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Structure of 1193-21-1 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With 1-methyl-pyrrolidin-2-one; iron(III)-acetylacetonate In tetrahydrofuran at 20℃; for 3 h;
To a solution of 4,6-dichloropyrimidine (1.0 g, 6.71 mmol) in tetrahydrofuran (30 mL) was added l-methyl-2-pyrrolidinone (3.2 mL, 6.71 mmol), iron(III) acetylacetonate (0.119 g, 0.336 mmol) and methylmagnesium bromide (2.237 mL, 6.71 mmol). The reaction mixture was stirred at RT for 3 h, then it was quenched with water and extracted with ethyl acetate (100 mL). The organic layer was separated out and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20percent ethyl acetate-hexane) to afford 4-chloro-6- methylpyrimidine (0.6 g, 3.08 mmol, 46percent yield) as a colorless gummy liquid. LCMS (ESI) m/e 129.0 [(M+H)+, calcd for C5H6C1N2 129.0]; LC/MS retention time (method D): /R = 1.36 min.
Reference：
[1] Journal of the Chemical Society, 1943, p. 574
4
[ 1193-21-1 ]
[ 5305-59-9 ]
Yield
Reaction Conditions
Operation in experiment
88%
With ammonia In isopropyl alcohol at 25℃; for 1 h;
General procedure: To a suspension of 4,6-dichloropyrimidine 53 (3.0 g, 20 mmol) in isopropanol (40 mL) was added appropriate amine at such a rate that the internal temperature did not rise above 40 °C. After completion of the addition, the reaction mixture was stirred for 1 h at 25 °C. Water (30 mL) was added, and the resulting suspensio nwas cooled in an ice bath to 0 °C. The precipitated product was filtered off and washed with cold isopropanol/water (2:1, 50 mL) and water. The collected material was dried in vacuo to afford the title compounds.
81%
at 30℃; for 15 h;
A mixture of 4, 6-dichloropyrimidine (20 g, 0.14 mol) and NH4OH (200 mL) was heated at 30 °C for 15 hours with stirring. The resulting precipitate was collected via filtration, and the filter cake was washed with water (100 mL). The resultant solid was purified by silica gel column chromatography, eluting with EtOAc to give the desired product as a white solid ( 14 g, 81 percent yield) . LCMS (ESI) m/z : 130.1 [M+H+] .
80%
at 100℃; Sealed tube
Step 1: 6-chloropyrimidin-4-amine Intermediate 14 4,6-Dichloropyrimidine (7.5 g, 50 mmol) was suspended in ammonium hydroxide (64 mL) in a sealed tube. The tube was sealed and heated at 100° C. in an oil bath overnight. The reaction mixture was cooled to rt. The solid was removed by filtration, washed with water and dried under high vacuum to afford 6-chloropyrimidin-4-amine (5.23 g, 80percent) LC-MS (AA) ES+ 130.
77%
With ammonia In ethanol at 80℃; for 1.5 h;
Compound 1-1-1 (10 g, 67.1 mmol) was disposed into a stainless steel vessel, and EtOH saturated with NH3 (g) in advance (40 mL) was added. The reaction mixture was heated to 80° C., reacted for 1.5 h, and then cooled down to r.t., concentrated in vacuo and stripped to give a crude product which was triturated with water and filtered to afford compound 8-6 (6.7 g, Yield 77percent). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.20 (s, 1H), 7.22 (s, 2H), 6.45 (s, 1H)
71%
With ammonia In ethanol at 100℃; for 1.5 h; In a stainless pressure vessel
4, 6-Dichloropyrimidine (10.0 g, 67. 1 mmol) in ammonia saturated ethanol (40 mL) was heated to 100°C in a stainless steel pressure vessel for 1.5 h. Removal of the solvent in vacuo gave a solid which was triturated with water (270 mL) then filtered to give 6-amino-4-chloropyrimidine (1) (6. 18 g, 71percent) as white crystals. APCI-MS Found [M + H] + = 130, 132.
67%
With ammonia In methanol at 85℃; for 16 h;
4,6-Dichloropyrimidine (20.85 g, 139 mmol) and 7 N Ammonia in methanol (200 mL) were heated to 85 C in a sealed glass bomb for 16 h. The reaction was cooled to ambient temperature, the solvent evaporated, and the residue recrystalized from water yielding compound 17 (12.07 g, 93.17 mmol, 67percent yield). 1H NMR (400 MHz, DMSO-D6): S 6.43 (s, 1 H), 7.22 (s, 2 H), 8.18 (s, 1 H). ESI-MS mXz : 130 (M + H) +.
67%
With ammonia In methanol at 85℃; for 16 h;
4,6-Dichloropyrimidine (20.85 g, 139 mmol) and 7 N Ammonia in methanol (200 mL) were heated to 85 C in a sealed glass bomb for 16 h. The reaction was cooled to ambient temperature, the solvent evaporated, and the residue recrystalized from water yielding compound 17 (12.07 g, 93.17 mmol, 67percent yield). 1H NMR (400 MHz, DMSO-D6): S 6.43 (s, 1 H), 7.22 (s, 2 H), 8.18 (s, 1 H). ESI-MS mXz : 130 (M + H) +.
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 20, p. 7066 - 7083
[2] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 11 - 20
[3] Patent: WO2012/35039, 2012, A1, . Location in patent: Page/Page column 84
[4] Patent: US2012/15943, 2012, A1, . Location in patent: Page/Page column 54
[5] ChemMedChem, 2017, vol. 12, # 16, p. 1390 - 1398
[6] Patent: US2017/313683, 2017, A1, . Location in patent: Paragraph 0346-0347
[7] Patent: WO2005/89763, 2005, A1, . Location in patent: Page/Page column 35
[8] Patent: WO2005/34840, 2005, A2, . Location in patent: Page/Page column 67-70
[9] Patent: WO2005/34840, 2005, A2, . Location in patent: Page/Page column 67-70
[10] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 5, p. 1146 - 1150
[11] Patent: US2004/23977, 2004, A1, . Location in patent: Page/Page column 7
[12] Journal of Physical Organic Chemistry, 2013, vol. 26, # 12, p. 1038 - 1043
[13] Patent: WO2007/104538, 2007, A1, . Location in patent: Page/Page column 52
5
[ 1193-21-1 ]
[ 71-36-3 ]
[ 5305-59-9 ]
Reference：
[1] Patent: US2002/137755, 2002, A1,
6
[ 1193-24-4 ]
[ 1193-21-1 ]
Yield
Reaction Conditions
Operation in experiment
99.1%
at 40 - 105℃; for 2 h;
In a four-necked flask equipped with a reflux condenser, the temperature was raised and stirred, and 228 g of 4,6-dihydroxypyrimidine was added by a constant pressure dropping funnel, the content was 98percent,and the content of 633 g of phosphorus oxychloride was 97percent.The temperature was raised to 40 to 45 ° C, and the content of 408 g of triethylamine was added dropwise with content of 99percent, 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 4,6-dihydroxypyrimidine was less than 0.2percent, 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 97.3percent, and the content was 39.91percent. The crude yield was 92percent. 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 98percent 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 4.2 h; Industrial scale
In the reaction container (such as test flat glass reaction bottle) by adding 4,6-dihydroxypyrimidine 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 97percent, the mass content is more than 99percent (determined by high performance liquid phase method)
96.2%
With cobalt(II) phthalocyanine; bis(trichloromethyl) carbonate; Triphenylphosphine oxide In nitrobenzene at 90 - 95℃; for 5 h;
212 g of triphosgene (content 99percent, 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 4,6-dihydroxypyrimidine (114 g, content 98percent, 1 mol), triphenylphosphine oxide (8.4 g, content 99percent,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 4,6-dihydroxypyrimidine was 0.25percent and the content of 4,6-dichloropyrimidine was 98.2percent by HPLC. The reaction was completed.Vacuum distillation reaction mixture (oil bath temperature 95 ° C, vacuum -0.095 Mpa),143.8 g (content 99.7percent) of 4,6-dichloropyrimidine was obtained in a yield of 96.2percent (based on 4,6-dihydroxypyrimidine).
94.9%
at 95 - 100℃; for 8 h; Large scale
In a device equipped with a reflux condenser, a thermometer, a stirrer and a constant pressure dropping funnel, 4,6-dihydroxypyrimidine(114.3 g, 98percent, 1 mol), phosphorus oxychloride (1140 g, 99percent) were stirred and mixed, the temperature was raised to 95-100 ° C,And slowly adding phosgene (220g, 99percent, 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 99percent); 4,6-dichloropyrimidine 142.8 g (content 99.0percent),The yield of 94.9percent (based on 4,6-dihydroxypyrimidine), 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%
at 95 - 100℃; for 8 h; Large scale
With a reflux condenser, thermometer,In the device of the agitator and the constant pressure dropping funnel,Add 4,6-dihydroxypyrimidine (114.3 g, content 98percent, 1 mol), phosphorus oxychloride (1140 g, 99percent) and mix well.The temperature was raised to 95-100 ° C, and phosgene (220 g, 99percent, 2.2 mol) was slowly added to carry out the reaction, and the sample was taken after 8 hours.HPLC analysis of 4,6-dihydroxypyrimidine content of 0.9percent,The content of 4,6-dichloropyrimidine was 98.3percent, 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 99percent); 142.8 g of 4,6-dichloropyrimidine (content 99.0percent),Yield 94.9percent (based on 4,6-dihydroxypyrimidine), 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 3 h;
0.5 mol of 4,6-dihydroxypyrimidine 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 78percent and the purity was 80percent.
58%
With trichlorophosphate In water; <i>N</i>,<i>N</i>-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 4,6-dihydroxypyrimidine (98percent 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 (=58percent of theory) are thus obtained.
Reference：
[1] Patent: CN108395409, 2018, A, . Location in patent: Paragraph 0039-0041; 0044
[2] Patent: CN105439963, 2016, A, . Location in patent: Paragraph 0011
[3] Patent: CN108341784, 2018, A, . Location in patent: Paragraph 0027; 0028; 0029; 0031-0033; 0039; 0040
[4] Patent: CN105732514, 2016, A, . Location in patent: Paragraph 0027; 0028
[5] Patent: CN108178749, 2018, A, . Location in patent: Paragraph 0027; 0028; 0030; 0032; 0034; 0036; 0038; 0040
[6] Synlett, 2010, # 14, p. 2179 - 2183
[7] Patent: CN105859637, 2016, A, . Location in patent: Paragraph 0023; 0024
[8] Patent: US5719285, 1998, A,
[9] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2676 - 2699
[10] Patent: US2002/42514, 2002, A1,
[11] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 2629 - 2634
[12] Patent: CN106045917, 2016, A, . Location in patent: Paragraph 0018; 0019
[13] Patent: CN106187913, 2016, A, . Location in patent: Paragraph 0014; 0015; 0016
[14] Patent: CN106187912, 2016, A, . Location in patent: Paragraph 0016; 0017
7
[ 75-44-5 ]
[ 77287-34-4 ]
[ 75-05-8 ]
[ 1193-21-1 ]
Yield
Reaction Conditions
Operation in experiment
62.21%
at 20 - 140℃; for 3 h; the Parr Reactor (17328-33)
A solution of 3.0536 g formamide and 33.1563 g acetonitrile was prepared and 33.1563 g of the solution was charged to a 100 ml Hastelloy-C Parr reactor equiped with valves for addition of materials and venting, a condenser, heating and stirring. The reactor was inerted with nitrogen and vented down to ambient pressure. Separately, 34 grams of phosgene were condensed in a 150 ml stainless steel sampling cylinder. The Parr reactor was sealed and heated to 124.9° C. using a heating mantle with agitation. The reactor pressure built up to 19 psig. Liquid phosgene was charged to the reactor using 400 psig nitrogen. The reaction temperature dropped immediately due to the addition of room temperature phosgene, but it rose to 140° C. within 10 minutes due to reaction. The combination of nitrogen pressure and reaction raised the reactor pressure to 320 psig within three minutes after phosgene was charged, at which time vent line was opened to slowly bring the reactor pressure down to 200 psig. A Hastelloy C tubular condenser was used to keep phosgene in the reactor. The highest pressure reached was 366 psig at four minutes after the phosgene charge. The temperature was controlled at 125° C. for three hour. The reactor was cooled down to room temperature three hours after phosgene was charged. The reaction mixture was collected and 102.9 g acetonitrile was used to wash the reactor. The resulting 137.9 g slurry was filtered and washed with acetonitrile to give 168.6 g filtrate and 12.25 g filter cake. Analysis of both the filtrate and filter cake gave 62.21percent yield on 4,6-dichloropyrimidine.
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 80percent (hplc analysis).
Reference：
[1] Patent: US5750694, 1998, A,
[2] Patent: US5750694, 1998, A,
9
[ 104-90-5 ]
[ 1193-24-4 ]
[ 1193-21-1 ]
Reference：
[1] Patent: US5719285, 1998, A,
[2] Patent: US5719285, 1998, A,
Reference：
[1] Bulletin de la Societe Chimique de France, 1959, p. 741
[2] Journal of the Chemical Society, 1943, p. 574
[3] Journal of the Chemical Society, 1951, p. 2214
19
[ 1193-21-1 ]
[ 4765-77-9 ]
Yield
Reaction Conditions
Operation in experiment
57%
With hydrogenchloride In 1,4-dioxane; ethanol; water
Intermediate 1: 6-Chloro-3H-pyrimidin-4-one A mixture of 4,6-dichloropyrimidine (Aldrich; 10.00 g, 67.1 mmol), concentrated hydrochloric acid (50 mL), water (50 mL) and dioxane (50 mL) was heated at about 70° C. for 6 h, and then allowed to cool to room temperature. This gave a pink solution. The solvents were evaporated under reduced pressure (vacuum pump) to give a pink solid. Ethanol (50 mL) was added and the mixture was heated. The solid went into solution. The solution was placed in a warm bath (about 50° C.) and allowed to cool slowly. After standing over the weekend, the off-white solid was filtered off to give 6-chloro-3H-pyrimidin-4-one (5.02 g, 57percent), mp 193-194° C. (lit. mp 192-193° C. in D. J. Brown and J. S. Harper J. Chem. Soc. 1961, 1298-1303). 1H NMR (d6-DMSO) δ 6.50 (s, 1H), 8.19 (s, 1H), 13.00 (br s, 1H).
