Structure of 3934-20-1
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Norman, Jacob Patrick ;
Abstract: Pd-catalyzed cross-couplings rank among the most powerful methods for constructing substituted biaryls, polyaryls, and heteroarenes. Frequently, di- or polyhalogenated (hetero)arenes are employed as starting materials in cross-couplings to access products with increased structural complexity via multiple cross-coupling or substitution steps. N-heteroarenes bearing multiple reactive handles—such as halides, are of particular interest as starting materials since their crosscoupled products can be medicinally relevant. Non-symmetrical dihalogenated N-heteroarenes typically exhibit a site-selectivity bias for C—X bonds which are adjacent to at least one heteroatom in Pd-catalyzed cross-couplings. However, some Pd catalysts—particularly those with hindered ligands, promote atypical selectivity at distal C—X bonds of 2,X-dichloropyridines and related heterocycles during the selectivity-determining oxidative addition step. This dissertation explores the mechanistic origins of these ligand trends and emphasizes the critical importance of Pd’s ligation state—either mono (PdL) or bis (PdL2), in controlling the site of oxidative addition. Ligation state is also relevant when selecting for the products of mono- vs difunctionalization in cross-couplings of dihalogenated substrates, since bisligated 14 e- Pd dissociates quickly from the monofunctionalized intermediate after an initial cross-coupling cycle, whereas monoligated 12 e- Pd is slow to dissociate and may "ring-walk" to the remaining reactive site(s). Additionally, this dissertation explores alternative methods to access minor regioisomers in cross-couplings of dichloro-azines. One approach involves ligand-free conditions where atypical site-selectivity at dichloropyridines and dichloropyrimidines arises from a change in Pd’s speciation from mono- to multinuclearity. Another approach employs a thiolation/Liebeskind-Srogl arylation sequence to achieve site-selectivity which is orthogonal to that of Suzuki-Miyaura couplings.
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CAS No. : | 3934-20-1 |
Formula : | C4H2Cl2N2 |
M.W : | 148.98 |
SMILES Code : | ClC1=NC(Cl)=NC=C1 |
MDL No. : | MFCD00006061 |
InChI Key : | BTTNYQZNBZNDOR-UHFFFAOYSA-N |
Pubchem ID : | 77531 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 8 |
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 | 32.05 |
TPSA ? Topological Polar Surface Area: Calculated from |
25.78 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.68 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.13 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.78 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.81 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.34 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.75 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.66 |
Solubility | 0.326 mg/ml ; 0.00218 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.3 |
Solubility | 0.742 mg/ml ; 0.00498 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.87 |
Solubility | 0.203 mg/ml ; 0.00136 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) |
Yes |
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 |
-5.7 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) |
1.47 |
* 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 |
---|---|---|
52% | at -10 - 20℃; for 5 h; | To a solution of ethyl 2,4-dichloropyrimidine (20.0 g, 0.13 mol) in 150 mL of anhydrous tetrahydrofurane was added sodium thiomethoxide (49.30mL, 0.15 mol) at -10 °C. The reaction mixture was allowed to warm up to room temperature and then stirred for 5 hours with monitoring a reaction with LC-MS or thin layer chromatography (TLC). The reaction mixture was diluted with ethyl acetate and washed with brine (x2). The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting solid was slurrified with diethyl ether and then collected by filtration to afford the desired intermediate 10 as a white solid (11.2 g, 52 percent |
