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Structure of 1193-21-1
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
4.5
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CAS No. : | 1193-21-1 |
Formula : | C4H2Cl2N2 |
M.W : | 148.98 |
SMILES Code : | ClC1=CC(Cl)=NC=N1 |
MDL No. : | MFCD00006109 |
InChI Key : | XJPZKYIHCLDXST-UHFFFAOYSA-N |
Pubchem ID : | 70943 |
GHS Pictogram: |
![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H302+H312+H332-H314-H335 |
Precautionary Statements: | P264-P270-P271-P272-P280-P304+P340-P305+P351+P338-P310-P330-P331-P363-P403+P233-P501 |
Class: | 8 |
UN#: | 3263 |
Packing Group: | Ⅱ |
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) |
1.35 |
* 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 |
---|---|---|
99.1% | With triethylamine; trichlorophosphate; at 40 - 105℃; for 2h; | In a four-necked flask equipped with a reflux condenser, the temperature was raised and stirred, and 228 g of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> was added by a constant pressure dropping funnel, the content was 98%,and the content of 633 g of phosphorus oxychloride was 97%.The temperature was raised to 40 to 45 C, and the content of 408 g of triethylamine was added dropwise with content of 99%, after the addition was completed, the temperature was raised to 100 to 105 C and kept for 2 hours. HPLC (high performance liquid phase) analysis of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> was less than 0.2%, and the reaction was completed. 880g of toluene was added and cooled tom 0~5 C, 800g of ice water mixture was added, the ice was decomposed to room temperature, the organic phase was decomposed and the aqueous layer was extracted (200 ml of toluene), the organic phase was combined and washed with alkaline water until neutral. Toluene was concentrated. 697 g of toluene dichloropyrimidine solution was obtained, and the purity of 4, 6-dichloropyrimidine was 97.3%, and the content was 39.91%. The crude yield was 92%. The 697 g crude solution was divided into three 240 g, 240 g, 217 g, respectively, as 1, 2, 3, to do the distillation experiment: The temperature of the top of the steam packed tower is required to reach 94 C ~ 96 C, when the temperature was reached, the concentrated organic phase was added dropwise, the feed rate was controlled, the balance was adjusted to prevent the stripper tower from cooling; The obtained organic phase, the quality of the aqueous phase and the purity and concentration of 4,6-dichloropyrimidine are shown in Table 1, the obtained organic phase was concentrated, cooled, crystallized, centrifuged or filtered to obtain a high purity product. The refined yield was as high as 98% or more, and the appearance was white crystal. The experimental results are shown in Table 1. |
97% | With bis(trichloromethyl) carbonate; sulfuric acid; In N,N-dimethyl-formamide; 1,2-dichloro-benzene; at 80℃; for 4.2h;Industrial scale; | In the reaction container (such as test flat glass reaction bottle) by adding <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> 11.2 grams, sulfuric acid 20 ml, N, N-dimethylformamide 0.5 ml, mixed evenly, heated to 80 C, Mixed solution, 30 grams of triphosgene dissolved in 50 ml of dichlorobenzene, 1.2 hours slowly dropping added to the mixed solution, continued to heat after stirring for 3 hours, cooled to room temperature, pour ice water, the separation of organic Solvent layer and organic solvent layer, and then dried with anhydrous magnesium sulfate to obtain 4,6-dichloropyrimidine, the yield is 97%, the mass content is more than 99% (determined by high performance liquid phase method) |
96.2% | With cobalt(II) phthalocyanine; bis(trichloromethyl) carbonate; Triphenylphosphine oxide; In nitrobenzene; at 90 - 95℃; for 5h; | 212 g of triphosgene (content 99%, 0.71 mol) was dissolved in 500 mL of nitrobenzene for use.In a device equipped with a reflux condenser, a thermometer, a stirrer and a constant pressure dropping funnel,Add <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (114 g, content 98%, 1 mol), triphenylphosphine oxide (8.4 g, content 99%,0.03 mol), cobalt phthalocyanine (0.57 g, 0.001 mol), stirred and mixed evenly,The temperature was raised to 90-95 C, and a solution of triphosgene in nitrobenzene was added dropwise.After 5 hours of reaction, the sample was analyzed, and the content of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> was 0.25% and the content of 4,6-dichloropyrimidine was 98.2% by HPLC. The reaction was completed.Vacuum distillation reaction mixture (oil bath temperature 95 C, vacuum -0.095 Mpa),143.8 g (content 99.7%) of 4,6-dichloropyrimidine was obtained in a yield of 96.2% (based on <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong>). |
94.9% | With phosgene; trichlorophosphate; at 95 - 100℃; for 8h;Large scale; | In a device equipped with a reflux condenser, a thermometer, a stirrer and a constant pressure dropping funnel, <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong>(114.3 g, 98%, 1 mol), phosphorus oxychloride (1140 g, 99%) were stirred and mixed, the temperature was raised to 95-100 C,And slowly adding phosgene (220g, 99%, 2.2mol) for 8 hours after the sample, HPLC analysis of 4,6 - dihydroxypyrimidine containing, The reaction was completed and the reaction mixture was distilled under reduced pressure (oil bath temperature 95 C,(Content 99%); 4,6-dichloropyrimidine 142.8 g (content 99.0%),The yield of 94.9% (based on <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong>), where W (DCP) meansDCP quality, W (DHP) refers to the quality of DHP, the content refers to the mass content of DCP, 112 for DHP moleculesAnd 149 is the molecular weight of DCP. |
