* 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.
Reference：
[1] Journal of the Chemical Society, 1951, p. 1218,1221
3
[ 1722-12-9 ]
[ 917-54-4 ]
[ 13036-57-2 ]
Yield
Reaction Conditions
Operation in experiment
67%
Stage #1: at -30 - 0℃; for 1 h; Stage #2: With water; acetic acid In tetrahydrofuran; diethyl ether at 0℃; for 0.166667 h; Stage #3: With 2,3-dicyano-5,6-dichloro-p-benzoquinone In tetrahydrofuran; diethyl ether at 20℃; for 0.5 h;
To a finely dispersed suspension of 2-chloropyrimidine (8.01 g, 69.9 mmol) in a 10: 1 mixture of [ET2O-THF] (500 mL) [AT-30°C] was added dropwise MeLi (46 mL, 1.6M in [ET20,] 73.6 mmol). The reaction mixture was stirred [AT-30°C] for 30 min, and was then warmed to [0°C] and stirred for 30 min. To the reaction mixture was then added a 1: 1: 20 mixture of H2O- [HOAC-THF] (100 mL), and the mixture was stirred at [0°C] for 10 min. To the mixture was then added a solution of DDQ (16.7 g, 73.6 mmol) in THF (100 [ML),] and the mixture was stirred and warmed to room temperature for 30 min. The mixture was then diluted with [ET2O] (300 mL) and washed with IN aq. [NAOH] [(3X100] [ML)] followed by brine (300 mL). The organic phase was then dried over anhydrous [MGSO4,] filtered, concentrated in vacuo, and purified by flash chromatography using EtOAc-hexanes (1: 2) as eluent to afford 6.06 g of 2-chloro-4- methylpyrimidine (67percent) as white crystalline plates. To a solution of 2-chloro-4-methylpyrimidine (6.06 g, 47.1 mmol) in [MEOH] (40 [ML)] was added hydrazine monohydrate (10 mL, 206 [MMOL).] The solution was stirred for 16 h at room temperature and then purified by reverse phase HPLC to provide 4.43 g of the title compound [(76percent)] as a white solid. MH+ 125.
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 17, p. 4137 - 4140
[2] Patent: WO2003/101442, 2003, A1, . Location in patent: Page 53
[3] Patent: US6342503, 2002, B1, . Location in patent: Example 8
With 3-quinuclidinol In dimethyl sulfoxide at 70℃; for 2.5 h;
General procedure: A mixture of 2-chloropyrimidines(10 mmol), potassium cyanide (13–15 mmol), water (20 mmol), and DMSO(20 mL) was heated to 60 C. A solution of 3-quinuclidinol (0.1–0.2 mmol) inDMSO(5 mL) was added to the reaction mixture over 0.5 h. The reaction mixturewas stirred at 50–70 C for additional hours as specified in Table 1. Uponcompletion, the mixture was cooled to room temperature and water (50 mL) wasadded. The resulting mixture was extracted with isopropyl acetate (3 40 mL)(product 7a precipitated out after water addition and was collected by filtration).The combined organic layers were washed with water (2 30 mL), dried overMgSO4, filtered, and concentrated under vacuum to give crude 2-cyanopyrimidines, which were purified by column chromatography (SiO2) to afford pureproducts.
65%
With 1,4-diaza-bicyclo[2.2.2]octane In water; dimethyl sulfoxide at 20℃; for 48 h;
Synthesis of Pyrimidine-2-carbonitrile [0504] To a stirred solution of 2-chloropyrimidine (20.0 g, 174.6 mmol) in DMSO (40 mL) were added DABCO (3.72 g, 33.17 mmol), KCN (12.48 g, 192 mmol) and drop-wise addition of H20 (15 mL) at RT. The resulting solution was stirred at RT for 48 h. After consumption of starting material by TLC, the reaction mixture was diluted with water and extracted with EtO Ac. Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude product. The crude material was triturated with Hexane to afford pyrimidine-2-carbonitrile (12 g, 65percent) as dark brown solid. 1H-NMR (DMSO-d6, 400 MHz): δ 9.04 (s, 2H), 8.92 (d, 1H); LC-MS: 99.41percent; 107.6 (M+2); (column; X-bridge C-18, (50x3.0 mm, 3.5μ); RT 1.14 min. 0.1percent Aq TFA: ACN; 0.8 ml/min); TLC: 30percent EtOAc/Hexane (Rf: 0.2)
Reference：
[1] Chemical Communications, 2006, # 3, p. 341 - 343
[2] Organic Preparations and Procedures International, 1994, vol. 26, # 6, p. 684 - 687
10
[ 1722-12-9 ]
[ 14080-23-0 ]
Reference：
[1] Pharmaceutical Bulletin, 1955, vol. 3, p. 175,176
[2] Annales de Chimie (Cachan, France), 1960, vol. <13>5, p. 351,399,402
[3] Patent: US5883254, 1999, A,
[4] Patent: US5883254, 1999, A,
11
[ 1722-12-9 ]
[ 143-33-9 ]
[ 14080-23-0 ]
Reference：
[1] Chimia, 1996, vol. 50, # 11, p. 538 - 543
[2] Journal of Medicinal Chemistry, 1997, vol. 40, # 26, p. 4420 - 4425
[3] Chimia, 1996, vol. 50, # 11, p. 538 - 543
12
[ 1722-12-9 ]
[ 773837-37-9 ]
[ 14080-23-0 ]
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2676 - 2699
13
[ 1722-12-9 ]
[ 75-50-3 ]
[ 14080-23-0 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 905
14
[ 1722-12-9 ]
[ 74-89-5 ]
[ 931-61-3 ]
Yield
Reaction Conditions
Operation in experiment
30%
With potassium carbonate In methanol at 80℃; Sealed tube
Intermediate AT: l-methyl-5-phenyl-1H-imidazol-2-amineStep 1: Synthesis of N-methylpyrimidin-2-amineTo a solution of 2-chloropyrimidine (1 g, 8.7 mmol) in methanol (10 mL) is added a 2M solution of methylamine (13.2 mL, 26.2 mmol) in methanol, followed by K2C03 (2.5 g, 18 mmol). The reaction flask is sealed and heated to 80 °C overnight. The reaction is then cooled to room temperature and concentrated to remove volatiles. The residue is partitioned between water and CH2C12. The organic layer is dried (Na2S04) and concentrated to afford the title compound (290 mg, 30percent) as a brown oil.
Reference：
[1] Bulletin of the Chemical Society of Japan, 1998, vol. 71, # 8, p. 1973 - 1991
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 17, p. 6626 - 6637
[3] Molecules, 2004, vol. 9, # 7, p. 520 - 526
[4] Patent: WO2011/71716, 2011, A1, . Location in patent: Page/Page column 99
[5] Journal of the American Chemical Society, 1954, vol. 76, p. 1065,1067
[6] Journal of the Chemical Society, 1953, p. 331,336
[7] Journal of Medicinal Chemistry, 2011, vol. 54, # 2, p. 472 - 484
[8] Patent: US2012/172374, 2012, A1, . Location in patent: Page/Page column 37-38
[9] Organic Letters, 2017, vol. 19, # 17, p. 4656 - 4659
15
[ 1722-12-9 ]
[ 7504-94-1 ]
Yield
Reaction Conditions
Operation in experiment
99.8%
at 100℃; for 0.5 h;
[1484] a mixture of 2-chloropyrimidine (15 g, 131 mmol), NH2NH2.H2O (30 ml), K2CO3 (15 g, 109 mmol) was stirred at 100 °C for 30 min. The mixture was ice cooled and the resulting crude crystals were collected by filtration. The crystals were washed with cold water, air dried, and recrystallized from petroleum ether (150 ml) to give compound 350a (14.4 g, 131 mmol, yield: 99.8percent) as a yellow solid. 1H NMR (400mhz, DMSO-d6) δ 8.30 (d, = 4.8 hz, 2h), 8.12 (br s, ih), 6.59 (t, j = 4.7 hz, ih), 4.13 (s, 2h).
80%
With hydrazine hydrate In ethanol for 2 h;
H2mphp was synthesized by the following procedure. 2-Chloropyrimidine (1.145 g, 20 mmol) was dissolvedin ethanol (30 mL). Then, excess hydrazine hydrate (85percent, 6 mL) was added to the above solutionunder stirring. A bright yellow solution formed, from which white needle crystals appeared after 2 h. The crystals were collected by filtration and recrystallized in ethanol (yield 80percent). 3-Methylsalicylaldehyde(1.36 g, 10 mmol) was added to an ethanolic solution (30 mL) of 2-hydrazinopyrimidine (1.10 g, 10 mmol)and light yellow precipitate formed immediately. After reflux for 3 h, the reaction mixture was filteredand the precipitate washed with ethanol to yield light yellow powder of H2mphp. Yield 95percent.
40%
With hydrazine In ethanol at 20℃; for 1.33333 h;
[Referential Example 34] 2-Hydrazinopyrimidine; [Show Image] Hydrazine monohydrate (20 ml) was added to a suspension of 2-chloropyrimidine (6.00 g) in ethanol (60 ml) at room temperature, and the mixture was stirred for 80 minutes. The solvent was evaporated under reduced pressure, and water (34 ml) was added to the residue. The solid precipitate was collected by filtration to give the title compound (2.30 g, 40percent). 1H-NMR (400 MHz, DMSO-d6)δ: 4.12 (2H, s), 6.57-6.60 (1H, m), 8.12 (1H, s), 8.30 (2H, d, J = 4.9 Hz). EI-MSm/z: 110 (M+).
40%
With hydrazine In ethanol at 20℃; for 1.33333 h;
[Referential Example 3] 2-Hydrazinopyrimidine [Show Image] Hydrazine monohydrate (20 mL) was added to a suspension of 2-chloropyrimidine (6.00 g) in ethanol (60 mL) at room temperature, followed by stirring for 80 minutes. The solvent of reaction mixture was evaporated under reduced pressure, and then water (34 mL) was added to the residue. The solid that precipitated was collected through filtration, to thereby give the title compound (2.30 g, 40percent). 1H-NMR(400MHz,DMSO-d6)δ:4.12(2H,s), 6.57-6.60 (1H,m), 8.12(1H,s), 8.30(2H,d,J=4.9Hz). EI-MS m/z:110(M+).
25%
at 20℃; for 1.6 h;
PREPARATION 9Preparation of 2-hydrazinylpyrimidine; A solution of 2-chloropyrimidine (0.70 g, 6.11 mmol) in pyridine (15 mL) and anhydrous hydrazine (2.5 mL) was stirred for 5 minutes at ambient temperature, and further pyridine (8 mL) was added. The reaction mixture was stirred at ambient temperature for 1.5 h and concentrated in vacuo. The residue was suspended in water (4 mL) and the resultant solid was collected by suction filtration and air-dried to afford 2-hydrazinylpyrimidine as a colorless solid in 25percent yield (0.171 g): 1H NMR (300 MHz, DMSO-d6) δ 8.29 (d, J = 4.8 Hz, 2H), 8.13 (br s, 1 H), 6.59 (t, J = 4.8 Hz, 1 H), 4.12 (br s, 2H).
Reference：
[1] Patent: WO2018/64119, 2018, A1, . Location in patent: Paragraph 1484
[2] Journal of Organic Chemistry, 1999, vol. 64, # 15, p. 5644 - 5649
[3] Patent: US2003/187014, 2003, A1,
[4] Journal of Coordination Chemistry, 2016, vol. 69, # 7, p. 1218 - 1225
[5] Journal of Physical Organic Chemistry, 2015, vol. 28, # 2, p. 108 - 115
[6] Patent: EP1698626, 2006, A1, . Location in patent: Page/Page column 47-48
[7] Patent: EP1762568, 2007, A1, . Location in patent: Page/Page column 22-23
[8] Patent: WO2008/121861, 2008, A2, . Location in patent: Page/Page column 65
[9] Yakugaku Zasshi, 1953, vol. 73, p. 598,600[10] Chem.Abstr., 1954, p. 9362
[11] Bulletin des Societes Chimiques Belges, 1959, vol. 68, p. 30,55
[12] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 21, p. 3191 - 3193
[13] Patent: EP967212, 1999, A1,
[14] Patent: EP2264105, 2010, A1, . Location in patent: Page/Page column 164
[15] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 2887 - 2889
[16] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5266 - 5269
[17] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1071 - 1074
[18] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 9, p. 2284 - 2288
[19] Molecules, 2018, vol. 23, # 9,
16
[ 1722-12-9 ]
[ 302-01-2 ]
[ 7504-94-1 ]
Yield
Reaction Conditions
Operation in experiment
83%
at 20℃; for 3 h;
Dissolve 2-chloropyrimidine (10.04 g, 87.7 mmol) in pyridine (200 mL) and add hydrazine (35.8 mL, 1.14 mol) to the mixture followed by pyridine (100 mL). Stir the mixture for 3 hr. at room temperature then concentrate. Suspend the residue in water and filter. Wash the cake with cold methanol. Collect the powder and dry under vacuum to give pyrimidin-2-ylhydrazine as a white powder (8.05 g, 83percent).
With sodium carbonate In ethanol; water; toluene at 100℃; for 20 h;
2-Phenylpyrimidine To a dried flask was added the 2-chloropyrimidine (0.50 g, 4.37 mmol), phenyl-boronic acid (0.69 g, 5.68 mmol), Na2CO3 (0.92 g, 8.70 mmol), PdCl2 (38.7 mg, 0.22 mmol) and dppb (92.9 mg, 0.22 mmol). The mixture was then purged under nitrogen for 10 minutes, followed by the addition of a degassed mixture of toluene (12 mL), water (6 mL), ethanol (2 mL). The reaction mixture was allowed to stir at 100° C. After 20 h, the mixture was filtered on a celite pad, then the volatiles were removed under reduced pressure. Purification via silica gel column chromatography using a mixture of 10percent Et2O/DCM gave a white solid (65percent). Spectral data is identical to previous reports.26
32 %Chromat.
With [Ni(9,10-phenanthrenequinonethiosemicarbazone)2]; potassium carbonate In N,N-dimethyl acetamide at 90℃; for 7 h;
General procedure: To a mixture of aryl halide (1 mmol), phenylboronic acid (1.5 mmol) and K2CO3 (1 mmol) in dimethylacetamide (4 mL) was added the catalyst (1 molpercent) as a dimethylacetamide solution (1 mL). The resultant mixture was then heated at 90C for 7 h. Then, the mixture was cooled, water was added and the product was extracted with ethylacetate. The organic layer was washed with brine, dried over Na2SO4, filtered, passed through celite, and analyzed by GC. GC yields were obtained based on corresponding aryl halide. The isolated yield was characterized by 1H NMR.