33% | at 20℃; | To a solution of 2,4-dichloropyrimidine (1 g, 6.71 mmol) in THF (12 mL) was added sodium thiomethoxide (565 mg, 8.05 mmol) and the resulting suspension was stirred at ambient temperature overnight. After TLC and MS showed completion of reaction, the mixture was quenched with water, extracted with EtOAc (2*25 mL), dried over anhydrous Na2SO4, filtered and evaporated to dryness. The resulting residue was purified by column chromatography on an ISCO® chromatography system (SiO2 column: hexanes/EtOAc 0 to 20percent gradient elution) to afford the title compound as yellow solid (348 g, 33percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.6% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 4h;Inert atmosphere; Green chemistry; | In a 250 mL three-necked flask,2,4-dichloropyrimidine (5.0 g, 33.56 mmol)Dissolved in 1,4-dioxaneAnd water (4: 1, 50 mL) A solution of 3-boronic acid pyridine (4.95 g, 40.27 mmol),Potassium carbonate (9.28 g, 67.12 mmol)And Pd (dppf) Cl2 (2.45 g, 3.36 mmol);The system was replaced with argon three times,Gradually heated to 90 C,Reaction for 4 hours;After the reaction, the system was concentrated under reduced pressure to remove most of the solvent,Ethyl acetate (150 mL)And water (100 mL),Extraction and separation,The aqueous phase was then extracted with ethyl acetate (80 mL)The organic phases were combined,Re-water (80 mL x 2) and saturateWashed with brine (80 mL x 2)Liquid separation,The organic phase was dried over anhydrous sodium sulfate for 3 hours,Filtration and concentration,Crude;The crude product was added petroleum ether (32 mL)And ethyl acetate (6 mL) were stirred for 1 hour,filter,Dried in vacuo to give 4.8 g of 2-chloro-4- (3-pyridyl) pyrimidine,The yield was 74.6%Purity HPLC was greater than 95%. |
73% | With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; water; for 16h;Heating; Reflux; Inert atmosphere; | Example 11 Preparation of 2-chloro-4-(pyridin-3-yl)pyrimidine[00106] Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of pyridin-3-ylboronic acid (4.42 g, 36.0 mmol, 1.00 equiv) in THF/H2O (30 mL), a solution of 2,4-dichloropyrimidine (5.40 g, 36.2 mmol, 1.00 equiv) in THF/H2O (30 mL), Na2CO3 (11.5 g, 108 mmol, 3.00 equiv) and PdCl2(PPh3)2 (1.80 g, 2.57 mmol, 0.06 equiv). The resulting solution was heated to reflux for 16 hrs in an oil bath. The reaction mixture was cooled and quenched by the addition of 100 mL of water. The resulting solution was extracted with 5x200 mL of ethyl acetate. The organic layers were combined, washed with 3x200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1: 1). This resulted in 5 g (73%) of 2-chloro-4-(pyridin-3-yl)pyrimidine as a yellow solid. |
52% | With bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; for 14h;Reflux; Inert atmosphere; | General procedure: To a solution of 2,4-dichloro-5-methylpyrimidine (500 mg, 3.1 mmol) and 4-trifluoromethoxylphenylboronic acid (644 mg, 3.1 mmol) in dioxane (15 mL), Pd(PPh3)2Cl2 (215 mg, 0.3 mmol) and 2M Na2CO3 (920 mg, 8.7 mmol) were added. The mixture was stirred at reflux for 14 h under N2 atmosphere. The reaction mixture was cooled to room temperature and filtrated. The filtrate was diluted with H2O (100 mL) and then extracted with EtOAc, and the organic layer was dried over anhydrous Na2SO4, After filtration, the filtrate was evaporation and purified by chromatography (petroleum ether/ EtOAc, 5:1) to give the product as oil (700 mg, 73 %). |
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; water; at 60℃; for 16h; | Step 1.Synthesis of 2-chloro-4-(3-pyridyl)pyrimidine nitrogen was bubbled through a solution of 2,4-dichloropyrimidine (1 eq) in tetrahydrofuran and water (3:1) for 0.5 h. bis(diphenylphosphino)ferrocene Palladium(II)chloride (0.05 eq) followed by pyridine-3-boronic acid (1 eq) and sodium carbonate (3 eq) was added and the mixture was heated to 60 C. for 16 h under nitrogen.The reaction mixture was concentrated and partitioned between ethyl acetate and water.The organic layer was washed with brine and dried with sodium sulfate and concentrated.Purification on silica gel gave 2-chloro-4-(3-pyridyl)pyrimidine. MS: MH+=190. | |
With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 1h; | 2-Chloro-4-(pyridin-3-yl)pyrimidine: Pyridin-3-ylboronic acid (263 mg, 2.14 mmol), PEPPSI - IPr (132 mg, 0.195 mmol), and potassium carbonate (2.4 ml of 2 M aqueous solution, 4.8 mmol) were added to 2,4-dichloropyrimidine (290 mg, 1 .95 mmol) in 1 ,2- dimethoxyethane (8 mL) . The reaction mixture was stirred at 100 C for 1 h. The solvents were removed under reduced pressure, and the residue was dissolved in DCM and filtered. The filtrate was purified with silica gel chromatography (20% - 60% EtOAc in hexanes) to yield 150 mg, 40.2 % yield of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) delta 1 H NMR (400 MHz, CHLOROFORM-d) delta 9.28 (br. s., 1 H), 8.79 (d, J = 3.92 Hz, 1 H), 8.73 (d, J = 5.09 Hz, 1 H), 8.46 (d, J = 8.03 Hz, 1 H), 7.72 (d, J = 5.29 Hz, 1 H), 7.49 (dd, 1 H). LCMS: tR = 0.47 min, 93%. MS m/z = 192 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In ethanol; at 100℃; for 1.0h;Heating / reflux;Product distribution / selectivity; | A mixture of 9.55 g of tert-butyl 1-piperazinecarboxylate, 7.64 g of 2,4-dichloropyrimidine and 8.6 g of NaHCO3 in 50 ml of EtOH is heated at reflux for 1 hour. It is concentrated under vacuum, the residue is taken up in water and extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/AcOEt (90/10 to 60/40; v/v) mixture. Two compounds are separated: the less polar compound, corresponding to tert-butyl 4-(4-chloro-2-pyrimidinyl)-1-piperazinecarboxylate, of which 1.75 g are obtained; the more polar compound, corresponding to the compound of step A), of which 12.9 g are obtained, and which is used as it is; A) tert-Butyl 4-(4-chloropyrimidin-2-yl)-1-piperazinecarboxylate and tert-butyl 4-(2-chloropyrimidin-4-yl)-1-piperazinecarboxylate A mixture of 9.55 g of tert-butyl 1-piperazinecarboxylate, 7.64 g of 2,4-dichloropyrimidine and 8.6 g of NaHCO3 in 90 ml of EtOH is heated at 100 C. for one hour. It is concentrated under vacuum, the residue is taken up in water and extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/AcOEt (90/10 to 60/40; v/v) mixture. Two compounds are separated: the less polar compound, tert-butyl 4-(4-chloropyrimidin-2-yl)-1-piperazinecarboxylate, of which 1.75 g are obtained; the more polar compound, tert-butyl 4-(2-chloropyrimidin-4-yl)-1-piperazinecarboxylate, of which 12.9 g are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In toluene; at 110℃; | A mixture of 2,4-dichloropyrimidine (50g, 336mmol), tert-butyl 4-methylpiperazine-1-carboxylate (67.2g, 336mmol), and toluene (500mL) was stirred at 110 C overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give 10 (109g, 73%) as a colorless powder. 1H NMR (300MHz, CDCl3) delta: 1.49 (9H, s), 3.44-3.53 (4H, m), 3.75-3.84 (4H, m), 6.53 (1H, d, J=5.1Hz), 8.16 (1H, d, J=5.1Hz). MS (ESI): m/z 299 [M+H]+. |
62% | In toluene; at 110℃;Product distribution / selectivity; | (2) Tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate A mixture of 4-methyltert-butyl piperazine-1-carboxylate (2.0 g, 9.98 mmol), 2,4-dichloropyrimidine (1.49 g, 9.98 mmol) and toluene (20 ml) was stirred at 110 C. overnight. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound (1.83 g, 62%) as a solid. 1H NMR (CDCl3) delta: 1.49 (9H, s), 3.44-3.53 (4H, m), 3.75-3.84 (4H, m), 6.53 (1H, d, J=5.1 Hz), 8.16 (1H, d, J=5.1 Hz). |
In water; toluene; | Example 2 Preparation of Intermediate 4-(4-chloro-pyrimidin-2-yl)-piperazine-1-carboxylic Acid Tert-Butyl Ester (I-2a): To a suspension of 2,4-dichloropyrimidine (1.00 g, 6.71 mmol) in 13.4 mL of toluene was added 4-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.34 g, 6.71 mmol). The reaction was heated to reflux overnight, then cooled to room temperature and concentrated in vacuo. The residue was taken up in 20 mL of water and extracted with ethyl acetate (2*40 mL). The combined organic layers were washed with brine (25 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo to an off-white solid. Flash column chromatography (silica gel, gradient elution from 5% ethyl acetate-hexanes to 20% ethyl acetate-hexanes) yielded 1.14 g of the title compound (I-2a). 1H NMR (400 MHz, CDCl3) delta 8.15 (d, 1H); 6.52 (d, 1H); 3.80 (m, 4H); 3.48 (m, 4H); 1.47 (s, 9H). MS (APCI+) Calc: 298, Found: 299.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In propan-1-ol; water; toluene; at 100℃; for 66h; | A round bottomed flask was charged with 4-methanesulfonylaminophenylboronic acid (4.3Og, 20 mmol) and 2,4-dichloropyrimidine (5.97 g, 40 mmol, 2 eq), toluene (75 mL), n- propanol (25 mL) and 2 M sodium carbonate solution (18 mL, 1.8 eq). The reaction vessel was then evacuated and backfilled with nitrogen three times before adding tetrakis(triphenylphosphine) palladium (0) catalyst (1.02 g, 4.4 mol%). The reaction vessel was again evacuated and backfilled with nitrogen three times before being heated at 100C under a nitrogen atmosphere for 66 hours. The reaction mixture was then cooled and stirred at room temperature for several hours during which time the product precipitated from the reaction mixture. The fine yellow solid (3.45 g, 61% yield) was collected by vacuum filtration washed with methanol and dried under high vacuum. 1H NMR and LC MS data confirmed this to be the desired iV-(4-(2-chloropyrimidin-4- yl)phenyl)methanesulfonamide. 1H NMR t°-DMSO, 300 MHz) delta 10.26 (IH, brs), 8.75 (IH, d, J= 5.5 Hz)5 8.17 (2H, d, J= 9.1 Hz), 8.05 (IH, d, J= 5.5 Hz), 7.35 (2H, d, J= 8.7 Hz), 3.10 (3H5 s). LC-MS: rt 5.54 min (br) m/z 284.2/286.1 [M+H]+. |
61% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In propan-1-ol; water; toluene; at 100℃; for 66h; | Example 4 - Synthesis of Compound 73A; round bottomed flask was charged with 4-methanesulfonylaminophenylboronic acid (4.30 g, 20 mmol) and 2,4-dichloropyrimidine (5.97 g, 40 mmol, 2 eq.), toluene (75 mL), n-propanol (25 mL) and aqueous sodium carbonate solution (2M, 18 mL, 1.8 eq.). The reaction mixture was evacuated and backfilled with nitrogen three times before adding tetrakis(triphenylphosphine) palladium (0) catalyst (1.02 g, 4.4 mol%). The reaction mixture was again evacuated and backfilled with nitrogen three times before being heated at 100C under a nitrogen atmosphere for 66 hours. The reaction mixture was cooled and stirred at room temperature for several hours during which time the product precipitated from the reaction mixture. The fine yellow solid (3.45 g, 61% yield) was collected by vacuum filtration, washed with methanol and dried under high vacuum. 1H NMR and LC MS data confirmed this to be the desired N-(4-(2-chloropyrimidin-4- yl)phenyl)methanesulfonamide. 1H NMR (300 MHz, </6-DMSO) delta 10.26 (IH, brs); 8.75 (IH, d, J= 5.5 Hz); 8.17 (2H, d, J= 9.1 Hz); 8.05 (IH, d, J= 5.5 Hz); 7.35 (2H, d, J =8.7 Hz); 3.10 (3H, s). LC-ESI-MS (method B): rt 5.5 min.; m/z 284.2/286.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In toluene; at 75 - 100℃; | Example 1 - Synthesis of Compound 3; A mixture of 4-ethoxycarbonylphenyl boronic acid (23.11 g, 119 mmol), 2,4- dichloropyrimidine (16.90 g, 113 mmol), toluene (230 mL) and aqueous sodium carbonate (2 M, 56 mL) was stirred vigorously and nitrogen was bubbled through the suspension for 15 minutes. Tetrakis(triphenylphosphine)palladium[0] (2.61 g, 2.26 mmol) was added. Nitrogen was bubbled through for another 10 min., the mixture was heated to 100C, then at 75C overnight. The mixture was cooled, diluted with ethyl acetate (200 mL), water (100 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (100 ml) and the two organic extracts were combined. The organics were washed with brine, filtered through sodium sulfate, <n="58"/>concentrated, and the resultant solid was triturated with methanol (100 niL) and filtered. The solids were washed with methanol (2 x 30 mL) and air dried. This material was dissolved in acetonitrile (150 mL) and dichloromethane (200 mL), stirred with MP.TMT Pd-scavenging resin (Agronaut part number 800471) (7.5 g) over 2 days. The solution was filtered, the solids were washed with dichloromethane (2 x 100 mL), and the filtrate concentrated to give ethyl 4-(2-chloropyrimidin-4-yl)benzoate as anoff-white solid (17.73 g, 60%) - additional washing with dichloromethane yielded a further 1.38 g and 0.5 g of product. 1H NMR (300 MHz, J6-DMSO) delta 8.89 (IH, d, J= 5.0 Hz); 8.32 (2H, d, J= 8.7 Hz); 8.22 (IH, d, J= 5.5 Hz); 8.12 (2H, d, J= 8.7 Hz); 4.35 (2H, q, J= 7.1 Hz); 1.34 (3H, t, J= 7.1 Hz); LC-ESI-MS (method B): rt 7.3 min.; m/z 263.0 / 265.0 [M+H]+. |
37% | Ester 1 : Preparation of Ethyl 4-(2-chloropyrimidin-4-yl)benzoate. To a solution of 2,4-dichloropyrimidine [70 g, 470 mmol] in DMF [600 mL] was added (PPh3)2PdCl2 [9.9 g, 14 mmol] and mixture was heated to 90C for 1 h. To this, (4-(ethoxycarbonyl)phenyl)boronic acid [91 g, 470 mmol] was added and mixture was heated to 90C for additional 0.5 h. A solution of potassium bicarbonate [282 g, 2.8 mol] in 200 mL of water was added to reaction mixture and stirred for 0.5 h at 90C. After completion of reaction, mixture was quanched in ice cooled water [500 mL]. The off white solid obtained was filtered, washed with water and dried under vacuum to get title compound. [45 g, 37%]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With N-ethyl-N,N-diisopropylamine; In pentanol, 2-; at 100℃; for 84h; | <strong>[37585-16-3](2-amino-4-chlorophenyl)methanol</strong> (100 mg, 0.63 mmol), 2,4-dichloropyrimidine (99 mg, 0.67 mmol) and N-ethyl-N-isopropylpropan-2-amine (DIPEA) (0.221 mL, 1.27 mmol) in 2-pentanol (2 mL) were stirred at 100 0C for 3.5 days. The reaction mixture was concentrated to dryness and partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with brine, dried over magnesium sulfate and concentrated to afford the crude product as an orange oil. The crude product was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford (4-chloro-2-(2-chloropyrimidin-4-ylamino)phenyl)methanol (38.0 mg, 22 %) as a colorless oil which crystallised on standing. Mass Spectrum: M+H+ 270.NMR Spectrum (DMSOdfl: 4.46 (s, 2H), 5.36 (bs, IH), 6.67 (d, IH), 7.32 (dd, IH), 7.51 (d, IH), 7.55 (d, IH), 8.15 (d, IH), 9.47 (bs, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18.97% | With triethylamine; In ethanol; for 20h;Heating / reflux; | A mixture of 2,4-dichloropyrimidine (1.5 g, 10.07 mmol), <strong>[57772-50-6]2-amino-3-methylbenzyl alcohol</strong> (commercial)(1.285 g, 9.36 mmol) and triethylamine (1.544 ml, 11.08 mmol) in ethanol (13 ml) was stirred at reflux for 20 hrs as described in Method 1. Work-up and purification gave (2-(2-chloropyrimidin-4-ylatnino)-3-methylphenyl)methanol (0.477 g, 18.97 %) as a beige foam. Mass Spectrum: M+H+ 250. NMR Spectrum (DMSOd6 at 323 <n="170"/>0K): 2.12 (s, 3H), 4.40 (bs, 2H), 4.97 (bs, IH), 7.22 (s, IH), 7.26 (s, IH), 7.39 (d, IH), 8.02(s, IH), 9.19 (bs, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 3h; | Compound 427:Dichloropyrimidine (298 mg, 2.0 mmol) was dissolved in dry THF (10 ml_) with Et3N (280 uL, 2.0 mmol). The mixture was cooled to 0 C, and isoindoline (380 mg, 2.1 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 3 hours. The EtOAc was added to dilute the mixture and the organics was washed with water, brine and dried over Na2SO4. After concentration, the residue was purified with column (silica gel, EtOAc/Hexane = 30:70) to give the product 427 (311 mg) as light yellow solid. HPLC-MS tR = 1.49 min (UV254 nm); mass calculated for formula C14H14CIN3O2 291.1 , observed LCMS m/z 292.