-4-yl)-l-(pyrimidin-2- yl)piperidin-4-amineThe title compound was prepared stepwise, as described below. A. 1 -Pyrimidin-2-yl-piperidin-4-one : A mixture of 4-piperidone monohydrate hydrochloride (4.84 g, 31.5 mmol), 2-chloropyrimidine (3.44 g, 30 mmol) and TEA (10.04 ml, 72 mmol) in EtOH (150 ml) was heated at reflux for overnight. The mixture was concentrated to almost dry and diluted with EtOAc (400 ml). The EtOAc layer was washed with water (2 x 50 ml) and brine (2x50 ml). The aq layer was back extracted with EtOAc (4 x 100 ml). The combined EtOAc was dried (Na2SO4) and the solvent was removed. The residue was subjected to ISCO (12Og column, hexane 5 min., 0-80% EtOAc in hexane over 70 min., then EtOAc for 15 min) to give the titled compound (3.5 g, 66%). HPLC: column, Luna Phenyl-Hexyl 5 mum 4.6x50 mm, 10-90% solvent B (acetonitrile) in solvent A (10 mM ammonium acetate aq.) over 3 min., flow rate 3 ml/min, retention time, 0.97 and 1.08 min.; MS (MH+: 178).1H NMR (300 MHz, chloroform- d), delta ppm 2.52 (t, J=6.29 Hz, 4 H), 4.15 (t, J=6.20 Hz, 4 H), 6.60 (t, J=4.67 Hz, 1 H), 8.38 (d, J=4.77 Hz, 2 H). |
53% | A. 1 -Pyrimidin-2-yl-piperidin-4-one : To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 8O0C overnight and concentrated under reduced pressure. The residue was treated with ethyl acetate (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40% ethyl acetate/hexanes) to give l-pyrimidin-2-yl-piperidin-4-one (320 mg, 53%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) delta 8.38 (d, J= 6.4 Hz, 2 H), 6.61 (t, J= 6.4 Hz, 9 H), 4.16 (t, J= 5.6 Hz, 2 H), 2.53 (t, J= 5.6 Hz, 2 H). | |
53% | A. 1 -Pyrimidin-2-yl-piperidin-4-one:; To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 8O0C overnight and concentrated under reduced pressure. The residue was treated with ethyl acetate (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40% ethyl acetate/hexanes) to give l-pyrimidin-2-yl-piperidin-4-one (320 mg, 53%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) delta 8.38 (d, J= 6.4 Hz, 2 H), 6.61 (t, J= 6.4 Hz, 9 H), 4.16 (t, J= 5.6 Hz, 2 H), 2.53 (t, J= 5.6 Hz, 2 H). |
53% | In 1,4-dioxane; at 20 - 80℃; | 6.8. Preparation of Biphenyl-4-yl-fl-pyrimidin-2-yl-l,2,3i6-tetrahydro- pyridin-4-vl)-methanone; To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 8O0C overnight and concentrated under reduced pressure. The residue was treated with EtOAc (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40% EtOAc/hexanes) to give l-pyrimidin-2-yl- piperidin-4-one (320 mg, 53%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) delta 8.38 (d, J = 6.4 Hz, 2 H), 6.61 (t, J = 6.4 Hz, 9 H), 4.16 (t, J= 5.6 Hz, 2 H), 2.53 (t, J= 5.6 Hz, 2 H). |
53% | In 1,4-dioxane; water; at 80℃; | To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 80 C. overnight and concentrated under reduced pressure. The residue was treated with EtOAc (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2×10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40% EtOAc/hexanes) to give 1-pyrimidin-2-yl-piperidin-4-one (320 mg, 53%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) delta 8.38 (d, J=6.4 Hz, 2 H), 6.61 (t, J=6.4 Hz, 9 H), 4.16 (t, J=5.6 Hz, 2 H), 2.53 (t, J=5.6 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.9% | With sodium hydrogencarbonate; In isopropyl alcohol;Heating / reflux; | 8-Pyrimidin-2-yl-8-aza-bicyclo[3.2.1]octan-3-one A solution of <strong>[25602-68-0]8-aza-bicyclo[3.2.1]octan-3-one hydrochloric acid</strong> (5.0 g, 30.9 mmol), 2-chloro-pyrimidine (4.95g, 43.2mmol), NaHCO3 (7.78g, 92.7 mmol) and isopropanol (200 ml) was maintained at reflux over weekend. The resulting reaction mixture was concentrated and purified by ISCO to afford 8-pyrimidin-2-yl-8-aza-bicyclo[3.2.1]octan-3-one (4.0 g, 52.9percent) as a white solid: MS (M+1)=204. 