* 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.
To 2,4-Dichloropyrimidine (1.0 g, 6.7 mmol) was added 28 percent w/v ammonium hydroxide solution (20 mL). The mixture was stirred overnight at ambient temperature then concentrated in vacuo. The residue was dry loaded and purified by FCC eluting with 2-10 percent EtOH in CHCI3 to afford 2-amino-4-chloropyrimidine and 2-chloro-4-aminopyrimidine. Yield: 2-amino-4-chloropyrimidine 200 mg, 23 percent; 2-chloro-4-aminopyrimidine 600 mg, 69 percent.
23%
With ammonia In water at 20℃; for 5 h;
Example 1 : 2-Amino-4-chloropyrimidine (2) and 4-amino-2-chloropyrimidine (3) A suspension of 2,4-dichloropyrimidine (7.45 g, 50.0 mmol) in ammonium hydroxide (25percent, 125 mL) is stirred at room temperature for 5 h. The appearance of the insoluble material changes from "salt-like" to "snow-like". The precipitate is collected by filtration and dried in vacuo. The crude material is redissolved in MeOHiCH2CI2 (1 :1), adsorbed on SiO2 and purified by column chromatography (gradient cyclohexane:ethyl acetate from 5:1 to 1 :1) to yield 1.48 g (23percent) of 2 and 1.73 g (26percent) of 3 (TLC cyclohexane:ethyl acetate 3:1 , Rf (2)=0.45, Rf (3)=0.32). ESI-MS m/z 129.8 [M+H]+.
Reference：
[1] Patent: WO2010/20556, 2010, A1, . Location in patent: Page/Page column 62
[2] Journal of the American Chemical Society, 2003, vol. 125, # 33, p. 9970 - 9982
[3] Tetrahedron, 2010, vol. 66, # 6, p. 1280 - 1288
[4] Patent: WO2006/114409, 2006, A1, . Location in patent: Page/Page column 18
[5] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 14, p. 1973 - 1978
[6] Chemische Berichte, 1905, vol. 38, p. 1690
[7] Chemische Berichte, 1905, vol. 38, p. 1690
[8] Journal of the American Chemical Society, 1930, vol. 52, p. 1152,1156; vgl. H 24 80
[9] Heterocycles, 2000, vol. 53, # 7, p. 1489 - 1498
[10] Patent: US2007/238737, 2007, A1, . Location in patent: Page/Page column 11
[11] Letters in Organic Chemistry, 2011, vol. 8, # 8, p. 545 - 548
[12] Archiv der Pharmazie, 2014, vol. 347, # 2, p. 77 - 88
[13] Patent: CN106317147, 2017, A, . Location in patent: Paragraph 0062; 0063; 0064; 0065; 0066; 0067
[14] Patent: US2007/37974, 2007, A1, . Location in patent: Page/Page column 10
2
[ 3934-20-1 ]
[ 7664-41-7 ]
[ 7461-50-9 ]
[ 3993-78-0 ]
Reference：
[1] Chemische Berichte, 1905, vol. 38, p. 1690
3
[ 3934-20-1 ]
[ 7461-50-9 ]
[ 3993-78-0 ]
Yield
Reaction Conditions
Operation in experiment
69%
With ammonium hydroxide In water at 20℃;
To 2,4-Dichloropyrimidine (1.0 g, 6.7 mmol) was added 28 percent w/v ammonium hydroxide solution (20 mL). The mixture was stirred overnight at ambient temperature then concentrated in vacuo. The residue was dry loaded and purified by FCC eluting with 2-10 percent EtOH in CHCI3 to afford 2-amino-4-chloropyrimidine and 2-chloro-4-aminopyrimidine. Yield: 2-amino-4-chloropyrimidine 200 mg, 23 percent; 2-chloro-4-aminopyrimidine 600 mg, 69 percent.
23%
With ammonia In water at 20℃; for 5 h;
Example 1 : 2-Amino-4-chloropyrimidine (2) and 4-amino-2-chloropyrimidine (3) A suspension of 2,4-dichloropyrimidine (7.45 g, 50.0 mmol) in ammonium hydroxide (25percent, 125 mL) is stirred at room temperature for 5 h. The appearance of the insoluble material changes from "salt-like" to "snow-like". The precipitate is collected by filtration and dried in vacuo. The crude material is redissolved in MeOHiCH2CI2 (1 :1), adsorbed on SiO2 and purified by column chromatography (gradient cyclohexane:ethyl acetate from 5:1 to 1 :1) to yield 1.48 g (23percent) of 2 and 1.73 g (26percent) of 3 (TLC cyclohexane:ethyl acetate 3:1 , Rf (2)=0.45, Rf (3)=0.32). ESI-MS m/z 129.8 [M+H]+.
Reference：
[1] Patent: WO2010/20556, 2010, A1, . Location in patent: Page/Page column 62
[2] Journal of the American Chemical Society, 2003, vol. 125, # 33, p. 9970 - 9982
[3] Tetrahedron, 2010, vol. 66, # 6, p. 1280 - 1288
[4] Patent: WO2006/114409, 2006, A1, . Location in patent: Page/Page column 18
[5] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 14, p. 1973 - 1978
[6] Chemische Berichte, 1905, vol. 38, p. 1690
[7] Chemische Berichte, 1905, vol. 38, p. 1690
[8] Journal of the American Chemical Society, 1930, vol. 52, p. 1152,1156; vgl. H 24 80
[9] Heterocycles, 2000, vol. 53, # 7, p. 1489 - 1498
[10] Patent: US2007/238737, 2007, A1, . Location in patent: Page/Page column 11
[11] Letters in Organic Chemistry, 2011, vol. 8, # 8, p. 545 - 548
[12] Archiv der Pharmazie, 2014, vol. 347, # 2, p. 77 - 88
[13] Patent: CN106317147, 2017, A, . Location in patent: Paragraph 0062; 0063; 0064; 0065; 0066; 0067
[14] Patent: US2007/37974, 2007, A1, . Location in patent: Page/Page column 10
4
[ 3934-20-1 ]
[ 7461-50-9 ]
Yield
Reaction Conditions
Operation in experiment
57%
With ammonia In water; isopropyl alcohol at 100℃; for 18 h; sealed tube
To a suspension of 2,4-dichloropyrimidine (2.0 g, 13 mmol) in isopropanol (20 mL) was added ammonium hydroxide 28-30percent (50 mL, 1385 mmol). The suspension went into solution immediately. The resulting solution was heated at 100 0C in a sealed tube for 18 h. The mixture was brought to RT, extracted with DCM and the combined organics were <n="87"/>dried over MgSO4, filtered, and concentrated to afford an off-white solid as 2- chloropyrimidin-4-amine (1.7 g, 57percent yield). MS m/z: 130.0 (M+l).
57%
With ammonium hydroxide In isopropyl alcohol at 100℃; for 18 h; Sealed tube
Step 1: 2-Chloropyrimidin-4-amine To a suspension of 2,4-dichloropyrimidine (2.0 g, 13 mmol) in isopropanol (20 mL) was added ammonium hydroxide 28-30percent (50 mL, 1385 mmol). The suspension went into solution immediately. The resulting solution was heated at 100° C. in a sealed tube for 18 h. The mixture was brought to RT, extracted with DCM and the combined organics were dried over MgSO4, filtered, and concentrated to afford an off-white solid as 2-chloropyrimidin-4-amine (1.7 g, 57percent yield). MS m/z: 130.0 (M+1).
Reference：
[1] Chemische Berichte, 1905, vol. 38, p. 1690
7
[ 7461-50-9 ]
[ 3289-47-2 ]
Yield
Reaction Conditions
Operation in experiment
50%
With sodium methylate In methanol
Pre Step A 2-(Methyloxy)-4-pyrimidinamine A mixture of 2-chloro-4-pyrimidinamine (150 mg, 1.158 mmol) and sodium methoxide (188 mg, 3.47 mmol) in methanol (2.9 ml) was heated to 100° C. via a Biotag microwave for 40 min. The crude product mixture was purified by RP-HPLC to give 2-(methyloxy)-4-pyrimidinamine (73 mg, 0.583 mmol, 50percent yield). MS (ES+) m/z 126.0 (MH+).
50%
With sodium methylate In methanol
Pre Step A 2-(Methyloxy)-4-pyrimidinamine A mixture of 2-chloro-4-pyrimidinamine (150 mg, 1.158 mmol) and sodium methoxide (188 mg, 3.47 mmol) in methanol (2.9 ml) was heated to 100° C. via a microwave reactor for 40 min. The crude product mixture was purified by RP-HPLC to give 2-(methyloxy)-4-pyrimidinamine (73 mg, 0.583 mmol, 50percent yield). MS (ES+) m/z 126.0 (MH+).
With potassium phosphate; 1,1'-bis(di-tertbutylphosphino)ferrocene; palladium diacetate In 1,4-dioxane at 100℃; for 5 h; Inert atmosphere; Sealed tube
General procedure: To a solution of the requisite chloro-amino-substituted heteroaromatic in anhydrous 1,4-dioxane (30 volumes wrt chloride) in a sealed tube was introduced phenylboronic acid (1.5 equiv) and finely ground potassium phosphate (2.0 equiv). The solution was degassed (N2 bubbling) for 5 min, Pd(OAc)2 (5 mol percent wrt chloride) and di-tert-butylphosphinoferrocene (5 mol percent wrt chloride) introduced and degassing continued for a further 5 min. The tube was sealed under nitrogen and heated with rapid stirring at 100 °C for 5 h. After cooling, the reaction mixture was filtered in vacuo through a celite pad and the precipitated material washed with 1,4-dioxane. The combined filtrates were evaporated and purified by flash column chromatography (neat hexane to 1:1 hexane/EtOAc gradient containing 2.5percent by volume Et3N) to furnish the biarylanilines 13, 14 and 15.
Reference：
[1] European Journal of Organic Chemistry, 2010, # 23, p. 4376 - 4380
[2] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 8, p. 2742 - 2750
11
[ 7461-50-9 ]
[ 63286-28-2 ]
Yield
Reaction Conditions
Operation in experiment
73%
With hydrazine In ethanol; water
2,3-Dichloropyrazine (2 mL, 13 mmol) was dissolved in 95percent ethanol (4 niL) and to this was added, dropwise and with stirring, hydrazine anhydrous (2 mL, 67 mmol). During the addition of the hydrazine the solution became warm and yellowish. Following cooling of this mixture in an ice bath, the resulting material was isolated by filtration, washed with cold aqueous 95percent ethanol to riled l-(3-chloropyrazin-2-yl)hydrazine (1.42 g, 73percent yield) as white crystals. No further purification was done. MS m/z: 145.0 (M+l).
To 2,4-Dichloropyrimidine (1.0 g, 6.7 mmol) was added 28 % w/v ammonium hydroxide solution (20 mL). The mixture was stirred overnight at ambient temperature then concentrated in vacuo. The residue was dry loaded and purified by FCC eluting with 2-10 % EtOH in CHCI3 to afford 2-amino-4-chloropyrimidine and 2-chloro-4-aminopyrimidine. Yield: 2-amino-4-chloropyrimidine 200 mg, 23 %; 2-chloro-4-aminopyrimidine 600 mg, 69 %.
26%; 23%
With ammonia; In water; at 20℃; for 5h;
Example 1 : 2-Amino-4-chloropyrimidine (2) and 4-amino-2-chloropyrimidine (3) A suspension of 2,4-dichloropyrimidine (7.45 g, 50.0 mmol) in ammonium hydroxide (25%, 125 mL) is stirred at room temperature for 5 h. The appearance of the insoluble material changes from "salt-like" to "snow-like". The precipitate is collected by filtration and dried in vacuo. The crude material is redissolved in MeOHiCH2CI2 (1 :1), adsorbed on SiO2 and purified by column chromatography (gradient cyclohexane:ethyl acetate from 5:1 to 1 :1) to yield 1.48 g (23%) of 2 and 1.73 g (26%) of 3 (TLC cyclohexane:ethyl acetate 3:1 , Rf (2)=0.45, Rf (3)=0.32). ESI-MS m/z 129.8 [M+H]+.
With ammonia; In ethanol; at 20℃; for 5h;
0.880 ammonia (50 ml) was slowly added to a suspension of 2,4-dichloropyrimidine (5.0 g, 33.6 mmol) in ethanol (50 ml) and the resulting mixture was stirred at room temperature for 5 h. It was concentrated under reduced pressure to 25 ml and the resulting solid was filtered, washed with water and dried in a vacuum oven for 4 h. The resulting mixture of the title compound (D9), MS (ES+) m/e 130, 132 and 2-chloro-4-pyrimidinamine MS (ES+) m/e 130, 132 was used without further purification in the next reaction.