94.9% | With phosgene; trichlorophosphate; at 95 - 100℃; for 8h;Large scale; | With a reflux condenser, thermometer,In the device of the agitator and the constant pressure dropping funnel,Add <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (114.3 g, content 98%, 1 mol), phosphorus oxychloride (1140 g, 99%) and mix well.The temperature was raised to 95-100 C, and phosgene (220 g, 99%, 2.2 mol) was slowly added to carry out the reaction, and the sample was taken after 8 hours.HPLC analysis of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> content of 0.9%,The content of 4,6-dichloropyrimidine was 98.3%, and the reaction was over.Vacuum distillation reaction mixture (oil bath temperature 95 C,Vacuum degree -0.095MPa),Obtained 1082 g of phosphorus oxychloride (content 99%); 142.8 g of 4,6-dichloropyrimidine (content 99.0%),Yield 94.9% (based on <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong>), wherein W (DCP) refers to the mass of DCP, and W (DHP) refers to the mass of DHP.The content refers to the mass content of DCP, and 112 is the molecular weight of DHP.149 is the molecular weight of DCP. |
78% | With pyridine; phosgene; In chloroform; at 50℃; for 3h; | 0.5 mol of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> was added to the reaction vessel,Solvents Trichloromethane,0.05 mol of pyridine catalyst,Then slowly into the phosgene 1.5mol,The reaction temperature was controlled within 50 C,After reaction for 3 h,After the completion of the reaction, the excess solvent chloroform was distilled off under reduced pressure,To give a 4,6-dichloropyrimidine solution,And then filtered, concentrated and crystallized to give 4,6-dichloropyrimidine as white needles.The yield of product 4,6-dichloropyrimidine prepared by the above method was 78% and the purity was 80%. |
58% | With trichlorophosphate; In water; N,N-dimethyl-aniline; chlorobenzene; | Example 7 (for comparison) 460 g of phosphorus oxychloride and 62 g of N,N-dimethylaniline were mixed and 116 g of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (98% pure) were metered into the mixture with a screw at 100 C. in the course of 5 hours. Thereafter, the reaction mixture was subsequently stirred at 106 to 128 C. for 8 hours. It was diluted with 300 g of chlorobenzene and discharged onto 1.2 kg of ice. The organic phase was separated off, washed twice with 100 ml of water each time and then subjected to fractional distillation. 85.7 g of 4,6-dichloropyrimidine (=58% of theory) are thus obtained. |
EXAMPLES 1-6 General Procedure for Conversion of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (DHP) to 4,6-dichloropyrimidine (DCP): The reaction vessel is a Morton-type flask fitted with a heating mantle, a mechanical agitator, a temperature probe, a phosgene dip pipe (which also serves as a nitrogen inlet when phosgene is not being introduced to the reactor), and a dry ice condenser. The dry ice condenser is vented into a caustic scrubber. The reactor is charged with <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong>, solvent, and catalyst, forming a slurry. The agitator is started and the mixture is heated to 105-110 C. When this temperature range is reached, phosgene gas is introduced subsurface to the reaction mixture via the dip pipe. Phosgene addition is continued over 3-5 hours. During the addition, phosgene escaping the reaction is condensed by the dry ice condenser and returned to the reactor. This reflux of phosgene begins shortly after the phosgene addition is begun, and continues throughout the course of the reaction. | ||
With pyridine; phosgene; In chloroform; at 50℃; | One-step process for preparing 4, 6 - dichloro pyrimidine synthesis process, the synthesis process comprises the following steps: (1) input to the tower in the reactor 1 parts by weight of 4, 6 - dihydroxy pyrimidine and 3 parts by weight of chloroform, opening the stirrer stirring, continue adding 0.5 parts by weight of pyridine catalyst, and then open the jacket steam make the tower the temperature in the reactor is increased to 50 C, from the tower bottom of the reactor 1 parts by weight of phosgene, phosgene first of all through the reactor internal gas distributor, the gas distributor is triangle shape is placed in the bottom of the tower type reactor, gas distributor there are a lot of small holes is uniform and compact, phosgene is too high and the tower type reactor internal, then react with the material; (2) after the reaction, the bottom of the tower type reactor by nitrogen catches up with was mad, mixing the gas via the gas outlet of the tower the top of the reactor, into the collecting tank, the upper part of the collecting tank is provided with a ammonia-water spray system, the bottom of the traps the pot installed with a fan, when the gas enters into the collecting tank, by the fan gas into the ammonia-water spray system, so as to avoid the leakage of phosgene and hydrogen chloride gas; then the tower in the reactor in product transfer to the rectifying tower, are respectively arranged successively rectification temperature is 55 - 70 C, 105 - 125 C and 170 - 180 C, respectively collecting the corresponding temperature of the fraction, can be recycled chloroform solvent and pyridine catalyst, to a temperature of 170 - 180 C fraction is washed by water after cooling, drying, to obtain the 4, 6 - dichloro pyrimidine. | |