1H NMR (MeOH) 8.36 (d, J=12 Hz 2H), 6.75 (m, 1H), 4.97 (m, 2H), 2.75 (d, J=12 Hz, 1H), 2.71 (d, J=12 Hz, 1H), 2.32 (d, J=50 Hz, 2H), 2.22 (m, 2H), 1.87 (m, 2H). |
With sodium hydrogencarbonate; In isopropyl alcohol; for 48h;Heating / reflux; | A. S-Pyrimidin^-yl-S-aza-bicycloP^.lioctan-S-one (3): A mixture of 8-aza- bicyclo[3.2.1]octan-3-one hydrochloride (1) (5g, 31mmol), 2-chloropyrimidine (2) ( 4.3g, 37 mmol), and sodium bicarbonate (7.8g, 93 mmol) were stirred at reflux in 2-propanol (200ml) for 48 h, filtered, evaporated and chromatographed (silica gel, 25percent(v/v) EtOAc/ hexane) to afford 4 grams. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dimethoxyethane; | (a) A solution of 96.5 g of 2-N,N-dibenzylaminoethanol in 200 ml of dimethoxyethane is added dropwise to a suspension of 9.6 g of sodium hydride in 100 ml of dimethoxyethane, whilst stirring at 25 C. After completion of the addition, the reaction mixture is stirred for 20 hours. A solution of 45.8 g of 2-chloropyrimidine in 200 ml of dimethoxyethane is then added dropwise at room temperature and thereafter the reaction mixture is heated to the boil for 4 hours, while stirring. After filtering off the sodium chloride which has separated out, and evaporating the solvent in vacuo, crude 2-(2-N,N-dibenzylaminoethoxy)-pyrimidine is obtained as a colourless oil, which is directly used further. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.4% | 0.117g (1mmol) of indole (purchased from Beijing Bailingwei Technology Co., Ltd.) was dissolved in 2ml of anhydrous N,N-dimethylformamide (DMF) and added at 0C 0.044 g (1.1 mmol) sodium hydride (60% dispersed in mineral oil). The reaction was warmed to room temperature and stirred for 30 minutes. After 30 minutes, 0.137g (1.2mmol) of 2-chloropyrimidine (purchased from Beijing Bailingwei Technology Co., Ltd.) was added, and the reaction was heated to 130C for 5.0 hours. The reaction was followed by TLC. The indole point disappeared and the reaction was complete. 10ml of saturated aqueous sodium chloride solution was added, and the solid precipitated out. The solid was collected by suction filtration and dried to obtain 0.188 g of compound (III-1) with a yield of 96.4%. | |
91% | To a stirred of indole ( R1 ) (500 mg, 4.26 mmol) in DMF 50 mL), sodium hydride (0.9 g, 21.3 mmol) was added in several portions. The mixture was stirred under nitrogen at 0 C for 1 h. Then, 2- chloropyrimidine (1.2 g, 10.65 mmol) was added and stirred for 32 h at 120 C. After the reaction mixture was allowed to cool down to rt and poured into water (200 mL) and extracted with EtOAc (2 ×100 mL). The organic layer was dried over anhy- drous magnesium sulfate, and the solvent was removed to give brow oil, which was purified by column chromatography on sil- ica gel (EtOAc/ acetone, 4:1) to give R2 (756 mg, 91 %) as a colorless solid mp: 68 C, R f : 0.51 (EtOAc). UV max (CH 3 OH): 225, 285, 318 nm. IR (KBr): 2932, 2851, 1616, 1577, 1508, 1456, 1352, 909, 744, 609 cm -1 . H NMR (400 MHz, CDCl 3 ): 6.68 (d, J = 4.1 Hz, 1H), 6.93 (t, J = 4.7 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H) 7.33 (t, J = 8.6 Hz, 1H), 7.65 (d, J = 7.4 Hz, 1H), 8.29 (d, J = 3.6 Hz, 1H), 8.64 (d, J = 4.5 Hz, 2H), 8.81 (d, J = 9.3 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ): 106.83, 116.01, 116.21, 120.75, 122.04, 123.56, 125.73, 131.23ssssssssssssssssssssssssssssssssss4, 135.29, 157.67, 157.98. Found: C, 73.77; H, 4.72; N, 21.45. C 12 H 9 N 3 . Calculated, % C, 73.83; H, 4.65; N, 21.52. | |