85 %Chromat.
With [Pd2(μ-1,1′-bis(diphenylphosphino)ferrocene)(4-methoxy-N′-(mesitylidene)benzohydrazide)2]; tetrabutylammomium bromide; potassium carbonate In water; N,N-dimethyl-formamide at 90℃; for 12 h;
An oven-dried round bottom flask (10 ml) was charged with 0.1ml dimethylformamide solution of complex IV (0.1 mol percent for aryl bromides and 0.2 mol percent for aryl chlorides), aryl boronic acid (1.2 mmol), aryl halide (1.0 mmol), K2CO3 (1.5 mmol), TBAB (1.0 mmol) and 2 ml water. The reaction mixture was then heated (to 70 °C for aryl bromides and 90 °C for aryl chlorides) with stirring under aerobic conditions for the required time. At the end of the reaction, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (2×5 ml). The combined extract was washed with water (2×10 ml), dried over anhydrous sodium sulfate and then subjected to GC-MS analysis for identification and yield determination (from the areas under the peaks) of the products. In the case of reactions with 2-naphthylboronic acid, the combined extract was evaporated to dryness under reduced pressure and the residue was purified by column chromatography (silica gel, ethyl acetate/n-hexane) to afford the coupling products. The products were identified by 1H and 13C NMR and HR-MS analysis.
Reference：
[1] European Journal of Organic Chemistry, 2010, # 23, p. 4376 - 4380
[2] Chemical Communications, 2014, vol. 50, # 91, p. 14129 - 14132
[3] Organic and Biomolecular Chemistry, 2013, vol. 11, # 17, p. 2756 - 2760
[4] European Journal of Organic Chemistry, 2012, # 31, p. 6248 - 6259,12
[5] European Journal of Organic Chemistry, 2012, # 31, p. 6248 - 6259
[6] Advanced Synthesis and Catalysis, 2013, vol. 355, # 11-12, p. 2274 - 2284
[7] Angewandte Chemie - International Edition, 2013, vol. 52, # 35, p. 9279 - 9283[8] Angew. Chem., 2013, vol. 125, # 35, p. 9449 - 9453,5
[9] Organic and Biomolecular Chemistry, 2017, vol. 15, # 28, p. 5993 - 6000
[10] Advanced Synthesis and Catalysis, 2010, vol. 352, # 2-3, p. 329 - 335
[11] Angewandte Chemie - International Edition, 2015, vol. 54, # 46, p. 13659 - 13663[12] Angew. Chem., 2015, vol. 127, # 46, p. 13863 - 13867
[13] Organic Letters, 2018, vol. 20, # 17, p. 5268 - 5273
[14] Advanced Synthesis and Catalysis, 2010, vol. 352, # 18, p. 3255 - 3266
[15] Dalton Transactions, 2011, vol. 40, # 47, p. 12765 - 12770
[16] Organic and Biomolecular Chemistry, 2014, vol. 12, # 35, p. 6944 - 6952
[17] Tetrahedron Letters, 1991, vol. 32, # 20, p. 2273 - 2276
[18] Tetrahedron, 1992, vol. 48, # 37, p. 8117 - 8126
[19] Angewandte Chemie - International Edition, 2006, vol. 45, # 46, p. 7781 - 7786
[20] Patent: US2008/132698, 2008, A1, . Location in patent: Page/Page column 19
[21] Journal of Organometallic Chemistry, 2009, vol. 694, # 19, p. 3050 - 3057
[22] Journal of Organometallic Chemistry, 2003, vol. 687, # 2, p. 327 - 336
[23] Journal of the American Chemical Society, 2011, vol. 133, # 7, p. 2160 - 2162
[24] Tetrahedron, 2012, vol. 68, # 30, p. 6010 - 6017
[25] Journal of the American Chemical Society, 2013, vol. 135, # 25, p. 9322 - 9325
[26] Organic Letters, 2013, vol. 15, # 21, p. 5444 - 5447
[27] Journal of Organic Chemistry, 2015, vol. 80, # 8, p. 4116 - 4122
[28] Journal of Chemical Sciences, 2015, vol. 127, # 4, p. 597 - 608
[29] Tetrahedron Letters, 2017, vol. 58, # 10, p. 1000 - 1005
[30] Chemistry - A European Journal, 2017, vol. 23, # 14, p. 3285 - 3290
[31] Chemical Communications, 2017, vol. 53, # 57, p. 7994 - 7997
[32] Organic and Biomolecular Chemistry, 2017, vol. 15, # 31, p. 6592 - 6603
18
[ 1722-12-9 ]
[ 3958-47-2 ]
[ 7431-45-0 ]
Yield
Reaction Conditions
Operation in experiment
91%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In tetrahydrofuran at 80℃; for 4 h; Inert atmosphere
To a solution of 2-chloropyrimidine (1.21 g, 10.0 mmol) and Pd(dppf)Cl2(408 mg, 0.5 mmol) in THF (50 mL), triphenylindium (4.0 mmol, ~0.3 M en THF) was added. Themixture was stirred at 80 °C for 4 h and the reaction quenched by addition of drops of MeOH. Thesolvent was evaporated and EtOAc (25 mL) was added. The organic phase was washed with HCl(5percent, 15 mL), satd. NH4Cl (15 mL) and brine (15 mL), dried, filtered, and concentrated. The crudewas purified by flash chromatography (20percent EtOAc/hexane) affording, after concentration and drying,12 (1.42 g, 9.09 mmol, 91percent) as a white solid. M.p. 36–38 °C (lit. [38], 36–38 °C). 1H NMR (CDCl3, 300 MHz) δ 6.95 (t, J = 4.9 Hz, 1 H), 7.42–7.49 (m, 3 H), 8.47–8.50 (m, 2 H), 8.66 (d, J = 4.9 Hz, 2 H) ppm;13C NMR (CDCl3, 75 MHz) δ 119.0 (CH), 128.2 (2 x CH), 128.6 (2 x CH), 130.8 (CH), 137.5 (C), 157.1(2 x CH), 164.5 (C) ppm; IR (ATR) 3087, 3066, 3039 cm-1; MS (EI) m/z (percent) 156 (M+, 92), 103 (100);HRMS (EI) m/z calcd for C10H8N2 156.0682, found 156.0683.
Reference：
[1] Molecules, 2018, vol. 23, # 7,
19
[ 1722-12-9 ]
[ 100-59-4 ]
[ 7431-45-0 ]
Reference：
[1] Organometallics, 2013, vol. 32, # 16, p. 4656 - 4663
[2] Tetrahedron, 2002, vol. 58, # 22, p. 4429 - 4438
[3] Synlett, 2007, # 2, p. 247 - 250
[4] Synthesis, 2006, # 21, p. 3547 - 3574
[5] Journal of Chemical Sciences, 2015, vol. 127, # 4, p. 597 - 608
Reference：
[1] Journal of Organic Chemistry, 2009, vol. 74, # 8, p. 3221 - 3224
22
[ 1722-12-9 ]
[ 7431-45-0 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2005, vol. 42, # 7, p. 1423 - 1428
23
[ 67-66-3 ]
[ 1722-12-9 ]
[ 7431-45-0 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 24, p. 3581 - 3585
24
[ 67-66-3 ]
[ 1722-12-9 ]
[ 7431-45-0 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 24, p. 3581 - 3585
25
[ 10199-67-4 ]
[ 67-66-3 ]
[ 1722-12-9 ]
[ 7431-45-0 ]
[ 244-76-8 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 24, p. 3581 - 3585
26
[ 930-36-9 ]
[ 67-66-3 ]
[ 4513-94-4 ]
[ 1722-12-9 ]
[ 51269-82-0 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 24, p. 3581 - 3585
[2] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 24, p. 3581 - 3585
27
[ 60-35-5 ]
[ 1722-12-9 ]
[ 13053-88-8 ]
Yield
Reaction Conditions
Operation in experiment
91%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane In 1,4-dioxane at 100℃; for 16 h; Inert atmosphere
A screw-cap vial was charged with benzamide (121 mg, 1.00 mmol), Cs2CO3 (456 mg, 1.40 mmol), Xantphos (87 mg, 0.15 mmol), Pd2(dba)3 (46 mg, 0.050 mmol), 2-chloropyrimidine (137 mg, 1.20 mmol), and 1,4-dioxane (2 mL). The mixture was sparged with nitrogen for 3 min, stirred for 16 h at 100 °C, and cooled to room temperature. The residue was diluted with dichloromethane, filtered through celite, and concentrated. The crude product was purified by silica gel flash chromatography (40-100percent ethylacetate/hexanes) to provide N-(pyrimidin-2-yl)benzamide (188 mg, 0.85 mmol, 94percent yield) as an amorphous solid (Table 1, entry 8).
General procedure: 2-Chloro-4,6-disubstituted-pyrimidines 17 were prepared bythe reaction of the diazoniumsalts of 4,6-disubstituted-pyrimidin-2-amines (16) with concentrated hydrochloric acid and ZnCl2 [35].Compound 18 was prepared according to literature [32], and themethod was improved. To a stirred solution of piperazine(45 mmol) and K2CO3 (16.5 mmol) in water (20 mL) was addedchloropyrimidine 17 (18 mmol) in small portions at 50e65 C. Themixture was stirred for 1 h at 60e65 C and cooled to 35 C. Theyellowsolid, 1,4-bispyrimidylpiperazine byproduct, was filtered off,and the filtrate was then extracted three times with chloroform,dried over Na2SO4, and evaporated in vacuum to give compound 18,which was used for the following reactions without further purification. 18a: yellow oil, yield 88percent.
83.8%
With ammonia In water at 98℃; for 3 h;
The 24 g anhydrous piperazine, 100 ml water and 8 ml ammonia water into the 250 ml three port into reaction, stirring and heating to 98 °C, dropwise 10 g of 2 - chloro pyrimidine and 90 ml water mixed solution, in 3 hours paused, 98 °C lower heat insulating 0.5 hours. To turns on lathe the distillation, removing about 120 ml water of, cooling to room temperature, dichloromethane is used for extraction 3 times, each time the 30 ml. The combined dichloromethane, adding 4 g anhydrous calcium chloride drying 1 hour, filtering, in the 40 °C lower steaming and removing dichloromethane, shall be 15.6 g product, liquid phase purity 90.04percent, disubstituted by-product (the second piperazine pyrimidine) 11percent. GC analysis of the residual piperazine 0.21percent, yield 83.8percent.
80.7%
Stage #1: With ammonium hydroxide In water at 95 - 100℃; Stage #2: at 95 - 100℃; for 4 h;
100 g of anhydrous piperazine, 360 ml of water and 32 ml of aqueous ammonia were poured into a 1000 ml three-necked reaction flask and heated to 95 ° C to 100 ° C with stirring. A mixed solution of 44 g of dichloropyrimidine and 360 ml of water was added dropwise, and the mixture was dropped at about 3 hours and incubated at 95 ° C to 100 ° C for 1 hour. Spin distillation, remove about 480ml of water, cooling to room temperature, extracted with dichloromethane 3 times, each 120m. The combined methylene chloride was added with 16 g of anhydrous calcium chloride for 1 hour, filtered and the dichloromethane was removed by steaming at 40 ° C to give 57 g of product, liquid purity of 89.74percent, disubstituted by-product (dipyrimidinyl piperazine) 10percent. GC analysis of piperazine residue 0.19percent, the yield of 80.7percent.
Reference：
[1] Chinese Journal of Chemistry, 2015, vol. 33, # 10, p. 1124 - 1134
[2] European Journal of Medicinal Chemistry, 2016, vol. 117, p. 167 - 178
[3] Organic Letters, 2016, vol. 18, # 20, p. 5272 - 5275
[4] Journal of the American Chemical Society, 2017, vol. 139, # 33, p. 11357 - 11360
[5] Patent: CN107216318, 2017, A, . Location in patent: Paragraph 0021; 0024; 0027
[6] Patent: CN106432212, 2017, A, . Location in patent: Paragraph 0010; 0018
[7] Journal of Organic Chemistry, 1953, vol. 18, p. 1484,1487
[8] Farmaco, 2005, vol. 60, # 5, p. 439 - 443
[9] Journal of Chemical Research, 2006, # 12, p. 809 - 811
[10] Patent: US35053, 1995, E1,
[11] Patent: US5099019, 1992, A,
[12] Patent: US4598078, 1986, A,
[13] Patent: US4668687, 1987, A,
[14] Patent: US4355031, 1982, A,
[15] Patent: EP263213, 1988, A1,
[16] Molecules, 2008, vol. 13, # 10, p. 2426 - 2441
[17] Patent: US2005/234046, 2005, A1, . Location in patent: Page/Page column 57
[18] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 16, p. 3886 - 3890
[19] Patent: CN107266429, 2017, A, . Location in patent: Paragraph 0021; 0024; 0027
34
[ 110-85-0 ]
[ 1722-12-9 ]
[ 20980-22-7 ]
[ 84746-24-7 ]
Reference：
[1] Journal of Agricultural and Food Chemistry, 2010, vol. 58, # 9, p. 5515 - 5522
35
[ 110-91-8 ]
[ 1722-12-9 ]
[ 57356-66-8 ]
Yield
Reaction Conditions
Operation in experiment
79%
With 1-methyl-3-(2-pyridinyl)-3,4,5,6-tetrahydropyrimidin-3-ium hexafluorophosphate; potassium <i>tert</i>-butylate; palladium diacetate In 1,2-dimethoxyethane at 100℃; for 0.666667 h; Microwave irradiation
General procedure: The Buchwald–Hartwig amination reaction under microwave irradiation was conducted in a CEM Discover apparatus. A 10-mL Teflon vessel was charged with 1.0 mmol of hetero-aryl halide, 3.0 mmol of amine, 2.0 of mmol base, 0.05 mmol of Pd(OAc)2 , 0.10 mmol of LHX, and 2.0 mL of solvent. The mixture was irradiated at 150 W at 100 °C for the specified time and then allowed to cool. The reaction mixture was extracted 3 times with diethyl ether, and the combined organic extracts were washed with water, dried (MgSO4) , and evaporated to dryness. Purification of the residue by flash chromatography on silica gel afforded the pure products.