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 70℃; for 18h; | 4-(2-Chloro-pyrimidin-4-yl)-benzoic acid tert-butyl ester A mixture of 2,4-dichloropyrimidine (0.745 g), 4-tert butoxycarbonylphenyl boronic acid (0.83 g), palladium tetrakis triphenylphosphine (0.29 g) and caesium carbonate (1.625 g) in DME (60 ml) and water (60 ml) was heated at 70 0C for 18 h. Water and ethyl acetate were added and the organic phase was washed with 2M hydrochloric acid, saturated sodium carbonate, dried over sodium sulphate and concentrated in vacuo. Chromatography on silica (DCM, acetone, acetonitrile, ethanol, methanol gradient) gave 4-(2-chloro-pyrimidin- 4-yl)-benzoic acid tert-butyl ester (0.797 g) as a colourless solid after crystallisation from ether/hexane.1U NMR (CDCl3) 1.56 (9H, s), 8.05 (2H, d), 8.22 (IH, d), 8.29 (2H, d), 8.89 (IH, s). LC-MS: m/z (M+l-tBu)+ 235/237 (2.73 min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium hydrogencarbonate; In tetrahydrofuran; ethanol; at 20 - 85℃; for 4.0h;Inert atmosphere; | Intermediate Example 12 Preparation of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine To a stirred solution of Intermediate Example 11 (2.97 g, .015 mol) and NaHCO3 (5.05 g, .06 mol) in THF (15 mL) and ethanol (60 mL) was added 2,4-dichloropyrimidine (6.70 g, .045 mol) at room temperature. After the reaction was stirred for four hours at 85 C, the suspension was cooled to rt., filtered and washed thoroughly with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting solid was triturated with ethyl acetate to yield 3.84 g (89 % yield) of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine. 1H NMR (400 MHz, d6DMSO) delta 7.28 (d, J = 9.0 Hz, 1H), 6.42 (d, J = 8.8 Hz, 1H), 6.37 (s, 1H), 5.18 (br s, 1H), 3.84 (s, 3H), 2.43 (s, 3H). MS (ES+, m/z) 274 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | With sodium hydrogencarbonate; In ethanol; for 1.5h;Heating / reflux;Product distribution / selectivity; | (1) Tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate To a solution of 2,4-dichloropyrimidine (50.0 g, 0.338 mol) in ethanol (500 ml) was added tert-butyl piperazine-1-carboxylate (62.8 g, 0.338 mol) and sodium hydrogencarbonate (56.8 g, 0.676 mol) and heated under reflux for 1.5 hours. The reaction was filtered and the filtrate was concentrated. To the residue was added methylene chloride and water followed by extracted. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the title compound (6.30 g, 6%). 1H NMR (CDCl3) delta: 1.49 (9H, s), 3.45-3.52 (4H, m), 3.75-3.83 (4H, m), 6.53 (1H, d, J=4.8 Hz), 8.16 (1H, d, J=4.8 Hz). |
With sodium hydrogencarbonate; In ethanol; for 1.0h;Reflux; | Preparation of compound 37: 2,4-dichloropyrimidine (801 mg, 0.0053 mole, 1 eq), N-Boc-piperazine (1.0 gm, 0.0053 mole, 1 eq) and sodium bicarbonate (903 mg, 0.0107 mole, 2 eq) were dissolved in ethanol (50 ml) and stirred at reflux for 1 h. Progress of the reaction was monitored by TLC. The excess solvent was removed, dissolved in water and extracted with DCM. The organic layer was washed with water, dried with sodium sulfate and concentrated under reduced pressure. The crude product was purified on silica gel (60-120 mesh) using 15% ethyl acetate-hexane to afford coupled product compound 37 (230 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With sodium hexamethyldisilazane; In tetrahydrofuran; at -20.0℃; for 2.0h; | 2-Chloro-N-(6-chloropyridin-2-yl)-N-methyl-pyrimidin-4-amine used as starting material was made as follows: NaHMDS (1.5 ml, 1.5 mmol, IN in THF) was added dropwise to a mixture of 2-chloro-6- methylaminopyridine (142 mg, 1 mmol, German Patent, DE3318560, p 9) and 2,4- dichloropyrimidine (222 mg, 1.5 mmol) in THF (20 ml) cooled at -200C. The mixture was stirred at -200C for 2 hours. Acetic acid (a few drops) were added and the mixture was concentrated. The mixture was taken in DCM, filtered and concentrated. The residue was purified by chromatography on silica gel (eluant: 40% to 50% ethyl acetate in petroleum ether) to give 2-chloro-N-(6-chloropyridin-2-yl)-N-methyl-pyrimidin-4-amine (86 mg, 34%). NMR Spectrum: (CDCl3) 3.61 (s, 3H), 6.93 (d, IH), 7.18 (d, IH), 7.28 (m, IH), 7.72 (t, IH), 8.17 (d, IH); Mass spectrum: MH+ 255. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 80% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 80℃; | Example 5: Synthesis of Pyrintegrin Derivatives; [0212] To a mixture of 2,4-dichloropyrimidine 4 (1.0 eq.), R1NH2 (1.2 eq.) and diisopropylethylamine (1.2 eq.) in n-butanol was heated at 80 0C overnight. The solvent was evaporated, and the residue was purified by flash column chromatography to intermediate 10 in excellent yield (> 80%), which was then treated with R2NH2 (1.2 eq.) in DMF was added /?-toluenesulfonic acid (2 M in dioxane) (1.2 eq.). The reaction mixture was stirred at 90 0C overnight, and then purified directly by preparative HPLC to give Pyrintegrin derivatives 11 in excellent yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 110.0℃; for 0.166667h;Inert atmosphere; Microwave irradiation; | A mixture of <strong>[136992-95-5]benzooxazol-7-amine</strong> (135 mg, 1.01 mmol, Astrazeneca, PCT Appl. WO2003053960), 2.4-dichloropyrimidine (150 mg, 1.01 mmol), DBU (0.197 ml, 1.32 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (58 mg, 0.1 mmol, also named xantphos) and tris(dibenzylideneacetone)dipalladium(0) (58 mg, 0.1 mmol, also named Pd2dba3) in dioxane (3 ml) under argon was irradiated in a Personal Chemistry EMRYS Optimizer EXP microwave synthesisor at 110 C. for 10 minutes. After cooling and evaporation of the solvents, the residue was dissolved in DCM and purified by chromatography on silica gel (eluant: 30% to 60% EtOAc in petroleum ether) to give N-(2-chloropyrimidin-4-yl)<strong>[136992-95-5]benzooxazol-7-amine</strong> (88 mg, 35%) as a beige solid. Mass spectrum: MH+ 247 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; acetonitrile;Reflux; Inert atmosphere; | A RBF was charged with 2, 4-dichloropyrimindine (784?mg, 5.2?mmol, 1 equiv.), compound 48 (1.5?g, 5.74?mmol, 1.1 equiv.), Pd(PPh3)4 (250?mg, 0.226?mmol, 0.05 equiv.) and sodium carbonate (991?mg, 9.36?mmol, 1.8 equiv.) MeCN: H2O (9: 1, 40?mL) were added into the RBF and the reaction mixture was degassed under N2, stirred and refluxed overnight under N2. The reaction was cooled, and the reaction mixture was concentrated under vacuum. EA and water were added for extraction. By collecting the organic layer and evaporating solvent, a light yellow crude product was obtained, which was purified using flash chromatography (elution system - EA/Hexane?=?1: 1 to MeOH/EA?=?2: 98) to give 5 a light yellow solid (1.25?g, 97%). Rf?=?0.43 (EA/Hexane?=?1: 1); 1H NMR (400?MHz, DMSO-d6) delta 10.27 (s, 1H), 8.75 (d, J?=?5.4?Hz, 1H), 8.16 (d, J?=?8.9?Hz, 2H), 8.06 (d, J?=?5.4?Hz, 1H), 7.77 (d, J?=?8.9?Hz, 2H), 2.09 (s, 3H); 13C NMR (100?MHz, DMSO-d6) delta 169.33, 166.20, 161.29, 160.98, 143.40, 129.14, 128.72, 119.39, 115.70, 24.64; MS (ESI) 248.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In tetrahydrofuran; ethanol; at 70 - 75℃; for 13h; | To a mixture of <strong>[6973-09-7]5-amino-2-methylbenzenesulfonamide</strong> (20 gm) in ethanol (208 ml) and tetrahydrofuran (52 ml) was added 2,4-dichloropryrimidine (44 gm) and sodium bicarbonate (36 gm) at room temperature. The contents were heated to 70 to 75°C and maintained for 13 hours. The reaction mass was then cooled to 10°C and maintained for 2 hours. The reaction mass was filtered and the solvent was distilled off under vacuum at below 50 to 55°C to obtain a residual mass. To the residual mass was added ethyl acetate (100 ml) and stirred for 1 hour, filtered. The solid obtained was dried to give 15.5 gm of 5-(4-chloropyrimidin-2ylamino)-2-methylbenzenesulfonamide. | |
15.5 g | With sodium hydrogencarbonate; In tetrahydrofuran; ethanol; at 20 - 75℃; for 13h; | To a mixture of <strong>[6973-09-7]5-amino-2-methylbenzenesulfonamide</strong> (20 gm) in ethanol (208 ml) and tetrahydrofuran (52 ml) was added 2,4-dichloropryrimidine (44 gm) and sodium bicarbonate (36 gm) at room temperature. The contents were heated to 70 to 75° C. and maintained for 13 hours. The reaction mass was then cooled to 10° C. and maintained for 2 hours. The reaction mass was filtered and the solvent was distilled off under vacuum at below 50 to 55° C. to obtain a residual mass. To the residual mass was added ethyl acetate (100 ml) and stirred for 1 hour, filtered. The solid obtained was dried to give 15.5 gm of 5-(4-chloropyrimidin-2ylamino)-2-methylbenzenesulfonamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | Step 1 : 2-(tert-butyl)-4-(2-chloropyrimidin-4-yl)phenol:A solution of <strong>[10323-39-4]4-bromo-2-(tert-butyl)phenol</strong> (6.5 g, 28 mmol), potassium acetate (8.35 g, 85 mmol), 