85% | Indole (5mmol), DMF (10mL) and NaH (5mmol) were added to a 25mL reaction flask.The reaction mixture was stirred at 0C for 10 minutes, and then 2-chloropyrimidine (6 mmol) was added, and then the temperature was raised to room temperature to 130C for reaction. TLC detected until the reaction was complete.Perform post-treatment and purification: add water (20 mL) for quenching, extract with EA (20 mL×3), combine the organic phases, and wash with saturated NaCl (20 mL×2).After separation, dry with anhydrous magnesium sulfate, remove the organic solvent under reduced pressure, and separate and purify by silica gel column chromatography [V (petroleum ether): V (ethyl acetate) = 15:1] to obtain a pure product, a white solid , Yield: 85%. |
74% | With sodium hydride; In N,N-dimethyl-formamide; at 20 - 120℃; for 18.03h; | 1 H-indole(468 mg) in DMF (8 mL) was added 60% sodium hydride (176 mg)After stirring at room temperature for 20 minutes,2-Chloropyrimidine (504 mg) was added,And the mixture was stirred at 120 C. for 18 hours. After cooling the reaction solution to room temperature,Water was added and the obtained solid was collected by filtration,By washing with water1- (pyrimidin-2-yl) -1 H-indole578 mg (yield 74%) was obtained. |
General procedure: NaH(60% dispersion in mineral oil, 3.6 mmol) was added in portions at 0 C to a stirred solution of indole (3.0 mmol) in DMF (10 mL). After stirring for 30 min at 0C, chloropyrimidine(3.6 mmol) was added and the mixture was stirred at 130 C for 4-24 h. Then,the reaction mixture was cooled to ambient temperature, poured into H2O(20 mL) and extracted with EtOAc (25 mL×2). The combined organic phase was dried over Na2SO4. After filtration and evaporation ofthe solvents under reduced pressure, the crude product was purified by column chromatography on silica gel to afford the corresponding product. | ||
General procedure: NaH (60% dispersion in mineral oil, 300 mg, 7.5 mmol) was added in portions at 0 C to a stirred solution of indole (5.0 mmol) in DMF (8.0 mL). After stirring for 40 min at 0 C, 2-chloropyrimidine (687.18 g, 6.0 mmol) was added and the mixture was stirred at 130 C for 24 h. The reaction mixture was cooled to ambient temperature, quenched with H2O (90 mL) and then extracted with EtOAc (3×30 mL). The combined organic phase was dried over with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was directly purified by column chromatography on silica gel (with EtOAc/petroleum) to get the corresponding product.1 | ||
Synthesis of 1,1'-bis (pyrimidin-2-yl) -1H, 1'H-2,2'- two indoleIn the reaction vessel, was added indole (6mmol, 702.9mg), NaH (mass fraction of 60%, 10.8mmol, 432mg) for 30 minutes, DMF solvent, low temperature; then 2-chloropyrimidine (9.6mmol, 1099.488mg ), the mixture was reacted at 100 after 24 hours, cooled to room temperature, the solvent was removed by extraction, separation by column to give the compound 1- (pyrimidin-2-yl) lH-indole reactants. | ||