With ammonium hydroxide; at 20℃;Inert atmosphere;
2,4-dichloropyrimidine was added to 28% concentrated aqueous ammonia solution,Stirred at room temperature overnight,After the reaction,Concentrated under reduced pressure,The crude product was separated by column chromatography,To give the product 2-chloro-4-aminopyrimidine and its isomer 2-amino-4-chloropyrimidine,After separation and purification,2-chloro-4-aminopyrimidine (2 g, 15.4 mmol) was added to an argon-protected sodium borohydronate solution (prepared as follows: selenium (3 g, 38.0 mmol) and sodium borohydride (1.75 g, 46.2 mmol) were added Anhydrous ethanol (100 mL) at 10 C for 30 minutes)Heated to reflux for 48 hours,cool down,Add 10 mL of water,Filter,The filter cake was suspended in 15 ml of absolute ethanol,Further, 220 mg of sodium borohydride was added,The reaction was stirred for 30 minutes,Filter,dry,To give 1.1 g (39%) of compound 8b,White solid.
With ammonia; In ethanol; water; at 20℃; for 18h;
(A) To a solution of 2,4-dichloropyrimidine (7.5 g, 50 mmol) in ethanol (EtOH, 25 ml) was added ammonium hydroxide (25 ml, 30%). The reaction mixture was stirred at RT for 18 h. The white precipitate that formed was filtered and washed with ethanol, and dried under vacuum to provide a mixture of 2-chloro-pyrimidin-4-ylamine (IIa) and 4-chloro-pyrimidin-2-ylamine (4.13 g, 64 % yield). (See G. Caravatti et al., Bioorg Med Chem Lett (1999) 9:1973-78.) M+=130.
Step 1: 2-(4-Cyclopentyl-piperazin-1-yl)-pyrimidin-4-ylamine (Intermediate 1) A mixture of 0.5 g (3.86 mmol) 2-chloro-4-pyrimidinylamine (commercially available) and <strong>[21043-40-3]1-<strong>[21043-40-3]cyclopentyl-piperazine</strong></strong> (commercially available) in 1 mL DMF was heated to 70 C. for 16 h. The residue after filtration washed with diethyl ether and dried to yield 0.49 g (51%) of the title compound (intermediate 1) as white solid. MS (m/e): 284.3 (MH+).
Example 1 N-(4-((4-Aminopyrimidin-2-yloxy)methyl)benzyl)-2,2,2-trifluoroacetamide (1) 760 mg (3.25 mmol) 2,2,2-Trifluoro-N-(4-hydroxymethyl-benzyl)-acetamide is dissolved in 3 mL dry dimethylacetamide under argon atmosphere, and 273 mg (8.15 mmol) NaH is added over 5 min. 211 mg (1.63 mmol) 2-Chloropyrimidin-4-amine is then added and the solution stirred at 90C over night. 1 mL Water is added carefully to quench all excess NaH, and the mixture poured into 50 ml of 0.5 N HCI. The crude product is extracted with ethyl acetate, the combined organic phases washed with brine and dried over MgSO4. After evaporation of the solvent, the product is purified by flash column chromatography (gradient ethyl acetate:cyclohexane from 1:1 to 3:1). Yield: 350 mg (52%). ESI-MS m/z 327 [M+H]+.
The chloro compound of preparation 5 (1.52g, 11.8mmol) was dissolved in methanol(17mL) and the solution treated with a 4.62M solution of sodium methoxide in methanol (2.8mL, 12.9mmol). The reaction mixture was thenrefluxed under nitrogen for 6 hours. The reaction mixture was filtered whilst hot and concentrated in vacuo to a volume of 2mL and the solid allowed to crystallise out. The crude product wasrecrystallised from methanol and dried in an oven to yield the title product, 390mg. 'H NMR (DMSO-D6,400MHz) 8 : 3.75 (s, 3H), 6.05 (d, 1 H), 6. 80 (m, 2H), 7.80 (d,1 H)
With ammonia; In water; isopropyl alcohol; at 100℃; for 18h;sealed tube;
To a suspension of 2,4-dichloropyrimidine (2.0 g, 13 mmol) in isopropanol (20 mL) was added ammonium hydroxide 28-30% (50 mL, 1385 mmol). The suspension went into solution immediately. The resulting solution was heated at 100 0C in a sealed tube for 18 h. The mixture was brought to RT, extracted with DCM and the combined organics were <n="87"/>dried over MgSO4, filtered, and concentrated to afford an off-white solid as 2- chloropyrimidin-4-amine (1.7 g, 57% yield). MS m/z: 130.0 (M+l).
57%
With ammonium hydroxide; In isopropyl alcohol; at 100℃; for 18h;Sealed tube;
Step 1: 2-Chloropyrimidin-4-amine To a suspension of 2,4-dichloropyrimidine (2.0 g, 13 mmol) in isopropanol (20 mL) was added ammonium hydroxide 28-30% (50 mL, 1385 mmol). The suspension went into solution immediately. The resulting solution was heated at 100 C. in a sealed tube for 18 h. The mixture was brought to RT, extracted with DCM and the combined organics were dried over MgSO4, filtered, and concentrated to afford an off-white solid as 2-chloropyrimidin-4-amine (1.7 g, 57% yield). MS m/z: 130.0 (M+1).
With ammonia; In butan-1-ol; at 100℃; for 0.333333h;
2, 4-Dichloropyrimidine (625mg, 4.23mmol) was dissolved in n-butanol (3mL) and the solution treated with ammonia (620 L). The reaction mixture was heated to100 C for 20 minutes before being allowed to cool to room temperature. Methanol was added to help dissolved the precipitate formed on cooling and the solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting withdichloromethane : methanol 100: 0 to 96: 4. 'H NMR(CD30D, 400MHz) a : 6.41 (d, 1 H), 7.90 (d,1 H)
9.6 g
With ammonium hydroxide; at 70℃; for 5h;
Toluene (100 mL) and sodium methoxide 11 g were added to a 1000 mL multi-mouth reaction flask.After stirring evenly, 7.5 g of ethyl formate was slowly added dropwise in an ice water bath.And methyl acetate 8.9gThe mixed solution is controlled at an internal temperature of 15 to 20 C, and a small amount of hydrogen is emitted.After the dropwise addition was completed, the temperature was raised to room temperature, and the reaction was further stirred for 1.5 hours, and then under nitrogen protection,80 mL of methanol solution containing 7.2 g of urea was slowly added dropwise, and after the addition was completed, the reaction was carried out for 4 hours.Sampling was detected by GC, the urea content was less than 2%, and the reaction was completed.Under vacuum conditions, the reaction solvent toluene and methanol were removed under reduced pressure until 0 C.150 mL of distilled water was added to the reaction solution, and glacial acetic acid was added dropwise to adjust the pH of the reaction solution to 4.The temperature was controlled to stir at about 10 C for 1 h, and then the reaction solution was extracted several times with chloroform.The organic phases were combined, concentrated, and then 100 mL of thionyl chloride was added.Stir at room temperature for a while,Digesting unreacted thionyl chloride under vacuum conditions,Finally, add 120 mL of saturated ammonia water and slowly heat up to 70 C.Stirring reaction for 5 h, the solution appeared turbid,200 mL of ethyl acetate was added to the reaction mixture, and the mixture was stirred and dissolved.Cool to 10 C, add 250 mL of saturated sodium bicarbonate solution,Stir for 15 min, and leave the organic phase for 30 min.The organic phase was dried over anhydrous sodium sulfate for 1 h and suction filtered.Concentrated to give 2-chloro-4-amino-pyrimidine9.6g;
2-Bromopyridine or 2-chloropyrimidine (2equiv.), 5-amino-2-substitutedphenol (lequiv) and 37percent HCl solution (2equiv) in 10percent aqueous EtOH solution (0.2M) was stirred at 9O0C for 24h. The reaction mixture was diluted with AcOEt and washed with 5percent aqueous K2CO3 solution and brine. The organic phase was dried over Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel.; Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 4- amino-2-chloropyrimidine (70 mg, 0.5 mmol) and 5-ammo-2-chlorophenol (78 mg, 0.5 mmol) in 10percent aqueous EtOH (2 mL) was heated at 90 0C for 18h. The title compound was obtained in 47 percent yield a (60 mg) and used for the next step without addittional purification.1H NMR (500 MHz, CD3OD) .pound.7.81 (d, J= 5.9 Hz, IH), 7.44 (d, J= 2.5 Hz, IH), 7.14 (d, J= 8.7 Hz, IH), 7.00 (dd, J= 8.7, 2.5 Hz, IH), 5.99 (d, J= 5.9 Hz, 2H); 13C NMR (125 MHz,CD3OD) .pound. 166.3, 161.6, 156.8, 154.5, 142.1, 130.8, 114.7, 113.5, 109.4, 98.6.
With hydrogenchloride; In ethanol; water; at 80 - 90℃;Product distribution / selectivity;
Typical syntheses of these derivatives was performed by reaction of 2-broniopyridine, 2-chloiOpyrimidine, 4-amino-2-chloropyrimidine15, 2-chloro-4-methylpyrimidine165 2-chloro- 4-metlioxypyrimidine17 and 2-amino-4-chloropyrimidine1 with the corresponding 5-arnino-2- substitutedphenols in the presence of HCl, followed by reaction with 4-bromo-2~methyl-2- butene in presence of Cs2CO3 as a base. Compounds 46 and 47 were synthesized by reaction of 2-chloro-5-(pyrimidin-2-ylamino)phenol 35d with 4-methylpent-3-en-2-ol18 and (2- methylcyclopent-l-yl)methanol19, respectively, using Mitsunobu conditions20.
The solution of 2-chloropyrimidin-4-amine (1 mmol) and sodiumn methoxide (1.5 mmol) in 10 ml methanol was refluxed for 2 h, after removing of solvent, the residue was dissolved in CH2Cl2 and washed with water, dried over anhydrous NaSO4, concentrated in vacuo to give 2-methoxypyrimidin-4-amine.
2,3-Dichloropyrazine (2 mL, 13 mmol) was dissolved in 95% ethanol (4 niL) and to this was added, dropwise and with stirring, hydrazine anhydrous (2 mL, 67 mmol). During the addition of the hydrazine the solution became warm and yellowish. Following cooling of this mixture in an ice bath, the resulting material was isolated by filtration, washed with cold aqueous 95% ethanol to riled l-(3-chloropyrazin-2-yl)hydrazine (1.42 g, 73% yield) as white crystals. No further purification was done. MS m/z: 145.0 (M+l).
General procedure AR: PyrimidinesTo a stirred solution of aniline (1.0 eq), in DMSO (10 vol) was added chloropyrimidine (1.2 - 1.8 eq). The mixture was stirred for 1.5 hours at 120 0C. The mixture was cooled to ambient temperature, washed with saturated aqueous NaHCOs (50 vol) and extracted with EtOAc (2 x 30 vol). The combined organic extracts were washed with brine (50 vol), dried over MgSO4, and concentrated in vacuo. The residue was purified by FCC eluting with DCM:MeOH:NH3, 92:7:1.; tert-buty (2-{4-[(4-aminopyrimidin-2-yl)amino]phenyl}ethyl)carbamate Int 7The title compound was prepared according to general procedure AR using tert-butyl [2-(4- aminophenyl)ethyl]carbamate (0.1 g, 0.42 mmol) DMSO (2 mL), and 2-chloro-4- aminopyrimidine (0.066 g, 0.51 mmol). The title product was obtained as a yellow oil. Yield: 130 mg, 93 %.1H NMR (250 MHz, CDCl3) delta ppm 7.90 (1 H, d, J 5.63 Hz), 7.79 (1 H, br. s.), 7.46 (2 H, d, J 8.38 Hz), 7.05 (2 H, d, J 8.22 Hz), 5.88 (1 H, d, J 5.63 Hz), 5.17 (2 H, br. s.), 4.82 (1 H, br. s.), 3.30 (2 H, d, J 5.94 Hz), 2.69 (2 H, t, J 7.01 Hz), 2.58 (2 H, s), 1.41 (11 H, s)
To a solution of solketal (10; 34.4 g, 260 mmol) in THF (150 niL) was added NaH (10.4 g, 260 mmol) at room temperature and the mixture stirred for Ih. 2- chloro-4-aminopyrimidine (82; 15.0 g, 115 mmol) was then added, and the mixture was stirred at 7O0C for 48 h. The reaction mixture was concentrated and the crude residue was purified by flash chromatography (dichloromethane: methanol = 15:1 - 10:1) to give 2-((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)pyrimidin-4-amine 83 (18.2 g, 70 % yield) as an oil. MS (ESI) calcd for Ci0Hi5N3O3: 225.2; found: 226 [M+l].