4,4,4',4', 5,5,5', 5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane (7.2 g, 28.4 mmol) and PdCI2(dppf)-CH2CI2adduct (1 .57 g, 2.84 mmol) in dioxane (100 ml) was heated at 100 C overnight. An aqueous solution of sodium carbonate (2N, 42.6 ml, 42.5 mmol), PdCI2(dppf)-CH2CI2adduct (1 .57g, 2.84 mmol) and 2,4-dichloropyrimidine (4.2 g, 28.4 mmol) were then added. The resulting solution was heated at 100 C for 4h. The organic phase was then decanted, dried over MgS04 and concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound (2.38 g, 32%).1H NMR (500 MHz, DMSO-d6): 10.3 (s, 1 H), 8.65 (d, 1 H), 8.01 (s, 1 H), 7.97 (d, 1 H), 7.90 (d, 1 H), 6.95 (d, 1 H), 1 .40 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.6% | With sodium hydrogencarbonate; In tetrahydrofuran; ethanol; for 20h;Reflux; | Formula III (5 g, 0.029 mol)And sodium bicarbonate (7.2 g, 0.086 mol)Was added to THF (20 ml)And absolute ethanol (80 ml).2,4-dichloropyrimidine (12.8 g, 0.086 mol) was added at room temperature,Heated to reflux for 20 h.The reaction was cooled to room temperature,filter,The filter cake was washed with absolute ethanol (20 ml x 2).The filtrates were combined,After concentration under reduced pressure to dryness, isopropyl ether (60 ml)And toluene (30 ml) were mixed,Stirred at room temperature for 1 h,filter,The filter cake was dried to give pale yellow solid 7 (6.7 g, 81.6%), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 8h; | To a solution of ethyl 3-methyl-iH-pyrazole-4-carboxylate (6.0 g, 38.9 mmol) in 50 mL of anhydrous N,N-dimethylformamide (DMF) were added potassium carbonate (10.8 g, 77.8 mmol) and 2,4-dichloropyrimidine (5.8 g, 38.9 mmol) at room temperature. The resulting suspension was stirred for 8 hours with monitoring a reaction with LC-MS or thin layer chromatography (TLC). Volatiles were removed and the residue was extracted with dichloromethane. The collected organic layer was washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a mixture of heptanes and ethyl acetate to afford the desired intermediate 1 as a white solid (5.45 g, 52 %); MS (ESI) m/z 267 [M+H]+, 1H NMR (300 MHz, CDC13) delta 8.99 (s, 1H), 8.68 (d, 1H, J = 5.4 Hz), 7.86 (d, 1H, / = 5.4 Hz), 4.35 (q, 2H, / = 7.2Hz), 2.57 (s, 3H), 1.40 (t, 3H, J = 12 H |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.0% | With sodium hydrogencarbonate; In ethanol; at 85℃; for 6.0h; | General procedure: To a stirred solution of the intermediate (3a) (5.00 g, 31 mmol) and NaHCO3(8.00 g, 95 mmol) in ethanol (150 mL) was added 2,4-dichloropyrimidine (6.00 g, 40 mmol) at room temperature. After the reaction was stirred for 6 h at 85C, the suspension was cooled to rt., filtered and washed thoroughly with CH2Cl2. The filtrate was concentrated under reduced pressure to give 4a as anoff-white solid (7.60 g, 89.5% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.6% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; | Compound Reg-1-1-c (4 g, 17.14 mmol) and 2,4-dichloropyrimidine (5.1 g, 34.28 mmol) were dissolved in N,Ndimethylformamide(60 mL), diisopropylethylamine (11.08 g, 85.8 mmol) was added, and the reaction was placed in anoil bath at 80°C, and allowed to proceed overnight. Thin layer chromatography (petroleum ether : ethyl acetate=2:1)indicated the reaction was complete. The reaction solution was cooled to room temperature, concentrated under reducedpressure to give a crude product, which was separated through preparative chromatography (petroleum ether : ethylacetate=100:1?1.5:1) to afford compound Reg-1-1 (3 g, yellow solid, yield: 50.60percent).1H NMR (400 MHz, CDCl3) delta 9.50 - 9.23 (m, 1H), 8.52 - 7.91 (m, 4H), 7.89 - 7.45 (m, 1H), 7.28 - 6.51 (m, 1H), 1.73 (s,9H). MS m/z (ESI): 346.1 [M+H]. |
50.6% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; | Compound Reg-1-1-c (4 g, 17.14 mmol) and 2,4-dichloropyrimidine (5.1 g, 34.28 mmol) were dissolved in N,N-dimethylformamide (60 mL), diisopropylethylamine (11.08 g, 85.8 mmol) was added, and the reaction was placed in an oil bath at 80°C, and allowed to proceed overnight. Thin layer chromatography (petroleum ether : ethyl acetate=2:1) indicated the reaction was complete. The reaction solution was cooled to room temperature, concentrated under reduced pressure to give a crude product, which was separated through preparative chromatography (petroleum ether : ethyl acetate=100:1?1.5:1) to afford compound Reg-1-1 (3 g, yellow solid, yield: 50.60percent). 1H NMR (400 MHz, CDCl3) delta 9.50 - 9.23 (m, 1H), 8.52 - 7.91 (m, 4H), 7.89 - 7.45 (m, 1H), 7.28 - 6.51 (m, 1H), 1.73 (s, 9H). MS m/z (ESI): 346.1 [M+H]. |
40% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 65℃; for 7h; | A mixture of 2,4-dichloropyrimidine (1.99 g, 13.4 mmol), tert-butyl 5-amino- lH-indazole-l-carboxylate (3.4 g, 14.7 mmol), DIEA (3 mL), and DMF (13 mL) was stirred at 65 °C for 7 h, concentrated in vacuo, and titurated with Et20. The precipitate was filtered and washed with IPA and dried to provide the title compound (1.83 g, 40percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | NaH (60% in mineral oil) 3.3 g (83.90 mmol) was diluted in DMF 10 mL. Compound 12-2 18.3 g(67.12 mmol) was dissolved in DMF 60 mL, and this solution was added into the above reaction solution, followed by stirring for 1 hour. 2,4-Dichloropyrimidine 10g(67.12mmol) was dissolved in DMF 60 mL, and this solution was added into the above reaction solution. The resultant material was stirred at room temperature for 4 hours, and then distilled water 40 mL was added thereinto. Then, extraction with EA, wash with distilled water and aqueous NaCl solution, drying over MgSO4, distillation under reduced pressure, and purification using column chromatography were sequentially performed, thereby obtaining Compound 12-3 5.4 g (14.0mmol, 21 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24.61% | In ethanol; at 45℃; for 16h; | To a solution of 2,4-dichloropyrimidine (0.428 g, 2.87 mmol) in EtOH (28.7 mL) was added tetrahydrofuran-3-amine (0.25 g, 2.87 mmol). The solution was stirred at 45° C. for 16 hours and then concentrated under vacuum. The crude product was purified by SiO2 column chromatography (25 g SNAP® column, 0percent MeOH/DCM for 5 minutes, 0-5percent MeOH/DCM for 25 minutes, and 5-10percent MeOH/DCM for 15 minutes) to afford 2-chloro-N-(tetrahydrofuran-3-yl)pyrimidin-4-amine (0.141 g, 0.706 mmol, 24.61percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; | General procedure: To a solution of 2,4-dichloro-5-fluoropyrimidine (0.5 g, 2.99 mmol) and (2-aminophenyl)dimethylphosphineoxide (0.323 g, 1.907 mmol) in DMF (6.36 mL) wasadded potassium carbonate (0.828 g, 5.99 mmol). The reactionmixture was stirred at 70 °C for overnight. After completion of thereaction, the resulting mixture was cooled to room temperature,quenched with water, extracted with DCM and washed with brine.The combined organic layer was dried over Na2SO4, filtered andconcentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (0-20percent MeOH in DCM)to give 3f as a yellowish solid (0.178 g, 31percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.4% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5h; | Intermediate 4 (3.14 g, 10 mmol) and starting material 2,4-dichloropyrimidine (5, 1.48 g, 10 mmol) were dissolved in DMF: 15 mL, potassium carbonate (1.52 g, 11 mmol) was added thereto, and the temperature was raised to 80C. , Reaction 5h.After the reaction was completed, the mixture was cooled to room temperature and 60 mL of water was added slowly under ice-water bath to precipitate a white solid. After stirring for 30 min, it was filtered and dried to give 3.72 g of an off-white solid with a yield of 87.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2-Chloro-N-(cyclopropylmethyl)-6-(3,3-difluoropiperidin-1-yl)pyrimidine-4-carboxamide (I-30) The title compound was prepared according to General Procedure B using dichloropyrimidine I-4 (0.10 g, 0.41 mmol, 1 eq), DiPEA (100 muL, 0.57 mmol, 2.4 eq) and <strong>[496807-97-7]3,3-difluoropiperidine HCl salt</strong> (68 mg, 0.43 mmol, 1.05 eq). Column chromatography (10% -> 40% EtOAc/pentane) afforded the product (88 mg, 0.26 mmol, 50%). TLC: Rf = 0.4 (20% EtOAc/pentane). 1H NMR (300 MHz, CDCl3) delta 7.91 (br s, 1H), 7.35 (s, 1H), 3.99 (br s, 2H), 3.74 (br s, 2H), 3.29 (t, J = 6.5 Hz, 2H), 2.13 (tt, J = 13.3, 6.3 Hz, 2H), 2.02 - 1.74 (m, 2H), 1.17 - 0.95 (m, 1H), 0.67 - 0.44 (m, 2H), 0.28 (q, J = 5.1 Hz, 2H). 13C NMR (75 MHz, CDCl3) delta 164.08, 162.15, 159.87, 158.33, 119.17 (t, J = 244.8 Hz), 99.62, 44.54, 44.05, 32.63 (t, J = 23.5 Hz), 29.76, 21.70 (t, J = 4.5 Hz). 10.72, 3.71. |
Tags: 3934-20-1 synthesis path| 3934-20-1 SDS| 3934-20-1 COA| 3934-20-1 purity| 3934-20-1 application| 3934-20-1 NMR| 3934-20-1 COA| 3934-20-1 structure
A165685 [10132-07-7]
4-Amino-2,6-dichloropyrimidine
Similarity: 0.86
A231363 [1780-31-0]
2,4-Dichloro-5-methylpyrimidine
Similarity: 0.84
A105418 [5424-21-5]
2,4-Dichloro-6-methylpyrimidine
Similarity: 0.82
A274787 [179051-78-6]
4-Chloropyrimidine hydrochloride
Similarity: 0.81
A165685 [10132-07-7]
4-Amino-2,6-dichloropyrimidine
Similarity: 0.86
A231363 [1780-31-0]
2,4-Dichloro-5-methylpyrimidine
Similarity: 0.84
A105418 [5424-21-5]
2,4-Dichloro-6-methylpyrimidine
Similarity: 0.82
A274787 [179051-78-6]
4-Chloropyrimidine hydrochloride
Similarity: 0.81
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P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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