In the reaction container, adding indole (6mmol, 702.9 mg), NaH (mass fraction of 60%, 10 . 8mmol, 432 mg), DMF solvent, under the condition of low temperature reaction 30 minutes; then adding 2 - chloro pyrimidine (9.6mmol, 1099.5 mg), the mixture 130 C reaction under 24 hours, 24h through the TLC monitoring completion of the reaction, ethyl acetate after dilution for transfer to 250 ml separatory funnel, water washing three times, after cleaning DMF, collecting the organic phase with anhydrous sodium sulfate removal, decompression and steaming and removing the organic solvent to obtain the crude product, through the column chromatography (ethyl acetate: petroleum ether=1:99) to obtain compound 1 - (pyrimidinyl -2 - yl) - 1H - indole reactants. For thousand electronic balance accurate weighing 1 - (pyrimidinyl -2 - yl) - 1H - indole reactant (0.2mmol, 39 . 16 mg), transfer to the 25 ml pressure tube, to the reaction in the container adding PdCl2(CH3CN)2(25 µM %, 10.4 mg), Cs2CO3(0.04mmol,13mg), AgSbF6(0.02mmol,7mg), Al2O3(0.2mmol, 20.4 mg), dropping 2 ml 1, 4 - dioxane solvent in thick-walled pressure tube, and finally adding three ISO propyl silicon-based acetylene bromine (0.3mmol, 73 μl), the reaction of the reaction system is screwed plug sealing, heating to 120 C, oil bath under the stirring condition of reaction 15h. After the reaction, the reaction is cooled down to the room temperature, using a short silica gel column to remove some of the metal impurities in the preliminary purification, steaming and the solvent is removed under reduced pressure to get the crude product, the crude product is carried out column chromatography (eluant: ethyl acetate/petroleum ether=1:99), get the pure dry product, yield 69%. | ||
In a reaction vessel, indole (6 mmol, 702.9 mg), NaH (60% by mass, 10.8 mmol, 432 mg) and DMF solvent were added and the mixture was reacted at low temperature for 30 minutes; then, 2-chloropyrimidine (9.6 mmol, 1099.488 mg) was added and the mixture was reacted at 130 C for 24 hours. After cooling to room temperature, the solvent was removed by extraction and the mixture was separated by column to give 1- (pyrimidin-2-yl) -1H-indole. The 1- (pyrimidinyl-2-yl) -1H-indole reactant (0.3 mmol, 58.50 mg) was accurately weighed with a one-thousandth electronic balance and transferred to a thick-walled pressure resistant tube of a reaction vessel. To the reaction vessel was added PhI(OAc)2 (3eq, 289.5mg) was added dropwise 2mL of acetic acid / acetic anhydride = 7/3 mixed solvent, the reaction tube was screwed to the reaction system sealed, heated to 60 C, the reaction was stirred in an oil bath 36h. After the reaction was completed, the reaction solution was cooled to room temperature, a short silica gel column was used to remove some metal impurities for preliminary purification, the solvent was extracted and the solvent was removed, and the solvent was distilled off under reduced pressure to give a crude product. The crude product was subjected to column chromatography Deprotecting: ethyl acetate / petroleum ether = 15: 75) gave pure and dried product in 65% yield. | ||