70%
To a solution of solketal (34.4 g, 260 mmol) in THF (150 mL) was added NaH (10.4 g, 260 mmol) at room temp and the mixture stirred for 1 h. <strong>[7461-50-9]2-chloro-4-aminopyrimidine</strong> (15.0 g, 115 mmol) was then added, and the mixture was stirred at 70 C for 48 h. The reaction mixture was concentrated and the crude residue was purified by flash chromatography (CH2Cl2:MeOH = 15: 1 - 10:1) to give 2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrimidin-4-amine (18.2 g, 70 % yield) as an oil. MS (ESI) calcd for C1oH15N303: 225.11
With potassium phosphate; 1,1'-bis(di-tertbutylphosphino)ferrocene; palladium diacetate; In 1,4-dioxane; at 100℃; for 5.0h;Inert atmosphere; Sealed tube;
General procedure: To a solution of the requisite chloro-amino-substituted heteroaromatic in anhydrous 1,4-dioxane (30 volumes wrt chloride) in a sealed tube was introduced phenylboronic acid (1.5 equiv) and finely ground potassium phosphate (2.0 equiv). The solution was degassed (N2 bubbling) for 5 min, Pd(OAc)2 (5 mol percent wrt chloride) and di-tert-butylphosphinoferrocene (5 mol percent wrt chloride) introduced and degassing continued for a further 5 min. The tube was sealed under nitrogen and heated with rapid stirring at 100 °C for 5 h. After cooling, the reaction mixture was filtered in vacuo through a celite pad and the precipitated material washed with 1,4-dioxane. The combined filtrates were evaporated and purified by flash column chromatography (neat hexane to 1:1 hexane/EtOAc gradient containing 2.5percent by volume Et3N) to furnish the biarylanilines 13, 14 and 15.
Intermediate 7:6-bromo-W-(2-ch]oro-4-pyrimidinyl)-1,3-benzothiazoi-2-amineTo a solution of 2-chloro-4-pyrimidinamine (1 g, 7.72 mmol) in anhydrous tetrahydrofuran (5 mL) at 0 C was added sodium hydride (60% w/w in mineral oil) (0.926 g, 23.16 mmol) portionwise. The reaction mixture was stirred for 10 minutes at 0 C under nitrogen atmosphere then 6-bromo-2-chloro-1 ,3-benzothiazole (2.11 g, 8.49 mmol) was added portionwise. The reaction mixture was stirred at 0 C under nitrogen atmosphere for 15 minutes, stirred allowing to warm up to room temperature and then heated to 65 C overnight under nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature then water (30 mL) was added and the mixture extracted with ethyl acetate (2 x 50 mL). The aqueous phase was filtered to give the title compound (393 mg, 1.150 mmol, 15 % yield) as a cream solid. LCMS: (Method C): Rt 3.06 minutes; m/z 341 , 343 (MH+).
Step 1-Synthesis of N-(5-bromo-4-fluoro-2-nitrophenyl)-<strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> To a solution of <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (1.31 g, 10.08 mmol) in THF (55 mL) at 0 C. was added sodium hydride (60% in oil, 806.69 mg, 20.17 mmol) portion-wise. The reaction mixture was stirred at 0 C. to RT for 10 minutes and 1-bromo-2,5-difluoro-4-nitrobenzene (1.2 g, 5.04 mmol) was added. The reaction mixture was stirred at 65 C. for 1 h. The reaction mixture was cooled to RT and water (30 mL) was added. Product extracted into DCM (2*30 mL) and washed with water (20 mL). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (Biotage) eluted with DCM:MeOH gradient (99:1 to 95:05) to afford the title compound as an orange solid (1005 mg, 56% yield); 1H NMR (250 MHz, DMSO) delta 6.87 (1H, d, J=5.83 Hz), 8.08 (1H, d, J=6.31 Hz), 8.18 (1H, d, J=8.35 Hz), 8.27 (1H, d, J=5.83 Hz), 10.32 (1H, br. s.); LC-MS: m/z+348.70 (M+H)+.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 110℃; for 1h;Microwave irradiation;
The following reaction was run in triplicate: 4-Amino-2-chloropyrimidine (1.00 g, 7.72 mmol, 1.0 equiv) was dissolved in dioxane (8 mL) in a 20-mL microwave vial, and to it was added 3,4-(methylenedioxy)phenylboronic acid (2.56 g, 15.4 mmol, 2.0 equiv), aqueous Na2CO3 (2.0 M, 8.5 mL, 17.0 mmol, 2.20 equiv), and Pd(PPh3)4 (892 mg, 0.77 mmol, 0.10 equiv). The sealed vial was placed in a microwave reactor and heated at 110 C for one hour. The three crude reaction mixtures were combined and partitioned between CH2Cl2 (50 mL)/H2O (50 mL), and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2 × 50 mL), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude reaction mixture was purified via silica gel column chromatography using MeOH/CH2Cl2 (1:19) as the mobile phase. The solid product was collected and washed with a 1:1 mixture of MeOH/CH2Cl2 to remove residual triphenylphosphine oxide. The pure solid product was set aside and the MeOH/CH2Cl2 wash mixture was concentrated under reduced pressure. The resulting solid was again washed with a 1:1 mixture of MeOH/CH2Cl2 and the washings discarded. The pure solid was combined with that from the first wash, affording the product as a white solid (3.41 g, 15.9 mmol, 68%). TLC: Rf = 0.33, (50% EtOAc in hexanes).
NaH (60% in oil, 2.47 g, 61.8 mmol) was washed twice with pentane and dried under vacuum. THF (25 mL) was added, followed by (3-methyloxetan-3-yl)methanol (6.1 mL, 61.8 mmol) dropwise. This was allowed to stir 1 h at room temp before addition of 15 mL more THF and 4-amino-2-chloropyrimidine (4.0 g, 30.9 mmol). The reaction was heated to reflux for 17 h, cooled and concentrated. Water was added (50 mL), and enough saturated NH4Cl to bring the pH down to 8. The mixture extracted with EtOAc (3x75 mL), and the combined organics were washed with saturated aqueous NaHCO3 and brine, dried with Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (0-10% MeOH/CH2Cl2) to give 2-((3-methyloxetan-3-yl)methoxy)pyrimidin-4-amine (1.84 g, 30%). MS (ESI) calcd for C9H13N3O2: 195.10; found: 196 [M+H]
30%
NaH (60% in oil, 2.47 g, 61.8 mmol) was washed twice with pentane and dried under vacuum. THF (25 mL) was added, followed by (3-methyloxetan-3-yl)methanol (6.1 mL, 61.8 mmol) dropwise. This was allowed to stir 1 h at room temp before addition of 15 mL more TNF and 4-amino-2-chloropyrimidine (4.0 g, 30.9 mmol). The reaction was heated to reflux for 17 h, cooled and concentrated. Water was added (50 mL), and enough saturated NH4Cl to bring the pH down to 8. The mixture extracted with EtOAc (3x75 mL), and the combined organics were washed with saturated aqueous NaHCO3 and brine, dried with Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (0-10% MeOH/CH2Cl2) to give 2-((3-methyloxetan-3-yl)methoxy)pyrimidin-4-amine (1.84 g, 30%). MS (ESI) calcd for C9H13N3O2: 195.10; found: 196 [M+H].
NaH (60% in oil, 126.0 mg, 3.15 mmol) was washed twice with pentane and dried under vacuum. THF (3.0 mL) was added, followed by tetrahydro-2H-pyran-4-ol (0.3 mL, 3.15 mmol) dropwise over 5 min. The mixture was allowed to stir at room temp for 1 h. <strong>[7461-50-9]2-chloro-4-aminopyrimidine</strong> (314.0 mg, 2.43 mmol) was added and the reaction was heated to reflux for 18 h. The mixture was cooled to room temp and water was added (5 mL), along with enough saturated aqueous NH4Cl to bring the pH down to 8. Minimal EtOAc was added (2 mL), but there was a precipitate between layers so the entire mixture was filtered and the solid was washed with water. The solid was dried under vacuum to give clean 2-(tetrahydro-2H-pyran-4-yloxy)pyrimidin-4-amine (220.0 mg, 46%). MS (ESI) calcd for C9H13N3O2: 195.10; found: 196 [M+H]
46%
NaH (60% in oil, 126.0 mg, 3.15 mmol) was washed twice with pentane and dried under vacuum. THF (3.0 mL) was added, followed by tetrahydro-2H-pyran-4-ol (0.3 mL, 3.15 mmol) dropwise over 5 min. The mixture was allowed to stir at room temp for 1 h. <strong>[7461-50-9]2-chloro-4-aminopyrimidine</strong> (314.0 mg, 2.43 mmol) was added and the reaction was heated to reflux for 18 h. The mixture was cooled to room temp and water was added (5 mL), along with enough saturated aqueous NH4Cl to bring the pH down to 8. Minimal EtOAc was added (2 mL), but there was a precipitate between layers so the entire mixture was filtered and the solid was washed with water. The solid was dried under vacuum to give clean 2-(tetrahydro-2H-pyran-4-yloxy)pyrimidin-4-amine (220.0 mg, 46%). MS (ESI) calcd for C9H13N3O2: 195.10; found: 196 [M+H].
16.31%
To a solution of tetrahydro-2H-pyran-4-ol (25g, 245 mmol) in Tetrahydrofuran (THF) (500 mL) stirred under nitrogen, was added NaH (22.52 g, 563 mmol) at 27C in 10 mints, after lhr was added <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (22.20 g, 171 mmol) at 27C. The reaction mixture was stirred at 85C for 36 hr. The progress of reaction was monitored by TLC. TLC indicated a polar spot along with SM. Reaction mass was poured in 200 ml ice cool water, extracted with EtOAc (3X200 ml), combined organic layers dried over Na2S04 filtered and concentrated under reduced pressure and was purified using column chromatography with (60-120) silica mesh SM was eluted at 50% EtOAc in Hexane and required compound was eluted at 90% EtOAc in Hexane, combined compound fractions concentrated to get 2-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-amine (9 g, 39.9 mmol, 16.31 % yield), LCMS (m/z): 196.00 [M+H]+.
Part A 2-[(2S)-2,4-Dimethyl-1-piperazinyl]-4-pyrimidinamine A mixture of 2-chloro-4-pyrimidinamine (200 mg, 1.544 mmol), Hunig's base (1348 mul, 7.72 mmol) and <strong>[1152367-80-0](3S)-1,3-dimethylpiperazine</strong> (Ref.: WO2009061879 (A1)) (318 mg, 1.698 mmol) in N,N-dimethylformamide (DMF) (1.7 ml) was heated to 220 C. via a microwave reactor for 15 min. The reaction mixture was purified by RP-HPLC to yield 2-[(2S)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinamine (88 mg, 0.425 mmol, 28% yield). MS (ES+) m/z 208.0 (MH+).
Pre Step A 2-(Methyloxy)-4-pyrimidinamine A mixture of 2-chloro-4-pyrimidinamine (150 mg, 1.158 mmol) and sodium methoxide (188 mg, 3.47 mmol) in methanol (2.9 ml) was heated to 100 C. via a Biotag microwave for 40 min. The crude product mixture was purified by RP-HPLC to give 2-(methyloxy)-4-pyrimidinamine (73 mg, 0.583 mmol, 50% yield). MS (ES+) m/z 126.0 (MH+).
50%
With sodium methylate; In methanol;
Pre Step A 2-(Methyloxy)-4-pyrimidinamine A mixture of 2-chloro-4-pyrimidinamine (150 mg, 1.158 mmol) and sodium methoxide (188 mg, 3.47 mmol) in methanol (2.9 ml) was heated to 100 C. via a microwave reactor for 40 min. The crude product mixture was purified by RP-HPLC to give 2-(methyloxy)-4-pyrimidinamine (73 mg, 0.583 mmol, 50% yield). MS (ES+) m/z 126.0 (MH+).
With dimethyl amine; In water; N,N-dimethyl-formamide;
Pre Step A N2,N2-Dimethyl-2,4-pyrimidinediamine 40% Dimethylamine in water (1466 mul, 11.58 mmol) was added into the mixture of 2-chloro-4-pyrimidinamine (300 mg, 2.316 mmol) in N,N-dimethylformamide (DMF) (1.5 ml). The resulting reaction mixture was heated in a microwave reactor at 220 C. for 30 min. The reaction mixture was purified by RP-HPLC to yield N,N-dimethyl-2,4-pyrimidinediamine (290 mg, 2.099 mmol, 91% yield) as a white solid. MS (ES+) m/z 139.2 (MH+).
Pre Step A 2-(4-Methyl-1-piperazinyl)-4-pyrimidinamine A mixture of 2-chloro-4-pyrimidinamine (300 mg, 2.316 mmol) and 1-methylpiperazine (771 mul, 6.95 mmol) in N,N-dimethylformamide (DMF) (3 ml) was heated to 220 C. via a microwave reactor for 60 min. The reaction was purified by RP-HPLC to yield 2-(4-methyl-1-piperazinyl)-4-pyrimidinamine (300 mg, 1.552 mmol, 67% yield). MS (ES+) m/z 194.2 (MH+).
With tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In 1,4-dioxane; water; at 100℃;Inert atmosphere;
A mixture of <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (0.50g, 3.8 mmol), N-isopropyl-2-(3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)acetamide (1.46 g, 4.6 mmol), CsF (1.75 g, 11.4 mmol), and Pd(PPli3)4 (0.2 g, 0.2 mmol) in a mixture of dioxane (8 mL) and H20 (2 mL) was stirred at 100 C overnight under N2. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (eluted with PE:EtOAc = 1 : 1 ) to provide the title compound (400 mg, yield 36%) as colourless oil.
36%
With tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In 1,4-dioxane; water; at 100℃;Inert atmosphere;
Example 111 2-(3-(4-aminopyrimidin-2-yl)phenoxy)-N-isopropylacetamide A mixture of <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (0.50g, 3.8 mmol), N-isopropyl-2-(3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)acetamide (1.46 g, 4.6 mmol), CsF (1.75 g, 11.4 mmol), and Pd(PPh3)4 (0.2 g, 0.2 mmol) in a mixture of dioxane (8 mL) and H20 (2 mL) was stirred at 100 C overnight under N2. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (eluted with PE:EtOAc = 1 : 1 ) to provide the title compound (400 mg, yield 36%) as colourless oil
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 1h;Sealed tube; Microwave irradiation;
Into a 30 mL sealed tube was added a solution of 2-chloropyrimidin-4-amine (589 mg, 4.55 mmol) in N,N-dimethylformamide (10 mL), 8-oxa-3-azabicyclo[3.2.1]octane (745 mg, 6.58 mmol) and potassium carbonate (1.59 g, 11.5 mmol). The reaction mixture was irradiated with microwave radiation for 1 h at 120 C. The resulting solution was diluted with H20 (20 mL). The resulting solution was extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography with dichloromethane/methanol (100:9.8) to afford 2-[8-oxa-3-azabicyclo[3.2.1]octan-3-yl]pyrimidin-4-amine (400 mg, 43%) as a white solid. LCMS (ESI): RT (min) = 1.00, [M+H]+ = 207, method = J.
With trifluoroacetic acid; In tert-butyl alcohol; at 120℃; for 72h;
A mixture of 2-chloropyrimidin-4-amine (106.7 mg, 0.8236 mmol), 2-aminoethylmethylsulfone hydrochloride (155.2 mg, 0.9236 mmol), trifluoroacetic acid (0.05 mL, 0.6 mmol) and tert-butanol (2.0 mL, 21 mmol) was heated at 120 C for 3 days. The reaction mixture was poured into 10 mL saturated aqueous sodium bicarbonate and extracted with dichloromethane (3 x 30 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to yield 84.5 mg (47%) of the title compound, which was carried forward without purification. LCMS (ESI): [M+H]+ = 217.1.
With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere;
Into a 250 niL 3 -necked round-bottom flask purged and maintained with nitrogen, was added a solution of 6-bromo-l -isopropyl-2-methyl-lH-imidazo[4,5-c]pyridine (3.50 g, 13.0 mmol) in 1,4- dioxane (70.0 mL), <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (1.70 g, 13.1 mmol), XantPhos (1.70 g, 2.94 mmol), Pd2(dba)3 CHCl3 (1.70 g, 1.64 mmol) and Cs2C03 (11.0 g, 33.7 mmol). The resulting mixture was stirred at 100 C for 4 h. The mixture was cooled to room temperature, the solids were filtered out and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography with dichloromethane/methanol (50: 1) to afford the title compound (1.10 g, 26.1%) as a yellow solid. LCMS (ESI): RT (min) = 1.215, [M+H]+ = 303, method = I. 'HNMR (300HZ, DMSO-d6): delta 10.55 (s, 1H), 8.57 (s, 1H), 8.27-8.25 (d, J= 5.7 Hz, 1H), 8.13 (s, 1H), 7.48 (s, 1H), 4.72-4.68 (m, 1H), 2.58 (s, 3H), 1.58-1.56 (d, 6H).
150 mg
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In 1,4-dioxane; at 100℃;Sealed tube;
A mixture of 6-Bromo-1-isopropyl-2-methyl-1H-imidazo[4,5-c]pyridine (467 mg, 1.85 mmol), <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (266 mg, 2.04 mmol), Pd2(dba)3 (213 mg, 0.37 mmol), xantphos (429 mg, 0.74 mmol), and Cs2CO3 (1.8 g, 5.55 mmol) in dioxane (10 mL) was heated to 100oC overnight in sealed tube with sand-bath. After cooling to rt, the mixture was filtered through Celite, and the filtered cake was washed with EtOAc. The filtrate was concentrated under vacuum. The residue was purified by prep-HPLC to afford the desired product N-(2-Chloropyrimidin-4-yl)- 1-isopropyl-2-methyl-1H-imidazo[4,5-c]pyridin-6-amine (150 mg , 27%). (2072) [00732] 1H NMR (400 MHz, DMSO): delta 8.57 (s, 1H), 8.25 (d, J = 5.6 Hz, 1H), 8.12 (br s, 1H), 7.48 (br s, 1H), 4.71-4.75 (m, 1H), 2.58 (s, 3H), 1.58 (d, J = 7.2 Hz, 6H). (2073) [00733] Chemical Formula: C14H15ClN6; Molecular Weight: 302.77
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 6h;Inert atmosphere;
To a pressure tube was added 6-bromo-l-isopropyl-lH-pyrrolo[3,2-c]pyridine-3-carboxamide (0.15 g, 0.53 mmol), 4-amino-2-chloropyrimidine (70 mg, 0.53 mmol), Xantphos (32 mg, 0.053 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Cs2C03 (0.35 g, 1.1 mmol) and dioxane (2 mL). The mixture was degassed by nitrogen bubbling for 20 min. The reaction vial was then sealed and stirred at 120 C for 6 h. The reaction was then filtered and concentrated. The crude product was purified by flash chromatography on silica gel (solvent gradient: 0-10 % MeOH in DCM) to give the title compound (0.70 g, 40%).
With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); sodium carbonate; In acetonitrile; at 110℃; for 2h;Inert atmosphere;
To a glass vial was added (4-methoxyphenyl)boronic acid (0.15 g, 1.0 mmol), 2-chloropyrimidin- 4-amine (0.13 mg, 1.0 mmol), Pd(Amphos)2Cl2 (35 mg, 0.050 mmol), a 2M solution of Na2C03 (0.75 mL, 1.5 mmol) and acetonitrile (2.5 mL). The mixture was degassed by nitrogen bubbling for 20 min. The reaction vial was sealed and stirred at 110 C in an oil bath for 2 h. The reaction mixture was cooled to room temperature, filtered and concentrated. The crude product was purified by flash chromatography on silica to give the title compound (141 mg, 70%).
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 18h;
2-Chloropyrimidin-4-ylamine (3.5 g, 27.0 mmol), <strong>[4045-25-4]4-methoxypiperidine hydrochloride</strong> (4.09 g, 27.0 mmol) and Cs2C03 (26.4 g, 81.0 mmol) were suspended in DMF (60 mL) and heated at 120 C for 18 h. The reaction mixture was partitioned between water and EtOAc. The aqueous phase was washed with EtOAc (x 2) and the combined organic phases were washed with brine, dried (MgSO i), and concentrated in vacuo affording the title compound as a solid (2.5 g). The aqueous phase was concentrated in vacuo and the slurry was extracted with EtOAc. The volatiles were removed in vacuo and the resulting residue was purified by chromatography (Si-PCC, gradient 0- 100% EtOAc in cyclohexane) and then triturated with cyclohexane affording a second batch of the title compound (2.38 g, 87% combining the two batches). lH NMR (400 MHz, CDC13) delta: 7.94 (1H, d, J=5.60 Hz), 5.74 (1H, d, J=5.60 Hz), 4.53 (2H s), 4.33-4.24 (2H, m), 3.47-3.37 (4H, m), 3.33-3.24 (2H, m), 1.98-1.87 (2H, m), 1.60-1.47 (2H, m).
87%
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 18h;
2-Chloropyrimidin-4-ylamine (3.5 g, 27.0 mmol), <strong>[4045-25-4]4-methoxypiperidine hydrochloride</strong> (4.09 g, 27.0 mmol) and cesium carbonate (26.4 g, 81.0 mmol) were suspended in NN-dimethylformamide (60 mL) and heated at 120 C for 18 h. The reaction mixture was cooled to room temperature and partitioned between water and EtOAc. The aqueous phase was washed with EtOAc (x 2) and the combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo affording the title compound as a solid (2.5 g). The aqueous phase was concentrated in vacuo and the slurry was extracted with EtOAc. The volatiles were removed in vacuo and the resulting residue was purified via flash chromatography on silica gel (solvent gradient: 0%-100% EtOAc in cyclohexane) and then triturated with cyclohexane affording a second batch of 2-(4-methoxypiperidin-l -yl)pyrimidin-4-amine (2.38 g, 87% combined yield). LCMS (ESI): [M+H]+ = 209.2; lH NMR (400 MHz, CDC13) delta: 7.94 (1H, d, J=5.60 Hz), 5.74 (1H, d, J=5.60 Hz), 4.53 (2H s), 4.33-4.24 (2H, m), 3.47-3.37 (4H, m), 3.33-3.24 (2H, m), 1.98-1.87 (2H, m), 1.60-1.47 (2H, m).
Part A 2-[(2S)-2,4-Dimethyl-1-piperazinyl]-4-pyrimidinamine A mixture of 2-chloro-4-pyrimidinamine (200 mg, 1.544 mmol), Hunig's base (1348 mul, 7.72 mmol) and <strong>[1152367-80-0](3S)-1,3-dimethylpiperazine</strong> (Ref.: WO2009061879 (A1)) (318 mg, 1.698 mmol) in N,N-dimethylformamide (DMF) (1.7 ml) was heated to 220 C. via a microwave reactor for 15 min. The reaction mixture was purified by RP-HPLC to yield 2-[(2S)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinamine (88 mg, 0.425 mmol, 28% yield). MS (ES+) m/z 208.0 (MH+).
(±)-tert-butyl cis-3-fluoro-4-methoxypiperidine-1-carboxylate[ No CAS ]
(±)-2-(cis-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-ylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
(±)-fert-Butyl-cz,y-3-fluoro-4-methoxypiperidine-l -carboxylate (530 mg, 2.27 mmol) was dissolved in HC1 in 1 ,4-dioxane (4N, 5 mL) and the reaction mixture was heated at 40 C for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a white solid. To the solid, <strong>[7461-50-9]2-chloro-4-aminopyrimidine</strong> (294 mg, 2.27 mmol), and triethylamine (949 mu^, 6.62 mmol) was added isopropanol (5 mL) and the reaction mixture was heated in a sealed tube at 120 C. After 18 h, the reaction mixture was adsorbed onto diatomaceous earth and purified via flash chromatography on silica gel (solvent gradient: 25%-100% EtOAc in cyclohexanes) to give (±)-2- (cw-3-fluoro-4-methoxypiperidin-l -yl)pyrimidin-4-ylamine as a white solid (370 mg, 70%). LCMS (ESI): [M+H]+ = 227.
(3RS,4SR)-3-fluoro-4-methylpiperidin-4-ol[ No CAS ]
(3RS,4SR)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With triethylamine; In isopropyl alcohol; at 150℃; for 1h;Microwave irradiation;
A mixture of (3RS,4SR)-3-fluoro-4-methylpiperidin-4-ol (1.89 g, 14.2 mmol), 2-chloro-4- aminopyrimidine (1.838 g, 14.2 mmol) and triethylamine (3.9 mL, 28 mmol) in isopropanol (30 mL) was heated under microwave irradiation at 150 C for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in a mixture of dichloromethane and methanol (30: 1, 124 mL), to which potassium carbonate (5.5 g) was added and the mixture stirred for 10 min, filtered and the filtrate concentrated in vacuo. Purification by chromatography on silica (solvent gradient: 50-100% isopropyl acetate in dichloromethane; 50- 100% ethyl acetate in isopropyl acetate) gave the product as a mixture of enantiomers as a white solid (2.09 g, 65%). lH NMR (CDC13): delta 7.92 (1H, d, J= 5.6 Hz), 5.76 (1H, d, J= 5.6 Hz), 4.56 (2H, br s), 4.48-4.40 (1H, m), 4.33 (1H, ddd, J= 47, 9.1, 4.5 Hz), 4.15-4.09 (1H, m), 3.59 (1H, ddd, J= 12.6, 8.8, 5.4 Hz), 3.47 (1H, ddd, J= 13.4, 10.6, 3.3 Hz), 1.95 (1H, dd, J= 2.7, 1.9 Hz), 1.88-1.81 (1H, m), 1.62-1.55 (1H, m), 1.33 (3H, t, J= 1.0 Hz).