79%
With potassium carbonate In N,N-dimethyl-formamide for 24 h;
To a solution of morpholine 5a (3.63 mL, 42 mmol) in DMF (50 mL), K2CO3 (5.8 g, 42 mmol) was added; after 20 min stirring, 2-chloropyrimidine (4.0 g,35 mmol) was added. The reaction mixture was stirred for 24 h, the solvent was removed in vacuo, the residue was purified by column chromatography (elution with ethyl acetate—hexane, 1 : 1).
12%
With (2-mesityl-1H-inden-3-yl)dicyclohexyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In 1,2-dimethoxyethane at 120℃; for 24 h; Inert atmosphere
General procedure: Pd(dba)2/1-catalyzed amination of aryl halides: An oven-dried Schlenk tube equipped with a magnetic stirring bar was charged with Pd(dba)2 (5.8 mg, 0.010 mmol), ligand 1 (8.6 mg, 0.020 mmol) and tBuONa (134 mg, 1.4 mmol). The flask was capped with a rubber septum, evacuated, and then flushed with argon. This cycle was repeated three times. Amine (1.2 mmol), aryl halide (1.0 mmol) and DME (4 mL) were then successively added by syringe. The tube was stirred at room temperature for several minutes and then placed into a preheated oil bath (120 °C) for the time period as indicated in tables. After completion of reaction as judged by GC analysis, the reaction tube was allowed to cool to room temperature and the reaction mixture was adsorbed onto silica gel, and then purified by column chromatography (hexane/ethyl acetate as eluent) to afford the desired product.
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 36, p. 5957 - 5963
[2] ChemSusChem, 2013, vol. 6, # 8, p. 1455 - 1460
[3] Journal of Organic Chemistry, 2017, vol. 82, # 7, p. 3741 - 3750
[4] Turkish Journal of Chemistry, 2015, vol. 39, # 1, p. 121 - 129
[5] Russian Chemical Bulletin, 2014, vol. 63, # 6, p. 1350 - 1358[6] Izv. Akad. Nauk, Ser. Khim., 2014, # 6, p. 1350 - 1358
[7] Journal of Organometallic Chemistry, 2012, vol. 706-707, p. 99 - 105
[8] Journal of the Chemical Society, 1954, p. 1190,1192
[9] European Journal of Medicinal Chemistry, 2017, vol. 136, p. 270 - 282
36
[ 110-91-8 ]
[ 1722-12-9 ]
[ 64-17-5 ]
[ 57356-66-8 ]
Reference：
[1] Journal of the Chemical Society, 1954, p. 1190,1192
37
[ 1722-12-9 ]
[ 63-74-1 ]
[ 68-35-9 ]
Reference：
[1] Yakugaku Zasshi, 1950, vol. 70, p. 283,284[2] Chem.Abstr., 1951, p. 2894
38
[ 1722-12-9 ]
[ 31462-54-1 ]
Yield
Reaction Conditions
Operation in experiment
90%
With hydrogen iodide In water at -10 - -5℃; for 1 - 2 h;
Under N2, 2-chloropyrimidine (200 g, 1.75 mol) was added in 5 portions to aqueous HI (850 ml, 57percent in water) at -10 to -5° C. The mixture was stirred at -10 to -5° C. and the reaction was followed by HPLC. After complete reaction (60 to 120 min), the pH was set to 7.25+/-0.25 with NaOH (30percent) and the temperature was increased to 18-23° C. To decolorize the mixture, 16 g Na2SO3 was added, decreasing the pH to 3+/-1. TBME (600 ml) was added to the mixture and the mixture was saturated with NaCl (300 g). The phases were separated and the aqueous phase was extracted with TBME (4.x.400 ml). The combined organic layers were washed with aqueous Na2SO3 (50 ml) (1percent) and water (100 ml). The organic layer was evaporated to dryness and co-evaporated with TBME (100 ml) under vacuum at 45 to 50° C. Yield: 330 g (90percent). Assay (HPLC): 98percent pure vs. standard.
55%
With hydrogen iodide In water at 0℃; for 0.25 h; Cooling with ice
Ice cooled hydriodic acid (Wako Pure Chemical Industries, Ltd.) (14.7 ml, 57percent) was added gradually to 3.68 g (32.0 mmoles) of 2-chloropyrimidine (Sigma-Aldrich Corporation), and the reaction mixture was agitated for fifty minutes at 0°C. Ice cooled aqueous sodium carbonate solution was added to the reaction solution until the solution was neutral, and aqueous sodium sulfite solution was subsequently added. The product was extracted using diethyl ether, and the organic layer was dried using anhydrous sodium sulfate after it was washed once using a saturated aqueous sodium chloride solution. The solvent was removed, and the pale yellow oil remaining was dissolved in boiling hexane. The solution was left standing to cool, and 3.62 g (17.6 mmoles, 55percent) of colorless needle-like crystals (Compound 2) was obtained. The analytical results for Compound 2 obtained (2-iodopyrimidene) are shown below. 1H-NMR (400 MHz, CDCl3, TMS, rt) δ 8.47 (2H, d, J = 4.8 Hz), 7.32 (1H, t, J = 4.9 Hz)
Reference：
[1] Patent: US2006/58343, 2006, A1, . Location in patent: Page/Page column 7
[2] Journal of Organic Chemistry, 2002, vol. 67, # 18, p. 6550 - 6552
[3] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1990, # 7, p. 1269 - 1274
[4] Patent: EP2395055, 2011, A1, . Location in patent: Page/Page column 8
[5] Journal of the American Chemical Society, 2012, vol. 134, # 12, p. 5528 - 5531
39
[ 1722-12-9 ]
[ 32779-36-5 ]
Yield
Reaction Conditions
Operation in experiment
14.1 g
With N-Bromosuccinimide; boron trifluoride diethyl etherate In acetonitrile at 20℃; Reflux
In a reaction flask was added 11.5 g (0.1 mol) of 2-chloropyrimidine, bromination reagent NBS 21.3 g (0.12 mol) and acetonitrile 80 mL. A catalytic amount of 2.8 g (0.02 mol) of BF3-Et2O was added at room temperature. After the addition was complete, heating to reflux for 5-8 hours. Completion of the reaction was detected by TLC. Cooling. After insoluble solids were filtered off, after distilling the solvent under reduced pressure, ethyl acetate was added to dissolve followed by dropwise addition of 45 mL of saturated Na2CO3 solution. The organic layer was separated. The aqueous layer was further mixed with 60 mL of ethyl acetate and stratified again. After combining the organic layers, washed with a saturated saline solution. Dried to give 14.1 g of pale yellow 2-chloro-5-bromopyrimidine as a solid. It was used directly in the next reaction.
29 g
Reflux
24g 2-chloropyrimidine was added to 200ml acetic acid, 50g bromine was added dropwise, heated to reflux overnight, cooled,Water and ethyl acetate were added, the extracts were separated, the organic phase was collected, dried and concentrated to give 29 g of 5-bromo-2-chloropyrimidine.
29 g
Reflux
24 g of 2-chloropyrimidine was added to 200 ml of acetic acid, and 50 g of bromine was added dropwise. The mixture was heated under reflux and stirred overnight. After cooling, water and ethyl acetate were added and the mixture was extracted and collected. The organic phase was collected, dried, and concentrated to give 29 g of 5-bromo-. 2-chloropyrimidine.
Reference：
[1] Patent: CN104788482, 2016, B, . Location in patent: Paragraph 0017
[2] Patent: CN107400113, 2017, A, . Location in patent: Paragraph 0021; 0022
[3] Patent: CN107698556, 2018, A, . Location in patent: Paragraph 0020; 0021; 0022
40
[ 1722-12-9 ]
[ 4595-60-2 ]
Reference：
[1] European Journal of Organic Chemistry, 2002, # 24, p. 4181 - 4184
[2] Tetrahedron Letters, 2000, vol. 41, # 10, p. 1653 - 1656
41
[ 1722-12-9 ]
[ 34671-83-5 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2005, vol. 42, # 7, p. 1423 - 1428
[2] Journal of Organic Chemistry, 2002, vol. 67, # 2, p. 443 - 449
[3] Synthetic Communications, 1991, vol. 21, # 7, p. 901 - 906
[4] Tetrahedron, 1994, vol. 50, # 41, p. 11893 - 11902
[5] Patent: EP2172470, 2010, A1, . Location in patent: Page/Page column 43
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at -78℃; for 0.166667 h; Stage #2: at 20 - 120℃; for 90 h;
To a solution of diethylmalonate (6.65 mL, 43.65 mmol) in DMF (30 mL) at -78 °C,was added NaH (1.76 g, 52.38 mmol, 60percent dispersion in mineral oil). The reaction was stirredfor 10 min at -78 °C, warmed to room temperature and 2-chloropyrimidine (1.0 g, 8.73 mmol)in DMF (3 mL) was added. The reaction mixture was heated to 80 °C for 72 hours, then to120 °C for 18 hours, and upon completion was cooled to room temperature. The solution was15 quenched by addition of IN HCl, neutralized with saturated aqueous NaHC03 and extractedwith EtOAc (3X). The combined organics were dried over Na2S04, filtered, concentrated andpurified by flash chromatography on silica gel (0-1 00percent EtOAc in hexanes) to give the titlecompound as a yellow-orange oil (1.34 g, 92percent). MS 167 (MH+).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 10, p. 2800 - 2803
[2] Patent: US2006/69110, 2006, A1, . Location in patent: Page/Page column 70
45
[ 1722-12-9 ]
[ 75-98-9 ]
[ 66522-06-3 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 9, p. 2750 - 2755
[2] Dalton Transactions, 2018, vol. 47, # 34, p. 11942 - 11952
46
[ 1722-12-9 ]
[ 815-17-8 ]
[ 66522-06-3 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 9, p. 2750 - 2755
47
[ 1722-12-9 ]
[ 75-61-6 ]
[ 133391-65-8 ]
[ 133391-64-7 ]
[ 116470-67-8 ]
Reference：
[1] Journal of Fluorine Chemistry, 1990, vol. 50, # 3, p. 411 - 426
48
[ 1722-12-9 ]
[ 75-61-6 ]
[ 116470-67-8 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1988, # 10, p. 638 - 639
49
[ 1722-12-9 ]
[ 3605-01-4 ]
Yield
Reaction Conditions
Operation in experiment
80%
With triethylamine In ethanol at 95 - 100℃; for 1 h;
The intermediate intermediate piperonyl piperazine, 360 ml of absolute ethanol and 120 ml of triethylamine were placed in a 1000 ml three-necked reaction flask and heated to 95 ° C to 100 ° C with stirring. A mixed solution of 70 g of dichloropyrimidine and 360 ml of absolute ethanol was added dropwise, and the mixture was incubated at 95 ° C to 100 ° C for 1 hour, distilled under reduced pressure, and about 400 ml of ethanol and triethylamine solution were removed, cool to room temperature and filter. Atmospheric distillation, remove the ethanol and triethylamine about 250ml, cooled to room temperature, filter the solid, add water, beating, pumping filter, to get piribedil crude 160g, content 92percent, the total yield of 80percent.
Reference：
[1] Patent: CN106432212, 2017, A, . Location in patent: Paragraph 0010; 0020
50
[ 1722-12-9 ]
[ 32231-06-4 ]
[ 3605-01-4 ]
Yield
Reaction Conditions
Operation in experiment
44%
With potassium carbonate In tetrahydrofuran for 2 h; Reflux
250 ml of a three-necked flask was added 50 g of piperonyl piperazine, 26 g of dichloropyrimidine, 330 ml of tetrahydrofuran and 65 g of potassium carbonate, and the mixture was heated under reflux for 2 hours. The mixture was cooled and cooled, and 1600 ml of distilled water was added thereto, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a dark red viscous liquid (56.3 g). Add 40ml of anhydrous ethanol, dissolve, slightly cold, add activated carbon 40g, reflux 30 minutes, hot filter, cooling, precipitation of white solid, filtration, 40 °C vacuum drying to get 30.2 g of white crystalline powder, yield 44percent.
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 16, p. 9144 - 9155
[2] Patent: CN106432212, 2017, A, . Location in patent: Paragraph 0015
51
[ 1722-12-9 ]
[ 57260-73-8 ]
[ 584-08-7 ]
[ 137583-05-2 ]
Reference：
[1] Patent: US6159964, 2000, A,
52
[ 1722-12-9 ]
[ 107-15-3 ]
[ 137583-05-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 1, p. 360 - 371
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 4, p. 705 - 716
53
[ 1722-12-9 ]
[ 1126-09-6 ]
[ 111247-60-0 ]
Yield
Reaction Conditions
Operation in experiment
81%
for 18 h; Reflux; Inert atmosphere
Method ACompound 1: l-Pyrimidin-2-yl-piperidine-4-carboxylic acid ethyl esterA mixture of 2-chloropyrimidine (2.28g, 20mmol) and ethyl isonipecotate (4.72g, 30mmol) in toluene (10ml) was heated at reflux for 18 h. then cooled to RT. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3. The organics were separated, dried, and the solvents removed in vacuo. The residue was purified by flash chromatography on silica (eluant: EtOAc/pet. ether 40/60 v/v) to yield the title compound as a colourless oil.Yield = 4.0Og, 81percent. (ESI+): [M+H]+ = 236.0
Reference：
[1] Farmaco, 1993, vol. 48, # 10, p. 1439 - 1445
[2] Patent: WO2010/97576, 2010, A1, . Location in patent: Page/Page column 39
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8696 - 8711
54
[ 1722-12-9 ]
[ 688-73-3 ]
[ 153435-63-3 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at 0℃; for 0.5 h; Inert atmosphere Stage #2: at 0 - 20℃; for 12 h; Inert atmosphere
After replacing the nitrogen in the round bottom flask, dissolve HSn (Bu) 3 (12.5 g) in 20 ml of anhydrous THF, add 2M LDA (18.75 g) while stirring at 0 ° C and stir for 30 minutes. Then, 2-chloropyrimidine (4 g, 35 mmole) dissolved in 20 mL of anhydrous THF at -18 ° C was slowly added dropwise. Subsequently, the reaction temperature was lowered to room temperature, and the mixture was stirred for 12 hours. After completion of the reaction, 30 ml of water was added and extracted with EA. Removal of the solvent followed by column purification hex to yield 11.68 g (90percent yield).