With pyridine; phosgene; In chloroform; at 50℃; | A kind of the improved 4, 6 - dichloro pyrimidine production process, characterized in that the production process comprises the following steps: (1) to the reaction kettle top feed port input 1 parts by weight of 4, 6 - dihydroxy pyrimidine and 3 parts by weight of chloroform, opening the stirrer stirring, continue adding 0.5 parts by weight of pyridine catalyst, and then open the jacket steam make the reaction kettle temperature to rise to 50 C, from the reactor into the bottom of the 1 parts by weight of phosgene to the phosgenation reaction, after the reaction is complete, to inject the nitrogen in the reactor catches up with was mad, at the same time the exhaust gas by the pipe into the absorption tower; (2) to be step 1 the product in the transfer to the rectifying tower, control rectification temperature is 65 C, collecting chloroform fraction, to be its after cooling to room temperature, the filling storage recycling; (3) collecting the step 2 in the remaining product, transferred to ice in the ice solution, slowly dropping concentration is 10% hydrochloric acid to adjust the pH of the solution to 5, standing the solution is layered, then methyl tert-butyl ether to the organic phase extraction, extraction 3 - 4 times, saturated copper sulfate solution for washing, until the copper sulfate solution is not color-changing, collecting pyridine circulation use; (4) the step 3 in the remaining product to filter, washing, and drying to obtain the target product 4, 6 - dichloro pyrimidine.The beneficial effects of the present invention: 1) using phosgene to replace the traditional process of phosphorus oxychloride, to avoid the emergence of phosphorus-containing by-product, the protection of the environment; 2) by adding pyridine catalyst, can accelerate the reaction of generating; 3) traditional use phosphorus oxychloride with 4, 6 - dihydroxy pyrimidine chloride obtained when the 4, 6 - two chlorine pyrimidine, easy to produce 3 different by-product, so that the trouble in processing after, and the yield of target product is not high, in the reaction of the present invention less by-products, and the yield of 4, 6 - dichloro pyrimidine higher; 4) by adjusting the solution pH, methyl tert-butyl ether extraction, and sulfuric acid copper and washing the collecting various pyridine, avoiding the traditional rectification, and steaming and method and the like caused by the leakage of pyridine, ensures the safety of the operators. | |
With trichlorophosphate; In N,N-dimethyl-formamide; toluene; at 120℃; for 3.5h;Reflux; | A 4,6-dichloropyrimidine production process,The production process includes the following steps:(1) To the reaction vessel was added 1 part by weight of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong>,2 parts by weight of phosphorus oxychloride and 5 parts by weight of toluene,Stir the stirrer,2 parts by weight of DMF was added dropwise with stirring,To ensure that in half an hour drop finished;(2) and then open the jacket steam to the reactor temperature rose to 120 reaction 2h,And then reflux reaction 3h,Until the solution appears stratified,When the thickness of the layer is no longer increased,Remove the upper solution,Transferred to the distillation tower,Atmospheric distillation,The control distillation temperature was 111 C and 150 C,Collect the fractions at these two temperatures,After cooling to room temperature,You can get toluene and DMF;(3) After the remaining product in step 2 is filtered,Transferred to the crystallization kettle for recrystallization,Collect crystalline solids,Washed,After drying, 4,6-dichloropyrimidine can be obtained,After crystallization of the mother liquor with a concentration of 10% sodium hydroxide solution to adjust the pH to 8,While reducing the solution temperature to 0 C,After crystallization,After centrifugation, the hydrated disodium hydrogen phosphate solid was collected. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In chlorobenzene; | EXAMPLE 12 4,6-Dihydroxypyrimidine (0.5 g, 4.46 mmol) was suspended in chlorobenzene (10 ml) and dichlorotriphenylphosphorane (1.44 g, 4.46 mmol; previously prepared by the reaction of triphenylphosphine oxide with phosgene) was added as a solid. The mixture was stirred at 80 C. to 90 C. under a nitrogen atmosphere. Analysis by thin layer chromatography (tlc) of a sample removed after 90 minutes showed some 4,6-dichloropyrimidine formation. However, quite a lot of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> remained out of solution. Another quantity of dichlorotriphenylphosphorane (1.44 g, 4.46 mmol) was added and stirring continued for a further hour at 110 C. A cloudy yellow solution was obtained with a solid residue. Analysis by tlc confirmed the formation of 4,6-dichloropyrimidine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With trichlorophosphate; | Example 2 2680 g of phosphorus oxychloride were initially introduced into the reaction vessel and 980 g of 2-methyl-5-ethyl-pyridine were added, while cooling. 460 g of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> were then metered in over a period of 1 hour. Further reaction and working up were carried out as described in Example 1. 4,6-Dichloropyrimidine was obtained in a yield of virtually 100% and 88% by weight of the amount of amine employed was recovered. |
98% | With trichlorophosphate; | Example 8 2680 g of phosphorus oxychloride were initially introduced into the reaction vessel and 980 g of 2-methyl-5-ethylpyridine were added, while cooling. 460 g of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> were then metered in such that the temperature did not rise above 40 C. After an after-reaction at 40 to 45 C. for half an hour, first phosphorus oxychloride and then 4,6-dichloropyrimidine were distilled off as described in Example 1. 1390 g of phosphorus oxychloride and 595 g of 4,6-dichloropyrimidine (content 98.2%) were obtained, which corresponds to a yield of 98% of theory. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile; | EXAMPLE 5 To a stirred mixture of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (5.18 g, 1 equivalent) and 4-(N,N,-dimethylamino)pyridine (0.55 g, 0.1 equivalent) in acetonitrile (100 ml) was added phosgene (28 g, 19.7 ml, 6.2 equivalents) in two aliquots. The resulting mixture was stirred for 10 minutes at room temperature and was then stirred for 4 hours at 55 C. The reaction mixture was purged with air after which water (200 ml) was added. The resulting mixture was extracted with dichloromethane (3*100 ml). The organic extracts were combined, washed with water (100 ml), dried over magnesium sulphate and evaporated to dryness to leave 4,6-dichloropyrimidine (4.63 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | EXAMPLE 4 To a mixture of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (5.14 g, 1 equivalent) and imidazole (6.19 g, 2 equivalents) in acetonitrile (100 ml) was added phosgene (28 g, 6.2 equivalents). The resulting mixture was stirred for 21/4 hours at room temperature and for 1 hour at 50 C. The reaction mixture was purged with nitrogen overnight and then partitioned between water and dichloromethane. The organic layer was separated and the aqueous extracted twice more with dichloromethane. The organic extracts were combined, washed with water (twice), dried over magnesium sulphate and evaporated to dryness to leave 4,6-dichloropyrimidine as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 2,3-Dimethylaniline; In dichloromethane; water; | EXAMPLE 2 4,6-Dihydroxypyrimidine (20.5 g) was dispersed with agitation in dichloromethane (400 ml). Dimethylaniline (40.4 g) was added to the agitated mixture and the system was sealed (except for a vent line to a scrubber). Phosgene gas (56 g) was introduced from a cylinder and condensed onto a cold finger and collected in a pressure equalised dropping funnel. Once collected, the phosgene liquid was added to the reaction mixture over 15 minutes. The mixture was heated and agitated at reflux (29 C. approximately) for 17 hours after which time the mixture was cooled to room temperature and the excess phosgene removed by sparging with nitrogen. Water (400 ml) was added slowly to the agitated reaction mass with cooling to maintain the temperature at ambient. The organic layer was separated, and the aqueous was then extracted with dichloromethane (2*100 ml). The combined extracts were dried over anhydrous sodium sulphate and concentrated by rotary evaporation to give 4,6-dichloropyrimidine as an orange crystalline solid (27 g), equivalent to a yield of 80% (hplc analysis). |
With N-ethyl-N,N-diisopropylamine; In water; acetonitrile; | EXAMPLE 6 To a stirred mixture of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (5.18 g, 1 equivalent) and N,N-diisopropylethylamine (11.75 g, 2 equivalents) in acetonitrile (100 ml) was added phosgene (28 g, 19.7 ml, 6.2 equivalents) in two aliquots. The resulting mixture was stirred for 10 minutes at room temperature and was then stirred for 4 hours at 55 C. The reaction mixture was sparged with air overnight after which water (100 ml) was added. The resulting mixture was extracted with dichloromethane (3*100 ml). The organic extracts were combined, washed with water (100 ml), dried over magnesium sulphate and evaporated to dryness to leave 4,6-dichloropyrimidine (6.35 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With acetic acid; In sodium hydroxide; | EXAMPLE 3 2-Amino-6-chloro-4(3H)-pyrimidinone A suspension of 250 g (0.1525 mole) of 2-amino, 4,6-dichloropyrimidine in 500 ml of 1N NaOH was heated to reflux. The solids gradually dissolved, and a complete solution formed after 4-5 hours. Acidification with about 70 ml of acetic acid gave a pH of 4 and precipitated a voluminous white solid that was filtered and washed with three 50-ml volumes of water. After drying in a vacuum over at 80° C./20 mm Hg, 21.75 g of product was obtained as fluffy white crystals, m.p. 260°-261° C., yield 99percent. NMR, IR and MS were consistent with the expected compound. Analysis: Calculated for: C4 H4 N3 OCl: C, 32.37; H, 2.93. Found: C, 32.75; H, 2.81. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 19 Preparation Of 4-(alpha,alpha,alpha-Trifluoro-N-methyl-m-toluidino)-6-[(alpha,alpha,alpha-trifluoro-m-tolyl)oxy]pyrimidine 4,6-Dichloropyrimidine (1.55 g, 0.01mol) and <strong>[2026-70-2]N-methyl-3-trifluoromethylaniline</strong> (2.0 g, 0.llmol) are combined and heated to 126 C under N2for 1.5 hours. The resulting oil is taken up in ethyl acetate, is washed with 10% sodium carbonate and dried over sodium sulphate. The organic phase is concentrated under reduced pressure to yield a yellow oil which is purified by column chromatography to give 4-chloro-6-(N-methyl-3-trifluoromethylanilino)-pyrimidine (1.78 g) as a white solid. 4-Chloro-6-(N-methyl-3-trifluoromethylanilino)-pyrimidine (0.30 g, 0.001 mol.) and sodium carbonate (0.28g, 0.003 mol.) in DMF are stirred for 10 minutes. m-Trifluoro-methylphenol (0.16g, 0.001mol) is added and the mixture is heated to 60 C for 12 hours. The mixture is then cooled and poured into water. The product is extracted into ethyl acetate, washed with 10% sodium hydroxide, 10% hydrochloric acid, and 5% potassium carbonate, dried over Na2SO4, filtered, and is concentrated under reduced pressure. 6-(N-methyl-3-trifluoromethylanilino)-4-(3-trifluoromethylphenoxy)pyrimidine (0.16g) obtained by chromatography as a white solid. M.p. 118-119 C. |
Yield | Reaction Conditions | Operation in experiment |
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In ethyl acetate; | EXAMPLE 19 Preparation Of 4-(alpha,alpha,alpha-Trifluoro-N-methyl-m-toluidino)-6-[(alpha,alpha,alpha-trifluorom-toly)oxy]pyrimidine 4,6-Dichloropyrimidine (1.55 g, 0.01 mol) and <strong>[2026-70-2]N-metyl-3-trifluoromethylaniline</strong> (2.0 g, 0.11 mol) are combined and heated to 126 C. under N2 for 1.5 hours. The resulting oil is taken up in ethyl acetate, is washed with 10% sodium carbonate and dried over sodium sulphate. The organic phase is concentrated under reduced pressure to yield a yellow oil which is purified by column chromatography to give 4-chloro-6-(N-methyl-3-trifluoromethylanilino)-pyrimidine (1.78 g) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
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In methanol; at 20 - 65℃; for 24.08h; | Preparation of Intermediate 4-chloro-6-(4-chlorophenyl)-5-(pyridin-4-yl)pyrimidine; A. Preparation of 4,6-dimethoxypyrimidine; To a suspension of 4,6-dichloropyrimidine (6.5 g, 43.9 mmol) in methanol (30 mL) at room temperature under argon was added NaOMe (7.1 g, 132 mmol) over 5 min. The resulting suspension was heated at 65 C. under argon for 24 h. Analysis by HPLC/MS indicated that the reaction was complete. Most of the solvent was removed under reduced pressure, then 1 M aqueous HCl (50 mL) and CH2Cl2 (50 mL) were added to the residue. The layers were separated and the organic phase was washed with saturated aqueous NaCl (30 mL), then dried (Na2SO4), filtered and evaporated. The crude product was purified by silica gel column chromatography eluted with ethyl acetate-hexanes to obtain the title compound (5.76 g) as a low melting solid. See also Synthesis 1998, page 36. |