Will be the substrate (1.0equiv),Anhydrous N,N-dimethylformamide is added to the reaction flask,After stirring at 0 C to cool to 0 C,Slowly add sodium hydride (60% by mass in mineral oil, 1.5 equiv) in batches.Then, the reaction solution was stirred at 0 C for 30 minutes,Add 2-chloropyrimidine (1.5equiv),The reaction solution was then transferred from 0 C to 140 C and stirred for 24 hours.After the reaction is completed, the heating is stopped, and after it is cooled to room temperature, an appropriate amount of water is added to quench the reaction, (sometimes due to the reaction The dosage should be large. After quenching the water, there will be a lot of solid impurities in the product. It needs to be filtered and washed with ethyl acetate several times to reduce the loss of the product. Then it is extracted with ethyl acetate until the water phase is almost no. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Then filter and remove the solvent with a rotary evaporator, and use the silica gel for the crude product. Column chromatography (eluent: petroleum ether: ethyl acetate = 20:1) gave purified product A as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In isopropyl alcohol; for 17h;Heating / reflux;Product distribution / selectivity; | A. 1 -Pyrimidin-2-yl-piperidin-4-one : 2-Propanol (125 ml) was added to a mixture of piperidine-4,4-diol hydrochloride (9.9g, 64.6 mmol), 2-chloropyrimidine (9.4 g, 81.8 mmol) and sodium bicarbonate (21.8g, 259.3 mmol). The rapidly stirred suspension was heated to reflux for 17 h, cooled, and filtered through celite, and evaporated to provide 13.2g of clear yellow oil which was used without further purification. MS: M+H = 178. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With pyridine; at 20℃; for 3h; | Dissolve 2-chloropyrimidine (10.04 g, 87.7 mmol) in pyridine (200 mL) and add hydrazine (35.8 mL, 1.14 mol) to the mixture followed by pyridine (100 mL). Stir the mixture for 3 hr. at room temperature then concentrate. Suspend the residue in water and filter. Wash the cake with cold methanol. Collect the powder and dry under vacuum to give pyrimidin-2-ylhydrazine as a white powder (8.05 g, 83%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 120℃; for 5.5h; | 3,5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.676 g) and 2-chloropyrimidine (716 mg) were combined, melted in an oil bath at 120°C, and stirred for 5 hr 30 min. Water (10 ml) was added and the mixture was stirred, extracted with ethyl acetate (30 ml), and washed with saturated brine. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (Yamazen HI-FLASH.(TM). COLUMN size L, elution solvent: hexane/ethyl acetate) to give the title compound (333 mg). 1H-NMR (CDCl3)delta:1.25(6H,d,J=6.9 Hz), 1.51(9H,s), 2.97-3.08(2H,m), 3.95-4.16(2H,m), 4.65-4.82(2H,m), 6.51(1H,t,J=4.5 Hz), 8.34(2H,d,J=4.8 Hz). MS:237 (M++1 when tert-butyl group was cleaved). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A solution of the corresponding lithium reagent (10 mmol) in THF (10 mL) was stirredat 50 C and treated dropwise with a solution of 2-chloropyrimidine, 2-chloro-5-propylpyrimidine or2-chloroquinazoline (12 mmol) in THF (15 mL). The mixture was allowed to reach 0 C within 2 h, thenquenched with a solution of water in THF (1:5, 6 mL), stirred at 0 C and treated with a solution of DDQ(2.3 g, 10 mmol) in THF (5 mL). After stirring for an additional 10 min at 0 C, the mixture was treatedwith a cold solution of sodium hydroxide (4 M, 5 mL, 20 mmol), stirred and extracted immediatelywith ether/hexanes (1:1, 3 x 10 mL). The combined extracts were dried with anhydrous sodium sulfate,decolorized by filtration through a pad of silica gel (5 g) and concentrated on a rotary evaporator. Theresultant crude 4-substituted 2-chloropyrimidine