56%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at 0℃; for 0.25 h; Stage #2: at -78 - 20℃;
A 2.0 M lithium diisopropylamide/heptane, tetrahydrofuran, an ethylbenzene solution (26.2 ml), and tri-n-butyltin hydride (14.1 ml) were added in that order to anhydrous tetrahydrofuran (100 ml) under an argon atmosphere at 0°C, and the mixture was stirred at 0°C for 15 min. The reaction mixture was cooled to -78°C, and 2-chloropyrimidine (5.0 g) dissolved in anhydrous tetrahydrofuran (20 ml) was added dropwise to the cooled mixture. The mixture was slowly brought to room temperature and was stirred overnight. Water was added to the reaction mixture to stop the reaction. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with a hexane-ethyl acetate system to give 2-tri-n-butylstannylpyrimidine (9.1 g, yield 56percent). To anhydrous tetrahydrofuran (100 ml) were added a 2.0 M lithium diisopropylamide/heptane, tetrahydrofuran, an ethylbenzene solution (26.2 ml), and tri-n-butyltin hydride (14.1 ml) in that order under an argon atmosphere at 0°C. The mixture was stirred at 0°C for 15 min. The reaction mixture was cooled to -78°C. 2-Chloropyrimidine (5.0 g) dissolved in anhydrous tetrahydrofuran (20 ml) was added dropwise to the cooled reaction mixture. The mixture was slowy brought to room temperature and was stirred overnight. Water was added to the reaction mixture to stop the reaction. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with a hexane-ethyl acetate system to give 2-tri-n-butylstannylpyrimidine (9.1 g, yield 56percent). 2-Tri-n-butylstannylpyrimidine (5.0 g) was dissolved in tetrahydrofuran (130 ml) under an argon atmosphere. A 1.6 M n-butyllithium/hexane solution (8.6 ml) was added dropwise to the solution at -78°C, and the mixture was stirred at -78°C for 30 min. 4,5-Dimethylfurfural (1.85 g) dissolved in tetrahydrofuran (20 ml) was added dropwise to the solution, and the mixture was brourgh to room temperature with stirring. Water was added to the reaction mixture to stop the reaction. The solvent was removed by distillation under the reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with a hexane-ethyl acetate system to give (5-ethylfuran-2-yl)-pyrimidin-2-yl-methanol (888 mg, yield 32percent). (5-Ethylfuran-2-yl)-pyrimidin-2-yl-methanol (880 mg) was dissolved in chloroform (15 ml), manganese dioxide (3.8 g) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite, and the solvent was removed from the filtrate by distillation under the reduced pressure. The residue was used in the next reaction without purification. The residue, methanol (7 ml), and a 28percent aqueous ammonia solution (8 ml) were placed in a sealed tube, and the mixture was stirred at 160°C overnight. The reaction mixture was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography with a hexane-acetone system to give 6-ethyl-2-pyrimidin-2-yl-pyridin-3-ol (305 mg, yield 35percent).
Reference：
[1] Patent: KR2018/75381, 2018, A, . Location in patent: Paragraph 0071; 0072-0074
[2] Patent: EP1724268, 2006, A1, . Location in patent: Page/Page column 58; 77; 95
55
[ 123-75-1 ]
[ 1722-12-9 ]
[ 192197-34-5 ]
Yield
Reaction Conditions
Operation in experiment
87%
With 1-methyl-3-(2-pyridinyl)-3,4,5,6-tetrahydropyrimidin-3-ium hexafluorophosphate; potassium <i>tert</i>-butylate; palladium diacetate In 1,2-dimethoxyethane at 100℃; for 0.666667 h; Microwave irradiation
General procedure: The Buchwald–Hartwig amination reaction under microwave irradiation was conducted in a CEM Discover apparatus. A 10-mL Teflon vessel was charged with 1.0 mmol of hetero-aryl halide, 3.0 mmol of amine, 2.0 of mmol base, 0.05 mmol of Pd(OAc)2 , 0.10 mmol of LHX, and 2.0 mL of solvent. The mixture was irradiated at 150 W at 100 °C for the specified time and then allowed to cool. The reaction mixture was extracted 3 times with diethyl ether, and the combined organic extracts were washed with water, dried (MgSO4) , and evaporated to dryness. Purification of the residue by flash chromatography on silica gel afforded the pure products.
76%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil for 0.5 h; Reflux Stage #2: for 48 h; Reflux
Example 5 Synthesis of HK-9, HK-11, HK-13 and HK-15 The following describes the general synthesis of 2-(pyrrolidine-1-yl)pyrimidine (HK-9), 4,6-dimethoxy-2-(pyrrolidine-1-yl)pyrimidine, HK-11, 2-(piperidine-1-yl)pyrimidine (HK-13), 4,6-dimethoxy-2-(piperidine-1-yl)pyrimidine (HK-15), 5-benzyloxy-2-(pyrrolidine-1-yl)pyrimidine (Compound 35), 5-benzyloxy-2-(piperidine-1-yl)pyrimidine (Compound 36), 5-benzyloxy-4,6-dimethoxy-2-(pyrrolidine-1-yl)pyrimidine (Compound 37), and 5-benzyloxy-4,6-dimethoxy-2-(piperidine-1-yl)pyrimidine (Compound 38). Referring to the reaction scheme of , to 9.53 mL (116 mmol) pyrrolidine (29) in 400 mL of anhydrous THF was added 2.78 g of sodium hydride (116 mmol) and the mixture was refluxed for 0.5 hr. After cooling to r.t., 12 g (105 mmol) of 2-chloropyrimidine (33) was added dropwise and the mixture was refluxed for 2 days and then cooled in an ice bath. Water (200 mL) was then added to the cooled reaction mixture and the THF was removed in vacuo. The aqueous residue was extracted with CHCl3 and the combined CHCl3 extracts were washed with brine, dried over magnesium sulfate, and filtered. After removal of solvent in vacuo, the residue was purified by silica gel column chromatography using 20:1 hexanes:EtOAc as eluent. The product was then recrystallized from diethyl ether (Et2O) to give a 12.0 g (76percent) of HK-9 as a yellow solid, mp 39.0-39.6° C. 1H NMR (CDCl3) δ 8.31 (d, J=4.88 Hz, 2H), 6.45 (t, J=4.88 Hz, 1H), 3.57 (t, J=4.4 Hz, 4H), 2.01-1.98 (m, 4H). Anal. Calcd for C8H11N3; C, 64.40; H, 7.43; N, 28.16. Found: C, 64.42; H, 7.53; N, 27.97.
Reference：
[1] Turkish Journal of Chemistry, 2015, vol. 39, # 1, p. 121 - 129
[2] European Journal of Organic Chemistry, 2016, vol. 2016, # 36, p. 5957 - 5963
[3] Tetrahedron Letters, 2004, vol. 45, # 4, p. 757 - 759
[4] ChemSusChem, 2013, vol. 6, # 8, p. 1455 - 1460
[5] Patent: US2014/235858, 2014, A1, . Location in patent: Paragraph 0077
[6] Journal of Medicinal Chemistry, 2015, vol. 58, # 22, p. 8796 - 8805
[7] Pesticide Science, 1997, vol. 50, # 3, p. 258 - 274
[8] Journal of Heterocyclic Chemistry, 2004, vol. 41, # 3, p. 343 - 348
56
[ 1722-12-9 ]
[ 269409-73-6 ]
[ 579476-26-9 ]
Yield
Reaction Conditions
Operation in experiment
79%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In water; N,N-dimethyl-formamide at 110℃; Inert atmosphere
To a degassed souton of DMF:H20 (10:1 raUo) (0.3 M), under an atmosphere of nitrogen, was added the pnaco ester (1 mmo), 2-bromopyrdne or 2-choropyrmdne (1 .5 eq.), and Cs2CO3 (4.4 eq.). The whoe mxture was degassed once agan and then Pd(PPh3)4 (5mopercent) was added. The resutng souton was heated to 110°C overnght. The sovent was removed in vacuo to give a dark gummy residue, which was taken up nto EtOAc and H20, then acdfied with 2 M HC to pH 2. The organic ayer was separated and the aqueous ayer was further extracted with EtOAc (2x). The combined organic ayers were dried over MgSO4 and concentrated in vacuo to gve a back ofly residue. The residue was dry oaded ontosWca ge in vacuo then purfied by flash coumn chromatography, eutng with 10-30percent EtOAc/petroeum benzne and 1percent acetic acid to afford the tWe compound.The foHowng compounds were made by Suzuk CoupUng F:CO2HP7BiOff-whte scUd (79percent) yed). 1H NMR (400 MHz,DM80) 6 8.99 (t, J = 1.5 Hz, 1 H), 8.95 (d, J = 4.9Hz, 2H), 8.61 (d, J= 7.9 Hz, 1H), 8.09 (d, J 7.7 Hz,1 H), 7.68 (d, J = 7.8 Hz, 1 H), 7.50 (t, J = 4.9 Hz, 1 H).LCMS B rt2.96 mn, m/z201.1 [M + H].
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 1 h; Inert atmosphere Stage #2: at -30 - 0℃; for 1.66667 h; Stage #3: With 2,3-dicyano-5,6-dichloro-p-benzoquinone In tetrahydrofuran; diethyl ether; hexane; water at 0 - 20℃; for 0.25 h;
Preparation of 2-chloro-4-pyridin-3-yl-pyrimidine lll-a To a solution of n-butyllithium (2.5 molar in hexane, 13.5 mL, 34 mmol) in anhydrous diethylether (50 mL) under argon at -78 ' was added 3-bromo pyridine (3 mL, 31 mmol). The mixture was stirred for 1 h, then a suspension of 2-chloro pyrimidine (3.6 g, 31 mmol) in anhydrous diethylether (30 mL) was added portionwise over 10 min. The resulting mixture was stirred at -30 °C for 30 min, and then allowed to warm to 0 °C for 1 h, at which point the reaction was successively quenched by addition of water (1 mL) in THF (10 mL) and DDQ (7.6 g, 34 mmol) in THF (25 mL). The resulting brown suspension was stirred at room temperature for 15 min, then cooled to 0 ', and treated with hexane (25 mL) and aqueous NaOH (3N, 25 mL). The mixture was stirred at 0 ' for 5 min, diluted with water (100 mL) and then extracted with ethyl acetate. The combined organic layers were washed with water, dried on MgS04, and concentrated to a minimum volume to afford after filtration lll-a as a pale brown solid (3.14 g, 53 percent). H NMR (400 MHz, DMSO- de) δ 9.35 (dd, J = 2.3, 0.8 Hz, 1 H), 8.90 (d, J = 5.3 Hz, 1 H), 8.79 (dd, J = 4.8, 1 .6 Hz, 1 H), 8.54 (ddd, J = 8.0, 2.3, 1 .7 Hz, 1 H), 8.26 (d, J = 5.3 Hz, 1 H), 7.62 (ddd, J = 8.0, 4.8, 0.8 Hz, 1 H).
With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 18 h;
Step 1 : 1-(2-Pyrimidinyl)-4-piperidinol (180) <n="157"/>4-Hydroxypiperidine (1.5 g, 14.7 mmol) was combined with 2-chloropyrimidine (1.5 g, 13.4 mmol) and diisopropylethylamine (6 ml_, 33.5 mmol) into 50 ml. acetonitrile. The mixture was heated at 80 0C for 18 hours. The reaction mixture was then concentrated to dryness and the crude residue was then purified on via flash column chromatography using a gradient of 0-60percent ethylacetate/hexane to give 2.1 g (81percent) of the desired compound 180 as a white solid. 1H NMR (400 MHz, CDCI3): δ 8.28 (d, J = 4.6 Hz 2 H), 6.49 (t, J = 4.8 Hz, 1 H), 4.49 - 4.33 (m, 2 H), 4.01 - 3.88 (m, 1 H), 3.37 - 3.21 (m, 2 H), 2.02 - 1.90 (m, 2 H), 1.60 - 1.45 (m, 2 H); LCMS (ESI): m/z 180 (M + H)+.
Reference：
[1] Patent: WO2008/8895, 2008, A1, . Location in patent: Page/Page column 155; 156
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 24, p. 10972 - 10994
62
[ 1722-12-9 ]
[ 395082-55-0 ]
Yield
Reaction Conditions
Operation in experiment
18%
Stage #1: With N,N,N,N,-tetramethylethylenediamine; zinc(II) chloride In tetrahydrofuran at 0℃; for 2 h; Inert atmosphere Stage #2: With iodine In tetrahydrofuranInert atmosphere
To a stirred, cooled (0 °C) solution of 2,2,6,6-tetramethylpiperidine (0.50 mL, 3.0 mmol) in THF (6 mL) were successively added BuLi(about 1.6 M hexanes solution, 3.0 mmol) and, 5 min later, ZnCl2·TMEDA7 (0.26 g, 1.0mmol). The mixture was stirred for 15 min at 0 °C before introduction of 2-chloropyrimidine(2, 0.11 g, 1.0 mmol). After 2 h at this temperature, a solution of I2 (0.76 g, 3.0 mmol) in THF(10 mL) was added. The mixture was stirred overnight before addition of an aqueoussaturated solution of Na2S2O3 (10 mL) and extraction with AcOEt (3 x 20 mL). The combinedorganic layers were dried over MgSO4, filtered and concentrated under reduced pressure.Purification was performed by chromatography on silica gel (eluent: heptane/AcOEt 95/5) toafford 4a in 18percent yield as a beige powder
Reference：
[1] Chemistry - A European Journal, 2009, vol. 15, # 6, p. 1468 - 1477
[2] Synlett, 2015, vol. 26, # 20, p. 2811 - 2816
63
[ 1722-12-9 ]
[ 109384-19-2 ]
[ 412293-91-5 ]
Yield
Reaction Conditions
Operation in experiment
68%
Stage #1: With sodium hydride In tetrahydrofuran at 5℃; for 0.5 h; Stage #2: at 20℃; for 18 h;
Preparation 28; tert-Butyl 4-(pyrimidin-2-yloxy)piperidine-1-carboxylate; 1-tert-Butoxycarbonyl-4-hydroxypiperidine (10g, 50mmol) was dissolved in tetrahydrofuran (200mL) and cooled to 5°C. Sodium hydride (60percent dispersion in mineral oil, 2.5g, 65mmol) was added portionwise and the resulting mixture was stirred for 30 minutes at 5°C. 1-Chloropyrimidine (11.4g, 99mmol) was added and the mixture was stirred for 18 hours at room temperature. The mixture was then filtered, concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. Re- crystallisation of the residue for diisopropyl ether (50mL) afforded the title compound in 68percent yield, 9.5g.