Yield | Reaction Conditions | Operation in experiment |
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Step 1 Preparation of compound 13a: 2-(6-Chloropyrimidin-4-yl)oxazole Bis(triphenylphosphine)palladium(II) dichloride (94.0 mg, 134 μmol) was added to a nitrogen purged mixture of 4,6-dichloropyrimidine (200 mg, 1.34 mmol), <strong>[145214-05-7]2-(tri-n-butylstannyl)oxazole</strong> (281 μL, 1.34 mmol) and DMF (5 mL) at room temperature under nitrogen. The solution was heated to 90 C. for 16 h, then cooled to room temperature. KF (50 mL of a saturated aqueous solution) was added and the mixture stirred for 1 h. Ethyl acetate (30 mL) was added and the layers were separated. The organic layer was washed with brine and concentrated under vacuum. The product was purified using column chromatography (hexanes to 1:1 hexanes/ethyl acetate) to give 141 mg of 2-(6-chloropyrimidin-4-yl)oxazole as an off-white solid. [M+H]+ 182.33. |
Yield | Reaction Conditions | Operation in experiment |
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83% | Synthesis of 4,6-dichloro-5-iodo-pyrimidine (8a): 4,6-Dichloropyrimidine 6 (149 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25 C. and the reaction mixture was then stirred at this temperature for 45 min according to TP 2. I2 (381 mg, 1.5 mmol) dissolved in dry THF (2 mL) was then dropwise added and the resulting mixture was stirred for 0.5 h. The reaction mixture was quenched with a sat. aq. Na2S2O3 solution (10 mL) and with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and driedanhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:4) furnished compound 8a (227 mg, 83%) as a colourless solid.m.p.: 134.9-136.5 C.1H NMR (300 MHz, CDCl3) delta: 8.65 (s, 1 H).13C NMR (75 MHz, CDCl3) delta: 166.6, 156.8, 98.9.MS (70 eV, El) m/z (%): 274 (100) [M+], 239 (27), 97 (12), 83 (12), 57 (21).IR (ATR) v (cm-1): 2923, 2855, 1900, 1499, 1386, 11341, 1296, 1214, 1080, 1014, 790, 763, 745.HRMS (El) for C4HCl2IN2 (273.8561): 273.8565. |
Yield | Reaction Conditions | Operation in experiment |
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95% | With triethylamine; In isopropyl alcohol; for 2.0h;Heating; Reflux; | Production Example 1062-{ 4- [2- (6~piperazin-l-ylpyrimidin-4- yl) ethyl] phenyl }acetohydrazide tetrahydrochloride step 1[0323] [0324]To a solution (60 ml) of 4, 6-dichloropyrimidine (2.00 g, 13.4 mmol) and tert-butyl piperazine-1-carboxylate (3.00 g, 16.1 mmol) in 2-propanol was added triethylamine (4.7 ml, 33.6 mmol), and the mixture was heated under reflux for 2 hrs . The mixture was concentrated under reduced pressure, dichloromethane was added to the residue, and the mixture was washed with water. The aqueous layer was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 1:2) to give tert-butyl 4- ( 6-chloropyrimidin-2-yl) piperazine-1-carboxylate (3.80 g, yield 95%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 110℃; for 20h; | Example 23Preparation of Compound 33Step A - Synthesis of Compound 23BCompound 23A (0.274 g, 1.04 mmol) was combined with 4,6- dichloropyrimidine (0.196 g, 1.31 mmol) and DIPEA (0.45 mL, 2.6 mmol) in dioxane (6 mL) and the resulting reaction was heated to 110 °C and allowed to stir at this temperature for 20 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, and the resulting residue was purified using preparative TLC to provide Compound 23B as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
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Example 10; 6-[3-amino-4-(2,4-dichlorophenyl)pyrrolidin-1-yl]-N-methyl-N-(pyridin-4-ylmethyl)pyrimidin-4-amine A solution of 4,6-dichloropyrimidine (16 mg, 0.1 mmol), i-Pr2EtN (0.26 g, 2 mmol), (methyl-pyridin-4-yl)methyl-amine (12 mg, 0.10 mmol) and isopropanol (500 μL) were heated in the microwave at 130 C. for 20 minutes. Tert-butyl 4-(2,4-dichlorophenyl)pyrrolidin-3-ylcarbamate (33 mg, 0.10 mmol) was added as a solid, and the solution was heated in the microwave at 180 C. for 1 hour. The reaction mixture was concentrated under reduced pressure and treated with 4N HCl in dioxane (1 mL). After stirring for 1 hour, the solution was concentrated under reduced pressure and purified employing reverse phase chromatography (samples were purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8 minutes (10 minutes run time) at a flow rate of 40 mL/minutes) to provide the title compound. 1H NMR (300 MHz, d6-DMSO) δ ppm 8.62 (d, J=6.2 Hz, 2H), 8.16 (s, 1H), 7.71-7.72 (m, 1H), 7.62-7.54 (m, 3H), 7.45 (d, J=5.8 Hz, 2H), 4.20-4.30 (m, 4H), 4.97 (s, 2H), 3.57-3.59 (m, 1H), 3.44-3.47 (m, 1H), 3.09 (s, 3H). MS (ESI+) m/z 429 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
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71% | Reference Example 17 1-(6-chloropyrimidin-4-yl)-<strong>[387350-92-7]5-(methylsulfonyl)-2,3-dihydro-1H-indole</strong>; A mixture of 4,6-dichloropyrimidine (4.1 g, 27.5 mmol), <strong>[387350-92-7]5-(methylsulfonyl)-2,3-dihydro-1H-indole</strong> (5.0 g, 25.0 mmol), and ethanol (160 mL) was heated under reflux for 4 hr. The reaction mixture was concentrated, aqueous sodium hydrogen carbonate solution was added thereto, and the resulting solid was washed with water and dried under reduced pressure to give the title compound (5.5 g, yield 71%) as colorless crystals. 1H-NMR (300 MHz, DMSO-d6)δ:3.17 (s, 3 H), 3.24 - 3.37 (m, 2 H), 4.16 (t, J=8.7 Hz, 2 H), 7.09 (s, 1 H), 7.73 - 7.85 (m, 2 H), 8.57 (d, J=9.4 Hz, 1 H), 8.68 (s, 1 H). | |