56%
With hydrogenchloride In 1,4-dioxane; water at 70℃; for 6 h;
A solution of 4,6-dichloropyrimidine (2 g, 13.42 mmol) in a mixture of 4N HC1 (10.49 mL, 121 mmol)- 1,4-dioxane (10 mL)-water (10 mL) was heated to 70 CC for 6 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford a pink solid. Ethanol (25 mL) was added to thesolid and the mixture was heated at 50 °C until the solid dissolved. The resulting pink solution was left overnight at room temperature and the precipitation formed was filtered and dried under vacuum to afford 6-chloropyrimidin-4(3B)-one (1 g, 7.51 mmol, 56percent yield) as an off-white solid. LCMS (ESI)m/e 130.8 [(M+H), calcd for C4H4C1N2O, 130.91; LC/MS retention time (Method C): tR = 0.51 mm.
Reference：
[1] Journal of the Chinese Chemical Society, 2013, vol. 60, # 1, p. 27 - 34
[2] Patent: US2009/149466, 2009, A1,
[3] Patent: WO2017/59080, 2017, A1, . Location in patent: Page/Page column 288; 289
20
[ 67-56-1 ]
[ 1193-21-1 ]
[ 26452-81-3 ]
Yield
Reaction Conditions
Operation in experiment
7.1 g
at 0 - 20℃; for 3 h;
6.01.04.01 4-Chloro-6-methoxy-pyrimidine 3.1 g sodiummethanolate was added to 7.2 g 4,6-dichlorpyrimidine in 150 mL methanol at 0° C. The reaction was warmed to RT and stirred additional 3 h. Water and EtOAC were added and the layers were seperated. The organic layer was dried and evaporated to give 7.1 g of the desired product. Rt: 0.85 min (method L), (M+H)+: 144
9.7 g
at 20℃;
6.01.01.1 4-chloro-6-methoxy-pyrimidine 5.8 g sodium methanolate was added to 10 g 4,6-dichloropyrimidine in 150 mL MeOH at 0° C. The reaction was warmed up to RT and stirred over night at RT. Then 3.63 g sodium methanolate was added and the reaction was stirred for 3 h. The mixture was treated with water and extracted with EtOAc. The organic layer was dried over magesiumsulfate and evaporated to give 9.7 g 4-chloro-6-methoxy-pyrimidine. Rt: 0.87 min (method B)
8.34 g
at 0 - 20℃;
8 g sodium methanolate was added to 10 g 4,6-dichlorpyrimidine in 100 mL methanol at 0° C. The reaction was stirred at RT over night. The mixture was added into water and extracted with ethylacetate. The organic layer was dried with magnesium sulfate and evaporated to give 8.34 g desired product. Rt: 0.97 min (method B), (M+H)+: 145
10.2 g
With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1 h; Inert atmosphere
A) 4-chloro-6-methoxypyrimidine Under a nitrogen atmosphere, methanol (5.4 mL) was added to a suspension of 60percent sodium hydride (8.05 g) in THF (200 mL) at 0°C. To the obtained suspension was added a solution of 4,6-dichloropyrimidine (20.0 g) in THF (45 mL) at 0°C, and the mixture was stirred at 0°C for 1 hr. 1N Hydrochloric acid was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized (hexane) to give the title compound (10.2 g) as pale-yellow crystals. 1H NMR (300 MHz, DMSO-d6) δ 3.96 (3H, s), 7.19 (1H, s), 8.69 (1H, s).
Reference：
[1] Tetrahedron Letters, 2005, vol. 46, # 23, p. 3977 - 3979
[2] European Journal of Medicinal Chemistry, 2005, vol. 40, # 9, p. 862 - 874
[3] Patent: US2013/143870, 2013, A1, . Location in patent: Paragraph 0267; 0268; 0269
[4] Patent: US2013/137688, 2013, A1, . Location in patent: Paragraph 0221; 0222; 0223; 0224
[5] Patent: US2013/158038, 2013, A1, . Location in patent: Paragraph 0134; 0135
[6] Patent: EP2816032, 2014, A1, . Location in patent: Paragraph 0275; 0276
[7] Journal of Inorganic Biochemistry, 2015, vol. 144, p. 18 - 30
21
[ 1193-21-1 ]
[ 124-41-4 ]
[ 26452-81-3 ]
Yield
Reaction Conditions
Operation in experiment
9.7 g
at 0 - 20℃;
6.01.01.1 4-chloro-6-methoxy-pyrimidine 5.8 g sodium methanolate was added to 10 g 4, 6-dichloropyrimidine in 150 mL MeOH at 0°C. The reaction was warmed up to RT and stirred over night at RT. Then 3.63 g sodiummethanolate was added and the reaction was stirred for 3 h. The mixture was treated with water and extracted with EtOAc. The organic layer was dried over magesiumsulfate and evaporated to give 9.7 g 4-chloro-6-methoxy-pyrimidine.Rt: 0.87 min (method B)
8.34 g
at 0 - 20℃;
4-chloro-6-methoxy-pyrimidine 8 g sodium methanolate was added to 10 g 4, 6-dichlorpyrimidine in 100 mL methanol at 0°C. The reaction was stirred at RT over night. The mixture was added into water and extracted with ethylacetate. The organic layer was dried with magnesium sulfate and evaporated to give 8.34 g desired product. Rt: 0.97 min (method B), (M+H)+: 145
4.6 g
at 20℃; for 8 h; Cooling with ice
To a mixture of 6 g of 4,6-dichloropyrimidine and 40 mL of methanol, 8.16 g of 28percent sodium methoxide methanol solution was added dropwise under ice cooling. After stirring for 2 hours under ice cooling, the temperature was raised to room temperature and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of ammonium chloride was added to the obtained oily substance, followed by extraction with ethyl acetate. After washing the organic layer with saturated brine, the organic layer was dried with sodium sulfate. The organic layer was concentrated under reduced pressure, and the obtained oily substance was subjected to silica gel chromatography to obtain 4.6 g of an intermediate (6-1)
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2676 - 2699
[2] Helvetica Chimica Acta, 1959, vol. 42, p. 1317,1321
[3] Pesticide Science, 1996, vol. 47, # 2, p. 103 - 114
[4] Patent: WO2013/79460, 2013, A1, . Location in patent: Page/Page column 44
[5] Patent: WO2013/87806, 2013, A1, . Location in patent: Page/Page column 30
[6] Patent: JP2017/36339, 2017, A, . Location in patent: Paragraph 0166
22
[ 1193-21-1 ]
[ 26452-81-3 ]
Reference：
[1] Patent: US5668140, 1997, A,
23
[ 1193-21-1 ]
[ 7440-44-0 ]
[ 26452-81-3 ]
Reference：
[1] Patent: US4997835, 1991, A,
24
[ 67-56-1 ]
[ 1193-21-1 ]
[ 124-41-4 ]
[ 26452-81-3 ]
Yield
Reaction Conditions
Operation in experiment
4.6 g
at 20℃; for 8 h; Cooling with ice
Preparation Example 6(1) o a mixture of 4,6-dichloropyrimidine 6 g and methanol 40 mL was added dropwise a 28percent sodium methoxide solution in methanol 8.16 g under ice-cooling. The resulting mixtures were stirred for 2 hours under ice-cooling and then warmed to room temperature, and stirred for 6 hours. The reaction mixtures were concentrated under reduced pressure, and to the resulting oily materials was added a saturated aqueous ammonium chloride solution, and then the resulting mixtures were extracted with ethyl acetate. The organic layers were washed with saturated brine, and then the organic layers were dried over sodium sulfate. The organic layers were concentrated under reduced pressure, and the resulting oily materials were subjected to a silica gel chromatography to give an intermediate compound (6-1) 4.6 g. 1H-NMR (CDCl3) δ: 8.59 (1H, s), 6.78 (1H, dd), 4.01-3.95 (3H, m).
With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 14 h;
Into a 100-mL round-bottom flask, was placed N,N-dimethylformamide (10 mL), 4,6- dichloropyrimidine (1 g, 6.71 mmol, 1 equiv), CS2CO3 (4.4 g, 13.50 mmol, 2.01 equiv), methanamine hydrochloride (905 mg, 13.40 mmol, 2.00 equiv). The resulting solution was stirred for 14 h at 80 °C. The resulting solution was diluted with 10 mL of H2O. The resulting solution was extracted with 4x10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1x10 mL of H2O. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 1). This resulted in 750 mg (78percent) of as a white solid. Analytical Data: LC-MS: (ES, m/z): RT = 0.476min, LCMS 32: m/z = 144 [M+l].
Reference：
[1] European Journal of Organic Chemistry, 2014, vol. 2014, # 7, p. 1514 - 1524
[2] European Journal of Organic Chemistry, 2014, vol. 2014, # 7, p. 1514 - 1524
[3] Patent: WO2017/181177, 2017, A1, . Location in patent: Paragraph 0950-0953
[4] Tetrahedron, 2007, vol. 63, # 25, p. 5394 - 5405
26
[ 1193-21-1 ]
[ 74-89-5 ]
[ 65766-32-7 ]
Yield
Reaction Conditions
Operation in experiment
97.43%
at 0 - 20℃;
A mixture of 79 (0.50g, 3.36mmol) and IPA (1.5ml) was stirred for a while and then 2M methylamine in THF (4.2ml, 8.40mmol) was added thereto at 0 °C. The resulting mixture was back to room temperature under stirring for overnight. The reaction was quenched by water and then the mixture was extracted by ethyl acetate (30ml x 3). The residue was purified by flash column over silica gel (ethyl acetate: n-Hexane = 1 :2, Rf = 0.20) to afford 83 (0.47g, 97.43percent) as a pale yellow solid. 1H-NMR (300MHz, CDCl3): δ 2.95 (d, J= 5.1 Hz, 3H), 5.26 (br, 1H), 6.34 (s, 1H), 8.34 (s, 1H).
93%
With triethylamine In tetrahydrofuran at 20℃; for 23 h; Cooling with ice
To a solution of 4,6-dichloropyrimidine (0.50 g) in tetrahydrofuran (0.84 mL), triethylamine (0.94 mL) was added,then a 2.0 mol/L solution of methylamine in tetrahydrofuran (1.7 mL) was added dropwise under ice cooling, and themixture was stirred at room temperature for 23 hours. The reaction solution was concentrated, and then, the obtaine dresidue was purified by silica gel column chromatography (MORITEX Purif Pack-NH, chloroform) to obtain the titlecompound (0.45 g, 93percent) as a colorless solid.1H NMR (300 MHz, CDCl3) δ ppm 2.96 (d, J=5.0Hz, 3H), 6.35 (s, 1H), 8.35 (s, 1H). MS (+): 144 [M+H]+.
93%
at 20℃; for 15 h;
Take 4,6-dichloropyrimidine (75.7 g, 0.51 mol),Isopropanol (0.98 L) and methylamine/tetrahydrofuran solution (2 mol/L, 0.76 L, 1.52 mol) were added.Stir at room temperature for 15 hours. The reaction was completely monitored by TLC, the reaction mixture was filtered, and the filtrate was concentrated.Distilled water (500 mL) and EA (300 mL) were added, liquid separation, aqueous phase EA extraction (300 mL×2), and the organic phase was combined.Wash with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate,Beat with ethyl acetate: petroleum ether (1:30, 800 mL),After drying, a brown solid (68.0 g, yield 93percent) was obtained.
91%
at 25℃; for 1 h;
General procedure: To a suspension of 4,6-dichloropyrimidine 53 (3.0 g, 20 mmol) in isopropanol (40 mL) was added appropriate amine at such a rate that the internal temperature did not rise above 40 °C. After completion of the addition, the reaction mixture was stirred for 1 h at 25 °C. Water (30 mL) was added, and the resulting suspensio nwas cooled in an ice bath to 0 °C. The precipitated product was filtered off and washed with cold isopropanol/water (2:1, 50 mL) and water. The collected material was dried in vacuo to afford the title compounds.
88%
at 20℃;
4,6-Dichloropyrimidine (10 g, 67 mmol) was dissolved in 100 ml isopropanol and the solution was cooled to 0 00 reprecipitating. Methylamine solution (33percent w/w, 17 ml, 140 mmol) was added slowly with stirring and the mixture was stirred overnight atroom temperature. The mixture was evaporated under reduced pressure. The residue was resuspended in water, stirred for 15 mm and then filtered. The solid was dried under reduced pressure. The filtrate was extracted three times with ethyl acetate. The combined organics were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The solid obtained was combined with the firstprecipitate to give 8.50 g (59 mmol, 88percent yield) of the title compound as a white solid. Purity 87percent.1H NMR (300 MHz, CHLOROFORM-d) ö ppm 8.40 (s, 1H), 6.38 (s, 1H), 2.98 (d, 3H, J = 5.1 Hz).UPLC/MS (3 mm) retention time 0.74 mm.LRMS: m/z 144 (M+1, ixOl).
87%
at -40 - 0℃; for 4 h;
6-Chloro-N-methylpyrimidin-4-amine (16)[00404] To a solution of 4,6-dichloropyrimidine (5.0 g, 33.79 mmol) in anhydrous THF (50 mL) was slowly added 2.0 M methylamine solution in THF (42.2 mL, 84.48 mmol) at -40 °C. The reaction mixture was stirred at 0 °C for 4 h and partitioned between CHCl3/2- propanol (4/1) and water. The organic layer was dried over anhydrous sodium sulfate, filtered through a pad of CELITE, and concentrated under reduced pressure. The white solid 6- chloro-N-methylpyrimidin-4-amine (4.2 g, 87percent yield) was used in the next reaction without purification. Rt = 1.55 min;1H NMR 600 MHz (CDCl3) 8.13 (br, 1H), 6.54 (m, 1H), 5.37 (br, 1H), 2.99 (m, 3H) ppm; MS m/z: 144.05 [M+1].