2-(2-methanesulfonyl-2-methylpropoxy)pyrimidin-4-ylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With potassium carbonate; In isopropyl alcohol; at 200℃; under 16501.7 Torr; for 2.5h;Microwave irradiation;
A microwave reaction vessel was charged with 4-amino-2-chloropyrimidine (100 mg, 0.774 mmol, 1.0 eq), 2-methanesulfonyl-2-methylpropan-l -ol (353 mg, 2.33 mmol, 3.0 eq), and potassium carbonate (160.3 mg, 1.16 mmol, 1.5 eq) in propan-2-ol (1 mL). The reaction was stirred at room temperature for 1 min and heated under microwave irradiation at 200 C for 2.5 h (Biotage Initiator, maximum pressure set at 22 bar). The reaction mixture was cooled to room temperature and purified by chromatography on silica (solvent gradient: 0-10% 2M methanolic ammonia in ethyl acetate) to afford the title compound (163 mg, 86%). LCMS (ESI): [M+H]+ 246.3.
(3RS,4SR)-3-fluoro-4-methylpiperidin-4-ol hydrochloride[ No CAS ]
(3RS,4SR)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With potassium carbonate; In acetonitrile; at 100℃; for 16h;
A mixture of (3RS,4SR)-3-fluoro-4-methylpiperidin-4-ol hydrochloride (400 mg, 2.36 mmol), 2- chloro-4-aminopyrimidine (255 mg, 1.97 mmol) and potassium carbonate (812 mg, 5.88 mmol) in acetonitrile (5 mL) was stirred for 16 h at 100 C. The solids were removed by filtration and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (solvent gradient: 0-10% methanol in dichloromethane) to afford the title compound (200 mg, 45%) as a yellow solid (mixture of diastereomers with known relative stereochemistry). LCMS (ESI): [M+H]+ = 227
2-(4-methoxypiperidin-4-yl)acetonitrile hydrochloride[ No CAS ]
2-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃;
A mixture of 2-(4-methoxypiperidin-4-yl)acetonitrile hydrochloride (200 mg, 1.05 mmol), 2- chloropyrimidin-4 -amine (90 mg, 0.70 mmol) and N-ethyl-N-isopropylpropan-2-amine (360 mg, 2.79 mmol) in NN-dimethylformamide (7 mL) was stirred overnight at 100 C. The solution was quenched with water, extracted with ethyl acetate (3x), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (solvent gradient: 0-10% methanol in dichloromethane) to afford the title compound (120 mg, 69 %) as a brown solid. LCMS (ESI): [M+H]+= 248.
1-(4-aminopyrimidin-2-yl)-4-methylpiperidin-4-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
In dimethyl sulfoxide; at 100℃;
A mixture of 2-chloropyrimidin-4-amine (2 g, 15.4 mmol) and <strong>[3970-68-1]4-methylpiperidin-4-ol</strong> (1.94 g, 16.8 mmol) in DMSO (20 mL) was stirred overnight at 100 C. The solution was diluted with water (100 mL), extracted with ethyl acetate (10 x), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (solvent gradient: 0-10% methanol in dichloromethane) to afford the title compound (1.9 g, 59%) as a yellow solid. LCMS (ESI): [M+H]+ = 209.
2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); sodium carbonate; In water; acetonitrile; at 80℃; for 24h;Sealed tube;
To a reaction vessel was added l-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-lH-pyrazole (1.0 g, 4.0 mmol), 2-chloropyrimidin-4-amine (550 mg, 4.2 mmol), bis(di-iert- butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (290 mg. 0.40 mmol), 1M sodium carbonate in water (8 mL) and acetonitrile (10 mL). The vessel was sealed and heated at 80 C. After 24 h, the reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified via flash chromatography on an amine-functionalized column (solvent gradient: 0%-20% methanol in dichloromethane) to provide 2-(l-(cyclopropylmethyl)- lH-pyrazol-4-yl)pyrimidin-4-amine (0.6 g, 70%) as a yellow solid. LCMS (ESI): [M+H]+ = 216.1; 'H NMR (400 MHz, DMSO-d6) delta 8.19 (s, 1H), 8.03 (d, J= 5.8 Hz, 1H), 7.88 (s, 1H), 6.75 (s, 2H), 6.22 (d, J= 5.8 Hz, 1H), 4.00 (d, J= 7.2 Hz, 2H), 1.26 (s, 1H), 0.63 - 0.47 (m, 2H), 0.38 (dd, J = 4.5, 1.8 Hz, 2H).
2-(5-methoxyisoindolin-2-yl)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35.4%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; for 16h;
To a solution compound <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (381 mg, 2.95 mmol) and DIEA (692 mg, 5.37 mmol) in CH3CN (20 mL) was added compound 5-methoxyisoindoline (400 mg, 2.68 mmol). Then the reaction was stirred at 90C lbr 16 h. After LCMS showed the reaction was complete. The crude product was purified byprep-TLC to give compound the title compound (230 mg, yield: 35.4 %).
35.4%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; for 16h;
2-(5-methoxyisoindolin-2-yl)pyrimidin-4-amine To a solution compound <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (381 mg, 2.95 mmol) and DIEA (692 mg, 5.37 mmol) in CH3CN (20 mL) was added compound 5-methoxyisoindoline (400 mg, 2.68 mmol). Then the reaction was stirred at 90C for 16 h. After LCMS showed the reaction was complete. The crude product was purified by prep-TLC to give compound the title compound (230 mg, yield: 35.4 %).
(R)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47.3%
With sodium hydride; In tetrahydrofuran; at 65℃; for 16h;
To a solution of sodium hydride (0.817 g, 34.1 mmol) in Tetrahydrofuran (THF) (30 mL) at room temperature was added a solution of (R)-(2,2-dimethyl-l,3-dioxolan-4- yl)methanol (3 g, 22.70 mmol) in THF (5 mL) over 1 min and stirred at room temperature for 15 min then add <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (2.059 g, 15.89 mmol) portion wise at room temperature. The reaction mixture was stirred at 65 C for 16h. The reaction mixture was poured in to water and extracted with EtOAc (3 X lOOmL). Then the combined organic layer was washed with water, brine solution, dried over sodium sulfate and evaporated to get 4.0 g of crude compound. The crude compound was purified by column chromatography using 100-200 silica gel mesh and eluted with 2-3% MeOH/DCM to get pure compound (2.5g, 10.42 mmol, 46%), LCMS (m/z) 226.2 [M+H]+.
46%
To a solution of sodium hydride (0.817 g, 34.1 mmol) in Tetrahydrofuran (THF) (30 mL) at room temperature was added a solution of (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (3 g, 22.70 mmol) in THF (5 mL) over 1 min and stirred at room temperature for 15 min then add <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (2.059 g, 15.89 mmol) portion wise at room temperature. The reaction mixture was stirred at 65 C. for 16 h. The reaction mixture was poured in to water and extracted with EtOAc (3×100 mL). Then the combined organic layer was washed with water, brine solution, dried over sodium sulfate and evaporated to get 4.0 g of crude compound. The crude compound was purified by column chromatography using 100-200 silica gel mesh and eluted with 2-3% MeOH/DCM to get pure compound (2.5 g, 10.42 mmol, 46%), LCMS (m/z) 226.2 [M+H]+.
(S)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30.7%
With sodium hydride; In tetrahydrofuran; at 70℃; for 16h;Inert atmosphere;
To suspension of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (10.20 g, 77 mmol), and NaH (4.63 g, 116 mmol) in tetrahydrofuran (THF) (50 mL) stirred under nitrogen at room temperature was added <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (5 g, 38.6 mmol) portion wise over 15 min. The reaction mixture was stirred at 70 C. for 16 hr. Next, the reaction mixture was quenched with solution of aq. NaHCO3 and then extracted with EtOAc, dried Na2SO4 and evaporated. The crude product was added to a silica gel column and was eluted with 50% Hex/EtOAc. Collected fractions were evaporated to give the desired product (3 g, 11.84 mmol, 30.7% yield) as off white solid, LCMS (m/z) 226.2 [M+H]+.
30.7%
With sodium hydride; In tetrahydrofuran; at 70℃; for 16h;Inert atmosphere;
To suspension of (S)-(2,2-dimethyl-l,3-dioxolan-4-yl)methanol (10.20 g, 77 mmol), and NaH (4.63 g, 1 16 mmol) in tetrahydrofuran (THF) (50 mL)stirred under nitrogen at room temperature was added <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (5 g, 38.6 mmol) portion wise over 15 min. The reaction mixture was stirred at 70 C for 16 hr. Next, the reaction mixture was quenched with solution of aq. NaHC03 and then extracted with EtOAc, dried Na2S04 and evaporated. The crude product was added to a silica gel column and was eluted with 50% Hex/EtOAc. Collected fractions were evaporated to give the desired product (3 g, 1 1.84 mmol, 30.7 % yield) as off white solid, LCMS (m/z) 226.2 [M+H]+.
With sodium hydride; In tetrahydrofuran; mineral oil; for 19h;
The reaction was run similarly to the above, with NaH (60% in oil, 227.0 mg, 5.67 mmol), THF (5.4 mL), (R)-tetrahydrofuran-3-ol (0.456 mL, 5.67 mmol), and <strong>[7461-50-9]2-chloro-4-aminopyrimidine</strong> (566.0 mg, 4.36 mmol) for 19 h. Water and EtOAc were added (10 mL each), along with enough saturated aqueous NH4Cl to bring the pH down to 8 (about 2 mL). The layers were separated and the aqueous layer was washed twice more with EtOAc (2x10 mL). The combined organics were washed with brine, dried with Na2SO4, filtered and concentrated to give 748.0 mg of crude product. This was triturated with Et2O and filtered. The solid was washed with Et2O and dried under vacuum to give (R)-2-(tetrahydrofuran-3-yloxy)pyrimidin-4-amine (419 mg, 53%). MS (ESI) calcd for C8H11N3O2: 181.09; found: 182 [M+H].
51.5%
To a stirred solution of (R)-tetrahydrofuran-3-ol (2.72 g, 30.9 mmol) in THF (30 mL) was added NaH (0.926 g, 23.16 mmol) and stirred for 30 min at room temperature. To this <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (2.0 g, 15.44 mmol) was added in portions for about 15 min and heated at 70 C. for 16 h. The reaction mixture was allowed to room temperature and subsequently cooled to 0 C., quenched with ice cold water and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude compound. The crude product was purified by flash column chromatography (silica-gel: 100-200 mesh) to afford (R)-2-(tetrahydrofuran-3-yloxy)pyrimidin-4-amine (1.6 g, 8.839 mmol, 51.5% yield) as an off white solid.
51.5%
To a stirred solution of (R)-tetrahydrofuran-3-ol (2.72 g, 30.9 mmol) in THF (30 mL) was added NaH (0.926 g, 23.16 mmol) and stirred for 30 min at room temperature. To this 2- chloropyrimidin-4-amine (2.0 g, 15.44 mmol) was added in portions for about 15 min and heated at 70 C for 16 h. The reaction mixture was allowed to room temperature and subsequently cooled to 0 C, quenched with ice cold water and extracted with ethyl acetate (3x50 ml). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude compound. The crude product was purified by flash column chromatography (silica-gel: 100-200 mesh) to afford (R)-2- (tetrahydrofuran-3-yloxy)pyrimidin-4-amine (1.6 g, 8.839 mmol, 51.5 % yield) as an off white solid.
3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol[ No CAS ]
2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With potassium carbonate; caesium carbonate; In N,N-dimethyl acetamide; at 120℃; for 15h;
A mixture of 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (17.0 g, 65.6 mmol), K2CO3 (13.6 g, 98.4 mmol), <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (8.9 g, 69 mmol), 18-crown-6 (0.87 g, 3.3 mmol), and DMA (131 mL) was stirred at 120 Celsius for 15 hours. Water (306 mL) was added, and the reaction mixture cooled to room temperature. Solid precipitate was collected by vacuum filtration and dried in a vacuum oven at 70 Celsius to give the crude product (23.1 g, 100%). The solid was recrystallized from EtOH and treated successively with activated charcoal and silica-supported thiol to remove residual Pd and afford the title compound (13.0 g, 56%). MS (ESI): mass calcd. for C18H17FN6O, 352.14; m/z found, 353.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) delta 8.25 (s, 1H), 8.01 (d, J=1.5, 1H), 7.83 (d, J=5.8, 1H), 7.66 (,m 1H), 7.23 (d, J=8.3, 1H), 7.06 (s, 2H), 6.67 (s, 2H), 6.17 (d, J=5.8, 1H), 3.60-3.47 (m, 1H), 2.19-2.01 (m, 4H), 1.98-1.85 (m, 1H), 1.80-1.68 (m, 1H).