5.1. Preparation of N-(3 '-chloro-3-methylbiphenyl-4-yl)-l-(pyrimidin-2- yl)piperidin-4-amineThe title compound was prepared stepwise, as described below. A. 1 -Pyrimidin-2-yl-piperidin-4-one : A mixture of 4-piperidone monohydrate hydrochloride (4.84 g, 31.5 mmol), 2-chloropyrimidine (3.44 g, 30 mmol) and TEA (10.04 ml, 72 mmol) in EtOH (150 ml) was heated at reflux for overnight. The mixture was concentrated to almost dry and diluted with EtOAc (400 ml). The EtOAc layer was washed with water (2 x 50 ml) and brine (2x50 ml). The aq layer was back extracted with EtOAc (4 x 100 ml). The combined EtOAc was dried (Na2SO4) and the solvent was removed. The residue was subjected to ISCO (12Og column, hexane 5 min., 0-80percent EtOAc in hexane over 70 min., then EtOAc for 15 min) to give the titled compound (3.5 g, 66percent). HPLC: column, Luna Phenyl-Hexyl 5 μm 4.6x50 mm, 10-90percent solvent B (acetonitrile) in solvent A (10 mM ammonium acetate aq.) over 3 min., flow rate 3 ml/min, retention time, 0.97 and 1.08 min.; MS (MH+: 178).1H NMR (300 MHz, chloroform- d), δ ppm 2.52 (t, J=6.29 Hz, 4 H), 4.15 (t, J=6.20 Hz, 4 H), 6.60 (t, J=4.67 Hz, 1 H), 8.38 (d, J=4.77 Hz, 2 H).
53%
Stage #1: at 20 - 80℃; Stage #2: With water; sodium hydrogencarbonate In ethyl acetate
A. 1 -Pyrimidin-2-yl-piperidin-4-one : To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 8O0C overnight and concentrated under reduced pressure. The residue was treated with ethyl acetate (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40percent ethyl acetate/hexanes) to give l-pyrimidin-2-yl-piperidin-4-one (320 mg, 53percent) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 8.38 (d, J= 6.4 Hz, 2 H), 6.61 (t, J= 6.4 Hz, 9 H), 4.16 (t, J= 5.6 Hz, 2 H), 2.53 (t, J= 5.6 Hz, 2 H).
53%
Stage #1: at 20 - 80℃; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate
A. 1 -Pyrimidin-2-yl-piperidin-4-one:; To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 8O0C overnight and concentrated under reduced pressure. The residue was treated with ethyl acetate (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40percent ethyl acetate/hexanes) to give l-pyrimidin-2-yl-piperidin-4-one (320 mg, 53percent) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 8.38 (d, J= 6.4 Hz, 2 H), 6.61 (t, J= 6.4 Hz, 9 H), 4.16 (t, J= 5.6 Hz, 2 H), 2.53 (t, J= 5.6 Hz, 2 H).
53%
at 20 - 80℃;
6.8. Preparation of Biphenyl-4-yl-fl-pyrimidin-2-yl-l,2,3i6-tetrahydro- pyridin-4-vl)-methanone; To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 8O0C overnight and concentrated under reduced pressure. The residue was treated with EtOAc (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40percent EtOAc/hexanes) to give l-pyrimidin-2-yl- piperidin-4-one (320 mg, 53percent) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 8.38 (d, J = 6.4 Hz, 2 H), 6.61 (t, J = 6.4 Hz, 9 H), 4.16 (t, J= 5.6 Hz, 2 H), 2.53 (t, J= 5.6 Hz, 2 H).
53%
at 80℃;
To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 80° C. overnight and concentrated under reduced pressure. The residue was treated with EtOAc (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2.x.10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40percent EtOAc/hexanes) to give 1-pyrimidin-2-yl-piperidin-4-one (320 mg, 53percent) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 8.38 (d, J=6.4 Hz, 2 H), 6.61 (t, J=6.4 Hz, 9 H), 4.16 (t, J=5.6 Hz, 2 H), 2.53 (t, J=5.6 Hz, 2 H).
With triethylamine In 1,4-dioxane at 90℃; for 12 h;
To a mixture of 2-chloropyrimidine (300.00 mg, 2.62 mmol, 1.00 eq) and piperidin-4-one (311.59 mg, 3.14 mmol, 1.20 eq) in dioxane (5.00 mL) was added triethylamine (795.35 mg, 7.86 mmol, 3.00 eq) and the mixture was stirred at 90 °C for 12 h. The mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (Si02, PE/EA=10/1 to 1/1) to afford l-pyrimidin-2-ylpiperidin-4- one (100.00 mg, 564.33 umol, 21.54percent yield) as a yellow solid. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.37 (d, J=4.9 Hz, 2H), 6.59 (t, J=4.6 Hz, 1H), 4.21 - 4.11 (m, 4H), 2.51 (t, J=6.2 Hz, 4H).
With potassium carbonate; In methanol; at 80℃;Sealed tube;
Intermediate AT: l-methyl-5-phenyl-1H-imidazol-2-amineStep 1: Synthesis of N-methylpyrimidin-2-amineTo a solution of 2-chloropyrimidine (1 g, 8.7 mmol) in methanol (10 mL) is added a 2M solution of methylamine (13.2 mL, 26.2 mmol) in methanol, followed by K2C03 (2.5 g, 18 mmol). The reaction flask is sealed and heated to 80 C overnight. The reaction is then cooled to room temperature and concentrated to remove volatiles. The residue is partitioned between water and CH2C12. The organic layer is dried (Na2S04) and concentrated to afford the title compound (290 mg, 30%) as a brown oil.
Example 7 N-(1-Methyl-5-phenyl-1H-imidazol-2-yl)-3-phenyl-propionamide (90) To a solution of 2-chloropyrimidine (90a, 2.0 g, 17.5 mmol) in THF (25 mL) was added 40% CH3NH2(aq) (7.5 mL) at 0 C. The reaction mixture was stirred at 50 C. for 1.0 hour and then poured into saturated NaHCO3(aq) and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4(s) and concentrated under reduced pressure to give N-methylpyrimidin-2-amine (90b).To a microwave vial containing a solution of N-methylpyrimidin-2-amine (90b, 290 mg, 2.7 mmol) in acetonitrile (5 mL) was added 2-bromo-1-phenylethanone (714 mg, 3.6 mmol). The vial was sealed and heated in a microwave reactor at 130 C. for 20 minutes and then cooled to room temperature. The reaction mixture was treated with hydrazine hydrate (0.65 mL, 13.3 mmol) and then heated in a microwave reactor at 100 C. for 5.0 minutes. The solution was poured into water and filtered the precipitate to give 1-methyl-5-phenyl-1H-imidazol-2-ylamine (90c).To a solution of 1-methyl-5-phenyl-1H-imidazol-2-amine (90c, 52.0 mg, 0.3 mmol) in pyridine (1.0 ml) was added 3-phenyl-propionyl chloride (60.7 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 16 hours, quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4(s) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give N-(1-Methyl-5-phenyl-1H-imidazol-2-yl)-3-phenyl-propionamide (90) : 1H NMR (500 MHz, DMSO) delta: 7.16-7.48 (m, 10H), 6.87 (s, 1H), 3.42 (s, 3H), 3.07 (t, 2H), 2.92 (t, 2H). ESI-MS: 305.7 (M+H)+.Compounds 91 was synthesized in a manner similar to that describe above and its observed ESI-MS was 309.8 (M+H)+.
With potassium carbonate; hydrazine hydrate; at 100℃; for 0.5h;
[1484] a mixture of 2-chloropyrimidine (15 g, 131 mmol), NH2NH2.H2O (30 ml), K2CO3 (15 g, 109 mmol) was stirred at 100 C for 30 min. The mixture was ice cooled and the resulting crude crystals were collected by filtration. The crystals were washed with cold water, air dried, and recrystallized from petroleum ether (150 ml) to give compound 350a (14.4 g, 131 mmol, yield: 99.8%) as a yellow solid. 1H NMR (400mhz, DMSO-d6) delta 8.30 (d, = 4.8 hz, 2h), 8.12 (br s, ih), 6.59 (t, j = 4.7 hz, ih), 4.13 (s, 2h).
87%
With hydrazine hydrate; In ethanol;Reflux;
General procedure: To 2-chloropyridine (1.1 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (2 mL) dropwise at room temperature. The mixture was refluxed until completion as monitored by TLC. The reaction mixture was cooled, ethanol was removed by evaporation. Then, the residue was partitioned between ethyl acetate and water. The combined organic phase was dried over anhydrous sodium sulfate and concentrated to give the product, which was used for the following cyclization reaction without purification.
82%
With potassium carbonate; hydrazine hydrate;
Reference Example 2-57 2-Hydrazinopyrimidine The title compound was prepared according to the method described in Yakugaku Zasshi, vol.73, p.598 (1953). A mixture of 2-chloropyrimidine (25.0 g, 218 mmol), potassium carbonate (25.0 g, 181 mmol), and hydrazine monohydrate (50 mL, 1.01 mol) was heated and stirred at 100 C. for 20 minutes. The mixture was ice cooled and the resulting crude crystals were collected by filtration. The crystals were washed with cold water, air dried, and recrystallized from benzene to give the title compound (19.7 g, 82% yield). NMR (DMSO-d6) delta: 4.12 (2H, br s), 6.60 (1H, t, J=4.8 Hz), 8.10 (1H, br s), 8.31 (2H, d, J=4.8 Hz).
80%
With hydrazine hydrate; In ethanol; for 2h;
H2mphp was synthesized by the following procedure. 2-Chloropyrimidine (1.145 g, 20 mmol) was dissolvedin ethanol (30 mL). Then, excess hydrazine hydrate (85%, 6 mL) was added to the above solutionunder stirring. A bright yellow solution formed, from which white needle crystals appeared after 2 h. The crystals were collected by filtration and recrystallized in ethanol (yield 80%). 3-Methylsalicylaldehyde(1.36 g, 10 mmol) was added to an ethanolic solution (30 mL) of 2-hydrazinopyrimidine (1.10 g, 10 mmol)and light yellow precipitate formed immediately. After reflux for 3 h, the reaction mixture was filteredand the precipitate washed with ethanol to yield light yellow powder of H2mphp. Yield 95%.
40%
With hydrazine; In ethanol; at 20℃; for 1.33333h;
[Referential Example 34] 2-Hydrazinopyrimidine; [Show Image] Hydrazine monohydrate (20 ml) was added to a suspension of 2-chloropyrimidine (6.00 g) in ethanol (60 ml) at room temperature, and the mixture was stirred for 80 minutes. The solvent was evaporated under reduced pressure, and water (34 ml) was added to the residue. The solid precipitate was collected by filtration to give the title compound (2.30 g, 40%). 1H-NMR (400 MHz, DMSO-d6)delta: 4.12 (2H, s), 6.57-6.60 (1H, m), 8.12 (1H, s), 8.30 (2H, d, J = 4.9 Hz). EI-MSm/z: 110 (M+).
40%
With hydrazine; In ethanol; at 20℃; for 1.33333h;
[Referential Example 3] 2-Hydrazinopyrimidine [Show Image] Hydrazine monohydrate (20 mL) was added to a suspension of 2-chloropyrimidine (6.00 g) in ethanol (60 mL) at room temperature, followed by stirring for 80 minutes. The solvent of reaction mixture was evaporated under reduced pressure, and then water (34 mL) was added to the residue. The solid that precipitated was collected through filtration, to thereby give the title compound (2.30 g, 40%). 1H-NMR(400MHz,DMSO-d6)delta:4.12(2H,s), 6.57-6.60 (1H,m), 8.12(1H,s), 8.30(2H,d,J=4.9Hz). EI-MS m/z:110(M+).
25%
With pyridine; hydrazine; at 20℃; for 1.6h;
PREPARATION 9Preparation of 2-hydrazinylpyrimidine; A solution of 2-chloropyrimidine (0.70 g, 6.11 mmol) in pyridine (15 mL) and anhydrous hydrazine (2.5 mL) was stirred for 5 minutes at ambient temperature, and further pyridine (8 mL) was added. The reaction mixture was stirred at ambient temperature for 1.5 h and concentrated in vacuo. The residue was suspended in water (4 mL) and the resultant solid was collected by suction filtration and air-dried to afford 2-hydrazinylpyrimidine as a colorless solid in 25% yield (0.171 g): 1H NMR (300 MHz, DMSO-d6) delta 8.29 (d, J = 4.8 Hz, 2H), 8.13 (br s, 1 H), 6.59 (t, J = 4.8 Hz, 1 H), 4.12 (br s, 2H).
With hydrazine hydrate; In ethanol;
Preparation Example 2 of Intermediate Compound Hydrazine monohydrate (43.5 g) was added to a solution of 2-chloropyrimidine (33 g) in ethanol, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the crystalline product thus obtained was recrystallized from ethyl acetate (50 ml) to give 2-hydrazinopyrimidine (20 g). Melting point 109.5C. 1H-NMR (CDCl3/DMSO-d6/TMS) delta (ppm): 8.34 (d, 2H), 6.38 (brs, 1H), 6.62 (t, 1H), 3.98 (brs, 2H).
With hydrazine hydrate; In methanol; at 10 - 40℃; for 1.5h;
1) Synthesis of compound B: A solution of 26.2 g of a hydrazine monohydrate (manufactured by Wako Pure Chemical Industries, Ltd.) and 30 mL of methanol was adjusted to an internal temperature of 10C, and 15 g of Compound (A) (manufactured by Wako Pure Chemical Industries, Ltd.) is gradually added thereto, followed by stirring for 0.5 hours at the same temperature. Then, an internal temperature was elevated to 40C, and the mixture was stirred for 1.0 hour. Subsequently, the reaction liquid was allowed to cool to room temperature, and 30 mL of water was added thereto, followed by filtration and washing with 30 mL of each of water and isopropyl alcohol. The resulting crystals were dried at room temperature for 8 hours to obtain 12.4 g of Compound (B). (1H-NMR(DMSO-d6), delta value TMS standard: 4.08 to 4.20(2H, brs), 6.55 to 6.72(2H, d), 8.10 to 8.15(1H, s), 8.27 to 8.35(2H, d))
With hydrazine hydrate; at 100℃;
General procedure: A mixture of 2-chloro-5-methyl-benzimidazole (10.2 g, 61.2 mmol) and hydrazine monohydrate (59 mL, 1.22 mol) was stirred at 100 C overnight. After being cooled to ambient temperature, to the reaction mixture was added to water (60 mL). After stirring under ice cooling, the resulting precipitates were collected by filtration. The precipitates were washed with water 3 times, and then dried in vacuo to give 2-hydrazino-5-methyl-benzimidazole (8.4 g, 84.6%).