86%
at 20℃; for 1 h;
[0174] To a suspension of 4,6-dichloropyrimidine (0.50 g, 3.4 mmol) in propan-2-ol (10 mL) was added dropwise methylamine (2 M, 3.4 mL). After addition was completed, the reaction mixture was stirred at room temperature for 1 hour. Upon completion, the reaction mixture was concentrated in vacuo. The residue was dissolved with dichloromethane (50 mL), washed with water (10 mL), brine (2x 10 mL) sequentially. The organic phase was collected and concentrated to give 6-chloro-N-methylpyrimidin-4-amine (0.42 g, 86percent yield) as a white solid.
82%
at 0 - 5℃;
Example J cr ^ ^N'CH3 H6-Chloro-Af-methylpyrimidin-4-amine; [00252] 4,6-Dichloropyrimidine (978 mg, 6.56 mmol) was taken up in isopropanol(1O mL, 131 mmol) and cooled to 0-5 0C. A solution of 33percent methylamine in ethanol (1.768 mL, 13.2 mmol) was added, and the reaction mixture was stirred for 15 hours. The mixture was concentrated under reduced pressure and suspended in water. The title compound was obtained after filtration and drying in vacuo (772 mg, 82percent). 1H NMR (400 MHz, DMSO- d6) δ 8.27 (s, IH), 7.65 (s, IH), 6.50 (s, IH), 2.99 - 2.67 (m, 3H). LC/MS: m/z 144.1 [M+l].
62%
at 20℃; for 18 h;
e. ( 6-Ch loro-pyrimidin~4~yl)~methyl-amine To a solution of 4,6-dic oro-pyrimidine (7.45 g, 50 mmol) in iPrOH (50 mL) was added a solution of methyl amine in THF (2M, 30 mL, 60 mmol) at room temperature. The resulting mixture was stirred for 18 hours. The mixture was concentrated and the residue was purified by flash chromatography on silica eiuting with DCM:EtOAc = 6:1-1 :1 to obtain the title compound (4.4 g, yield: 62percent) as a white solid. lU NMR (400 MHz, CDC13) δ 2.96 (d, 3H), 5.22-5.36 (bs, 1H), 6.35 (s, 1H), 8.35 (s, 1H); MS (ESI): 144 [M+H]+.
62%
at 20℃; for 18 h;
To a solution of 4,6-dichloro-pyrimidine (7.45 g, 50 mmol) in iPrOH (50 mL) was added a solution of methyl amine in THF (2M, 30 mL, 60 mmol) at room temperature. The resulting mixture was stirred for 18 hours. The mixture was concentrated and the residue was purified by flash chromatography on silica eluting with DCM:EtOAc = 6: 1—1 : 1 to obtain the title compound (4.4 g, yield: 62percent) as a white solid. 1H-NMR (400 MHz, CDC13) δ 2.96 (d, 3H), 5.22-5.36 (bs, 1H), 6.35 (s, 1H), 8.35 s, 1H); MS (ESI): 144 [M+H]+.
62%
at 20℃; for 2 h;
General procedure: A solution of 4,6-dichloropyrimidine (20.14 mmol, 3.0 g) (A1) in 20 ml of isopropanol was slowly added dropwise to 10 ml of aqueous ammonia or methylamine or ethylamine at room temperature for 2 h. The solvent was evaporated under reduced pressure, Solid, adding 20 ml of water stirring filter, filter cake washed with water, vacuum drying, in intermediate A2 or A3.4 - methylamino -6 - chloro pyrimidine (A2), the white crystal, yield 62percent.
Reference：
[1] Patent: WO2017/15400, 2017, A1, . Location in patent: Paragraph 0044; 0059
[2] Patent: EP3173408, 2017, A1, . Location in patent: Paragraph 0320; 0321
[3] Patent: CN108239069, 2018, A, . Location in patent: Paragraph 0110; 0113-0116
[4] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 11 - 20
[5] Patent: WO2017/64068, 2017, A1, . Location in patent: Page/Page column 40; 41
[6] Patent: WO2016/23014, 2016, A2, . Location in patent: Paragraph 00403-00404
[7] Journal of Medicinal Chemistry, 2011, vol. 54, # 20, p. 7066 - 7083
[8] Patent: WO2018/191587, 2018, A1, . Location in patent: Paragraph 0173; 0174
[9] Patent: WO2011/25965, 2011, A1, . Location in patent: Page/Page column 43-44
[10] Journal of Medicinal Chemistry, 2012, vol. 55, # 6, p. 2869 - 2881
[11] Patent: WO2015/57938, 2015, A1, . Location in patent: Page/Page column 36
[12] Patent: WO2016/164754, 2016, A1, . Location in patent: Page/Page column 34
[13] Patent: CN106045918, 2016, A, . Location in patent: Paragraph 0093; 0094; 0095; 0096
[14] Journal of Applied Chemistry, 1955, vol. 5, p. 358,362
[15] Patent: WO2006/420, 2006, A1, . Location in patent: Page/Page column 161; 229-230
[16] Patent: WO2006/420, 2006, A1, . Location in patent: Page/Page column 245-246
[17] Patent: WO2006/420, 2006, A1, . Location in patent: Page/Page column 248-249
[18] Patent: WO2008/42639, 2008, A1, . Location in patent: Page/Page column 78
[19] Patent: US2007/49592, 2007, A1, . Location in patent: Page/Page column 39
[20] Tetrahedron, 2012, vol. 68, # 10, p. 2294 - 2298
[21] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 1819 - 1825
[22] Patent: WO2017/60488, 2017, A1, . Location in patent: Page/Page column 62; 63
[23] Patent: WO2008/42639, 2008, A1, . Location in patent: Page/Page column 78
27
[ 1193-21-1 ]
[ 1194-21-4 ]
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.
Reference：
[1] Patent: US4939252, 1990, A,
28
[ 1193-21-1 ]
[ 5767-35-1 ]
Yield
Reaction Conditions
Operation in experiment
95%
With hydrazine hydrate In ethanol at 20℃; for 1.5 h;
A solution of 22 4,6-Dichloropyrimidine (15g, 100mmol) in 23 ethanol was cooled to 0–5°C in 250mL three-necked flask. To the above flask 24 Hydrazine hydrate (4.7mL, 120mmol) was added dropwise under cooling atmosphere. After that, the reaction mixture was stirred for 90min at room temperature. Reaction progress was checked on TLC and poured into water to get crude product. Pure 4-chloro-6-hydrazinylpyrimidine (A) as Pale yellow solids [47] obtained by recrystallization in ethanol. Yield 95percent; Yellowish white solid; Rf=0.5 (hexane:ethyl acetate, 4:1); m.p. 164°C, 1H NMR (DMSO‑d6, 400MHz) δ=8.83 (s, 1H), 8.17 (s, 1H),6.76 (s, 1H), 4.50 (s, 2H); EI-MS, (m/z): 145.02 (M+1).
94%
With hydrazine In isopropyl alcohol at 20℃; for 3 h;
A mixture of 4,6-dichloro-pyrimidine (18.68 g, 125 mmol), hydrazine monohydrate (18.28 mL, 376 mmol), and 2-propanol (300 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated, triturated with water, and filtered. The solid was washed with water, air-dried to give (6-chloro-pyrimidin-4-yl)- hydrazine (16.97 g, Yield 94percent): 1H NMR 400 MHz (d6-DMSO) δ 8.83 (5, IH), 8.17 (5, IH), 6.76 (5, IH), 4.50 (5, 2H); MS m/z 145.02 (M + 1).
94%
With hydrazine In isopropyl alcohol at 20℃; for 3 h;
A mixture of 4,6-dichloro-pyrimidine (18.68 g, 125 mmol), hydrazine monohydrate (18.28 mL, 376 mmol), and 2-propanol (300 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated, triturated with water, and filtered. The solid was washed with water, air-dried to give (6-chloro-pyrimidin-4-yl)- hydrazine (16.97 g, Yield 94percent): 1H NMR 400 MHz (d6-DMSO) δ 8.83 (5, IH), 8.17 (5, IH), 6.76 (5, IH), 4.50 (5, 2H); MS m/z 145.02 (M + 1).
87%
With hydrazine hydrate In ethanol at 20℃; for 12 h;
11.8 ml (12.1 g, 241.6 mmol) hydrazine hydrate are added dropwise to a solution of 20.0 g (134.3 mmol) 4,6-dichloropyrimidine in ethanol at RT, while stirring. If clouding of the solution occurs during metering in of the hydrazine hydrate, further ethanol (approx. 400 ml) is added. The reaction solution is subsequently stirred at RT for 12 h. For working up, the solid which has precipitated out is filtered off, the residue on the filter is washed twice with 150 ml water each time and twice with 100 ml diethyl ether each time and the product is dried in vacuo. A further crystalline product fraction is obtained from the concentrated mother liquor.Yield: 16.8 g (87percent of th.)LC-MS (Method 1): Rt=1.17 min; MS (ESIpos): m/z=145 [M+H]+;1H-NMR (400 MHz, DMSO-d6): δ=8.81 (s, 1H), 8.17 (br. s, 1H), 6.75 (s, 1H), 4.48 (br. s, 2H).
87%
With hydrazine hydrate In ethanol at 20℃;
With stirring and at RT, 11.8 ml (12.1 g, 241.6 mmol) of hydrazine hydrate are added dropwise to a solution of 20.0 g (134.3 mmol) of 4,6-dichloropyrimidine in 300 ml of ethanol. If the solution becomes turbid during the addition of the hydrazine hydrate, more solvent (about 400 ml of ethanol) is added. The reaction solution is stirred at RT for a further 12 h. For work-up, the precipitated solid is filtered off, the filter residue is washed twice with in each case 150 ml of water and twice with in each case 100 ml of diethyl ether and the product is dried under reduced pressure. A further crystalline fraction is obtained from the concentrated mother liquor.Yield: 16.8 g (87percent of theory)LC-MS (Method 1): Rt=1.17 min; MS (ESIpos): m/z=145 [M+H]+;1H-NMR (400 MHz, DMSO-d6): δ=8.81 (s, 1H), 8.17 (br. s, 1H), 6.75 (s, 1H), 4.48 (br. s, 2H).
Reference：
[1] Journal of Molecular Structure, 2019, vol. 1175, p. 551 - 565
[2] Chemical Biology and Drug Design, 2018, vol. 92, # 3, p. 1683 - 1691
[3] Patent: WO2008/42639, 2008, A1, . Location in patent: Page/Page column 81
[4] Patent: WO2008/42639, 2008, A1, . Location in patent: Page/Page column 81
[5] Synlett, 2010, # 14, p. 2179 - 2183
[6] Patent: US2010/305085, 2010, A1, . Location in patent: Page/Page column 16
[7] Patent: US2012/264704, 2012, A1, . Location in patent: Page/Page column 15
[8] ChemMedChem, 2018, vol. 13, # 10, p. 988 - 1003
[9] Transition Metal Chemistry, 2016, vol. 41, # 6, p. 685 - 692
[10] Journal of the Chemical Society, 1955, p. 3478,3481
[11] Patent: US2009/269420, 2009, A1,
[12] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 2629 - 2634
[13] Synthesis (Germany), 2014, vol. 46, # 20, p. 2734 - 2746
[14] Research on Chemical Intermediates, 2017, vol. 43, # 11, p. 6601 - 6616
29
[ 1193-21-1 ]
[ 108-86-1 ]
[ 3740-92-9 ]
Yield
Reaction Conditions
Operation in experiment
35%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2 h; Stage #2: at -78℃; for 0.5 h;
4,6-dichloro-2-phenylpyrimidineN-Butyl lithium (3.22 g, 50.3 mmol, and 1.6N in hexane) was added dropwise to a stirred solution of bromobenzene (7.9 g, 50.3 mmol) in THF (70 mL) over a period of 30 min at -78 °C, and reaction was continued stirring for 2 h. The generated phenyl lithium was added dropwise to a stirred solution of 4, 6-dichloropyrimidine (5 g, 33.5 mmol) in THF (50 mL) over a period of 45 min at -78 0C, and reaction was continued stirring for 30 min. Then, the reaction mixture was slowly heated to 0 °C and quenched with water (100 ml), DDQ (7 g, 30. 8 mmol) dissolved in THF (70 mL) was added portionwise and stirred for 10 min. Then, the reaction mixture was washed with 10percent NaOH (50 mL), extracted with CH2Cl2 (3x100 mL), washed with brine (100 mL), dried (Na2SO4) and concentrated. The concentrated product was purified through silica column chromatography using pet. ether to afford 4,6-dichloro-2- phenylpyrmimidine (example 21, 2.6 g, 35 percent) as a white solid. Rf: 0.3 (100percent PE). 1H NMR (400 MHz, CD3OD): δ 8.41-8.39 (m, 2H), 7.60 (s, IH), 7.58-7.50 (m, 3H). m/e (M+l): 224.8.
Reference：
[1] Tetrahedron, 2007, vol. 63, # 25, p. 5394 - 5405
[2] Patent: WO2005/95357, 2005, A2, . Location in patent: Page/Page column 106
[3] Angewandte Chemie - International Edition, 2013, vol. 52, # 26, p. 6776 - 6780[4] Angew. Chem., 2013, p. 6909 - 6913
31
[ 1193-21-1 ]
[ 2802-62-2 ]
Yield
Reaction Conditions
Operation in experiment
66%
With potassium fluoride; tetrabutylammomium bromide In sulfolane
a) Preparation of 4,6-Difluoropyrimidine STR13 A mixture of 4,6-dichloropyrimidine (223.5 g, 1.5 mol), potassium fluoride (279.6 g, 4.8 mol) and tetrabutylammonium bromide (6.0 g, 0.0186 mol) in sulfolane (1 L) is heated at 180-190° C. for 3.5 hours and distilled to give the title product as a white liquid (115 g, 66percent yield).