56%
With 18-crown-6 ether; potassium carbonate; In N,N-dimethyl acetamide; at 120℃; for 15h;
A mixture of 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (17.0 g, 65.6 mmol), K2CO3 (13.6 g, 98.4 mmol), <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (8.9 g, 69 mmol), 18-crown-6 (0.87 g, 3.3 mmol), and DMA (131 mL) was stirred at 120 Celsius for 15 hours. Water (306 mL) was added, and the reaction mixture cooled to room temperature. Solid precipitate was collected by vacuum filtration and dried in a vacuum oven at 70 Celsius to give the crude product (23.1 g, 100%). The solid was recrystallized from EtOH and treated successively with activated charcoal and silica-supported thiol to remove residual Pd and afford the title compound (13.0 g, 56%). MS (ESI): mass calcd. for C18H17FN6O, 352.14; m/z found, 353.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) delta 8.25 (s, 1H), 8.01 (d, J=1.5, 1H), 7.83 (d, J=5.8, 1H), 7.66 (m 1H), 7.23 (d, J=8.3, 1H), 7.06 (s, 2H), 6.67 (s, 2H), 6.17 (d, J=5.8, 1H), 3.60-3.47 (m, 1H), 2.19-2.01 (m, 4H), 1.98-1.85 (m, 1H), 1.80-1.68 (m, 1H).
1-(4-aminopyrimidin-2-yl)pyrrolidine-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With triethylamine; In isopropyl alcohol; at 80℃;
Step 1: 1-(4-Aminopyrimidin-2-yl) <strong>[59378-87-9]pyrrolidine-3-carboxylic acid</strong> 102a A 100 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with <strong>[59378-87-9]pyrrolidine-3-carboxylic acid</strong> (1.20 g, 10 mmol), 2-chloropyrimidin-4-amine (1.30 g, 10 mmol), isopropyl alcohol (IPA, 40 mL), and TEA (6 mL). The mixture was heated at 80 C. overnight (O/N). After this time the reaction was cooled to room temperature (r.t.). It was then filtered and the filter cake was washed with DCM to afford 102a (1.4 g, 67%) as a pale yellow solid. MS: [M+H]+ 209.1
2-(2,2-dimethylpyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine[ No CAS ]
2’-(2,2-dimethylpyrrolidin-1-yl)-[2,5’-bipyrimidin]-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
> 100%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;
To a mixture of 2-(2,2-dimethylpyrrolidin-l-yl)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrimidine (9.5 g, 31 mmol) in 1,4-dioxane (140 mL) was added 4-amino-2- chloropyrimidine (4.5 g, 34.5 mmol) and 2M K2C03 (20.4 mL, 40.7 mmol). The orange mixture was degassed with N2; then Pd(PPh3)4 (3.65 g, 3.1 mmol) was added. The reaction was stirred at 80 C overnight. The reaction was cooled to RT, poured into water and extracted with EtOAc (3 x 150 mL). The combined organic layer was washed with brine, dried over Na2S04, and concentrated. The residue was purified by chromatography eluting with PE : EA (1 : 1) to afford compound 2'-(2,2-dimethylpyrrolidin-l-yl)-[2,5'-bipyrimidin]-4-amine (8.96 g, >100%) as a yellow solid. MH+ 271.
(S)-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)boronic acid[ No CAS ]
(S)-2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 110℃; for 3h;Inert atmosphere;
To a mixture of (S)-2-(2-(trifluoromethyl)pyrrolidin-l-yl)pyrimidin-5-ylboronic acid (9.5 g, 36.4 mmol), <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (4.3 g, 33.1 mmol) and Na2C03 (7.0 g, 66.2 mmol) in dioxane (105 mL) and water (35 mL) was added Pd(PPh3)4 (3.8 mg, 3.31 mmol). The mixture was degassed with nitrogen and then stirred at 110 C for 3 h. The reaction was cooled and filtered through Celite. The filtrate was partitioned with EA (300 mL) and water (150 mL). The organic phase was washed with brine (100 mL), dried over Na2S04 and concentrated. The residue was purified by chromatography eluting with DCM/MeOH (100 : 1 to 80 : 1 to 70 : 1) to give (S)-2-(2-(2- (trifluoromethyl)pyrrolidin-l-yl)pyrimidin-5-yl)pyrimidin-4-amine (8 g, 78%) as a white solid. 1H-NMR (CDC13) delta 9.16 (s, 2H), 8.13-8.14 (d, J = 10 Hz, 1H), 6.97 (s, 2H), 6.34-6.35 (d, J = 6 Hz, 1H), 5.09-5.13 (m, 1H), 3.67-3.72 (m, 2H), 2.06-2.21 (m, 4H). MH+ 311.
78%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 110℃; for 3h;Inert atmosphere;
To a mixture of (S)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-ylboronic acid (9.5 g, 36.4 mmol), <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (4.3 g, 33.1 mmol) and Na2CO3 (7.0 g, 66.2 mmol) in dioxane (105 mL) and water (35 mL) was added Pd(PPh3)4 (3.8 mg, 3.31 mmol). The mixture was degassed with nitrogen and then stirred at 110o C for 3 h. The reaction was cooled and filtered through Celite. The filtrate was partitioned with EA (300 mL) and water (150 mL). The organic phase was washed with brine (100 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography eluting with DCM/MeOH (100 : 1 to 80 : 1 to 70 : 1) to give (S)-2-(2-(2- (trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrimidin-4-amine (8 g, 78%) as a white solid. 1H-NMR (CDCl3) delta 9.16 (s, 2H), 8.13-8.14 (d, J = 10 Hz, 1H), 6.97 (s, 2H), 6.34-6.35 (d, J = 6 Hz, 1H), 5.09-5.13 (m, 1H), 3.67-3.72 (m, 2H), 2.06-2.21 (m, 4H). MH+ 311.
(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)boronic acid[ No CAS ]
2’-(3-azabicyclo[3.1.0]hexan-3-yl)-[2,5’-bipyrimidin]-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63.17%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 2h;Inert atmosphere;
To a mixture of <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (100.0 mg, 0.772 mmol)2-(3- azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-ylboronic acid (158.0 mg, 0.772 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was added Na2CO3 (204.5 mg, 1.93 mmol). After the mixture was degassed with N2 for 3 times, Pd(PPh3)4 (11.5 mg, 0.01 mmol) was added under N2 and the mixture was stirred at 90 oC for 2 hrs. The reaction mixture was cooled down and diluted with EA, washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography (eluted with PE: EA = 1: 1) to afford 2'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,5'-bipyrimidin-4-amine (124 mg, 63.17 % yield) as a yellow solid. Retention time (LC-MS): 0.573 min. MH+255.
33.8%
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;
A mixture of (2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)boronic acid (150.0 mg, 1.2 mmol), <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (237.9 mg, 1.2 mmol), Pd(PPh3)2Cl2 (86.0 mg, 0.1 mmol) and Na2C03 (245.9 mg, 2.3 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was degassed with nitrogen and stirred at 80 C overnight. The reaction was cooled to RT and poured into EA. The organic phase was separated, washed with water and brine, dried over Na2S04 and concentrated. The residue was dissolved in ether. An insoluble residue was removed by filtration and the filtrate was concentrated to give 2'-(3-azabicyclo[3.1.0]hexan-3-yl)-[2,5'-bipyrimidin]-4- amine (100 mg, 33.8%) as a white solid. MH+ 255.
(2-(3-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)boronic acid[ No CAS ]
2’-(3-(trifluoromethyl)pyrrolidin-1-yl)-[2,5‘-bipyrimidin]-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52.6%
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere;
A mixture of (2-(3-(trifluoromethyl)pyrrolidin-l-yl)pyrimidin-5-yl)boronic acid (320.0 mg, 1.2 mmol), <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (158.1 mg, 1.2 mmol), Pd(PPh3)2Cl2 (86.0 mg, 0.1 mmol) and Na2C03 (260.0 mg, 2.5 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was degassed with nitrogen and stirred at 90 C overnight. The reaction was cooled to RT and poured into EA. The organic phase was washed with water and brine, dried over Na2S04 and concentrated. The residue was dissolved in ether. An insoluble residue was removed by filtration and the filtrate was concentrated to give 2'-(3-(trifluoromethyl)pyrrolidin-l-yl)-[2,5'-bipyrimidin]-4- amine (200 mg, 52.6%) as a white solid. MH+ 311
(S)-(2-(2-methylpiperidin-1-yl)pyrimidin-5-yl)boronic acid[ No CAS ]
(S)-2’-(2-methylpiperidin-1-yl)-2,5‘-bipyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81.8%
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere;
A mixture of (S)-2-(2-methylpiperidin-l-yl)pyrimidin-5-ylboronic acid (752 mg, 3.4 mmol), 4-amino-2-chloropyrimidine (400 mg, 3.09 mmol), Pd(PPh3)2Cl2 (216.0 mg, 0.3 mmol) and Na2C03 (655 mg, 6.18 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) was degassed with nitrogen and stirred at 80 C for 2 h. The reaction was cooled to RT and partitioned between EA (20 mL) and water (15 mL). The organic phase was washed with water and brine, dried over Na2SC"4 and concentrated. The residue was dissolved in ether. An insoluble residue was removed by filtration and the filtrate was concentrated to give (S)-2'-(2-methylpiperidin-l-yl)- 2,5'-bipyrimidin-4-amine (682 mg, 81.8%) as a white solid. MH+ 271
(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)boronic acid[ No CAS ]
2’-(6,6-difluoro-3-azabicyclo[3. 1.0]hexan-3-yl)-[2,5’-bipyrimidin]-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72.6%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 3h;Inert atmosphere;
A mixture of (2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)boronic acid (241.0 mg, 1.0 mmol), <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (129.0 mg, 1.0 mmol), Pd(PPh3)4 (57.8 mg, 0.05 mmol) and K2C03 (276.4 mg, 2.0 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was degassed and purged with N2 three times. The reaction was heated at 90 C with stirring for 3 h. The resulting mixture was cooled to RT and poured into EA. The organic phase was separated, washed with water and brine, dried over Na2S04 and concentrated. The residue was purified with chromatography eluting with DCM:MeOH (50: 1) to afford 2'-(6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)-[2,5'-bipyrimidin]-4-amine (210 mg, 72.3% yield) as a white solid. MH+ 291.
72.3%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 3h;Inert atmosphere;
A mixture of (2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)boronic acid (241.0 mg, 1.0 mmol)<strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (129.0 mg, 1.0 mmol), Pd(PPh3)4 (57.8 mg, 0.05 mmol) and potassium carbonate(276.4 mg, 2.0 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was degassed and purged with N2 for three times and stirred at 90 oC under N2 for 3 hrs. The reaction mixture was cooled down and poured into EA. The organic phase was separated, washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified with column chromatography (eluted with DCM: MeOH = 50: 1) to afford 2'-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-[2,5'-bipyrimidin]-4- amine (210 mg, 72.3% yield) as a white solid. Retention time (LC-MS): 0.37 min. MH+ 291.
3-(2-chloropyrimidin-4-yl)-1,1-dimethylurea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64.1%
To a solution of <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (0.250 g, 1.930 mmol) in DMF (19.30 mL) at 0 C. was added 60% NaH (0.154 g, 3.86 mmol). The reaction mixture was stirred at 0 C. for 30 minutes, then dimethylcarbamic chloride (0.177 mL, 1.930 mmol) was added. The reaction was allowed to reach room temperature and was stirred at room temperature for 1 hour. The reaction was poured on ice/water (50 mL), and the product was extracted into EtOAc (3*20 mL). The combined organic phases were dried over MgSO4, and the volatiles were removed under reduced pressure. 3-(2-Chloropyrimidin-4-yl)-1,1-dimethylurea (0.248 g, 1.236 mmol, 64.1% yield) was isolated and used in the next step without further purification.
N-(2-chloropyrimidin-4-yl)cyclopropanecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
To an ice-cold solution of <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (400 mg, 3.1 mmol) in 6 mL of DMF was added NaH (148 mg, 3.7 mmol) and the reaction mixture was stirred at 0 C. for 30-40 min. Neat cyclopropanecarbonyl chloride (0.36 mL, 0.40 mmol) was added dropwise to the reaction mixture which was allowed to warm to room temperature overnight. The reaction was quenched with NaHCO3 (satu.) followed by extraction with EtOAc. Organic layer was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The crude was purified by ISCO, using 40 g normal phase column with a gradient elution of EtOAc in CH2Cl2 providing 250 mg (41% yield) of the title compound III-10. 1H NMR (300 MHz, DMSO-d6) delta ppm 11.57 (s, 1H), 8.52 (d, J=5.86 Hz, 1H), 7.99 (d, J=5.57 Hz, 1H), 1.96 (m, 1H), 0.81-1.04 (m, 4H). LCMS (Method 1): Rt 1.92 min, m/z 198.06 [M+H]+.
(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)boronic acid[ No CAS ]
2-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.1%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 3h;Inert atmosphere;
To a mixture of (6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)boronic acid (240.0 mg, 1.0 mmol)<strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (129.0 mg, 1.0 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was added potassium carbonate (276.4 mg, 2.0 mmol). After the mixture was degassed with N2 for 3 times, Pd(PPh3)4 (57.8 mg, 0.05mmol) was added under N2 and the mixture was stirred at 90 oC for 3 hrs. The reaction mixture was cooled down and poured into EA. The organic phase was separated, washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography (eluted with PE : EA = 1: 1) to afford the title product (140 mg, 58.1 % yield) as a white solid. Retention time (LC-MS): 0.365 min. MH+ 290.