With hydrazine hydrate; In ethanol; at 60℃;
General procedure: Hydrazine hydrate (5 mL) and 14a (10 mmol)was added to EtOH, and the mixture was heated to 60C overnight. After cooling, the solvent was evaporated, and the residue was diluted with 50 mL water, and extracted with DCM (50 mL×3). The combined organic extract was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to get the crude product 15a which was used in the next step without further purification. A solution of 2-hydroxybenzaldehyde (122 mg, 1 mmol) in 5 mL MeOH was added slowly to a solution of 15a (1 mmol), and the mixture was heated at 40C overnight. The residue was filtered, and washed with water, brine and petrol ether to give the product 16b.
With triethylamine; In chloroform; at 25℃; for 4h;
[2-CHLOROPYRIMIDINE] (1.14 g, 10.0 mmol), 2-methylpiperazine (1.20 g, 12.0 mmol), and triethylamine (1.52 g, 15 mmol) were dissolved in 10 mL of chloroform and the resulting mixture was stirred at room temperature, about [25C,] for 4 hours. The reaction was quenched with water and the resulting mixture was extracted with chloroform. The organic layer was dried, concentrated, and purified using a silica gel column eluted with gradient elution from ethyl acetate to 2/1 ethyl acetate/methanol to provide Compound O as a yellow oil (95% yield). [A] solution of Compound O (178 mg, [1.] 0 mmol), Compound F (219 mg, 1.5 [MMOL),] HOBt (203mg, 1.5 mmol), and DIC (189 mg. [1.] 5 mmol) in 4.5 [ML] dichloromethane ("DCM") was stirred at room temperature, about [25C,] for 4 hours. After evaporation, the product was purified using a silica gel column eluted with gradient elution from hexane to 1/1 hexane/ethyl acetate to provide 153 mg of Compound AFX [(IIB)] as a slight yellowish solid (50% yield). The structure of Compound AFX [(IIB)] was confirmed [BY'H NMR] and mass spectral [(MS)] analysis. Compound AFX [(IIB)] [:'H] NMR [(CDC13)] 8 8.35 (d, J = 4.7 Hz, 2H), 7.61 (m, 2H), 7.40 [(M,] 3H), 6. [55] (dd, J = 4.7, 4.7 Hz, [1H),] 4.91 [(M,] [0. 6H),] 4. 78 (m, 2H), 4.63 (dt, J = 1.8, 11. [6 HZ,] 0.4H), 4.52 (d, [J = 13. 3 HZ,] 0.4H), 4.33 (d, [J = 13. 3 HZ,] 0.6H), 3.59 [(M,] 0.6H), 3.20 (m, 2.4H), 1.36 (d, J = 6.8 Hz, 1.2H), 1.25 (d, [J =] 6.8 Hz, 1.8H) ; MS [(EL)] : m/z 329 [(M+NA+).]
With hydrogen iodide; In water; at -10 - -5℃; for 1 - 2h;
Under N2, 2-chloropyrimidine (200 g, 1.75 mol) was added in 5 portions to aqueous HI (850 ml, 57% in water) at -10 to -5 C. The mixture was stirred at -10 to -5 C. and the reaction was followed by HPLC. After complete reaction (60 to 120 min), the pH was set to 7.25+/-0.25 with NaOH (30%) and the temperature was increased to 18-23 C. To decolorize the mixture, 16 g Na2SO3 was added, decreasing the pH to 3+/-1. TBME (600 ml) was added to the mixture and the mixture was saturated with NaCl (300 g). The phases were separated and the aqueous phase was extracted with TBME (4×400 ml). The combined organic layers were washed with aqueous Na2SO3 (50 ml) (1%) and water (100 ml). The organic layer was evaporated to dryness and co-evaporated with TBME (100 ml) under vacuum at 45 to 50 C. Yield: 330 g (90%). Assay (HPLC): 98% pure vs. standard.
55%
With hydrogen iodide; In water; at 0℃; for 0.25h;Cooling with ice;
Ice cooled hydriodic acid (Wako Pure Chemical Industries, Ltd.) (14.7 ml, 57%) was added gradually to 3.68 g (32.0 mmoles) of 2-chloropyrimidine (Sigma-Aldrich Corporation), and the reaction mixture was agitated for fifty minutes at 0C. Ice cooled aqueous sodium carbonate solution was added to the reaction solution until the solution was neutral, and aqueous sodium sulfite solution was subsequently added. The product was extracted using diethyl ether, and the organic layer was dried using anhydrous sodium sulfate after it was washed once using a saturated aqueous sodium chloride solution. The solvent was removed, and the pale yellow oil remaining was dissolved in boiling hexane. The solution was left standing to cool, and 3.62 g (17.6 mmoles, 55%) of colorless needle-like crystals (Compound 2) was obtained. The analytical results for Compound 2 obtained (2-iodopyrimidene) are shown below. 1H-NMR (400 MHz, CDCl3, TMS, rt) delta 8.47 (2H, d, J = 4.8 Hz), 7.32 (1H, t, J = 4.9 Hz)
2-Chloropyrimidine (1.5 g, 13.3 mmol), <strong>[6358-06-1]5-amino-2-chlorophenol</strong> (318mg, 2.2mmol) and 37percent HCl solution (LImL5 13.3mmol) in 10percent aqueous EtOH solution (1OmL) was stirred at 9O0C for 24h. Afterwards, 2-chloropyrimidine (1.5g, 13.3) was added and after 24 h, 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 (179mg, 36percent yield) was used for the next step without additional purification. 1H NMR (500 MHz, CD3OD) .pound.8.43 (d, J= 4.9 Hz, 2H), 7.58 (d, J= 2.4 Hz, IH), 7.17 (d, J = 8.7 Hz, IH), 7.03 (dd, J= 8.3, 2.5 Hz, IH), 6.79 (t, J= 4.8 Hz5 IH); 13C NMR (125 MHz5 CD3OD) .pound. 161.9, 159.5, 154.6, 141.7, 130.9, 115.0, 114.0, 113.3, 109.2.
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.
2-Bromopyridine or 2-chloropyrimidine (2equiv.), 5-amino-2-substitutedphenol (lequiv) and 37% HCl solution (2equiv) in 10% aqueous EtOH solution (0.2M) was stirred at 9O0C for 24h. The reaction mixture was diluted with AcOEt and washed with 5% 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, 2- chloropyrimidine (209 mg, 1.8 minol) and <strong>[67608-58-6]4-amino-2-hydroxybenzonitrile</strong> (123 mg, 0.9 mmol) in 10% aqueous EtOH (5 niL) was heated at 90 0C for 18h. The title compound was obtained in 5 % yield a (10 mg) and used for the next step without addittional purification.1H NMR (500 MHz5 CD3OD) £8.51 (d, J= 4.8 Hz, 2H), 7.86 (d, J= 2.0 Hz, IH), 7.39 (d, J= 8.6 Hz, IH), 7.10 (dd, J= 8.6, 2.0 Hz, IH), 6.91 (t, J= 4.8 Hz, IH); 13C NMR (125 MHz,CD3OD) £ 162.9, 161.6, 159.6, 159.5, 134.7, 116.6, 115.1, 112.0, 106.3, 101.1.
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.
With acetic acid; bunazosin; In tetrahydrofuran; at -78℃; for 3.0h;
A mixture of 2-chloropyrimidine (5.7 g, 0.05 mol) in THF (50 mL) was cooled to -78 C. t-Butyl lithium (32 mL 1.7M, 0.055 mol) was added and stirred 2 h warming to 0 C. Acetic acid (5 mL, 50%) was added followed by DDQ (5 g, 0.22 mol) and stirring continued for 1 h. The solvent was concentrated and the residue dissolved in ether. The ether layer was washed with 10% sodium hydroxide, sat sodium chloride, dried over magnesium sulfate, concentrated and chromatographed on silica gel with 10% EtOAc/Hexane. MS m/z 191 (MH)+.
Example 16 Benzyl 4-[(2-pyrimidinylamino)methyl]-1-piperidinecarboxylate The title compound was prepared as described in EXAMPLE 13, except using benzyl 4-(aminomethyl)-1-piperidinecarboxylate (6.50 g, 26.19 mmol) and 2-chloropyrimidine (990 mg, 8.64 mmol) as starting materials without a solvent to give the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3): delta8.26 (d, J=4.85 Hz, 1H, Pyr-H), 7.36-7.29 (m, 5H, Ar-H), 6.52 (t, J=4.85 Hz, 1H, Pyr-H), 5.12 (s, 2H, CH2-Ar), 4.21 (brs, 2H, CHH), 3.30 (t, J=6.26 Hz, 2H, CH2-N), 2.78 (brs, 2H, CHH), 1.76-1.62 (m, 3H, CHH, CH), 1.28-1.12 (m, 2H, CHH).
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 18h;
Step 1 : 1-(2-Pyrimidinyl)-4-piperidinol (180) <n="157"/>4-Hydroxypiperidine (1.5 g, 14.7 mmol) was combined with 2-chloropyrimidine (1.5 g, 13.4 mmol) and diisopropylethylamine (6 ml_, 33.5 mmol) into 50 ml. acetonitrile. The mixture was heated at 80 0C for 18 hours. The reaction mixture was then concentrated to dryness and the crude residue was then purified on via flash column chromatography using a gradient of 0-60% ethylacetate/hexane to give 2.1 g (81%) of the desired compound 180 as a white solid. 1H NMR (400 MHz, CDCI3): delta 8.28 (d, J = 4.6 Hz 2 H), 6.49 (t, J = 4.8 Hz, 1 H), 4.49 - 4.33 (m, 2 H), 4.01 - 3.88 (m, 1 H), 3.37 - 3.21 (m, 2 H), 2.02 - 1.90 (m, 2 H), 1.60 - 1.45 (m, 2 H); LCMS (ESI): m/z 180 (M + H)+.
To a solution of butyllithium (1.6M in hexanes, 9.7 ml, 16 mmol) in 25 ml of anhydrous ether at -78C was added 3-bromopyridine (1.5 ml, 16 mmol) over 5 min. The resulting mixture was stirred at -75C for 1 h. A suspension of 2- chloropyrimidine (1.8 g, 16 mmol) in 15 ml of ether was then added in portions <n="36"/>over 8 min. The resulting suspension was stirred for 30 min at -30C and allowed to warm to O'C for 1 h. The reaction was quenched with water (0.5 ml, 1.5 eq.) in THF (5 ml) and then 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.8 g, 17 mmol) in THF (12 ml) was added. The resulting suspension was stirred at RT for 15 min, then cooled to 0C. Hexane (13 nriL) was added followed by 0*C solution of NaOH (12 ml, 3N). The suspension was stirred at 0C for 5 min, 50 ml of water was added and the layers were separated. The organic layer was dried (Na2SO4) and concentrated in vacuo. The crude product was dissolved in DCM and chromatographed through a Redi-Sep pre-packed silica gel column (120 g), eluting with a gradient of 20% to 65% EtOAc in hexane, to provide 2-chloro-4- (pyridin-3-yl)pyrimidine as off-white solid. Found M+H* = 192, 194
2-PIPERAZINECARBOXYLIC acid and 2-CHLORO-1, 3-pyrimidine were stirred with triethylamine and MeOH. After stirring overnight at reflux, the mixture was filtered and concentrated in vacuo to give the desired compound which was used directly in Step B (MH+ = 209).
With triethylamine; In methanol;Heating / reflux;
2-Piperazinecarboxylic acid and 2-chloro-l,3-py-rimidine were stirred with triethylamine and MeOH. After stirring overnight at reflux, the mixture was filtered and concentrated in vacuo to give the desired compound which was used directly in Step B (MH+=209).
With triethylamine;Heating / reflux;
2-Piperazinecarboxylic acid and 2-chloro-1,3-pyrimidine were stirred with triethylamine and MeOH. After stirring overnight at reflux, the mixture was filtered and concentrated in vacuo to give the desired compound which was used directly in Step B (MH+=209).
With triethylamine; In methanol;Heating / reflux;
PREPARATIVE EXAMPLE 2.9; Step A; N Yco H Step B CN C02H N COSY ) 10 N N P w H 1-YN H N I HO2C O OH H02C 0 OH O OH btep A 2-Piperazinecarboxylic acid and 2-chloro-1, 3-pyrimidine were stirred with triethylamine and MeOH. After stirring overnight at reflux, the mixture was filtered and concentrated in vacuo to give the desired compound which was used directly in Step B (MH+ = 209).
With triethylamine; In methanol;Heating / reflux;
2-Piperazinecarboxylic acid and 2-chloro-1, 3-pyrimidine were stirred with triethylamine and MeOH. After stirring overnight at reflux, the mixture was filtered and concentrated in vacuo to give the desired compound which was used directly in Step B (MH+ = 209).
4-tert-butoxycarbonylamino-4-methyl-1-(2-pyrimidinyl)piperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In 1,4-dioxane; for 48h;Heating / reflux;
(1) To a solution of <strong>[163271-08-7]4-tert-butoxycarbonylamino-4-methylpiperidine</strong> (1.28 g, 6.0 mmol) described in European Patent No. 647,639 in 1,4-dioxane (25 mL) were added potassium carbonate (4.15 g, 30.0 mmol) and 2-chloropyrimidine (2.06 g, 18.0 mmol), and the mixture was refluxed for 2 days. After the reaction mixture was stand for cooling to room temperature and filtered, the filtrate was concentrated. The obtained residue was partially purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) to obtain a mixture (1.97 g) of 4-tert-butoxycarbonylamino-4-methyl- 1-(2-pyrimidinyl)piperidine and unreacted 2-chloropyrimidine.APCIMS (m/z): 293 (M + H)+<1>H NMR (CDCl3) delta (ppm): 8.29 (2H, d, J = 4.6 Hz), 6.45 (1H, t, J = 4.6 Hz), 4.98 (1H, br s), 4.18 (2H, ddd, J = 13.5, 4.6, 4.6 Hz), 3.44 (2H, ddd, J = 13.5, 10.3, 3.2 Hz), 2.04 (2H, d, J = 14.0 Hz), 1.60 (2H, ddd, J = 14.0, 10.0, 4.1 Hz), 1.44 (9H, s), 1.40 (3H, s)
EXAMPLE 9 This Example illustrates the preparation of (E)-methyl 2-[2-(4-phenylpyrimidin-2-yloxy)phenyl]-3-methoxypropenoate (Compound No.180 of Table III). To a stirred suspension of sodium methanethiolate (0.35 g) in DMF (5 ml) at 0 C. was added dropwise a solution of 2-chloro-4-phenylpyrimidine (0.86 g, prepared from 2-chloropyrimidine according to the method of D B Harden et al., J.Org.Chem., 1988, 53, 4137) in DMF (5 ml). Stirring was continued at 0 C. for 15 minutes and then the temperature was allowed to rise to room temperature. After a further 2 hours, the reaction mixture was diluted with water and then extracted with ether (*3). The combined ether extracts were washed with water, dried, filtered and evaporated to give 2-methylthio-4-phenylpyrimidine (0.76 g) as a brown solid which was used directly in the next stage.