66%
With potassium fluoride; tetrabutylammomium bromide In sulfolane
a) Preparation of 4,6-Difluoropyrimidine STR21 A mixture of 4,6-dichloropyrimidine (223.5 g, 1.5 mol), potassium fluoride (279.6 g, 4.8 mol) and tetrabutylammonium bromide (6.0 g, 0.0186 mol) in sulfolane (1 L) is heated at 180-190° C. for 3.5 hours and distilled to give the title product as a white liquid (115 g, 66percent yield).
66%
With potassium fluoride; tetrabutylammomium bromide In sulfolane
a) Preparation of 4,6-Difluoropyrimidine A mixture of 4,6-dichloropyrimidine (223.5 g, 1.5 mol), potassium fluoride (279.6 g, 4.8 mol) and tetrabutylammonium bromide (6.0 g, 0.0186 mol) in sulfolane (1 L) is heated at 180-190 °C for 3.5 hours and distilled to give the title product as a white liquid (115 g, 66percent yield).
66%
With potassium fluoride; tetrabutylammomium bromide In sulfolane
a) Preparation of 4,6-Difluoropyrimidine A mixture of 4,6-dichloropyrimidine (223.5 g, 1.5 mol), potassium fluoride (279.6 g, 4.8 mol) and tetrabutylammonium bromide (6.0 g, 0.0186 mol) in sulfolane (1 L) is heated at 180-190 °C for 3.5 hours and distilled to give the title product as a white liquid (115 g, 66percent yield).
Stage #1: at 0℃; for 1 h; Stage #2: at 120℃; for 3 h;
A mixture of phosphorus oxychloride (20ML, 0. 22 mol) and N,-DIMETHYLFORMAMIDE (6.4 mL) was stirred at 0°C for 1 hour. 4,6-Dichloropyrimidine (5.00 g, 44.6 mmol) was added to the reaction mixture, which was then stirred for 3 hours at 120°C. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with ice-water and extracted with ether. The separated organic phase was washed with saturated sodium hydrogen carbonate solution and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residual solid was triturated with hexane to give 4,6-dichloro- pyrimidine-5-carbaldehyde (4.73 g, 60percent).
Example 12;: Synthesis of 6-methyl-3-(6-(methylsuIfmyl)pyrimidin-4- vI)pyrazolori,5-a]pyrimidin-2-amine EPO <DP n="238"/>[0299] Synthesis of 4-chloro-6-(methylthio)pyrimidine[0300] 4,6 Dichloropyrimidine (15.4 g, 0.10 mol) was dissolved in THF (120 mL) at room temperature and NaSMe (8.5g, 0.12 mol) was added as a solid. The reaction mixture was heated to 60 °C for 16 hours then let cool to room temperature and then diluted with ethyl acetate (300 mL) and water (300 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated to an orange oil which was recrystalized from hexanes to give a pale yellow solid, 9.85 g, 0.061 mol, 61percent. H NMR(500 MHz, CDC13) 8.74 (s, 1H), 7.23 (s, 1H), 2.58 (s, 3H).
9%
at 60℃;
Example 20; l-{4-[6-(2-Hydroxy-ethylamino)-pyrimidin-4-yloxy]-phenyl}-3-(3- trifluoromethyl-phenyl)-ureai) 4-Chloro-6-methylsulfanyl-pyrimidine To a solution of 4,6-dichloro-pyrimidine (10.0 g, 67 mmol) in THF (55 ml), sodium thiomethylate (5.175 g, 74 mmol) is added under inert gas atmosphere. The reaction mixture is stirred at 60 0C overnight. After cooling down to r.t., the reaction mixture is diluted with ethyl acetate and water (100 ml each). The organic phase is removed and the aqueous phase is extracted with ethyl actetate. The combined organic phases are washed and dried, and the solvent is evaporated to give 9.74 g (90 percent) of a pale yellow solid (contains ca. 9 percent of starting material and ca. 9 percent of 4,6-dimethylsulfanyl-pyrimidine) which is used without any further purification. MS: 160.76 (AP+). 1H-NMR^OOHz, [D6]DMSO): δ = 2.57 (s, 3H, SCH3), 7.68 (s, IH, 5-H- pyrimidine), 8.79 (s, IH, 2-H-pyrimidine).
Reference：
[1] Patent: WO2006/52913, 2006, A1, . Location in patent: Page/Page column 236-237
[2] Patent: WO2008/77548, 2008, A1, . Location in patent: Page/Page column 46
[3] Patent: WO2009/85913, 2009, A1, . Location in patent: Page/Page column 64-65
[4] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 23, p. 6529 - 6533
[5] Patent: WO2011/45353, 2011, A1, . Location in patent: Page/Page column 42-43
[6] Journal of Organic Chemistry, 2017, vol. 82, # 5, p. 2664 - 2671
Stage #1: With 2,2,6,6-tetramethylpiperidine zinc chloride lithium chloride complex In tetrahydrofuran at 25℃; for 0.75 h; Stage #2: With copper(I) cyanide di(lithium chloride) In tetrahydrofuran at -20℃; Stage #3: at -60 - 0℃; for 4 h;
Synthesis of 5-allyl-4,6-dichloropyrimidlne (8c): 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. CuCN.2LiCl (1 M in THE; 0.05 mL, 5 mol percent) was then slowly added at -20° C. Allyl bromide (242 mg, 2.0 mmol) was then slowly added at -60° C. The resulting mixture was then allowed to warm up slowly to 0° C. for 4 h. The reaction mixture was quenched with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (5.x.30 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane 1:2) furnished 8c as a colourless solid (215 mg, 89percent). 1H NMR (300 MHz, CDCl3) δ: 8.64 (s, 1 H), 5.80-5.90 (m, 1 H), 5.09-5.18 (m, 2 H), 3.64 (dt, 3J=6.4 Hz, 4J=1.4 Hz, 2 H).13C NMR (75 MHz, CDCl3) δ: 162.0, 155.8, 130.9, 130.6, 118.2, 34.0.MS (70 eV, El) m/z (percent): 188 (70) [M+], 125 (22), 117 (44), 90 (59), 64 (35), 49 (43), 41 (100).IR (ATR) {tilde over (v)} (cm-1): 2969, 2360, 1739, 1639, 1539, 1513, 1435, 1406, 1375, 1348, 1313, 1290, 1200, 1162, 1129, 1090, 989, 929, 906, 839, 777, 687, 668, 627, 621, 616.HRMS (El) for C7H6Cl2N2 (187.9908): 187.9913.
75%
Stage #1: With 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex In tetrahydrofuran at -78℃; for 1 h; Stage #2: With copper(I) bromide In tetrahydrofuran for 0.5 h;
The alkylation step by conducted using a modified procedure: TMPMgCl·LiCl (0.8M, 11.0 mL, 8.8 mmol) was added to a solution of 2,4,6-trichloropyrimidine (1.47 g, 8.0 mmol) in anhydrous THF (20 mL) at -78 oC. After stirring for 1 hour, CuBr (230 mg, 1.6 mmol) was added and stirring was continued for 30 min before allyl bromide (0.73 mL, 8.4 mmol) was added. The reaction was allowed to warm to room temperature, then quenched by addition of sat. NH4Cl solution. EtOAc was added and the layers were separated. The organic phase was dried and Na2SO4 and concentrated. The residue was purified by silica gel chromatography [heptane/EtOAc, 95:5 – 3:1] to give the alkylated product as a white solid (1.31 g, 73 percent). This was transformed to the final product by the same procedure as for 2 using allylamine followed by standard N-Boc protection to give the productas a colourless oil (1.51 g, 75percent).
Reference：
[1] European Journal of Medicinal Chemistry, 2005, vol. 40, # 9, p. 862 - 874
[2] Pharmaceutical Chemistry Journal, 1989, vol. 23, # 6, p. 500 - 503[3] Khimiko-Farmatsevticheskii Zhurnal, 1989, vol. 23, # 6, p. 705 - 707
40
[ 1193-21-1 ]
[ 67-63-0 ]
[ 83774-13-4 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2005, vol. 40, # 9, p. 862 - 874
[2] Patent: WO2003/76415, 2003, A1, . Location in patent: Page/Page column 54
41
[ 1193-21-1 ]
[ 83774-13-4 ]
Reference：
[1] Patent: US4435401, 1984, A,
42
[ 1193-21-1 ]
[ 128796-39-4 ]
[ 659729-09-6 ]
Yield
Reaction Conditions
Operation in experiment
49%
With palladium diacetate; sodium carbonate; triphenylphosphine In tetrahydrofuran; water at 60℃; for 16 h; Inert atmosphere
General procedure: All solvents and solutions used for this reaction were sparged with argonfor 15 minutes. In a round-bottomed flask was dissolved 4,6-dichloropyrimidine (1.5 equiv.) inTHF (1 M), under argon atmosphere. The arylboronic acid (1.0 equiv.), palladium acetate (0.02equiv., 2 molpercent), triphenylphosphine (0.04 equiv., 4 molpercent) and 1 M aqueous Na2CO3 solution(2.0 equiv.) were added and the mixture was stirred at 60 °C, overnight. After cooling to roomtemperature, the aqueous layer was extracted with Et2O and the organic layers were combined,washed with brine, dried over MgSO4, filtered and evaporated under vacuum. The crude materialwas purified by flash column chromatography to obtain the desired product.
47.2%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran; water at 120℃; for 8 h; Inert atmosphere; Sealed tube
2 g (0.011 mol) of 4-trifluoromethylbenzeneboronic acid was weighed out,4,6-dichloropyrimidine (1.60 g, 0.011 mol)Tetrakis (triphenyl palladium 0.15g with 2.5 g of anhydrous sodium carbonate was placed in a 120 mL sealed tube,A mixture of tetrahydrofen sitan 30 mL and 20 mL of deionized water was placed in a sealed tube as a solvent, and a stirrer was added and the stopper was capped.The whole device was purged with nitrogen for 3 to 4 times, placed in an oil bath and heated to 120 ° C for about 8 hours with stirring on a magnetic stirrer.After completion of the reaction, the sealing tube was cooled to room temperature, and the solution in the sealed tube was placed in a rotary vial, and the tetrahydrofuran solvent was distilled off under reduced pressure by rotary evaporator. And then extracted with ethyl acetate and water organic products 3 ~ 4 times, vacuum distillation solvent to petroleum ether: ethyl acetate 10: 1 will be steamed after the productionThe samples were separated by column chromatography and separated by separate column chromatography using dichloromethane to give about 1.28 g of a white solid in 47.2percent yield.
2.7 g
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,2-dimethoxyethane; ethanol; water at 130℃; for 7 h;
Example 21 2-[(4-Fluoro-benzenesulfonyl)-methyl-amino]-N-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4- ylmethyl] - acetamide A solution of 4-(trifluoromethyl)phenylboronic acid (5.0 g, 25.8 mmol), 4,6-dichloropyrimidine (3.92 g, 25.8 mmol), bis(triphenylphosphine)palladium(II) dichloride (362 mg, 516 μιηο) and sodium carbonate (8.2 g, 77.4 mmol, Eq: 3) in a three solvent mixture of 50 mL DME, 7.5 mL ethanol and 7.5 mL water was heated at 130°C for 7 h. Upon cooling to rt, the reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with three times with ethyl acetate. The combined organic layers were washed with water and brine and dried over Na2S04. Filtration followed by removal of volatiles under reduced pressure gave a dark red solid. The mixture was purified by flash chromatography (5percent diethyl ether in hexane) to give 4-chloro-6-(4-trifluoromethyl- phenyl)-pyrimidine(2.76g) as a white solid.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 299 - 302
[2] Patent: CN106632488, 2017, A, . Location in patent: Paragraph 0167-0169
[3] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3497 - 3514
[4] Patent: US2006/241296, 2006, A1, . Location in patent: Page/Page column 27
[5] Patent: WO2010/134478, 2010, A1, . Location in patent: Page/Page column 165
[6] Patent: WO2014/49047, 2014, A1, . Location in patent: Page/Page column 63
[7] Patent: WO2015/28989, 2015, A1, . Location in patent: Page/Page column 86
With triethylamine In acetonitrile at 120℃; for 2 h; microwave irradiation
Step 1: tert-butyl 4-(6-chloropyrimidin-4-yl)piperazine- 1-carboxylate:A solution of 4,6-dichloropyrimidine (0.5 g, 3.36 mmol), tert-butyl piperazine-1 - carboxylate (0.69 g, 3.69 mmol) and triethylamine (0.34 g, 3.36 mmol) in acetonitrile (10ml) was heated in a microwave vial at 120 °C for 2 h. The solution was then diluted with ethyl acetate, washed with a saturated solution of ammonium chloride, dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound (0.82 g, 91 percent).1H NMR (500 MHz, CDCI3): 8.39 (s, 1 H), 6.50 (s, 1 H), 3.65 (m, 4H), 3.52 (m, 4H), 1 .48 (s, 9H).
83%
With triethylamine In methanol at 50℃; for 4 h;
4,6-dichloropyrimidine (A1) (12.75 mmol, 1.9 g)And 1-tert-butoxycarbonylpiperazine(16.13 mmol, 3.0 g) was dissolved in 20 ml of methanol, 2.3 ml of triethylamine (16.13 mmol) was added, and the mixture was heated to 50 ° C and refluxed for 4 hours. The solvent was distilled off under reduced pressure, 20 ml of water was added and the mixture was stirred. The cake was rinsed with water and dried in vacuo to give a white solid. Yield 83percent.
72%
With sodium t-butanolate In toluene at 100℃; for 6 h;
(1) Tert-butyl 4-(6-chloropyrimidin-4-yl)piperazine-1-carboxylate A mixture of 4,6-dichloropyrimidine (2.08 g, 14.0 mmol), tert-butyl piperazine-1-carboxylate (2.0 g, 10.7 mmol), trisdibenzylideneacetone dipalladium (197 mg, 0.215 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (373 mg, 0.644 mmol), sodium tert-butoxide (1.55 g, 16.1 mmol) and toluene (100 ml) was stirred at 100° C. for 6 hours. 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 (2.31 g, 72percent) as a solid. 1H NMR (CDCl3) δ: 1.49 (9H, s), 3.50-3.57 (4H, m), 3.61-3.70 (4H, m), 6.50 (1H, s), 8.39 (1H, s).