71% | A mixture of 4,6-dichloropyrimidine (4.10 g, 27.5 mmol), compound 1 (5.00 g, 25.0 mmol), and EtOH (160 mL) was refluxed for 4 h. After the mixture was concentrated under reduced pressure, to the residue was added aqueous NaHCO3 solution. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound as a colorless solid (5.50 g, 71%). 1H NMR (300 MHz, DMSO-d6) δ 3.17 (3H, s), 3.24-3.37 (2H, m), 4.16 (2H, t, J = 8.7 Hz), 7.09 (1H, s), 7.73-7.85 (2H, m), 8.57 (1H, d, J = 9.4 Hz), 8.68 (1H, s). | |
71% | In ethanol; for 4h;Reflux; | A mixture of 4,6-dichloropyrimidine (4.10g, 27.5mmol), <strong>[387350-92-7]5-(methylsulfonyl)-2,3-dihydro-1H-indole</strong> (5.00g, 25.0mmol), and EtOH (160mL) was refluxed for 4h. After the mixture was concentrated under reduced pressure, saturated aqueous NaHCO3 solution was added to the residue. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound as a colorless solid (5.50g, 71%). MS (ESI/APCI) m/z 310 [M+H]+. 1H NMR (300MHz, DMSO-d6) δ 3.17 (3H, s), 3.24-3.37 (2H, m), 4.16 (2H, t, J=8.7Hz), 7.09 (1H, s), 7.73-7.85 (2H, m), 8.57 (1H, d, J=9.4Hz), 8.68 (1H, s). |
41% | To a suspension of sodium hydride (0.24 g, 1.5 eq) in 10 rnL of DMF at 0 0C, was added 5-methanesulfonyl-2,3-dihydro-lH-indole (0.8 g , 4.05 mmol). The mixture was stirred at 0 0C for 10 minutes, then 4,6-pyrimidine dichloride (0.8 g, 1 eq) was added. The resulting mixture was stirred at room temperature for 4h. The reaction mixture was then quenched with brine (100 mL) and extracted with ethyl acetate (100 mL then 3 x 50 mL). The combined extracts were washed with brine, dried over magnesium sulfate and filtered. The solvent was removed under vacuum and the crude product was purified by 3 consecutive column chromatography (elution with 25-100% ethyl acetate and 0.1% TEA in hexanes) to give 0.51 g of 6a (41% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31 mg | Compound 104 was prepared by a two-step procedure similar to that of Cai and coworkers22 and Plate and co-workers.23 In the first step, a similar procedure22 to that previously described for 98 was followed, using 4-acetamidophenylboronic acid pinacol ester (91) (0.10 g, 0.38 mmol), 4,6dichloropyrimidine (95) (0.18 g, 1.23 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). The reaction was allowed to cool, diluted with ethyl acetate (50 mL), washed with water (50 mL), the separated aqueous layer further extracted with ethyl acetate (2 × 50 mL), and the combined organic phases dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to afford crude 6-chloro-4-(4'-acetamidophenyl)pyrimidine (101) as a light brown solid (31 mg), which was used without further purification. In the second step, to a stirring solution of crude 6chloro-4-(4'-acetamidophenyl)pyrimidine (101) (31 mg) in tetrahydrofuran (5 mL) and aqueous ammonia (2.20 mL, 32.25 mmol, 15 M) was added zinc powder (0.22 g, 3.31 mmol), and the reaction mixture heated under reflux for 5 h. The solution was filtered through celite and the solvent removed in vacuo. The resulting residue was taken up in ethyl acetate (50 mL), washed with water (50 mL), the separated aqueous layer further extracted with ethyl acetate (2 × 50 mL) and the combined organic phases dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo. Purification by flash chromatography (hexane:ethyl acetate 1:1) afforded 104 as a pale brown solid (12 mg, 0.06 mmol, 15% over two steps); Rf = 0.15 (hexane:ethyl acetate, 1:1); mp 206-210 C [ lit.24 mp 213-214 C]; 1H NMR (400MHz; CDCl3) deltaH 2.19 (3H, s, CH3), 7.72-7.74 (3H, m, H-3', H-5', H-5), 8.05 (2H, d, J = 8.4 Hz, H-2', H-6'), 8.71 (1H, dd, J = 5.2 Hz, J = 1.2 Hz, H-6) and 9.18 (1H, s, H-2); 13C NMR (100MHz, CDCl3) deltaC 23.9 (CH3), 116.7 (CH), 119.6 (CH), 127.9 (CH), 131.1 (C), 141.4 (C), 156.9 (CH), 158.4 (CH), 163.6 (C) and 169.8 (C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 5h;Reflux; | Step 2: 4-(6-chloro-pyrimidin-4-ylamino)-2,6-dimethyl-phenol; 250 mg (1.68 mmol) 4,6-dichloropyrimidine, 240 mg (1.75 mmol) 4-amino-2,6-dimethyl-phenol and 0.650 mL (3.78 mmol) DIPEA in 5 mL DMF were combined and refluxed for 5 h. The reaction mixture was evaporated down, the residue was taken up in EtOAC and extracted with saturated sodium chloride solution. The organic phase was dried on magnesium sulphate, filtered and evaporated down. The residue was stirred with DIPE, the precipitate formed was suction filtered and dried i. vac.Yield: 260 mg (62% of theory)ESI-MS: m/z=250/252 (Cl) (M+H)+ Rf: 0.3 (silica gel: PE/EtOAc=2:1) |
Yield | Reaction Conditions | Operation in experiment |
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27.1% | With n-butyllithium; In tetrahydrofuran; hexane; at -78℃; | EXAMPLE 200 Step-1: n-Butyl lithium (0.895 g, 0.0140 mol, 1.6 M in hexane) was added dropwise to a stirred solution of 2, 3-difluorobromobenzene (3.0 g, 0.0155 mol) in THF (40 ml) over a period of 20 min at -78 0C, and reaction was continued stirring for 2 h at the same temperature. Then, 4,6-dichloropyrimidine (2.316 g, 0.0155 mol) in THF (20 ml) was added drop wise to the generated 2,3-difluorophenyl lithium mixture over a period of 15 min at -78 °C, and reaction was continued stirring for 30 min. Then, the reaction mixture was slowly warmed to 0 °C and was quenched with water (30 ml), and then DDQ (3.53 g, 0.0155 mol) in THF (30 ml) was added portionwise with stirred for 10 min. The resultant reaction mixture was extracted with CH2Cl2 (3x50 ml), washed with brine (50 ml), dried (Na2SO4), and concentrated. The concentrated product was purified through silica column chromatography using pet. ether to afford step-1 product (1.1g, 27.1 percent) as an off white solid. Rf: 0.3 (100percent PE). 1H NMR (400 MHz, CD3OD): delta 8.82 (s, IH), 7.91-7.78 (m, IH), 7.48-7.45 (m, IH), 7.32-7.26 (m, IH). m/e (M+l): 260.8 |
Yield | Reaction Conditions | Operation in experiment |