(5-methyl-6-(trifluoromethyl)pyridin-3-yl)boronic acid[ No CAS ]
2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93.5%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere;
To a mixture of 5-methyl-6-(trifluoromethyl)pyridin-3-ylboronic acid (50 mg, 0.24 mmol)2- chloropyrimidin-4-amine (35 mg, 0.27 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was added Na2CO3 (78 mg, 0.73 mmol). After the mixture was degassed with N2 for 3 times, Pd(PPh3)4 (5.0 mg, 0.01 mmol) was added under N2 and the mixture was stirred at 100 oC overnight. The reaction mixture was cooled down and poured into EA. The organic phase was separated, washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography (eluted with PE: EA = 5: 1) to afford 2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-amine (58 mg, 93.5% yield) as light yellow solid. Retention time (LC-MS): 0.522 min. MH+ 255.
(6-methyl-5-(trifluoromethyl)pyridin-3-yl)boronic acid[ No CAS ]
2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73.99%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere;
To a mixture of 6-methyl-5-(trifluoromethyl)pyridin-3-ylboronic acid (359.0 mg, 1.93 mmol)<strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (250.0 mg, 1.93 mmol) in 1,4-dioxane (8 mL) and H2O (2 mL) was added Na2CO3 (465.0 mg, 4.4 mmol). After the mixture was degassed with N2 for 3 times, Pd(PPh3)4 (21.5 mg, 0.019mmol) was added under N2 and the mixture was stirred at 100 oC for 3 hrs. The reaction mixture was cooled down and poured into EA. The organic phase was separated, washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography (eluted with PE : EA = 5: 1) to afford 2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-amine (330 mg, 73.99 % yield) as a yellow solid. Retention time (LC-MS): 0.812 min. MH+ 255.
(R)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-ylboronic acid[ No CAS ]
(R)-2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere;
To a mixture of (R)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-ylboronic acid (200 mg, 0.766 mmol)<strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (88 mg, 0.689mmol) in 1,4-dioxane (2.3 mL) and H2O (0.75 mL) was added Na2CO3 (162 mg, 1.52 mmol). After the mixture was degassed with N2 for 3 times, Pd(PPh3)4 (28 mg, 0.029mmol) was added under N2 and the mixture was stirred at 100 oC for 3 hrs. The reaction mixture was cooled down and poured into EA. The organic phase was separated, washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified with column chromatography (eluted with PE: acetone =4: 1) to afford (R)-2'-(2-(trifluoromethyl)pyrrolidin- 1-yl)-2,5'-bipyrimidin-4-amine (200 mg,84 % yield) as a white solid. Retention time (LC-MS): Retention 0.361min. MH+ 311.
To a solution of 4-amino-2-chloropyrimidine (2.90 g, 22.4 mmol) in DMF (40 mL) was added 60% NaH in oil (1.07 g, 26.9 mmol) at 0 C. After stirring for 20 minutes, acetic anhydride (4.2 mL, 44.8 mmol) was added. The mixture was stirred at room temperature overnight. Once LCMS and TLC showed reaction completion, the reaction mixture was quenched by the addition of water and extracted with EtOAc. The organic layer was washed with water and brine dried (Na2SO4) and concentrated. The crude material was recrystallized from Hexanes/EtOAc to afford the product III-4 as white crystals (2.40 g, 62% yield). 1H NMR (300 MHz, DMSO-d6): delta ppm 11.29 (s, 1H), 8.57 (d, J=5.8 Hz, 1H), 8.03 (d, J=5.8 Hz, 1H), 2.13 (s, 3H). LCMS: m/z 172.0, 174.0 [M+H].
29%
at 140℃; for 3h;
4-Amino-2-chloropyrimindine (1.3 g, 10.03 mmol) was suspended in Ac20 (9.47 mL, 100 mmol) then heated at 140 C for 3 h. The reaction was cooled to rt then Et20 (50 mL) was added and the resulting precipitate was filtered off This solid was purified by normal phase column chromatography [CyH/(EtOAc/EtOH 3:1) 90/10 to 50/501 to afford N-(2- chloropyrimindin-4-yl)acetaminde (500 mg, 2.91 mmol, purity: 100 %, recovery: 29 %) as awhite powder. LCMS (m/z) 172 and 174 (M+H), retention time: 1.29 min LC/MS Method1.
With pyridine; In dichloromethane; at 0 - 75℃; for 6h;
To a stirred solution of 4-amino-2-chloro pyrimidine (0.6 g, 4.65 mmol) in DCM (5 mL), pyridine (1.8 mL) and acetic anhydride (0.71 g, 6.9 mmol) were added at 0 C and stirred at 75C for 6 h. The reaction mixture was concentrated under vacuum and the resulting crude product was dissolved in EtOAc (15 mL). The organic layer was washed with water (10 mL), brine (10 mL) and dried over anhydrous Na2SO4. After concentration under vacuum, the crude product was taken as such for next step. Yield: 56.9% (0.45 g, pale brown solid). LCMS: (Method A) 172.0 (M+H), Rt. 1.58 min, 80.2% (Max).
With pyridine; In dichloromethane; at 0 - 75℃; for 6h;
To a stirred solution of 4-amino-2-chloro pyrimidine (0.6 g, 4.65 mmol) in DCM (5 mL), pyridine (1 .8 mL) and acetic anhydride (0.71 g, 6.9 mmol) were added at 0 C and stirred at 75C for 6 h. The reaction mixture was concentrated under vacuum and the resulting crude product was dissolved in EtOAc (15 mL). The organic layer waswashed with water (10 mL), brine (10 mL) and dried over anhydrous Na2SO4. After concentration under vacuum, the crude product was taken as such for next step. Yield:56.9% (0.45 g, pale brown solid). LCMS: (Method A) 172.0 (M+H), Rt. 1.58 mm, 80.2% (Max).
methyl (2-chloropyrimidin-4-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
To a solution of <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (1 g, 7.71 mmol) in DMF (10 mL) was added sodium hydride (60% in paraffin oil, 620 mg, 15.43 mmol). The resulting suspension was stirred at ambient temperature for 20 minutes. To this mixture was added methyl carbonochloridate (0.9 mL, 11.57 mmol), and the mixture was then stirred at room temperature overnight. Once TLC and MS showed completion of reaction, the mixture was poured on to crushed ice, the resulting solid was filtered, washed with water and dried to afford the title compound as a yellow solid (890 mg, 62% yield). The compound was used in the next step without further purification.
methyl 2-((2-chloropyrimidin-4-yl)amino)thiazole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A solution of a mixture of 2-chloropyrimidin-4-amine (5.0 g, 38.5 mmol) and <strong>[72605-86-8]methyl 2-chlorothiazole-5-carboxylate</strong> (6.85 g, 38.5 mmol, 1 equivalent (eq)) in dry N,N- dimethylformamide (75 ml) was cooled to 0 C and was treated portionwise over 5 min with sodium hydride (60% w/w in mineral oil, 3.1 g, 76.9 mmol, 2 eq). The reaction mixture was stirred at 0 C for 1 h and warmed to ambient temperature for a further 1 h. The mixture was treated with saturated ammonium chloride, followed by saturated aqueous Na2C03 solution to reach pH 9, and the resulting mixture was extracted with 1: 1 mixture of dichloromethane and ethyl acetate. The organic extracts were combined, dried using a hydrophobic frit, and evaporated under reduced pressure. The residue was purified by chromatography on silica to afford the title compound as an off-white solid. LCMS retention time (RT): 2.70 (Method A), Mass mlz: 270.99 (M+l).
4-((4-aminopyrimidin-2-yl)oxy)-2-methylbutan-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65.3%
To a stirred suspension of NaH (1.698 g, 42.5 mmol) in 1,4-Dioxane (100 mL) under nitrogen at 0C was added a solution of 3-methylbutane-l,3-diol (4.42 g, 42.5 mmol) in 1,4-Dioxane (50 mL) dropwise during 15 min at 0C. After 10 min added 2- chloropyrimidin-4-amine (5.00 g, 38.6 mmol) portion wise during 15 min at 0C. The reaction mixture was heated at 100 C for 16 hr. Progress of the reaction was monitored by TLC. Reaction mixture was poured into ice water, concentrated to get sticky mass as a crude. The crude was purified by column chromatography by using silica gel (60-120 mesh) by eluting with 50-70% EtOAc in hexane to get 4-((4-aminopyrimidin-2-yl)oxy)-2- methylbutan-2-ol (6.3 g, 29.6 mmol, 77 % yield) as and off-white solid, LCMS (m/z): 198.30 [M+H]+.
2-chloro-N-(4-methoxy-2-nitrophenyl)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
2-chloropyrimidin-4-amine (518.2 mg, 4 mmol) and DMF (10 mL) was added in a 100 mL of round-bottom flask. Under the protection of N2, the mixture was cooled to 0 C with an ice-salt bath, and then NaH (295 mg, 8 mmol) was added. After stirring for 30 minutes, <strong>[61324-93-4]1-fluoro-4-methoxy-2-nitrobenzene</strong> (684.5 mg, 4 mmol) was added, and the reaction solution was warmed up slowly to room temperature and stirred for 1 h. In an ice-salt bath, 30 mL of water was added, and a solid was precipitated. The solid was filtered, and the filter cake was dissolved in dichloromethane. The solution was dried over anhydrous sodium sulfate and concentrated to obtain 2-chloro-N-(4-methoxy-2-nitrophenyl)pyrimidin-4-amine (1 g, 89%). MS m/z (ESI): 281.0 [M+H]+.
2-[3-(2-chlorobenzyl)-1H-indazol-1-yl]pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With hydrogenchloride; In 1,4-dioxane; 1-methyl-pyrrolidin-2-one; at 140℃; for 1.5h;Microwave irradiation;
270 mg 3-(2-chlorobenzyl)-1H-indazole 1-3 (1.11 mmol, 1.0 eq.), 144 mg 2-chloro- pyrimidin-4-amine (1.11 mmol, 1.0 eq.) and 310 pL hydrochloric acid in dioxane (4 M) were dissolved in 2.7 mL NMP. The reaction mixture was heated vor 90 mm in a microwave oven at 140G. After adding of several mL of water, the pH value wasadjusted to 8 to 9 by adding of aqueous sodium hydroxid solution. The precipitated crude product was filtered off and was purified by flash chromatography yielding 246 mg (0.73 mmol, 65 %) of the title compound.1HNMR (300 MHz, DMSO-d6): o[ppm]= 4.43 (5, 2H), 6.28 (d, 1H), 7.16-7.34 (m, 6H),7.41 -7.50 (m, 2H), 7.59 (d, 1H), 8.10 (d, 1H), 8.70 (d, 1H).LC-MS: retention time: 1 .01 mmMS (ES÷): 336.0 [M+H]+ (Method 1)
tert-butyl 4-(4-aminopyrimidinyl-2-yl)pyrazole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59.49%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere;
<strong>[7461-50-9]2-chloro-4-aminopyrimidine</strong>(3.0 g, 23.2 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazol-1-carboxylic ester(8.2 g, 27.8 mmol), and potassium carbonate(9.6 g, 69.5 mmol) were dissolved in the mixed solvent of dioxane(30 mL) and water(5 mL). Then Pd(dppf)Cl2(1.7 g, 2.3 mmol) was added. It was evacuated and replaced with nitrogen. The reaction mixture was stirred at 80C in an oil bath for 2 hours under the protection of nitrogen, and the complete reaction was tracked and determined by TLC. After cooling, the mixture was filtered through diatomaceous earth and filter cake washed with ethyl acetate (100 mL) and tetrahydrofuran(100 mL). The filtrate was dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by using silica gel column chromatography(eluting with petroleum ether/ethyl acetate=2/1?1/1) to give tert-butyl 4-(4-amidopyrimidinyl-2-yl) pyrazole-1-carboxylate(4.50 g, 59.49% yield) as a pale yellow oil. 1H NMR (400MHz, DMSO-d6) delta = 8.50 (s, 1H), 8.17 (s, 1H), 8.07 (d, J=5.8 Hz, 1H), 6.92 (br. s., 2H), 6.30 (d, J=5.8 Hz, 1H), 1.58 (s, 9H). MS (ESI). Calcd. for C12H15N5O2 [M + H]+262, Found 262.
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 110℃; for 16h;
2-Chloropyrimidin-4-amine (5 g, 38.6 mmol) was dissolved in 50 ml of dioxane. 4- Methoxypiperidine (4.9 g, 42.5 mmol, 1.1 equiv.) and Hunig's base (5.5 g, 7.41 ml, 42.5 mmol, 1.1 equiv.) were added at room temperature. The mixture was stirred at H0C for 16 hours. The reaction mixture was evaporated to dryness and the residue suspended in diisopropylether. The solid was filtered, washed with diisopropylether and dried for 2 hours at 50C and <10 mbar. The desired 2-(4-methoxy-l-piperidyl)pyrimidin-4-amine (6.6 g, 82% yield) was obtained as a light yellow solid, MS: m/e = 209.1 (M+H+).