64%
With triethylamine In 1,4-dioxane at 75℃; for 4 h;
A stirring solution of 4,6-dichloro-pyrimidine (2.2 g, 15 mmol) in dioxane (50 rnL) was treated with TEA (6.2 niL, 45 mmol) and piperazine-1-carboxylic acid tert-butyl ester (3.5 g, 18.8 mmol). This was then heated to 75 0C and stirred for 4 h. Solvents then cooled to room temperature and evaporated. Crude product purified by column chromatography (silica gel) to afford title intermediate as white powder (2.9 g, 64percent).
50%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 14 h;
(1) Tert-butyl 4-(6-chloropyrimidin-4-yl)piperazine-1-carboxylate To a solution of 4,6-dichloropyrimidine (15.0 g, 0.100 mol) in N,N-dimethylformamide (150 ml) was added tert-butyl piperazine-1-carboxylate (22.0 g, 0.12 mol) and triethylamine (12.0 g, 0.12 mol), and the mixture was stirred at room temperature for 14 hours. The reaction was poured into water and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from diethylether to obtain the title compound (15.0 g, 50percent) as a solid. 1H NMR (CDCl3) δ: 1.45 (9H, s), 3.41-3.53 (4H, m), 3.55-3.65 (4H, m), 6.47 (1H, s), 8.35 (1H, s).
With tris-(dibenzylideneacetone)dipalladium(0); [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane; sodium t-butanolate In toluene at 100℃; Inert atmosphere
General procedure: A mixture of 4-bromo-2-chloropyridine (3.87 mL, 34.9 mmol), N-Boc-piperazine (5.00 g, 26.9 mmol), sodium tert-butoxide (3.87g, 40.3mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene(932.2 mg, 1.61 mmol), tris(dibenzylideneacetone)dipalladium (0) (492mg, 0.537mmol), and toluene (270mL) was stirred at 100°C overnight under N2 atmosphere. The mixture was diluted with 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 29 (5.62g, 70percent) as a colorless powder.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 4, p. 1468 - 1478
46
[ 1193-21-1 ]
[ 57260-71-6 ]
[ 479691-42-4 ]
Yield
Reaction Conditions
Operation in experiment
95%
With triethylamine In isopropyl alcohol for 2 h; 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 95percent) as a white solid.
Stage #1: With 2,2,6,6-tetramethylpiperidine zinc chloride lithium chloride complex In tetrahydrofuran at 25℃; for 0.75 h; Stage #2: With iodine In tetrahydrofuran for 0.5 h;
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.x.50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:4) furnished compound 8a (227 mg, 83percent) as a colourless solid.m.p.: 134.9-136.5 ° C.1H NMR (300 MHz, CDCl3) δ: 8.65 (s, 1 H).13C NMR (75 MHz, CDCl3) δ: 166.6, 156.8, 98.9.MS (70 eV, El) m/z (percent): 274 (100) [M+], 239 (27), 97 (12), 83 (12), 57 (21).IR (ATR) {tilde over (v)} (cm-1): 2923, 2855, 1900, 1499, 1386, 11341, 1296, 1214, 1080, 1014, 790, 763, 745.HRMS (El) for C4HCl2IN2 (273.8561): 273.8565.
Reference：
[1] Chemistry - A European Journal, 2009, vol. 15, # 6, p. 1468 - 1477
[2] Organic Letters, 2009, vol. 11, # 8, p. 1837 - 1840
[3] Patent: US2011/288296, 2011, A1, . Location in patent: Page/Page column 10
48
[ 1193-21-1 ]
[ 95-76-1 ]
[ 6303-46-4 ]
Reference：
[1] Journal of the American Chemical Society, 2010, vol. 132, # 20, p. 7043 - 7048
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 3, p. 1159 - 1183
[3] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 24, p. 6876 - 6884
6.01.01.1 4-chloro-6-methoxy-pyrimidine 5.8 g sodium methanolate was added to 10 g 4, 6-dichloropyrimidine in 150 mL MeOH at 0°C. The reaction was warmed up to RT and stirred over night at RT. Then 3.63 g sodiummethanolate was added and the reaction was stirred for 3 h. The mixture was treated with water and extracted with EtOAc. The organic layer was dried over magesiumsulfate and evaporated to give 9.7 g 4-chloro-6-methoxy-pyrimidine.Rt: 0.87 min (method B)
8.34 g
With methanol; at 0 - 20℃;
4-chloro-6-methoxy-pyrimidine 8 g sodium methanolate was added to 10 g 4, 6-dichlorpyrimidine in 100 mL methanol at 0°C. The reaction was stirred at RT over night. The mixture was added into water and extracted with ethylacetate. The organic layer was dried with magnesium sulfate and evaporated to give 8.34 g desired product. Rt: 0.97 min (method B), (M+H)+: 145
4.6 g
In methanol; at 20℃; for 8h;Cooling with ice;
To a mixture of 6 g of 4,6-dichloropyrimidine and 40 mL of methanol, 8.16 g of 28percent sodium methoxide methanol solution was added dropwise under ice cooling. After stirring for 2 hours under ice cooling, the temperature was raised to room temperature and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of ammonium chloride was added to the obtained oily substance, followed by extraction with ethyl acetate. After washing the organic layer with saturated brine, the organic layer was dried with sodium sulfate. The organic layer was concentrated under reduced pressure, and the obtained oily substance was subjected to silica gel chromatography to obtain 4.6 g of an intermediate (6-1)
(1) To a solution of 4,6-dichloropyrimidine (1.33 g) and 4-tertbutylbenzenesulfonamide (1.96 g) in dimethylformamide (20 ml) is added sodium hydride (60percent dispersion-type, 714 mg). The mixture is stirred at room temperature for two hours, and the reaction solution is diluted with 10percent hydrochloric acid and water. The mixture is extracted with ethyl acetate, and the ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is recrystallized from ethyl acetate to give 4-tert-butyl-N-(6-chloropyrimidin-4-yl)benzenesulfonamide (2.02 g). M.p. 225°-226.5° C. IR (nujol, cm-1): 3035, 1630, 1595, 1575 MS (m/z): 325 (M+)
6.01.04.01 4-Chloro-6-methoxy-pyrimidine 3.1 g sodiummethanolate was added to 7.2 g 4,6-dichlorpyrimidine in 150 mL methanol at 0° C. The reaction was warmed to RT and stirred additional 3 h. Water and EtOAC were added and the layers were seperated. The organic layer was dried and evaporated to give 7.1 g of the desired product. Rt: 0.85 min (method L), (M+H)+: 144
9.7 g
With sodium methylate; at 20℃;
6.01.01.1 4-chloro-6-methoxy-pyrimidine 5.8 g sodium methanolate was added to 10 g 4,6-dichloropyrimidine in 150 mL MeOH at 0° C. The reaction was warmed up to RT and stirred over night at RT. Then 3.63 g sodium methanolate was added and the reaction was stirred for 3 h. The mixture was treated with water and extracted with EtOAc. The organic layer was dried over magesiumsulfate and evaporated to give 9.7 g 4-chloro-6-methoxy-pyrimidine. Rt: 0.87 min (method B)
8.34 g
With sodium methylate; at 0 - 20℃;
8 g sodium methanolate was added to 10 g 4,6-dichlorpyrimidine in 100 mL methanol at 0° C. The reaction was stirred at RT over night. The mixture was added into water and extracted with ethylacetate. The organic layer was dried with magnesium sulfate and evaporated to give 8.34 g desired product. Rt: 0.97 min (method B), (M+H)+: 145
10.2 g
With sodium hydride; In tetrahydrofuran; mineral oil; at 0℃; for 1h;Inert atmosphere;
A) 4-chloro-6-methoxypyrimidine Under a nitrogen atmosphere, methanol (5.4 mL) was added to a suspension of 60percent sodium hydride (8.05 g) in THF (200 mL) at 0°C. To the obtained suspension was added a solution of 4,6-dichloropyrimidine (20.0 g) in THF (45 mL) at 0°C, and the mixture was stirred at 0°C for 1 hr. 1N Hydrochloric acid was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized (hexane) to give the title compound (10.2 g) as pale-yellow crystals. 1H NMR (300 MHz, DMSO-d6) delta 3.96 (3H, s), 7.19 (1H, s), 8.69 (1H, s).
With sodium hydride; at -10 - 20℃; for 48h;
To a cooled solution (?10 °C) of 4,6-dichloropyrimidine (1193-21-1, 5 g, 33.56 mmol) in dry methanol, one equivalent of sodium hydride(titrated solution in dry methanol)was added, the solutionwas allowedto warm to room temperature and react for 48 h (depicted in step aof Scheme 1). The solvent was removed; the crude product wasdissolved in brine, extracted with CHCl3, and was used withoutfurther purification. 1H NMR (500 MHz, DMSO-d6): delta = 8.68(d, 5J(H,H) = 0.8 Hz, 1H, H-2), 7.18 (d, 5J(H,H) = 0.9 Hz, 1H, H-5),3.96 (s, 3H, OCH3).
With potassium carbonate; In dimethyl sulfoxide; at 20 - 95℃; for 20.5h;
To a 100-mL, round-bottomed flask containing 4,6-dichloro-pyrimidine (9.0 g, 60 mmol, Aldrich) and <strong>[7471-03-6]2-amino-benzothiazol-4-ol</strong> (5.0 g, 30 mmol, CarboGen) was added potassium carbonate (4.1 g, 30 mmol, Aldrich) and dimethylsulfoxide (10 mL). The reaction mixture was heated at 95° C. with stirring for 4.5 h, and at room temperature for 16 h. The resulting solid was collected by filtration, washed with water (500 mL) and dichloromethane (500 mL), and dried in vacuo to obtain the title compound as a yellow solid.; 2-Aminobenzo[d]thiazol-4-ol (166 mg, 1 mmol, Carbogen) was reacted with 4,6-dichloropyrimidine, (150 mg, 1 mmol, Aldrich) under the conditions of Example 34(a) to give the title compound as a white solid. MS (ESI, pos. ion.) m/z: 279 (M+1).
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 100℃; for 24h;
(c) (6-Chloropyrimidin-4-yl)-quinolin-7-yl-amine. A mixture of 4,6-dichloro-pyrimidine (1.04 g, 7.0 mmol, Lancaster), <strong>[580-19-8]7-aminoquinoline</strong> (1.00 g, 7.0 mmol, SynChem Inc.) and potassium carbonate (1.93 g, 14.0 mmol) in DMF (5.0 mL) was heated at 100° C. with stirring for 24 h. The reaction mixture was allowed to cool to room temperature, diluted with water, and the resulting solid precipitate was filtered. The filter cake was dissolved in a mixture of CH2Cl2 and MeOH (3:1), washed with water and brine, dried over Na2SO4, and filtered. The filtrate was evaporated under reduced pressure, and the brown-yellow solid residue was suspended in CH2Cl2, filtered, and washed with CH2Cl2. The filter cake was dried in vacuo to give the title compound as a light-yellow solid. MS (ESI, pos. ion.) m/z: 257 (M+1).
With N-ethyl-N,N-diisopropylamine; In ethanol; at 110℃; for 0.1h;microwave synthesizer;
(c) 7-(6-Chloropyrimidin-4-ylamino)-3,4-dihydroquinolin-2(1H)-one. A mixture of <strong>[22246-07-7]7-amino-3,4-dihydroquinolin-2(1H)-one</strong> from step (b) above (0.4 g, 2.47 mmol), 4,6-dichloropyrimidine (0.33 g, 2.22 mmol, Aldrich) and diisopropylethylamine (0.7 mL, 4.02 mmol) in EtOH (2.8 mL) was heated in a microwave synthesizer at 110 C. for 6 min. The reaction mixture was cooled to room temperature and diluted with MeOH (3 mL). The solid precipitate was filtered and dried under vacuo to give the title compound as pale-yellow amorphous solid. MS (ESI, pos. ion.) m/z: 275 (M+1).
EXAMPLES 7-12 General Procedure for Conversion of <strong>[26452-81-3]4-chloro-6-methoxypyrimidine</strong> (CMP) 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 CMP, solvent, and catalyst. The agitator is started and the mixture is heated to 100°-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 mixture is condensed by the dry ice condenser and returned to the reaction mixture. This reflux of phosgene begins shortly after the phosgene addition is begun, and continues throughout the course of the reaction.
Example 1 90 parts by weight of phosphorus oxychloride and 10 parts by weight of <strong>[26452-81-3]4-chloro-6-methoxypyrimidine</strong> were introduced into a stirred vessel. The mixture was heated with stirring to 100° C. and, at this temperature, 6 parts by weight of water were metered in at a constant rate over the course of 4 hours. The mixture was then stirred at 100° C. for 1 hour. After cooling to room temperature, 99.6 parts by weight of a reaction mixture whose HPLC analysis showed contents of 0.2percent <strong>[26452-81-3]4-chloro-6-methoxypyrimidine</strong> and 9.3 parts by weight of 4,6-dichloropyrimidine were obtained.
8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(6-chloro-pyrimidin-4-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24%
With potassium carbonate;copper(l) chloride; In 5,5-dimethyl-1,3-cyclohexadiene; water;
EXAMPLE 61 8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(6-chloro-pyrimidin-4-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one A mixture of 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.1 g, 0.21 mmol), potassium carbonate (59 mg, 0.42 mmol), CuCl (2 mg, 0.021 mmol), tris[2-(2-methoxyethoxy)-ethyl]-amine (1.5 muL) and 4,6-dichloropyrimidine (32 mg, 0.21 mmol) in xylene (5 mL) was stirred and boiled for 18 h. The mixture was cooled, washed with water, ammonia in water (10percent) and water again. Evaporation of the solvent yielded a residue which was purified by chromatography on silica gel (ethyl acetate/n-hexane 1:2) to yield the desired product (29 mg, 24percent), m.p. 212-214° C. and MS: m/e=584.1 (M+H+).