or 2-chloroquinazoline was treated with a primaryor secondary amine (30 mmol) in toluene (20 mL) in the presence of anhydrous potassium carbonateand the mixture was heated at 75 C for 5-10 h, after which time a TLC analysis on silica gel elutingwith ether/triethylamine (9:1) showed the absence of the substrate. Preparative chromatography wasconducted eluting with ether/triethylamine/hexanes (9:5:5) to give product 1, 2, 21, 23, 24, 26, 29, 30,32, 36-46 (Scheme 1) and 48 (Scheme 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | A similar procedure22 to that previously described for the preparation of 98 was followed using 4-acetamidophenylboronic acid pinacol ester (91) (0.10 g, 0.38 mmol), 2chloropyrimidine (94) (52 mg, 0.46 mmol), sodium hydrogen carbonate (97 mg, 1.15 mmol) and bis(triphenylphosphine)palladium(II) chloride (14 mg, 0.02 mmol) in toluene (2 mL), ethanol (1 mL) and water (0.5 mL). Purification by flash chromatography (hexane:ethyl acetate 1:1) afforded 100 as a pale brown solid (46 mg, 0.21 mmol, 56%). Rf = 0.15 (hexane:ethyl acetate, 1:1); mp 116-121 C; 1H NMR (400MHz; CDCl3) deltaH 2.21 (3H, s, CH3), 7.15 (1H, t, J = 4.8 Hz, H-5), 7.41 (1H, s, NH), 7.65 (2H, d, J = 8.8 Hz, H-3', H-5'), 8.42 (2H, d, J = 8.8 Hz, H-2', H-6') and 8.78 (2H, d, J = 5.2 Hz, H-4, H-6); 13C NMR (100MHz, CDCl3) deltaC 24.8 (CH3), 118.8 (CH), 119.3 (CH), 129.1 (CH), 132.0 (C), 140.3 (C), 157.2 (CH), 164.2 (C) and 168.3 (C); IR (numax/cm-1) 721, 795, 1116, 1171, 1262 (C-N), 1314, 1410, 1529, 1560, 1596 (N-H), 1695 (C=O), 3049, 3087, 3183 and 3241; MS (ESI, 70 eV) m/z 214 (M+, 100%); Found (M+, 214.0977), C12H12N3O requires 214.0975. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.52 g | With triethylamine; In isopropyl alcohol; at 80℃; for 36h;Inert atmosphere; | General procedure: A mixture of ent-5 (15.25 mmol, 3.27 g), triethylamine (18.31 mmol, 2.53 mL) and 2-chloropyrimidine (18.31 mmol, 2.09 g) in 2-propanol was stirred for 36 h at 80 C under argon atmosphere. The mixture was concentrated in vacuo and the residue was dissolved in CH2Cl2 (10 mL) and washed with H2O (3 20 mL). After removal of the solvent under reduced pressure the resulting reside was purified by flash chromatography (hexane/ ethyl acetate) to give 3.52 g of Boc-protected 8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
539 mg | With potassium carbonate; In acetonitrile; at 90℃; for 12h; | 5-methyl-3-nitro -1H- pyrazole (450 mg of) in 30mLacetonitrile and carbonatePotassium (733 mg) and 2-chloropyrimidine (608 mg of the),and the mixture was stirred at 90 12 smallTime. The mixture was concentrated under reduced pressure,the residue was mixed with water and extracted with ethyl acetate, withThe organic phase was dried over sodium sulfate, filteredand concentrated under reduced pressure. The crude product was stirred inn-hexane,Suction filtered and dried under reducedpressure. To give 539mg of the title compound |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | A 3-neck 200 mL round bottom flask fitted witha reflux condenser and stir bar was charged with t-butyl methyl malonate (8.86 mL, 52.4 mmol) followedby dry DMF (43.7 mL). The atmosphere was exchanged for nitrogen and sodium hydride (60percentdispersion in mineral oil, 2110 mg, 52.8 mmol) was added portion-wise at 25 °C . After bubbling wascomplete (15 min), the 2-chloropyrimidine (2.5 g, 21.83 mmol) was added. The reaction turned orangeupon addition and was heated to 80 °C for 16 h. The reaction was cooled to 25 °C and quenched via theaddition of saturated ammonium chloride (50 mL) and diluted with EtOAc (50 mL). The layers wereseparated and the aq. phase was further extracted with EtOAc (3 x 50 mL). The organic phase was dried(MgSO4) and concentrated. The crude material was purified via column chromatography to provide theproduct (2.97 g, 54percent). 