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43% | With palladium diacetate; potassium carbonate; triphenylphosphine; In water; isopropyl alcohol; at 80 - 90℃; for 20h;Inert atmosphere; | To a 100 mL flask containing 4,6-dichloropyrimidine (4.9 g, 32.9 mmol) in isopropyl alcohol (40 mL) was added <strong>[133730-34-4]2,4-dimethoxyphenylboronic acid</strong> (5 g, 27.4 mmol), palladium acetate (0.31 g, 1 .3 mmol) and triphenyl phosphine (1 .74 g, 6.6 mmol). Potassium carbonate (5.69 g, 3.2 mmol) was dissolved in water (12.5 mL) and was added to the reaction mixture. The reaction mixture was stirred under nitrogen at 80-90 C for 20 h. The reaction mixture was cooled to room temperature and was concentrated. The residue was partitioned between ethyl acetate (2 x 25 mL) and water (20 mL). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the title compound, which was further purified by column chromatography to obtain the title compound. Yield: 3.5 g (43 %); 1H NMR (300 MHz, DMSO-d6):5 9.01 (s, 1 H), 8.10 (m, 2H), 6.73 (m, 2H), 3.93 (s, 3H), 3.85 (s, 3H); MS (ES+): 251 .4 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
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72% | <a> Synthesis of Intermediate (44- 1) A flask was charged with 4,6-dichloropyridine (596 mg, 4.0 mmol), followed by being purged with argon gas. To the flask, thereafter, dioxane (60 mL), which had been deaerated with argon gas, 4-(4-pyridyl)phenyl boronic acid pinacol ester (4.0 mmol, 2.26 g), bis(triphenylphosphine) palladium(II) dichloride (0.3 mmol, 210 mg) were added. After bubbling the solution with argon gas, 2M K2CO3 (20 mL) was added, and the resultant was heated and stirred at 50C for 4 hours. Subsequently, 4-(4,4, 5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridine (4 mmol, 820 mg) was added, and the resulting mixture was heated and stirred at 100C for 4 hours. The resultant was filtered with Celite, and water and chloroform were added to the filtrate to separate an organic layer. Thereafter, a water layer was extracted 5 times with chloroform. The combined organic layer was washed with saturated salt water, followed by drying with sodium sulfate to condensate the filtrate, to thereby obtain a crude product. The crude product was purified by silica-gel column chromatography (eluenf- chloroform/methanol = 93/7), and the obtained solids were dispersed and washed in chloroform/hexane. The solids were collected by filtration, and the obtained solids were vacuum dried to thereby obtain an intermediate (44- 1) as pale yellow solids (the yielded amount: 892 mg, the yield: 72%). NMR (500 MHz, CDCI3, delta) : 9.42 (d, J = 1.7 Hz, 1H), 8.85(dd, Ji = 5.8 Hz, J2 = 1.8 Hz, 2H), 8.73(dd, Ji = 6.3 Hz, J2 = 1.7 Hz, 2H), 8.31 (d, J =8.6 Hz, 2H), 8.2l(d, J = 1.7 Hz, 1H), 8.04 (dd, Ji = 6.3 Hz, J2 = 1.7 Hz, 2H), 7.84 (d, J =6.9 Hz, 2H), 7.59 (d, Ji = 5.8 Hz, J2 = 1.8 Hz, 2H) |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80 - 120℃; | A mixture of 4,6-dichioropyrimidine (300mg, 2.01 mmol), tert-butyl 5- amino-i H-indazo le- 1 -carbo xylate (470 mg, 2.01 mmol), diisopropylethylamine (0.74 mL, 3.03 mmol), and DMF (2.01 mL) was stirred at 80 °C overnight Ibilowed by 120 °C lbr 4 h. The mixture was cooled to rt, diluted with water, and extracted with EtOAc. The organic layer was concentrated in vacuo to provide the title compound which was carried out directly for next step reaction without liirther purification. | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80 - 120℃; | N-(6-chloropyrimidin-4-yl)-lH-indazol-5 -amine A mixture of 4,6-dichloropyrimidine (300 mg, 2.01 mmol), tert-butyl 5-amino- lH-indazole-l-carboxylate (470 mg, 2.01 mmol), diisopropylethylamine (0.74 mL, 3.03 mmol), and DMF (2.01 mL) was stirred at 80 °C overnight followed by 120 °C for 4 h. The mixture was cooled to rt, diluted with water, and extracted with EtOAc. The organic layer was concentrated in vacuo to provide the title compound which was carried out directly for next step reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.3% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In water; acetonitrile; at 95℃; for 2.0h;Inert atmosphere; | A solution of <strong>[1308298-23-8]2-(trifluoromethyl)pyrimidin-5-ylboronic acid</strong> (100 mg, 0.50 mmol), 4,6- dichloropyrimidine (0.742559 mmol), cesium carbonate (322.595 mg, 0.99 mmol) and [1,1?- bis(diphenylphosphino)feffocene] dichloropalladium(ii) dichloromethane adduct (0.10 equiv., 0.050 mmol) in acetonitrile (6.0 ml) and water (3.0 mL) was degassed. The reaction mixture was heated at 95 °C for 2h. The reaction was filtered thru celite. The crude product was purified by flash chromatography (EtOAc/Hex_eluted at 20percentEtOAc) to give 74mg, 57.3percent yield. LCMS (ESI) mlz:260.9 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
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29.7% | 4.00 g of 3,9?-bi-9H-carbazole (12.0 mmol) was placed in a 300-mE three-neck flask, the interior of the flask was substituted with nitrogen, and 100 mE of tetrahydroffiran wasthen added thereto, followed by stirring at -78 C. for 20 minutes. 9.03 mE of a 1.60 mol/E hexane solution of n-butyllithium (14.4 mmol) was added dropwise to the solution with a syringe.The solution was stirred under a nitrogen atmosphere at-78 C. for 2 hours. Afier stirring, a mixed solution of 0.813 g of 4,6-dichioropyrimidine (5.45 mmol) and 20 mE of tetrahydrofuran was added to the solution, followed by stirring. The solution was slowly returned from -78 C. to room temperature, and then the solution was stirred at 80 C. for 5 hours.Afier stirring, 100 mE of water was added to the solution, followed by stirring. After stirring, toluene was added to the mixture, which was thus extracted therewith. Afier extracting, the organic layer and the aqueous layer were separated,and the organic layer was dried with magnesium sulfate added thereto. Afier drying, the mixture was filtered to provide a filtrate.The resulting filtrate was concentrated and purified by silica gel column chromatography. After puri1zing, the purified product was thrther purified with a GPC preparative