With sodium methylate; In methanol; dichloromethane; water;
Preparation of 4-chloro-6-methoxypyrimidine 22.4 g (0.15 mol) of 4,6-dichloropyrimidine were introduced into 250 ml of methanol. 27 g of a 30percent strength sodium methylate solution were added dropwise at 0° C. After concentration, the mixture was worked up using a water/methylene chloride mixture. 15.0 g (69.2percent of theory) of yellow crystals were obtained; m.p. 32°-34° C.
trimethyl{6-[(α,α,α,4-tetrafluoro-m-tolyl)oxy]-4-pyrimidyl}ammonium chloride[ No CAS ]
[ 61721-07-1 ]
[ 6294-93-5 ]
4-[(4-chloro-α,α,α-trifluoro-m-tolyl)-oxy]-6-[(α,α,α,4-tetrafluoro-m-tolyl)-oxy]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide;
c) Preparation of 4-[(4-Chloro-alpha,alpha,alpha-trifluoro-m-tolyl)oxy]-6-[(alpha,alpha,alpha,4-tetrafluoro-m-tolyl)oxy]pyrimidine STR18 alpha,alpha,alpha-Trifluoro-4-chloro-m-cresol (1,118.9 g, 5.69 mol) is added to a mixture of trimethyl{6-[(alpha,alpha,alpha,4-tetrafluoro-m-tolyl)oxy]-4-pyrimidyl}ammonium chloride (1,962.0 g, 5.58 mol) and potassium carbonate (793.2 g, 5.74 mol) in N,N-dimethylformamide (8.5 L). The reaction mixture is stirred overnight at room temperature, cooled to 5° C. and slowly diluted with water (2.27 L). The resultant aqueous mixture is filtered to give a solid. The solid is washed sequentially with water, hexanes and water, dried overnight in a vacuum oven at 40°-45° C. and recrystallized from hexanes to obtain the title product as a yellow solid (1,731.5 g, 69percent yield). As can be seen from the data in Example 4, the art process provides the title product in 55percent overall yield starting from 4,6-dichloropyrimidine and alpha,alpha,alpha,4-tetrafluoro-m-cresol. Advantageously, the process of the present invention provides 4-[(4-chloro-alpha,alpha,alpha-trifluoro-m-tolyl)oxy]-6-[(alpha,alpha,alpha,4-tetrafluoro-m-tolyl)oxy]pyrimidine in significantly higher yield starting from 4,6-dichloropyrimidine and alpha,alpha,alpha,4-tetrafluoro-m-cresol than the art process (67percent vs. 55percent).
4-Chloro-6-[(4-chloro-α,α,α-trifluoro-m-tolyl)oxy]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide;
a) Preparation of 4-Chloro-6-[(4-chloro-alpha,alpha,alpha-trifluoro-m-tolyl)oxy]pyrimidine STR19 A mixture of 4,6-dichloropyrimidine (119.2 g, 0.8 mol) and potassium carbonate (110.6 g, 0.8 mol) in N,N-dimethylformamide (585 mL) is treated with alpha,alpha,alpha-trifluoro-4-chloro-m-cresol (157.3 g, 0.8 mol) over 20 minutes, stirred at 45° C. for 5 hours, stirred overnight at room temperature, and diluted with water (1200 mL). The resultant aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed sequentially with 5percent sodium hydroxide solution and water, and concentrated in vacuo to obtain the title product as an oil (249.4 g).
6,8-dichloro-9-isopropyl-9<i>H</i>-purine[ No CAS ]
[ 3934-20-1 ]
[ 141-30-0 ]
[ 1193-21-1 ]
[ 4858-85-9 ]
[ 5424-21-5 ]
[ 56-05-3 ]
[ 1780-31-0 ]
[ 2213-63-0 ]
[ 607-68-1 ]
[ 7253-22-7 ]
[ 2148-57-4 ]
[ 4752-10-7 ]
C17H20NO4Pol[ No CAS ]
[ 4774-14-5 ]
[ 7148-34-7 ]
[ 2148-55-2 ]
[ 203436-45-7 ]
C21H21ClN3O4Pol[ No CAS ]
C21H21ClN3O4Pol[ No CAS ]
C21H21ClN3O4Pol[ No CAS ]
C21H21ClN3O4Pol[ No CAS ]
C21H21ClN3O4Pol[ No CAS ]
C22H23ClN3O4Pol[ No CAS ]
C22H23ClN3O4Pol[ No CAS ]
C21H22ClN4O4Pol[ No CAS ]
C25H23ClN3O4Pol[ No CAS ]
C25H23ClN3O4Pol[ No CAS ]
C25H23ClN3O4Pol[ No CAS ]
C25H23ClN3O4Pol[ No CAS ]
C25H23ClN3O4Pol[ No CAS ]
C25H23ClN3O4Pol[ No CAS ]
C25H23ClN3O4Pol[ No CAS ]
C25H27ClN5O4Pol[ No CAS ]
C25H27ClN5O4Pol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 90℃; for 12h;Combinatorial reaction / High throughput screening (HTS);
To a solution of dichloro-heterocycle (S) (15.0 mmol) in n-butanol (200 mL) was added PAL-resin-bound amine 1 (10.0 mmol), followed by addition of diisopropylethylamine (5.2 mL, 30.0 mmol). The suspension was heated to 90[deg.] C. under argon. After 12 hours, the resin was washed by methanol (200 mL*4) and dichloromethane (200 mL*4) and dried under vacuum. The complete conversion of secondary amine (PAL-amine) to tertiary amine was confirmed by bromophenol blue test.
EXAMPLE 25 Preparation of 5-ethylpyridine-2-aldehyde-6'-methoxy-4'-pyrimidylhydrazone (PH 22-33) 3 g of 4,6-dichloropyrimidine were dissolved in 30 ml of dried methanol and mixed dropwise at -10° C. with a solution of 0.46 g of sodium in 20 ml of dried methanol and stirred at -10° C. for 5 hours and at room temperature for 12 hours. The solution was rotated in, the residue taken up with 50 ml of dichloromethane and a little activated carbon was added. After filtration, rotation in to dryness took place. The initially liquid residue became crystalline solid when left to stand. 2.5 g of 4-chloro-6-methoxypyrimidine were obtained.
6-chloro-N-(1H-indol-1-yl)-4-pyrimidinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In isopropyl alcohol;
EXAMPLE 7 6-Chloro-N-(1H-indol-1-yl)-4-pyrimidinamine To 250 ml isopropanol, was added 4,6-dichloropyrimidine (12 g), 1 ml ethereal -HCl, and <strong>[53406-38-5]1H-indol-1-amine</strong> (15 g). After stirring at 90 C. for seven hours, the mixture was poured into 300 ml iced water, stirred for five minutes, then extracted three times with 200 ml of ethyl acetate. The organic layer was washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solution was evaporated to an oil, approximately 25 g; which was eluted on a silica gel column with DCM via flash chromatography. The desired fractions were combined, then evaporated to a solid, 6.0 g (35%), 140 C. (dec.). A sample of this material, product 6-Chloro-N-(1H-indol-1-yl)-4-pyrimidinamine, was sublimed to a solid at about 135 C./1 mm Hg, m.p. 170-171 C. Analysis: Calculated for C12 H9 ClN4: 58.91% C; 3.71% H; 22.90% N. Found: 59.02% C; 3.63% H; 22.71% N.
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.
4-chloro-6-(1-methyl-2-imidazolylmethoxy)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; dichloromethane;
PREPARATION 5 4-Chloro-6-(1-methyl-2-imidazolylmethoxy)pyrimidine Sodium hydride (0.30 g as an 80% dispersion by weight in oil) was added to a solution of <strong>[17334-08-6]1-methyl-2-hydroxymethylimidazole</strong> (1.12 g) in tetrahydrofuran (30 ml) and the mixture stirred at room temperature for one hour. A solution of 4,6-dichloropyrimidine (1.48 g) in tetrahydrofuran (10 ml) was added to the reaction mixture dropwise over 30 minutes and the mixture stirred at room temperature for 3 hours and evaporated. The residue was taken up in dichloromethane and the solution extracted into 2M hydrochloric acid. The acidic layer was washed with dichloromethane, basified with saturated aqueous sodium hydrogen carbonate solution and extracted into dichloromethane. The organic layer was dried over Na2 SO4 and evaporated to give the title compound (1.2 g), m.p. 126-128 C. This compound was used directly in subsequent reactions.
4,6-bis(4-chloro-3-trifluoromethylphenoxy)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In dimethyl sulfoxide;
EXAMPLE 3 Preparation of 4,6-bis(4-chloro-3-trifluoromethylphenoxy)pyrimidine 4-Chloro-3-trifluoromethylphenol (10.0 g, 0.051 mol) and 4,6-dichloropyrimidine (3.7 g, 0.025 mol) were heated to 60° C. in dimethylsulphoxide (75 ml) with potassium carbonate (10 g) under nitrogen for 12 hours. The mixture was then poured into water and the product extracted into diethyl ether. The organic layer was dried using Na2 SO4, filtered and concentrated. The product, 4,6-bis(4-chloro-3-tri-fluoromethylphenoxy)pyrimidine, was obtained by column chromatography (eluding with 5:1, hexane:ethyl acetate) and recrystallization (diethyl ether/hexane). Yield 11.0 g (94percent); melting point 111° C.
6-chloro-N4-(1-methylcyclopropyl)pyrimidine-2.4-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
With sodium methylate; In 1-methyl-pyrrolidin-2-one; at 90℃; for 16h;
Preparation 44:6-Chloro-N4-(1-methylcyclopropyl)pyrimidine-2.4-diamine; 2-amino-4,6-dichloropyrimidine (508 mg, 3.1 mmol) was added to a suspension of <strong>[88887-87-0]1-methylcyclopropylamine hydrochloride</strong> (1.0 g, 9.3 mmol) and sodium methoxide (502mg, 9.30 mmol) in NMP (3 ml). The resulting mixture was heated at 90° C. for 16 hours and then cooled to room temperature. The reaction mixture was diluted with water (20 ml) and the resulting precipitate filtered off, washed with further water (20 ml) and dried in vacuo to give the title compound as a colourless solid (280 mg, 15percent). 1H NMR (400 MHz, CDCl3): delta 6.71 (1H, s), 1.37 (3H, s), 0.83-0.79 (2H, m), 0.72-0.65 (2H, m) ppm. MS (ESI) m/z 199 [M+H]+
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In acetonitrile; at 80℃; for 2h;
4-Chloro-6-(2-chloro-pyridin-3-ylVpyrimidine; [0084] 2-Chloropyridine-3-boronic acid 5.0g (31.8mmol) is mixed with 9.55g 4,6- chloropyrimidine (63.7mmol), 1.84g Pd(PPh3)4 (5%, 1.59mmol), and 8.79g K2CO3 (63.7mmol). Degassed 1 to 1 ratio MeCN and water as solvent 6OmL is added then heated at 80 0C for 2 hours in the capped flask. After cooling down the reaction, separate out the organic layer, and use 20OmL ethyl acetate to do the extraction 3 times. Combine the organic <n="29"/>layers and use saturated NaCl solution to wash once. The organic layer is dried by Na2SO4 and evaporated under the vacuum. The crude product is purified by flash chromatography in 3%MeOH in DCM. The final product is 3.9Og white solid.
With sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; water; for 8h;Heating / reflux;
c. Synthesis of 4-chloro-6-(2-isopropoxyphenyl)-pyrimidine.; To a solution of 4,6-dichloropyrimidine (0.207 g, 1.38 mmol) and 2- isopropoxyphenylboronic acid (0.18 g, 1.0 mmol) in mixture of dimethoxyethane (4 ml_) and water (0.6 ml_) were added NaHCO3 (0.231 g, 2.76 mmol) and (PPh3^PdCI2 (0.029 g) and the reaction mixture was refluxed for 8 h, then was evaporated. The residue was dissolved in CH2CI2 (10 ml_) and washed with water, dried over anhydrous K2CO3 and evaporated. The crude product was isolated by column chromatography on silica (eluent CH2CI2) as oil. Yield of 4-chloro-6-(2-isopropoxyphenyl)-pyhmidine 0.18 g (72%).
With hydrogenchloride; In 1,4-dioxane; ethanol; water;
Intermediate 1: 6-Chloro-3H-pyrimidin-4-one A mixture of 4,6-dichloropyrimidine (Aldrich; 10.00 g, 67.1 mmol), concentrated hydrochloric acid (50 mL), water (50 mL) and dioxane (50 mL) was heated at about 70 C. for 6 h, and then allowed to cool to room temperature. This gave a pink solution. The solvents were evaporated under reduced pressure (vacuum pump) to give a pink solid. Ethanol (50 mL) was added and the mixture was heated. The solid went into solution. The solution was placed in a warm bath (about 50 C.) and allowed to cool slowly. After standing over the weekend, the off-white solid was filtered off to give 6-chloro-3H-pyrimidin-4-one (5.02 g, 57%), mp 193-194 C. (lit. mp 192-193 C. in D. J. Brown and J. S. Harper J. Chem. Soc. 1961, 1298-1303). 1H NMR (d6-DMSO) delta 6.50 (s, 1H), 8.19 (s, 1H), 13.00 (br s, 1H).
56%
With hydrogenchloride; In 1,4-dioxane; water; at 70℃; for 6.0h;
A solution of 4,6-dichloropyrimidine (2 g, 13.42 mmol) in a mixture of 4N HC1 (10.49 mL, 121 mmol)- 1,4-dioxane (10 mL)-water (10 mL) was heated to 70 CC for 6 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford a pink solid. Ethanol (25 mL) was added to thesolid and the mixture was heated at 50 C until the solid dissolved. The resulting pink solution was left overnight at room temperature and the precipitation formed was filtered and dried under vacuum to afford 6-chloropyrimidin-4(3B)-one (1 g, 7.51 mmol, 56% yield) as an off-white solid. LCMS (ESI)m/e 130.8 [(M+H), calcd for C4H4C1N2O, 130.91; LC/MS retention time (Method C): tR = 0.51 mm.