1H NMR (400 MHz, CDCl3) delta 8.78-8.77 (d, J = 4.7 Hz, 2H), 7.28-7.26 (m, 1H), 5.07 (s, 1H), 3.84 (s, 3H), 1.51(s, 9H).13C NMR (101 MHz, CDCl3) delta 167.37, 165.59, 163.81, 157.47, 119.77, 82.92, 62.63, 52.69, 27.90.LRMS (ESI) m/z: calc?d for C12H16N2O4 [M+H] 253.12, found 253.23 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21.54% | With triethylamine; In 1,4-dioxane; at 90℃; for 12h; | To a mixture of 2-chloropyrimidine (300.00 mg, 2.62 mmol, 1.00 eq) and piperidin-4-one (311.59 mg, 3.14 mmol, 1.20 eq) in dioxane (5.00 mL) was added triethylamine (795.35 mg, 7.86 mmol, 3.00 eq) and the mixture was stirred at 90 C for 12 h. The mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (Si02, PE/EA=10/1 to 1/1) to afford l-pyrimidin-2-ylpiperidin-4- one (100.00 mg, 564.33 umol, 21.54% yield) as a yellow solid. 1H NMR (400MHz, CHLOROFORM-d) delta = 8.37 (d, J=4.9 Hz, 2H), 6.59 (t, J=4.6 Hz, 1H), 4.21 - 4.11 (m, 4H), 2.51 (t, J=6.2 Hz, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With caesium carbonate; In N,N-dimethyl-formamide; at 85℃; for 4h; | Cesium carbonate 288 mg (0.882 mmol) was added to a DMF solution (1 mL) of <strong>[150008-24-5]tert-butyl 4-(hydroxyimino)piperidine-1-carboxylate</strong> 148 mg (0.689 mmol) and 2-chloropyrimidine 51.9 mg (0.453 mmol), and the mixture was stirred at 85C for 4 hours. After the completion of the reaction, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate:methanol) to give the title compound 37.1 mg (0.127 mmol, yield 28%) as a dark brown solid. 1H-NMR spectrum (400MHz, CDCl3) delta:8.63 (d, J = 4.8 Hz, 2H), 7.08 - 7.04 (m, 1H), 3.69 - 3.49 (m, 4H), 2.95 - 2.85 (m, 2H), 2.71 - 2.52 (m, 2H), 1.49 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
N-(Cyclopropylmethyl)-2-(methyl(2-(pyridin-3-yl)ethyl)amino)-6-morpholinopyrimidine-4-carboxamide (Example 80) The title compound was prepared according to the general procedure E using 2-chloropyrimidine I-35 (30 mg, 0.10 mmol, 1 eq), <strong>[19690-13-2]N-methyl-2-(pyridin-3-yl)ethan-1-amine</strong> (21 muL, 0.15 mmol, 1.5 eq) and DiPEA (70 muL, 0.40 mmol, 4 eq). Total heating time: 17 h at 120 C. Column chromatography (2% -> 6% MeOH/DCM) afforded the product (11 mg, 29 mumol, 29%). TLC: Rf = 0.15 (4% MeOH/DCM). 1H NMR (400 MHz, CDCl3) delta 8.65 - 8.28 (m, 2H), 7.95 (br s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.21 (dd, J = 7.9, 4.8 Hz, 1H), 6.72 (s, 1H), 3.89 - 3.69 (m, 6H), 3.69 - 3.53 (m, 4H), 3.29 (t, J = 6.4 Hz, 2H), 3.11 (s, 3H), 2.92 (t, J = 7.4 Hz, 2H), 1.12 - 0.99 (m, 1H), 0.66 - 0.45 (m, 2H), 0.36 - 0.19 (m, 2H). 13C NMR (101 MHz, CDCl3) delta 164.57, 163.95, 160.86, 156.77, 150.27, 147.86, 136.33, 135.30, 123.50, 90.36, 66.74, 51.19, 44.49, 44.15, 35.84, 31.23, 10.91, 3.51. HRMS [C21H28N6O2 + H]+ : 397.2347 calculated, 397.2345 (found (Delta = -0.38 ppm). |
Tags: 1722-12-9 synthesis path| 1722-12-9 SDS| 1722-12-9 COA| 1722-12-9 purity| 1722-12-9 application| 1722-12-9 NMR| 1722-12-9 COA| 1722-12-9 structure
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