6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-[3-methyl-4-(2-pyrimidinyl)piperazin-1-yl]quinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In pyridine; ethanol; N,N-dimethyl-formamide;
EXAMPLE 31 Synthesis of 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-[3-methyl-4-(2-pyrimidinyl)piperazin-1-yl]quinoline-3-carboxylic acid In 30 ml of pyridine were dissolved 1.5 g (0.0049 mole) of 6,7-difluoro-8-trifluoromethyl-1,4-dihydro-1-methyl-4-oxoquinoline-3-carboxylic acid and 1.5 g (0.015 mole) of 2-methylpiperazine, the mixture was stirred at 105 C. for 3 hours, and then the solvent was removed by evaporation under reduced pressure. Ethanol was added to the residue, precipitated crystals were collected by filtration, the crystals obtained were washed with ethanol and dried, and then 1.49 g of 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-(3-methylpiperazin-1-yl)quinoline-3-carboxylic acid was obtained as yellow powder. To 20 ml of N,N-dimethylformamide were added 1.49 g (0.0039 mole) of the obtained 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-(3-methylpiperazin-1-yl)quinoline-3-carboxylic acid, 0.88 g (0.0077 mole) of 2-chloropyrimidine and 0.78 g (0.0077 mole) of triethylamine, the mixture was stirred at 130 C. for 10 hours, and then the solvent was removed by evaporation under reduced pressure. The residue was applied to silica gel column chromatography (eluent; a chloroform:methanol=9:1 mixed solution) to obtain 0.35 g of 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-[3-methyl-4-(2-pyrimidinyl)piperazin-1-yl]-quinoline-3-carboxylic acid as ocher yellow powder. Melting point: 283 to 284.5 C. MS spectrum (CI): m/e 466 (M+ +1)
With triethylamine; In methanol; at 20 - 50℃; for 5h;
6.13. Preparation of Biphenyl-4-yl-( l-pyrimidin-2-yl-azetidin-3-vD- methanone; To a stirred solution of <strong>[100202-39-9]3-azetidine carboxylic acid methyl ester hydrochloride</strong> (150 mg, 0.99 mmol) and 2-chloropyrimidine (113.4 mg, 0.99 mmol) in methanol, was added TEA (200 mg, 1.98 mmol) at room temperature. The mixture was stirred at 5O0C for 5 hours and concentrated under reduced pressure. The residue was suspended inEtOAc (50 ml) and washed with water (15 ml), brine (5 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (40% EtOAc/hexanes) to give l-pyrimidin-2-yl- azetidine-3 -carboxylic acid methyl ester as a light yellow solid (137.3 mg, 72%): 1H NMR (CDCl3, 400 MHz) delta 8.37 (d, J= 6.4 Hz, 2 H), 6.58 (t, J= 6.4 Hz, 1 H), 4.30 (m, 4 H), 3.77 (s, 3 H), 3.56 (m, 1 H).
72%
With triethylamine; In methanol; at 50℃; for 5h;
To a stirred solution of <strong>[100202-39-9]3-azetidine carboxylic acid methyl ester hydrochloride</strong> (150 mg, 0.99 mmol) and 2-chloropyrimidine (113.4 mg, 0.99 mmol) in methanol, was added TEA (200 mg, 1.98 mmol) at room temperature. The mixture was stirred at 50 C. for 5 hours and concentrated under reduced pressure. The residue was suspended in EtOAc (50 ml) and washed with water (15 ml), brine (5 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (40% EtOAc/hexanes) to give 1-pyrimidin-2-yl-azetidine-3-carboxylic acid methyl ester as a light yellow solid (137.3 mg, 72%): 1H NMR (CDCl3, 400 MHz) delta 8.37 (d, J=6.4 Hz, 2 H), 6.58 (t, J=6.4 Hz, 1 H), 4.30 (m, 4 H), 3.77 (s, 3 H), 3.56 (m, 1 H).
With sodium hydrogencarbonate; In isopropyl alcohol;Heating / reflux;
8-Pyrimidin-2-yl-8-aza-bicyclo[3.2.1]octan-3-one A solution of <strong>[25602-68-0]8-aza-bicyclo[3.2.1]octan-3-one hydrochloric acid</strong> (5.0 g, 30.9 mmol), 2-chloro-pyrimidine (4.95g, 43.2mmol), NaHCO3 (7.78g, 92.7 mmol) and isopropanol (200 ml) was maintained at reflux over weekend. The resulting reaction mixture was concentrated and purified by ISCO to afford 8-pyrimidin-2-yl-8-aza-bicyclo[3.2.1]octan-3-one (4.0 g, 52.9percent) as a white solid: MS (M+1)=204. 1H NMR (MeOH) 8.36 (d, J=12 Hz 2H), 6.75 (m, 1H), 4.97 (m, 2H), 2.75 (d, J=12 Hz, 1H), 2.71 (d, J=12 Hz, 1H), 2.32 (d, J=50 Hz, 2H), 2.22 (m, 2H), 1.87 (m, 2H).
With sodium hydrogencarbonate; In isopropyl alcohol; for 48h;Heating / reflux;
A. S-Pyrimidin^-yl-S-aza-bicycloP^.lioctan-S-one (3): A mixture of 8-aza- bicyclo[3.2.1]octan-3-one hydrochloride (1) (5g, 31mmol), 2-chloropyrimidine (2) ( 4.3g, 37 mmol), and sodium bicarbonate (7.8g, 93 mmol) were stirred at reflux in 2-propanol (200ml) for 48 h, filtered, evaporated and chromatographed (silica gel, 25percent(v/v) EtOAc/ hexane) to afford 4 grams.
6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-(3-methylpiperazin-1-yl)quinoline-3-carboxylic acid[ No CAS ]
[ 109-07-9 ]
6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-[3-methyl-4-(2-pyrimidinyl)piperazin-1-yl]quinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In pyridine; methanol; ethanol; chloroform; N,N-dimethyl-formamide;
(Preparation example 142) Synthesis of 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-[3-methyl-4-(2-pyrimidinyl)piperazin-1-yl]quinoline-3-carboxylic acid 1.5 g (0.0049 mol) of 6,7-difluoro-8-trifluoromethyl-1,4-dihydro-1-methyl-4-oxoquinoline-3-carboxylic acid and 1.5 g (0.015 mol) of 2-methylpiperazine were dissolved in 30 ml of pyridine, and the solution was stirred at 105C for 3 hours, followed by evaporation of the solvent under reduced pressure. Ethanol was added to the residue and precipitate was collected by filtration. The precipitate thus obtained was washed with ethanol and followed by distilling off the solvent to obtain 1.49 g of 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-(3-methylpiperazin-1-yl)quinoline-3-carboxylic acid as a yellow powder. 1.49 g (0.0039 mol) of the 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-(3-methylpiperazin-1-yl)quinoline-3-carboxylic acid thus obtained, 0.88 g (0.0077 mol) of 2-chloropyrimidine and 0.78 g (0.0077 mol) of triethylamine were added to 20 ml of N,N-dimethylformamide, and the mixture was stirred at 130C for 10 hours, followed by evaporation of the solvent under reduced pressure. The residue was subjected to silica gel column chromatography (eluding solution: mixture of chloroform:methanol = 9:1) to obtain 0.35 g of 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-[3-methyl-4-(2-pyrimidinyl)piperazin-1-yl]quinoline-3-carboxylic acid as an ocher powder. m.p.: 283-284.5C MS spectrum (CI): m/e 466 (M++1)
Dissolve 2-chloropyrimidine (10.04 g, 87.7 mmol) in pyridine (200 mL) and add hydrazine (35.8 mL, 1.14 mol) to the mixture followed by pyridine (100 mL). Stir the mixture for 3 hr. at room temperature then concentrate. Suspend the residue in water and filter. Wash the cake with cold methanol. Collect the powder and dry under vacuum to give pyrimidin-2-ylhydrazine as a white powder (8.05 g, 83%).
Step 4. Ethyl 3-methoxy-l-pyrimidin-2-yl-lH-pyrazole-4-carboxylate; Sodium hydride (60% in mineral oil, 528 mg, 13.2 mmol) is added portion wise to a solution of ethyl 3-methoxy-lH-pyrazole-4-carboxylate (1.5 g, 8.81 mmol) in 40 mL of THF at RT. Evolution of H2 (g) is observed. After about 5-10 min, 2-chloropyrirnidine (1.0 g, 8.81 mmol) is added, and the resulting reaction mixture is stirred at reflux for 15 h. After cooling to RT, the reaction is quenched with 10 mL of sat. NH4Cl and 10 mL of water and extracted with CH2Cl2 (2 x 40 mL). The combined organic extracts are dried (Na2SO4), filtered, and evaporated in vacuo to give a brown solid. Purification by silica gel column chromatography (gradient from 50% EtOAc/hexane to EtOAc) affords the title compound as a fluffy white solid.
With caesium carbonate; In 1,4-dioxane; at 100℃; for 15h;
A mixture of 4-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (220 mg, 1.22 mmol), 2-chloropyrimidine (210 mg, 1.83 mmol), and cesium carbonate (476 mg, 1.46 mmol) in 5-10 ml of dioxane is heated to 100 0C. After stirring for 15 h, the reaction mixture is cooled and the dioxane is removed in vacuo. The residue is slurried in water and filtered. The collected solid is washed with more water and dried in vacuo to afford the title compound as a light brown solid. Mass spec. (258.95, M+H).
With caesium carbonate; In 1,4-dioxane; at 100℃; for 15h;
Step 2. 4-Chloro-l-pyrimidin-2-yl-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde; A mixture of 4-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (220 mg, 1.22 mmol), 2-chloropyrimidine (210 mg, 1.83 mmol), and cesium carbonate (476 mg, 1.46 mmol) in 5-10 ml of dioxane is heated to 100 0C. After stirring for 15 h, the reaction mixture is cooled and the dioxane is removed in vacuo. The residue is slurried in water and filtered. The collected solid is washed with more water and dried in vacuo to afford the title compound as a light brown solid. Mass spec. (258.95, M+H).
To a stirred, cooled (0 °C) solution of 2,2,6,6-tetramethylpiperidine (0.50 mL, 3.0 mmol) in THF (6 mL) were successively added BuLi(about 1.6 M hexanes solution, 3.0 mmol) and, 5 min later, ZnCl2·TMEDA7 (0.26 g, 1.0mmol). The mixture was stirred for 15 min at 0 °C before introduction of 2-chloropyrimidine(2, 0.11 g, 1.0 mmol). After 2 h at this temperature, a solution of I2 (0.76 g, 3.0 mmol) in THF(10 mL) was added. The mixture was stirred overnight before addition of an aqueoussaturated solution of Na2S2O3 (10 mL) and extraction with AcOEt (3 x 20 mL). The combinedorganic layers were dried over MgSO4, filtered and concentrated under reduced pressure.Purification was performed by chromatography on silica gel (eluent: heptane/AcOEt 95/5) toafford 4a in 18percent yield as a beige powder
3,5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.676 g) and 2-chloropyrimidine (716 mg) were combined, melted in an oil bath at 120°C, and stirred for 5 hr 30 min. Water (10 ml) was added and the mixture was stirred, extracted with ethyl acetate (30 ml), and washed with saturated brine. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (Yamazen HI-FLASH.(TM). COLUMN size L, elution solvent: hexane/ethyl acetate) to give the title compound (333 mg). 1H-NMR (CDCl3)delta:1.25(6H,d,J=6.9 Hz), 1.51(9H,s), 2.97-3.08(2H,m), 3.95-4.16(2H,m), 4.65-4.82(2H,m), 6.51(1H,t,J=4.5 Hz), 8.34(2H,d,J=4.8 Hz). MS:237 (M++1 when tert-butyl group was cleaved).
General procedure: A solution of the corresponding lithium reagent (10 mmol) in THF (10 mL) was stirredat 50 C and treated dropwise with a solution of 2-chloropyrimidine, 2-chloro-5-propylpyrimidine or2-chloroquinazoline (12 mmol) in THF (15 mL). The mixture was allowed to reach 0 C within 2 h, thenquenched with a solution of water in THF (1:5, 6 mL), stirred at 0 C and treated with a solution of DDQ(2.3 g, 10 mmol) in THF (5 mL). After stirring for an additional 10 min at 0 C, the mixture was treatedwith a cold solution of sodium hydroxide (4 M, 5 mL, 20 mmol), stirred and extracted immediatelywith ether/hexanes (1:1, 3 x 10 mL). The combined extracts were dried with anhydrous sodium sulfate,decolorized by filtration through a pad of silica gel (5 g) and concentrated on a rotary evaporator. Theresultant crude 4-substituted 2-chloropyrimidine or 2-chloroquinazoline was treated with a primaryor secondary amine (30 mmol) in toluene (20 mL) in the presence of anhydrous potassium carbonateand the mixture was heated at 75 C for 5-10 h, after which time a TLC analysis on silica gel elutingwith ether/triethylamine (9:1) showed the absence of the substrate. Preparative chromatography wasconducted eluting with ether/triethylamine/hexanes (9:5:5) to give product 1, 2, 21, 23, 24, 26, 29, 30,32, 36-46 (Scheme 1) and 48 (Scheme 2).
Isopropylmagnesium chloride-LiCl (37.9 ml, 36.5 mmol) was added portion wise (in overall 10 min) to a solution of <strong>[717843-48-6]3-bromo-6-methyl-2-pyridinecarbonitrile</strong> (4 g, 20.30 mmol) in THF (150 ml) cooled to -70 C. (internal temperature). The reaction was kept to that temperature for 15 min. Then it was allowed to gently warm up to -40 C. in overall 1 hour. Then, it was cooled to -78 C. and zinc chloride (3.32 g, 24.36 mmol) was added. The resulting mixture was allowed to warm up to room temperature in 1 hour. Pd(Ph3P)4 (2.346 g, 2.030 mmol), 2-chloropyrimidine (3 g, 26.2 mmol) were added and the mixture was refluxed (external temperature 100 C.) until complete consumption of starting chloropyrimidine (3 hours). The reaction mixture was cooled to room temperature and poured into water (200 ml) cooled to 10 C. It was then extracted with EtOAc (5×200 mls). The collected organic phases, containing large amount of colloid material and water, were washed with brine (200 ml). The water phase was filtered over a gouch, and the solid material was washed with further EtOAc (2×300 mls). The collected organic phases were dried overnight over Na2SO4, filtered and concentrated to give (7 g) the crude material which was purified (Biotage Sp1 over a 240 g Silica Anolgix column, with a 25 g pre-column) to give the title compound D68 as yellow solid (1.8 g). UPLC (Acid GEN_QC SS): rt=0.58 minutes, peak observed: 197 (M+1). C11H8N4 requires 196.