(5-chloro-2-(4-methoxyphenyl)imidazo[1,2-c]pyrimidin-3-yl)(phenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen; lithium carbonate; copper(II) bis(trifluoromethanesulfonate); In toluene; at 120℃; for 8h;Schlenk technique;
Phenylacetylene 1b (44 muL, 0.40 mmol) was sequentially added to a 15 mL Schlenk reaction tube under an atmospheric pressure of oxygen.4-methoxybenzyl bromide 2g (43.7 muL, 0.30 mmol), <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> 3j (51.8 mg, 0.40 mmol), copper trifluoromethanesulfonate (28.9 mg, 0.08 mmol),Lithium carbonate (3.1 mg, 0.04 mmol), 2,2,6,6-tetramethylpiperidinooxy(12.7 mg, 0.08 mmol), toluene (1 mL), and reacted at a temperature of 120 C for 8 hours;After the reaction is completed, it is cooled to room temperature, suction filtered through celite, and concentrated to give a crude product;The crude product was chromatographed on the prepared silica gel plate, and the selected developing agent or eluent was a volume ratio of petroleum ether to ethyl acetate of 5:1.The product (5-chloro-2-(4-methoxyphenyl)imidazo[1,2-c]pyrimidin-3-yl)(phenyl)methanone (4j): white solid, yield 76% (110.6 mg).
Benzyl alcohol (4.0 mL, 39.0 mmol) was added drop wise to a stirring mixture of NaN (0.36 g, 15.0 mmol) in dry THF (12 mL) at 0C, under nitrogen atmosphere. The mixture was stirred for another 30 minutes until it forms a clear solution followed by the addition of 4-Amino-2-chloropyrimidine (0.33 g, 2.55 mmol) at 0 C and then heated at 80 C for 12 h. The reaction mixture was concentrated under reduced pressure. The Crude mixture was purified using column chromatography (60% EtOAc/Hexanes) to afford the desired product as a white solid. M.P. 76-78 C (lit. 80-81 C). ?H NMR (400 MHz, CDCI3): 8 ppm 7.82 (d, IH), 7.36 (d, 2H), 7.25-7.2 1 (m, 3H), 5.95 (d, IH), 5.89 (hr s, 2H), 5.28 (s, 2H). ?3C NMR (100 MHz, CDCI3); 8 ppm 165.0, 164.7, 156.5, 136.6, 128.1, 127.6, 127.5, 99.7, 68.1 ppm. IR (neat) 3465, 3324, 3034, 3034, 1635, 1559, 1455, 1352, 1292 cm1. HRMS (ESI) Calculated for C, 1H,2N30 rn/z (Mj 202.0980, Obs?d 202.0977.
In a reaction apparatus with a reflux condenser, 2,3-dimethyl-6-chloro-2H-carbazole 18gAnd 14.5 g of 2-chloro-4-amino-pyrimidine were added to 220 mL of N,N-dimethylformamide.In an ice salt bath at 0 C under nitrogen protection,50 mL of a tetrahydrofuran solution containing 12% of sodium hydride in a content of 60% was slowly added dropwise.After the addition was completed, the temperature was raised to room temperature, and the reaction was continued for 5 hours.Then use the existing strong alkaline environment of the reaction system,100 mL of tetrahydrofuran solution in which 14 g of methyl iodide was dissolved was added dropwise.The reaction was continued for 6 h at room temperature, and new substances appeared in the reaction system monitored by TLC.And the content of the new substance in the reaction system is determined by HPLC to occupy 90% to 95%,The reaction system was cooled to 10 C, and then dilute hydrochloric acid was slowly added dropwise.The pH of the reaction solution was adjusted to be neutral, and then tetrahydrofuran was removed by evaporation under vacuum.The reaction solution was allowed to stand for a while, and then 70 mL of a saturated ammonium chloride solution was added to the reaction solution.Then, 250 mL of chloroform was added to the reaction solution.After stirring for 10 min, the organic phase was separated and the organic phase was concentrated.The concentrate is recrystallized from acetone and cyclohexane to giveN-(2-chloropyrimidin-4-yl)-N-methyl-2,3-dimethyl-2H-indazole-6-amine 20.7 g;
N-(2-chloropyrimidin-4-yl)-4-fluorobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89.1%
With triethylamine; In dichloromethane; at 20℃;Inert atmosphere;
4-Fluorobenzoic acid (10g, 69.2mmol) was dissolved in toluene (100mL), cooled to 0 C, and dichlorosulfoxide (27g, 142.9mmol) was slowly added dropwise under nitrogen protection, and the reaction was moved to room temperature for 1 hour , Refluxed overnight. TLC monitoring. After the reaction was completed, the solvent and dichlorosulfoxide were removed to obtain 4-fluorobenzoyl chloride.Dissolve <strong>[7461-50-9]2-chloro-4-aminopyrimidine</strong> (7.5g, 57.7mmol) and TEA (9.8mL, 69.8mmol) in dichloromethane (100mL), cool to 0 C, and obtain 4-fluorobenzene under nitrogen protection. The formyl chloride was slowly added dropwise, naturally allowed to warm to room temperature, and stirred overnight. TLC monitoring. After the reaction was completed, the solvent was removed, diluted with ethyl acetate (200 mL), washed with saturated brine, dried over anhydrous Na 2 SO 4, filtered, and dried. Purification by silica gel column chromatography gave a white solid (13 g, 89.1% yield).
With pyridine; In dichloromethane; at 20℃; for 16h;
In a round bottom flask, acetyl chloride (0.823 mL, 11.58 mmol) was added to a solution of <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (750 mg, 5.79 mmol) in pyridine (1.873 mL, 23.16 mmol) and CH2CL2 (30 mL). The reaction mixture was stirred at rt for 16 h. The reaction mixture was washed with cold 1 N HC1 (2 x 40 L), saturated aqueous sodium bicarbonate (50 mL), and brine (50 mL), dried over MgS04, filtered, and concentrated. The product was purified by column chromatography on silica gel (20% ----> 65% ethyl acetate in hexanes; 120 g column) to afford iV-(2-chloropyrimidin-4-yl)acetamide (610 mg, 3 56 mmol, 61% yield) as a pale yellow solid lH NMR (400 MHz, CHLOROFORM-d) 6 8.53 (d, >5.8 Hz, Hi), 8.13 (d, >5.8 Hz, 1H), 2 27 (s, 31 1 ); LC/MS (ESI) m/e 171.9 [(M+Naf, calcd for 0,1 LCTvONa 172.1], fe = 0.72 min (Method 2).
With DABCO; In water; dimethyl sulfoxide; at 60.0℃; for 6.0h;
A solution of Example 143a (2.0 g, 15.5 mmol) in DMSO/H2O (20 mL/ 20 mL) were treated with NaCN (1.52 g, 31.0 mmol) and DABCO (1.74 g, 15.5 mmol). The mixture was stirred at 60oC for 6 h. After reaction completed, the solvent was extracted by DCM (50 mL) and concentrated to give crude product, which was purified directly by Prep-HPLC to give the desired product Example 143b (500 mg, 26.8% yield) as a white solid. LCMS [M+1] + = 121.0
Stage #1: iodotrifluoromethane In dimethyl sulfoxide at 6 - 10℃; for 2.16667h;
Stage #2: 2-chloropyrimidin-4-amine With ferrous(II) sulfate heptahydrate; dihydrogen peroxide In water; dimethyl sulfoxide at 0 - 20℃; for 3h;
1.A2 Step A2: Alternative Preparation of 2-chloro-5-(trifluoromethyl)-4-pyrimidinamine
In a round-bottom flask, trifluoroiodomethane (CF3I) gas (113.95 g, 581.39 mmol) was sparged into dimethylsulfoxide (150 mL) at 10 °C for 2 h. The resulting solution was added dropwise at 6 °C for 10 min to a stirred solution of 2-chloro-4-pyrimidinamine (25.0 g, 193.8 mmol) in dimethylsulfoxide (120 mL). Ferrous sulfate (FeSO4.7 H2O) (16.0 g, 58.1 mmol) in water (75 mL) was added to this mixture dropwise at 0 °C and then 30% hydrogen peroxide solution (13.17 g, 44 mL, 387.6 mmol) was added very slowly (dropwise) at 0 °C for 1 h. The resulting mixture was stirred at ambeint temperature for 2 h. Concentrated hydrochloric acid (50 mL) was added dropwise to the reaction mixture at 0 °C for 30 min and the reaction mixture was stirred at 0 °C for 30 min. Progress of the reaction was monitored by thin layer chromatograpy. The reaction mixture was poured into ice water, and the resultant precipitated solid was collected by filtration and dried. The crude solid material was purified by column chromatography on silica gel and eluted with ethyl acetate/petroleum ether (1:10) to isolate the title compound as an off-white solid (12.0 g, 31% yield), the identity of which was confirmed by 1H NMR and LCMS
With ferrous(II) sulfate heptahydrate; dihydrogen peroxide In water; dimethyl sulfoxide at 0 - 20℃; for 3h;
1.A2 Step A2: Alternative Preparation of 2-chloro-5-(trifluoromethyl)-4-pyrimidinamine
In a round-bottom flask, trifluoroiodomethane (CF3I) gas (113.95 g, 581.39 mmol was sparged into dimethylsulfoxide (150 mL) at 10 °C for 2 h). The resulting solution was added dropwise at 6 °C for 10 min to a stirred solution of 4-amino-2-chloropyrimidine (25.0 g, 193.8 mmol) in dimethylsulfoxide (120 mL). Ferrous sulfate (FeS04-7 HoO) (16.0 g, 58.1 mmol) in water (75 mL) was added to this mixture dropwise at 0 °C and then 30% hydrogen peroxide solution (13.17 g, 44 mL, 387.6 mmol) was added very slowly (dropwise) at 0 °C for 1 h. The resulting mixture was stirred at room temperature for 2 h. Concentrated hydrochloric acid (50 mL) was added dropwise to the reaction mixture at 0 °C for 30 min and the reaction mixture was stirred at 0 °C for 30 min. Progress of the reaction was monitored by thin layer chromatograpy. The reaction mixture was poured into ice water, and the resultant precipitated solid was collected by filtration and dried. The crude solid material was purified by column chromatography on silica gel and eluted with ethyl acetate/petroleum ether (1: 10) to isolate the title compound as an off-white solid (12.0 g, 31% yield), the identity of which was confirmed by 1 H NMR and LCMS (94%).
With manganese triacetate; acetic acid at 10 - 20℃; for 24h;
1.A3 Step A3: Alternative Preparation of 2-chloro-5-(trifluoromethyl)-4-pyrimidinamine
To a stirred solution of 4-amino-2-chloropyrimidine (1.0 g, 7.8 mmol) in acetic acid (10 mL) was added sodium trifluromethanesufinate (2.13 g, 23.3 mmol) at 10 °C. To this mixture was added portionwise manganese(III) acetate (8.31 g, 31.0 mmol) at the same temperature. The resulting mixture was stirred at room temperature for 24 h. The mixture was poured into ice water and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and petroleum ether (1: 10) to give the title compound as an off-white solid (0.30 g, 19% yield), the identity of which was confirmed by in NMR and LCMS (94%).
2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With triethylamine; In isopropyl alcohol; at 100.0℃;
To a solution of commercially available (3aR,6aS)-hexahydro-lH-furo[3,4-c]pyrrole (841 mg, 6.49 mmol, 1 equiv.) in IPA were added commercially available hexahydro-lH-furo[3,4-c]pyrrole (970 mg, 8.57 mmol, 1.32 equiv.) and TEA (1.30 g, 12.9 mmol, 2 equiv.) and heated to 100 C and stirred overnight. LCMS showed the reaction was complete. The mixture was added water and extracted with EA. The organic phase was concentrated and purified by FLASH (5% MeOH in DCM). This is obtained the title compound, 500mg (37%) as pale-yellow solid.Analytical Data: LC-MS: (ES, m/z) = 207 [M+l]
With manganese triacetate; acetic acid at 10 - 20℃; for 24h;
1.A3 Step A3: Alternative Preparation of 2-chloro-5-(trifluoromethyl)-4-pyrimidinamine
To a stirred solution of 2-chloro-4-pyrimidinamine (1.0 g, 7.8 mmol) in acetic acid (10 mL) was added sodium trifluromethanesufinate (2.13 g, 23.3 mmol) at 10 °C. To this mixture was added portionwise manganese(III) acetate (8.31 g, 31.0 mmol) at the same temperature. The resulting mixture was stirred at ambient temperature for 24 h. The mixture was poured into ice water and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and petroleum ether (1:10) to give the title compound as an off-white solid (0.30 g, 19% yield), the identity of which was confirmed by 1H NMR and LCMS
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