Synthesis of 5-allyl-4,6-dichloropyrimidlne (8c): 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. CuCN.2LiCl (1 M in THE; 0.05 mL, 5 mol %) was then slowly added at -20 C. Allyl bromide (242 mg, 2.0 mmol) was then slowly added at -60 C. The resulting mixture was then allowed to warm up slowly to 0 C. for 4 h. The reaction mixture was quenched with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (5×30 mL) and driedanhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane 1:2) furnished 8c as a colourless solid (215 mg, 89%). 1H NMR (300 MHz, CDCl3) delta: 8.64 (s, 1 H), 5.80-5.90 (m, 1 H), 5.09-5.18 (m, 2 H), 3.64 (dt, 3J=6.4 Hz, 4J=1.4 Hz, 2 H).13C NMR (75 MHz, CDCl3) delta: 162.0, 155.8, 130.9, 130.6, 118.2, 34.0.MS (70 eV, El) m/z (%): 188 (70) [M+], 125 (22), 117 (44), 90 (59), 64 (35), 49 (43), 41 (100).IR (ATR) v (cm-1): 2969, 2360, 1739, 1639, 1539, 1513, 1435, 1406, 1375, 1348, 1313, 1290, 1200, 1162, 1129, 1090, 989, 929, 906, 839, 777, 687, 668, 627, 621, 616.HRMS (El) for C7H6Cl2N2 (187.9908): 187.9913.
75%
The alkylation step by conducted using a modified procedure: TMPMgCl·LiCl (0.8M, 11.0 mL, 8.8 mmol) was added to a solution of 2,4,6-trichloropyrimidine (1.47 g, 8.0 mmol) in anhydrous THF (20 mL) at -78 oC. After stirring for 1 hour, CuBr (230 mg, 1.6 mmol) was added and stirring was continued for 30 min before allyl bromide (0.73 mL, 8.4 mmol) was added. The reaction was allowed to warm to room temperature, then quenched by addition of sat. NH4Cl solution. EtOAc was added and the layers were separated. The organic phase was dried and Na2SO4 and concentrated. The residue was purified by silica gel chromatography [heptane/EtOAc, 95:5 - 3:1] to give the alkylated product as a white solid (1.31 g, 73 %). This was transformed to the final product by the same procedure as for 2 using allylamine followed by standard N-Boc protection to give the productas a colourless oil (1.51 g, 75%).
2-chloro-4-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-benzoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4, 6-Dichloropyrimidine (0. 72mmol), 2-METHOXYPHENYLBORONIC acid (0. 66 mmol), sodium carbonate (1. 97 mmol), and Pd (PPh3) 2CI2 (3 mol%) were suspended in a mixture of DME/ETOH/WATER (2. 5 ML/0. 38 ML/0. 38 ML). The mixture was heated in a Personal Chemistry Optimizer microwave system at 130C for 900 s. 'PrOH (5 ml) and the corresponding aniline derivative (0. 66 MMOL) were added, and the mixture was treated with conc. HCI under stirring to reach a pH value of 1- 2. The mixture was then heated in the microwave at 150C for 900 s. The solvent was evaporated under reduced pressure and the residue suspended in H20 (10 mL). With sat. NAHC03 solution the mixture was set to pH = 6-7 and extracted with EtOAc (3x 20 ML). The combined organics were washed with brine and dried over NA2SO4. After evaporation of the solvent the residue was taken up in DMSO and purified via prep.-HPLC (XTerra Prep. MS C18 5 um, 19 x 150 mm, gradient from water to MeCN over 13 min). In the case of products with an acid group in the anilino part, the corresponding methyl esters were prepared via treatment with TMSCHN2 (2-4 eq.) in DCM/MEOH (2 mL/1 mL) at room temperature.
A mixture of <strong>[91188-13-5]azetidin-3-yl-carbamic acid tert-butyl ester</strong> (635mg, 3.4mmol), 2,4- dichloropyhmidine (500mg, 3.4mmol) and thethylamine (0.5ml, 3.6mmol) in methanol (10ml) was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography (0-40% ethyl acetate/ petroleum ether) furnishing 561 mg title compound. MS: [M+H]+ = 283/285
A mixture of 4,6-dichloropyrimidine (1.00 g, 6.7 mmol), <strong>[113305-94-5]2-amino-5-cyanopyrazine</strong> (806 mg, 6.7 mmol) and bis(triphenylphosphine)palladium (II) chloride (94 mg, 0.134 mmol) in dry THF (24 mL) was degassed under a stream of nitrogen gas for 10 minutes with stirring. Lithium bis(trimethylsilyl)amide in THF (1M, 7.38 mL, 7.4mmol) was added and the mixture was heated at 135C for 20 minutes using microwave irradiation. The reaction mixture was adsorbed onto silica and purified by flash column chromatography, eluting with 30% ethyl acetate in hexane, to give 5-(6-chloropyrimidin-4-ylamino)pyrazine- 2-carbonitrile (300 mg, 19%).LCMS (1) Rt = 1.64 min; m/z (ESI") 231.
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.
6-[3-amino-4-(2,4-dichlorophenyl)pyrrolidin-1-yl]-N-methyl-N-(pyridin-4-ylmethyl)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
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 muL) 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) delta 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)+
To a solution of 4,6-dichloropyrimidine (815 mg, 4.60 mmol) in n-propanol (12.0 ml.) was added 2,3-dihydro-1 H-indole-5-carboxylic acid methyl ester (Bioorg. Med. Chem. Lett. 2008, 18, 5684 - 8) (754 mg, 5.06 mmol). The resulting yellow solution was heated to reflux for 2 hours. After allowing the reaction to cool to room temperature, the reaction mixture was diluted with methyl te/t-butyl ether and then filtered. The collected solids were partitioned between chloroform and saturated aqueous sodium bicarbonate solution. The separated organic phase was dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to afford 1-(6-chloro-pyrimidin-4-yl)- 2,3-dihydro-1 H-indole-5-carboxylic acid methyl ester (929 mg, 69.7 %) as an off-white solid. 1H NMR (400 MHz, deuterochloroform) delta 3.32 (t, J=8.49 Hz, 2 H) 3.91 (s, 3 H) 4.08 (t, J=8.69 Hz, 2 H) 6.67 (s, 1 H) 7.90 (d, J=0.98 Hz, 1 H) 7.96 (dd, J=8.49, 1.46 Hz, 1 H) 8.46 (d, J=8.59 Hz, 1 H) 8.65 (s, 1 H).
69%
Reference Example 15 methyl 1-(6-chloropyrimidin-4-yl)-2,3-dihydro-1H-indole-5-carboxylate; A mixture of <strong>[141452-01-9]methyl 2,3-dihydro-1H-indole-5-carboxylate</strong> (5.19 g), 4,6-dichloropyrimidine (4.37 g), and ethanol (50 mL) was stirred overnight with heating under reflux, and concentrated under reduced pressure. To the residue were added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, and the mixture was stirred for 30 min. Insoluble materials were collected by filtration to give the title compound (5.87 g, 69%) as a white solid. 1H-NMR (300 MHz, CDCl3)delta:3.32 (t, J=8.7 Hz, 2 H), 3.91 (s, 3 H), 4.08 (t, J=8.7 Hz, 2 H), 6. 66 (s, 1 H), 7.90 (s, 1 H), 7.95 (d, J=8.5 Hz, 1 H), 8.46 (d, J=8.5 Hz, 1 H), 8.64 (s, 1 H).
With DIEA; triphenylphosphine; In ethanol; sodium carbonate; acetonitrile;
Example 2 3-[6-(4-Trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-benzamide (GNF-2) 4,6-dichloropyrimidine (1 g, 6.7 mmol) is dissolved with p-trifluoromethoxy aniline (1.2 g, 6.7 mmol) in 15 mL ethanol, then 1.75 mL DIEA (10 mmol) is added. Reaction is under reflux for 2 hours, and cooled down to room temperature. After evaporating the solvent, the crude product is purified by flash chromatography (EA/Hexane=3:7) to give (6-chloro-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine as a white solid. To a degassed solution of (6-chloropyrimidin-4-yl)-(4-trifluoromethoxyphenyl)-amine (73 mg, 0.25 mmol) and (3-aminocarbonylphenyl)-boronic acid (42 mg, 0.25 mmol) in 0.4 M sodium carbonate aqueous solution (1.3 mL) and acetonitrile (1.3 mL) is added PPh3 (15 mg, 0.01 mmol). After stirring at about 90 C. under N2 for 12 hours, the reaction mixture is partitioned between saturated NaHCO3 and CHCl3/2-propanol (4:1). The aqueous layer is extracted with additional CHCl3/2-propanol (4:1) and the combined organic layers are dried over MgSO4, filtered, and concentrated under reduced pressure. The resultant yellowish oil is purified by column chromatography (SiO2, ethyl acetate) to give 3-[6-(4-trifluoromethoxyphenyl-amino)-pyrimidin-4-yl]-benzamide as a white solid. MSm/z 375.10(M+1).
EXAMPLE 6: 5-CHLORO-2-(l-(6-(TETRAHYDRO-2H-PYRAN-4-YL)PYRIMIDIN-4- YL)AZETIDTN-3 -YL)- 1 H-BENZO [ ]IMIDAZOLESTEP 1. 4-CHLORO-6-(TETRAHYDRO-2H-PYRAN-4-YL)PYRIMIDTNE; [00207] Step la. Preparation of Zinc Reagent.[00208] To a suspension of zinc dust (0.70 g, 10.75 mmol) in DMA (9 mL) was added 0.32 mL of a 7:5 v/v mixture of TMSCl/l,2-dibromoethane over 5 min. The solution was stirred for an additional 15 min and <strong>[25637-18-7]4-iodotetrahydro-2H-pyran</strong> (1.9 g, 8.96 mmol) was added over 15 min. After the addition, the mixture was stirred for an additional 30 min before being used directly in the next step (see below).[00209] Step lb. A mixture of copper(I) iodide (0.067 g, 0.35 mmol), Pd(dppf)Cl2 (0.14 g, 0.18 mmol) , and 4,6-dichloropyrimidine (0.52 g, 3.50 mmol) in DMA (3 mL) was placed under argon atmosphere using 3 evacuation/backfill cycles. The zinc reagent prepared in Step la above (4.5 mL, about 4.5 mmol) was added dropwise via syringe and the mixture was heated to 80 °C for 4 h, then cooled to RT. Ethyl acetate and saturated aqueous ammonium chloride were added, the resulting layers were separated, and the organic layer was washed with water (2x), brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography to give 4-chloro-6-(tetrahydro-2H-pyran-4- yl)pyrimidine (0.13 g, 0.64 mmol, 14percent yield) as a light yellow solid.
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 (3.37 g, 20.09 mmol) in isopropyl alcohol (30 mL) was added <strong>[101251-09-6](4-acetamidophenyl)boronic acid</strong> (3 g, 16.7 mmol), palladium acetate (0.188 g, 0.83 mmol) and triphenyl phosphine (1 .06 g, 4.0 mmol). Potassium carbonate (3.46 g, 25.1 mmol) was dissolved in water (7.5 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: 3.2 g (64 %); 1H NMR (300 MHz, DMSO-d6):5 10.26 (s, 1 H), 9.02 (s, 1 H), 8.23 (m, 3H), 7.77 (d, 2H), 2.05 (s, 3H); MS (ES+): 248.8 (M+1 ).
4,6-dichloro-2-phenylpyrimidineN-Butyl lithium (3.22 g, 50.3 mmol, and 1.6N in hexane) was added dropwise to a stirred solution of bromobenzene (7.9 g, 50.3 mmol) in THF (70 mL) over a period of 30 min at -78 °C, and reaction was continued stirring for 2 h. The generated phenyl lithium was added dropwise to a stirred solution of 4, 6-dichloropyrimidine (5 g, 33.5 mmol) in THF (50 mL) over a period of 45 min at -78 0C, and reaction was continued stirring for 30 min. Then, the reaction mixture was slowly heated to 0 °C and quenched with water (100 ml), DDQ (7 g, 30. 8 mmol) dissolved in THF (70 mL) was added portionwise and stirred for 10 min. Then, the reaction mixture was washed with 10percent NaOH (50 mL), extracted with CH2Cl2 (3x100 mL), washed with brine (100 mL), dried (Na2SO4) and concentrated. The concentrated product was purified through silica column chromatography using pet. ether to afford 4,6-dichloro-2- phenylpyrmimidine (example 21, 2.6 g, 35 percent) as a white solid. Rf: 0.3 (100percent PE). 1H NMR (400 MHz, CD3OD): delta 8.41-8.39 (m, 2H), 7.60 (s, IH), 7.58-7.50 (m, 3H). m/e (M+l): 224.8.
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
With potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 130.0℃; for 1.0h;Microwave irradiation;
PREPARATION 274-amino-/V-[2-(methyloxy)ethyl]benzamide,RhoOmicron,Dioxan A mixture of 4,6-dichloropyrimidine (476 mg, 3.22 mmol, 6-bromo-4-methyl-2- pyridinamine (300 mg, 1.62 mmol, prepared according to procedures outlined in WO2005061496 and references therein), Pd2(dba)3 (28 mg, 0.032 mmol), Xantphos (36 mg, 0.064 mmol) and potassium carbonate (670 mg, 4.89 mmol) in 1 ,4-dioxane (5 ml.) was heated in the microwave at 130 C for 1 h. The reaction mixture was then poured onto water and the resultant solid collected by filtration and then purified via flash column chromatography (silica gel, 10:1 to 5:1 petroleum Et20: EtOAc) to afford 4-amino-/V-[2- (methyloxy)ethyl]benzamide (160 mg, 33%) as a white solid, MS (m/z) 300.9 (M+H)+.