colunm to provide a solid mattet The resulting solid matter was added to a mixed solvent of toluene and methanol, followed by heating to 60 C. Afier heating, the mixture was suction-filtered to recover a solid matter, thereby providing a compound 40 in the form of white powder solid with a yield amount of 1.20 g (yield: 29.7%). The identification of the compound was performed by ?H-NMR, ?3C-NMR and elemental analysis.?H-NMR (500 MHz, CDC13, TMS, oe): 9.45 (s, 1H), 8.50 (d, J=8.5 Hz, 2H), 8.29 (d, J=1.5 Hz, 2H), 8.21-8.18 (m, 6H), 8.13-8.11 (m, 3H), 7.70 (dd, J=8.5 Hz, 2.0 Hz, 2H), 7.59 (t, J=7.7 Hz, 2H), 7.46-7.41 (m, 1OH), 7.34-7.30 (m, 4H)?3C-NMR (125 MHz, CDC13, oe): 160.12, 159.96, 141.55,139.24, 137.84, 132.49, 127.58, 126.79, 126.24, 126.00,125.16, 123.31, 122.98, 120.91, 120.39, 119.91, 119.33,114.17, 112.46, 109.70, 105.57Elemental analysis: calculated for C52H32N5: C, 84.30%; H, 4.35%; N, 11.34%. found: C, 84.17%; H, 4.27%; N, 11.33% |
Yield | Reaction Conditions | Operation in experiment |
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92% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100℃;Sealed tube; | To a solution of 1-(4-aminopiperidin-1 -yl)ethanone hydrochloride I44 (1 .0 g, 5.6 mmol) in /- PrOH (10 mL) were added DIPEA (2.17 g, 16.8 mmol) and 4,6-dichloropyrimidine (0.83 g, 5.6 mmol). The resulting mixture was stirred at 100 C in a sealed tube overnight. The solvent was removed under reduced pressure, the residue was diluted with water (50 mL) and the pH adjusted to 12 by addition of 1 M NaOH. The aqueous layer was extracted with DCM (4 50 mL), the combined organic layers were washed with brine (100 mL), dried over a2SC>4 and concentrated. The residue was purified by column chromatography (100% (0705) EtOAc) to give the desired compound (1 .3 g, 92% yield) as a yellow oil. 1H NMR (400 MHz, d4-MeOD) delta 8.24 (s, 1 H), 6.50 (s, 1 H), 4.44-4.41 (m, 1 H), 4.17 (m, 1 H), 3.94-3.90 (m, 1 H), 3.28-3.20 (m, 1 H), 2.91 -2.84 (m, 1 H), 2.12-2.05 (m, 5H), 1 .52 - 1.40 (m, 2H). LCMS-C: RT 0.73 min; m/z 255.1 [M+H]' |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,4-dioxane; at 100℃; for 8h;Inert atmosphere; | 4,6-Dichloropyrimidine (1.49 g, 10 mmol) was placed in a flask, and after substitution with argon gas, dioxane (120 mL) degassed with argon gas,4- (4-pyridyl) phenylboronic acid pinacol ester (20 mmol, 5.6 g),Bis (triphenylphosphine) palladium (II) dichloride (0.2 mmol, 140 mg) was added.After bubbling the solution with argon gas, 2 M aqueous potassium carbonate solution (40 mL) was added,And the mixture was heated and stirred at 100 C. for 8 hours.The contents were filtered through celite, water and chloroform were added to the filtrate to separate the organic layer, and the aqueous layer was extracted with chloroform.The combined organic layer was dried over sodium sulfate and the filtrate was concentrated to give a crude product.This was purified by silica gel chromatography (developing solvent: chloroform / methanol), the obtained solid was washed with chloroform / hexane, and the solid collected by filtration was vacuum-dried to obtain the desired product as a pale yellow solid (yield 1 .58 g, yield 41%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | To a stirred solution of 4,6-dichloropyrimidine (0.3 g, 2.014 mmol) in DMF (10 mL) at 0 °C, was added NaH (0.242 g, 6.04 mmol). After stirred for 5 mm, tetrahydrofuran-3-amine (0.175 g, 2.014 mmol) was added and stirred overnight atRT The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with DCM (80 mL). The organic layer was washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 6-chloro-N- (tetrahydrofuran-3-yl)pyrimidin-4-amine (0.3 g, 0.872 mmol, 43percent yield) as ayellowish semi-solid. LCMS (ESI) m/e 200.4 [(M+H), calcd for C8H11C1N3O,200.11; LC/MS retention time (method B): tR = 0.60 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.7% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4h; | <strong>[76205-19-1]1-(4-chlorophenyl)-1H-pyrazol-3-ol</strong> (19.45 g, 0.1 mol) was used. Potassium carbonate (27.6 g, 0.2 mol), 250 mL of N,N-dimethylformamide added to the reaction flask, Stir at room temperature To the above solution was added 4,6-dichloropyrimidine (14.9 g, 0.1 mol). The reaction was heated to 100C for about 4 hours, and the solution gradually turned yellow during the reaction. After the completion of the TLC monitoring reaction, join Ethyl acetate and water were extracted, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and dissolved under reduced pressure. Column chromatography of the residue gave a pale yellow solid (25.7 g, 0.084 mol), yield: 83.7% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 85℃; for 18h;Sealed tube; | A solution of 4,6-dichloropyrimidine (542.96 mg, 3.64 mmol) and <strong>[326827-21-8]5-cyclobutyl-1H-pyrazol-3-amine</strong> (500 mg, 3.64 mmol) in isopropanol (5 mL) was added DIPEA (1.90 mL, 1.41 g, 10.93 mmol). The mixture was stirred for 18 h in a sealed tube at 85 C. The reaction mixture was quenched with half-saturated NH4Cl solution and extracted with 10% IPA/DCM (3×50 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to obtain compound 4 as yellow oil (855 mg, 94%). The crude product was used for the next step without further purification. MS (ESI): Calcd. for C11H12ClN5: 249, found 250 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 50.0℃; for 24.0h; | A solution of <strong>[791098-84-5](R)-1-(2,4-difluorophenyl)ethan-1-amine</strong> (250 mg, 1.59 mmol) and 4,6-dichloropyrimidine (260.67 mg, 1.75 mmol) in isopropanol (5 mL) was added DIPEA (0.55 mL, 3.18 mmol). The mixture was stirred for 24 h at 50 C. TLC was checked and the reaction was complete. Solvent IPA was removed under reduced pressure to obtain compound 11 as yellow oil (400 mg, 93%). The crude product was used for the next step without further purification. MS (ESI): Calcd. for C12H10ClF2N3: 269, found 270 (MH+). |
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