With caesium carbonate; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl;palladium diacetate; In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation;
PREPARATION 286-chloro-/V-(3,5-dichloro-2-pyridinyl)-4-pyrimidinamineCs2C03 DioxanA mixture of 4,6-dichloropyrimidine (823 mg, 5.52 mmol), 3,5-dichloro-2- pyridinamine (450 mg, 2.76 mmol), Cs2C03 (2698 mg, 8.28 mmol), BINAP (68.8 mg, 0.1 10 mmol) and PdOAc2 (24.79 mg, 0.1 10 mmol) was dissolved in 1 ,4-dioxane (6902 muIota) and heated in the microwave at 150°C for 30 min. The reaction was then concentrated and the residue was then purified by silica SPE (20 g, eluted with 50-50 CH2CI2:hexanes, CH2CI2, 75-25 CH2CI2: Et20). Concentration of the appropriate fractions yielded 6-chloro- A/-(3,5-dichloro-2-pyridinyl)-4-pyrimidinamine (126 mg, crude) as a yellow solid and a second batch of 6-chloro-/V-(3,5-dichloro-2-pyridinyl)-4-pyrimidinamine (310 mg, crude) both batches were used as is in the next step.
General procedure: Methyl 2-(methylsulfonyl)acetate (8.58 g, 56.39 mmol) was dissolved in DMF (100 ml),to this was added NaH (4.92 g, 102.53 mmol) and the reaction was stirred for 5min. before the addition of 4,6-dichloro-2-(methylthio)pyrimidine (10g, 51.26 mmol). The reaction was stirredfor 24 hours quenched with 2M HCl (100 ml), extracted with Et2O (3 x100 ml), the organic layer was dried over MgSO4, filtered andevaporated to afford a yellow gum. The crude product was purified by flashsilica chromatography, elution gradient 100% Et2O. Fractions wereevaporated to dryness to afford a yellow gum.The gum was triturated with Et2O to give a solid which was collected by filtration anddried under vacuum to give methyl2-(6-chloro-2-(methylthio)pyrimidin-4-yl)-2-(methylsulfonyl)acetate (9.30 g,58.4 %) as a white solid. 1H NMR (400 MHz, CDCl3)delta 7.36 (s,1H), 5.03 (s, 1H), 3.86 (s, 3H), 3.19 (s, 3H) and 2.55 (s, 3H); m/z (ES+) (M+H)+ = 311
4-chloro-6-(2-methylpyridin-3-yl)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24%
With tetrakis(triphenylphosphine) palladium(0); potassium acetate; sodium carbonate; In water; acetonitrile; at 70℃; for 2h;Inert atmosphere; Microwave irradiation;
First, 3.01 g of 4,6-dichloropyrimidine, 10.9 g of <strong>[1012084-56-8]2-methylpyridine-3-boronic acid pinacol ester</strong>, 60 mL of 1M aqueous solution of potassium acetate, 60 mL of 1M aqueous solution of sodium carbonate, and 60 mL of acetonitrile were put in a 300 mL three-neck flask, and the air in the flask was replaced with argon. To this mixture, 1.40 g of tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was irradiated with microwaves under conditions of 70 C. and 400 W and for 2 hours to cause a reaction. This reaction mixture was extracted with ethyl acetate, and washing with saturated brine was performed. Anhydrous magnesium sulfate was added to the obtained solution of the extract for drying, and the resulting mixture was gravity-filtered to give a filtrate. A residue obtained by condensing the filtrate was purified by flash column chromatography using ethyl acetate as a developing solvent. A solid obtained by condensing the fraction was purified by flash column chromatography using hexane and ethyl acetate in a ratio of 1:1 as a developing solvent, so that 4-chloro-6-(2-methylpyridin-3-yl)pyrimidine was obtained (a yellow white solid, yield of 24%). A synthetic scheme of Step 1 is shown in (c-1) below.
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.
6-chloro-2’-(trifluoromethyl)-4,5’-bipyrimidine[ No CAS ]
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]+
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; for 3h;
[0464] A mixture of 4,6-dichloropyrimidine (2 g, 13.42 mmol), DIPEA (0.65 mL, 3.93 mmol), 4- (trifluoromethyl)piperidine (9.74 g, 63.60 mmol) in DMF (20 mL) was stuffed for 3 h at 25°C. The reaction mixture was then quenched with water (100 mL), extracted with EtOAc (3x 100 mL). The combined organic layers were washed with water (3x) and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with EtOAc/petroleum ether (3:7) to afford the title compound (3.4 g) as a white solid.
4-chloro-2-(6-chloropyrimidin-4-yl)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate; triphenyl-arsane; In 1,4-dioxane; at 75℃; for 3h;
Into a 250-mL round bottom flask, was placed a solution of <strong>[1073371-77-3]4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine</strong> (3 g, 11.83 mmol, 1.00 equiv) in dioxane (120 mL), water (20 mL), 4,6-dichloropyrimidine (4.4 g, 29.53 mmol, 2.50 equiv), triphenylarsine (360 mg, 1.18 mmol, 0.10 equiv), K3PO4 (3.8 g, 17.90 mmol, 1.50 equiv), Pd(PPh3)2Cl2 (390 mg, 0.56 mmol, 0.05 equiv). The resulting solution was stirred for 3 h at 75 C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50?1:10). This resulted in 1.5 g (53%) of 4-chloro-2-(6-chloropyrimidin-4-yl)benzenamine as a yellow solid.
With palladium diacetate; sodium carbonate; triphenylphosphine; In tetrahydrofuran; water; at 60℃; for 16h;Inert atmosphere;
General procedure: All solvents and solutions used for this reaction were sparged with argonfor 15 minutes. In a round-bottomed flask was dissolved 4,6-dichloropyrimidine (1.5 equiv.) inTHF (1 M), under argon atmosphere. The arylboronic acid (1.0 equiv.), palladium acetate (0.02equiv., 2 mol%), triphenylphosphine (0.04 equiv., 4 mol%) and 1 M aqueous Na2CO3 solution(2.0 equiv.) were added and the mixture was stirred at 60 C, overnight. After cooling to roomtemperature, the aqueous layer was extracted with Et2O and the organic layers were combined,washed with brine, dried over MgSO4, filtered and evaporated under vacuum. The crude materialwas purified by flash column chromatography to obtain the desired product.
General procedure: A suspensionof 4,6-dichloro-pyrimidine (5.70 g, 38.16 mmol) and aluminumchloride (5.10 g, 38.16 mmol) in DME (60 mL) was stirred atambient temperature for 10 min. To this was added 1-methyl-1Hindole(5.00 g, 38.16 mmol) and the mixture was stirred at refluxovernight. The cooled reaction mixture was added to stirring water(100 mL) and the mixture was stirred for 1 h, filtered and the solidwas washed with EtOH (20 mL). The crude product was dried in avacuum oven to give a red solid (4.30 g, 46.2% yield).
6-chloro-N-(tetrahydrofuran-3-yl)pyrimidin-4-amine[ No CAS ]
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.
Preparation Example 6(1) o a mixture of 4,6-dichloropyrimidine 6 g and methanol 40 mL was added dropwise a 28percent sodium methoxide solution in methanol 8.16 g under ice-cooling. The resulting mixtures were stirred for 2 hours under ice-cooling and then warmed to room temperature, and stirred for 6 hours. The reaction mixtures were concentrated under reduced pressure, and to the resulting oily materials was added a saturated aqueous ammonium chloride solution, and then the resulting mixtures were extracted with ethyl acetate. The organic layers were washed with saturated brine, and then the organic layers were dried over sodium sulfate. The organic layers were concentrated under reduced pressure, and the resulting oily materials were subjected to a silica gel chromatography to give an intermediate compound (6-1) 4.6 g. 1H-NMR (CDCl3) delta: 8.59 (1H, s), 6.78 (1H, dd), 4.01-3.95 (3H, m).
4-chloro-6-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)-oxy)pyrimidine[ No CAS ]
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%
4-chloro-6-[2-methoxy-4-(trifluoromethyl)phenyl]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 110℃; for 4h;Inert atmosphere;
To 4,6-dichloropyrimidine (15.4 g, 103 mmol), <strong>[312936-89-3]2-methoxy-4-(trifluoromethyl)phenylboronic acid</strong> (25.0 g, 114 mmol), potassium carbonate (28.5 g, 206 mmol) and tetrakistriphenylphosphinepalladium(0) (6 g) were added 1,4-dioxane (500 mL) and water (50 mL), and the mixture was stirred under a nitrogen atmosphere at 110C for 4 hr. The insoluble material was filtered off, the filtrate was added to water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over sodium sulfate. The desiccant was filtered off, the filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the title compound (20 g, 69.4 mmol, 67%). MS (ESI) m/z 289 (M+H)+
tert-butyl 2-(6-chloropyrimidin-4-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;
To 4,6-dichloropyrimidine (674 mg, 4.52 mmol) in dimethylformamide (3.4 ml) under an atmosphere of argon was added <strong>[1280210-79-8]tert-butyl 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate</strong> (946 mg, 4.52 mmol) and cesium carbonate (1.47 g, 4.52 mmol) and the reaction stirred overnight at room temperature. The reaction was poured onto water (25 ml) and stirred for 60 minutes. The precipitate was filtered and purified by HPLC (Method 20) to yield 748 mg (100% purity, 51 % yield) of the desired product. LC-MS (Method 10): Rt = 2.10 min; MS (ESIpos): m/z = 322 [M+H]+1H-NMR (600 MHz, dimethylsulfoxide-d6) delta [ppm]: 1.466 (16.00), 4.400 (1.20), 4.427 (1.38), 4.456 (1.47), 4.477 (1.29), 7.884 (0.67), 7.903 (0.79), 8.467 (0.69), 8.493 (0.62), 8.925 (1.44).
[4-(6-chloropyrimidin-4-yloxy)cyclohexyl]carbamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride; In tetrahydrofuran; at 20℃; for 20h;Inert atmosphere;
Add in round bottom flask<strong>[224309-64-2](4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester</strong> (5.0 g), then added tetrahydrofuran (100 ml),Sodium hydride (0.93 g) and 4,6-dichloro-pyrimidine (6.9 g).The reaction system was reacted at room temperature for 20 hours under argon gas protection. After the reaction is over,The solvent was evaporated to dryness under reduced pressure.The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate.The organic phase was filtered and evaporated to dryness then evaporated.The crude product is purified by pressurized silica gel column chromatography.(A12),
4-chloro-6-(4-chloro-1H-imidazol-1-yl)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54.6%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;
A mixture of 4,6-dichloropyrimidine (1.8 g, 12mmol), 4-chloro-IH-imidazole (1.23 g, 12.00 mmol), andcesium carbonate (3.91 g, 12.00 mmol) was stirred in DMF (8mL) at room temperature for 18 h. The reaction was dilutedinto water and extracted with EtOAc. The combined organiclayers were concentrated and purified by flash chromatographyon a 120 g silica gel cartridge with 0 to 40% ethyl acetatein hexane to yield 4-chloro-6-(4-chloro-1H-imidazol-1-yl)pyrimidine (1.41 g, 54.6% yield). The positive identificationof the <strong>[15965-31-8]4-chloroimidazole</strong> regioisomer was accomplished by its NMR NOE properties.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; acetonitrile; at 65 - 70℃; for 7h;Inert atmosphere;
Add in 100mL three-necked bottles1-methylcarbazole-5-boronic acid (300 mg, 1.70 mmol), 4,6-dichloropyrimidine (330 mg, 2.216 mmol), sodium carbonate (360 mg, 3.41 mmol)And acetonitrile / water = 4 / 1 (15 mL).Tetrakis(triphenylphosphine)palladium (200 mg, 0.171 mmol) was added under argon atmosphere.The oil bath was heated to 65-70 C for about 7 h, and naturally cooled to room temperature.Water (50 mL), dichloromethane (50 mL) was added and stirred for 5 min. The organic phase was combined and the organic phase was washed twice with saturated brine (50 mL×2).Dry over anhydrous sodium sulfate for half an hour. Filtration, and the filtrate was concentrated under reduced pressure to give a crude material.Purified by column chromatography and eluted with PE/EA = 6/1.The product was collected and concentrated under reduced pressure to give Intermediate A1: 330 mg.
With methanesulfonic acid; In isopropyl alcohol; for 7h;Reflux;
2,4-Dichloro-5-methoxyl aniline (11.5g, 60 mmol), 4,6-dichloro pyrimidine (13.4 g, 90 mmol) and methanesulfonic acid (6.9 g, 72 mmol) were added to 100mL of isopropyl alcoho and then stirred under reflux for 7h. The reaction mixture was cooled to room temperature and the filtered to give the title intermediate (18g). m/z:ESI MH+ 304.0.
6-chloro-4-(S)-(tetrahydrofuran-2-yl)methylaminopyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 80℃; for 16h;
4,6-Dichloropyrimidine (1.473 g, 9.89 mmol) was added to a round bottom flask, and to n-butanol (60 mL)After dissolving (tetrahydrofuran-2-yl) methanamine (1.02 mL, 9.89 mmol) andDiisopropylethylamine (5.16 mL, 29.66 mmol) was added thereto and stirred at 80 DEG C for 16 hours.When the reaction was completed, the solvent was removed by distillation under reduced pressure, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. After drying with anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (1.24 g, 59%).
2-(3-(benzyloxy)cyclobutyl)-4,6-dichloropyrimidine[ No CAS ]
2-(3-(benzyloxy)cyclobutyl)-4,6-dichloropyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With ammonium persulfate; silver nitrate; In water; acetonitrile; at 60℃; for 16h;
To a solution of 4,6-dichloropyrimidine (2.0 g, 13.4 mmol) in MeCN (50 mL) were added <strong>[4958-02-5]3-(benzyloxy)cyclobutanecarboxylic acid</strong> (8.31 g, 40.3 mmol, cis:trans = 3:1) and AgNO3 (9.12 g, 53.7 mmol). The reaction mixture was heated to 60C and then a solution of ammonium persulfate (15.3 g, 67.1 mmol) in H20 (50 mL) was added dropwise. The reaction mixture was then stirred for 16 h at 60 C. The reaction mixture was concentrated under reduced pressure and the residue was partioned between EtOAc (50 mL) and H20 (50 mL). The mixture was filtered, and the filter cake was washed with EtOAc (2 x 50 mL). The organics were separated, washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to give the desired product (cis:trans = 3:1).
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