Isopropylmagnesium chloride-LiCl (37.9 ml, 36.5 mmol) was added portion wise (in overall 10 min) to a solution of <strong>[717843-48-6]3-bromo-6-methyl-2-pyridinecarbonitrile</strong> (4 g, 20.30 mmol) in THF (150 ml) cooled to -70 0C (internal temperature). The reaction was kept to that temperature for 15 min. Then it was allowed to gently warm up to -40 0C in overall 1 hour. Then, it was cooled to -78 0C and zinc chloride (3.32 g, 24.36 mmol) was added. The resulting mixture was allowed to warm up to room temperature in 1 hour. Pd(PtLsP)4 (2.346 g, 2.030 mmol), 2-chloropyrimidine (3 g, 26.2 mmol) were added and the mixture was refluxed (external temperature 100 0C) until complete consumption of starting chloropyrimidine (3 hours). The reaction mixture was cooled to room temperature and poured into water (200 ml) cooled to 10 0C. It was then extracted with EtOAc (5 x 20OmIs). The collected organic phases, containing large amount of colloid material and water, were washed with brine (200 ml). The water phase was filtered over a gouch, and the solid material was washed with further EtOAc (2 x 30OmIs). The collected organic phases were dried overnight over Na2SO4, filtered and concentrated to give (7 g) the crude material which was purified (Biotage SpI over a 240 g Silica Anolgix column, with a 25 g pre- column) to give the title compound D63 as yellow solid (1.8 g). UPLC (Acid GEN_QC_SS): rt = 0.58 minutes, peak observed: 197 (M+l). CnH8N4 requires 196.
Description 58: 6-methyl-3-(2-pyrimidinyl)-2-pyridinecarbonitrile (D58); Isopropylmagnesium chloride LiCl (37.9 ml, 36.5 mmol) was added portion wise (in overall 10 minutes) to a solution of <strong>[717843-48-6]3-bromo-6-methyl-2-pyridinecarbonitrile</strong> (4 g, 20.30 mmol) in THF (150 ml) cooled to -70 0C (internal temperature). The reaction was kept to that temperature for 15 minutes, then it was allowed to gently warm up to -40 0C in overall 1 hour. Then, it was cooled to -78 0C and zinc chloride (3.32 g, 24.36 mmol) was added. The resulting mixture was allowed to warm up to room temperature in 1 hour. Pd(Ph3P)4 (2.346 g, 2.030 mmol), 2-chloropyrimidine (3 g, 26.2 mmol) were added and the mixture was refluxed (external temperature 100 0C) until complete consumption of starting choropyrimidine (3 hours). The reaction mixture was cooled to room temperature and poured into water (200 ml) cooled to 10 0C. It was then extracted with EtOAc. The collected organic phases, containing large amount of colloid material and water, were washed with brine (200 ml). The aqueous phase was filtered over a gouch, and the solid material was washed with further EtOAc. The collected organic phases were dried overnight over Na2SO4, filtered and concentrated to give the crude material (7 g) which was purified (Biotage SpI over a 240 g Silica Analogix column, with a 25 g pre-column) to give the title compound D58 as yellow solid (1.8 g).UPLC (Acid GEN_QC_SS): rt = 0.58 minutes, peak observed: 197 (M+l) C11H8N4 requires 196.
Isopropylmagnesium chloride-LiCl (37.9 ml, 36.5 mmol) was added portion wise (in overall 10 min) to a solution of <strong>[717843-48-6]3-bromo-6-methyl-2-pyridinecarbonitrile</strong> (4 g, 20.30 mmol) in THF (150 ml) cooled to -70 0C (internal temperature). The reaction was kept to that temperature for 15 min. Then it was allowed to gently warm up to -40 0C in overall 1 hour. Then, it was cooled to -78 0C and zinc chloride (3.32 g, 24.36 mmol) was added. The resulting mixture was allowed to warm up to room temperature in 1 hour. Pd(Ph3P)4 (2.346 g, 2.030 mmol), 2-chloropyrimidine (3 g, 26.2 mmol) were added and the mixture was refluxed (external temperature 100 0C) until complete consumption of startingchloropyrimidine (3 hours). The reaction mixture was cooled to room temperature and poured into water (200 ml) cooled to 10 0C. It was then extracted with EtOAc. The collected organic phases, containing large amount of colloid material and water, were washed with brine (200 ml). The water phase was filtered over a gouch, and the solid material was washed with further EtOAc. The collected organic phases were dried overnight over Na2SO4, filtered and concentrated to give (7 g) the crude material which was purified (Biotage SpI over a 240 g Silica Anolgix column, with a 25 g pre-column) to give the title compound D8 as yellow solid (1.8 g). UPLC (Acid GEN QC SS): rt = 0.58 minutes, peak observed: 197 (M+l). C11H8N4 requires 196.
Isopropylmagnesium chloride-LiCl (37.9 ml, 36.5 mmol) was added portion wise (in overall 10 min) to a solution of <strong>[717843-48-6]3-bromo-6-methyl-2-pyridinecarbonitrile</strong> (4 g, 20.30 mmol) in THF (150 ml) cooled to -70 0C (internal temperature). The reaction was kept to that temperature for 15 min. Then it was allowed to gently warm up to -40 0C in overall 1 hour. Then, it was cooled to -78 0C and zinc chloride (3.32 g, 24.36 mmol) was added. The resulting mixture was allowed to warm up to room temperature in 1 hour. Pd(Ph3P)4 (2.346 g, 2.030 mmol), 2-chloropyrimidine (3 g, 26.2 mmol) were added and the mixture was refluxed (external temperature 100 0C) until complete consumption of startingchloropyrimidine (3 hours). The reaction mixture was cooled to room temperature and poured into water (200 ml) cooled to 10 0C. It was then extracted with EtOAc. The collected organic phases, containing large amount of colloid material and water, were washed with brine (200 ml). The water phase was filtered over a gouch, and the solid material was washed with further EtOAc. The collected organic phases were dried overnight over Na2SO4, filtered and concentrated to give (7 g) the crude material which was purified (Biotage SpI over a 240 g Silica Anolgix column, with a 25 g pre-column) to give the title compound DlO Nl 1358-28-1 as yellow solid (1.8 g). UPLC (Acid GEN_QC_SS): rt = 0.58 minutes, peak observed: 197 (M+l). C11HsN4 requires 196.
A) Isopropylmagnesium chloride-LiCl (37.9 ml, 36.5 mmol) was added portion wise (in overall 10 min) to a solution of <strong>[717843-48-6]3-bromo-6-methyl-2-pyridinecarbonitrile</strong> (4 g, 20.30 mmol) in THF (150 ml) cooled to -70 C (internal temperature). The reaction was kept to that temperature for 15 min. Then it was allowed to gently warm up to -40 C in overall 1 hour. Then, it was cooled to -78 C and zinc chloride (3.32 g, 24.36 mmol) was added. The resulting mixture was allowed to warm up to room temperature in 1 hour. Pd(Ph3P)4 (2.346 g, 2.030 mmol), 2-chloropyrimidine (3 g, 26.2 mmol) were added and the mixture was refluxed (external temperature 100 C) until complete consumption of startingchloropyrimidine (3 hours). The reaction mixture was cooled to room temperature and poured into water (200 ml) cooled to 10 C. It was then extracted with EtOAc (5 x 200 ml). The collected organic phases, containing large amount of colloid material and water, were washed with brine (200 ml). The water phase was filtered over a gouch, and the solid material was washed with further EtOAc (2 x 300ml). The collected organic phases were dried overnight over Na2S04, filtered and concentrated to give the crude material (7 g) which was purified (Biotage Spl over a 240 g Silica Analogix column, with a 25 g pre- column) to give the title compound D32 as yellow solid (1.8 g). UPLC (AcidGEN_QC_SS): rt = 0.58 minutes, peak observed: 197 (M+l). CnH8N4 requires 196.
A) Isopropylmagnesium chloride-LiCl (37.9 ml, 36.5 mmol) was added portion wise (in overall 10 min) to a solution of <strong>[717843-48-6]3-bromo-6-methyl-2-pyridinecarbonitrile</strong> (4 g, 20.30 mmol in THF (150 ml) cooled to -70 C (internal temperature). The reaction was kept to that temperature for 15 min. Then it was allowed to gently warm up to -40 C in overall 1 hour. Then, it was cooled to -78 C and zinc chloride (3.32 g, 24.36 mmol) was added. The resulting mixture was allowed to warm up to room temperature in 1 hour. Pd(Ph3P)4 (2.346 g, 2.030 mmol), 2-chloropyrimidine (3 g, 26.2 mmol) were added and the mixture was refluxed (external temperature 100 C) until complete consumption of startingchloropyrimidine (3 hours). The reaction mixture was cooled to room temperature and poured into water (200 ml) cooled to 10 C. It was then extracted with EtOAc (5 x 200mls). The collected organic phases, containing large amount of colloid material and water, were washed with brine (200 ml). The water phase was filtered over a gouch, and the solid material was washed with further EtOAc (2 x 300mls). The collected organic phases were dried overnight over Na2S04, filtered and concentrated to give (7 g) the crude material which was purified (Biotage Spl over a 240 g Silica Anolgix column, with a 25 g pre- column) to give the title compound D68 as yellow solid (1.8 g). UPLC (AcidGEN_QC_SS): rt = 0.58 minutes, peak observed: 197 (M+l). Cn¾N4 requires 196.
Isopropylmagnesium chloride-LiCl (37.9 ml, 36.5 mmol) was added portion wise (in overall 10 min) to a solution of <strong>[717843-48-6]3-bromo-6-methyl-2-pyridinecarbonitrile</strong> (4 g, 20.30 mmol) in THF (150 ml) cooled to -70 0C (internal temperature). The reaction was kept to that temperature for 15 min. Then it was allowed to gently warm up to -40 0C in overall 1 hour. Then, it was cooled to -78 0C and zinc chloride (3.32 g, 24.36 mmol) was added. The resulting mixture was allowed to warm up to room temperature in 1 hour. Pd(Ph3P)4 (2.346 g, 2.030 mmol), 2-chloropyrimidine (3 g, 26.2 mmol) were added and the mixture was refluxed (external temperature 100 0C) until complete consumption of starting chloropyrimidine (3 hours). The reaction mixture was cooled to room temperature and poured into water (200 ml) cooled to 10 0C. It was then extracted with EtOAc (5 x 200 mis). The collected organic phases, containing large amount of colloid material and water, were washed with brine (200 ml). The water phase was filtered over a gouch, and the solid material was washed with further EtOAc 2 x 300 mis). The collected organic phases were dried overnight over Na2SO4, filtered and concentrated to give (7 g) the crude material which was purified (Biotage SpI over a 240 g Silica Anolgix column, with a 25 g pre- column) to give the title compound D 18 as yellow solid (1.8 g). UPLC (Acid GEN_QC_SS): rt = 0.58 minutes, peak observed: 197 (M+l). CnH8N4 requires 196
Preparation 23 Preparation of ethyl 1-pyrimidin-2-yl-1 H-indazole-3-carboxvlate.To a suspension of ethyl 1 H-indazole-3-carboxylate (available from SynChem, Inc., Des Plaines, IL, 60018-1804 and other suppliers) (5.5 g, 30 mmol) in N- methylpyrrolidinone (30 ml.) at 0 0C was added sodium hydride (1.3 g, 33 mmol, 60% dispersion) portionwise. The suspension was stirred for 40 min followed by the addition of 2-chloropyrimidine (3.3 g, 30 mmol). The mixture was stirred at room temperature for 15 h and was quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate two times, and the combined extracts were washed with water and dried over Na2SO4. The mixture was filtered and concentrated under reduced pressure, and the residue was redissolved in hot diethyl ether. Upon cooling, the product precipitated. The solids were filtered and were further purified by flash chromatography (100% ether and then 100% ethyl acetate) to give the product as a solid (3.4 g). 1H NMR (400 MHz, CDCI3): delta 1.47 (t, 3H), 4.54 (q, 2H), 7.24 (dd, 1 H), 7.29 (dd, 1 H), 7.55 (dd, 1 H), 8.32 (d, 1 H), 8.77 (d, 1 H), 8.87 (d, 2H); MS (ES+) calc: 269 (M+1 ).
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; N,N-dimethyl acetamide; at 120℃; for 0.5h;Microwave irradiation; Autoclave;
Step 1: tert-Butyl 8-(pyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate A stirred mixture of <strong>[336191-17-4]ter<strong>[336191-17-4]t-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate</strong></strong> (0.2 mmol, 1 eq.), 2-chloropyrimidine (0.4 mmol, 2 eq.), DIPEA (2 eq.), DMA (2 eq.) in 1,4-dioxane (0.5 ml) was subjected to microwave radiation in a 10 ml pressure tube at 120 C. for 30 min. After concentration, the crude product was purified by column chromatography (silica gel, 20% ethyl acetate in hexane) in order to obtain the desired product. Yield: 51%
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 100.0℃; for 16.0h;Inert atmosphere;
A screw-cap vial was charged with benzamide (121 mg, 1.00 mmol), Cs2CO3 (456 mg, 1.40 mmol), Xantphos (87 mg, 0.15 mmol), Pd2(dba)3 (46 mg, 0.050 mmol), 2-chloropyrimidine (137 mg, 1.20 mmol), and 1,4-dioxane (2 mL). The mixture was sparged with nitrogen for 3 min, stirred for 16 h at 100 C, and cooled to room temperature. The residue was diluted with dichloromethane, filtered through celite, and concentrated. The crude product was purified by silica gel flash chromatography (40-100% ethylacetate/hexanes) to provide N-(pyrimidin-2-yl)benzamide (188 mg, 0.85 mmol, 94% yield) as an amorphous solid (Table 1, entry 8).
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 160℃; for 1.0h;Inert atmosphere; Microwave irradiation;
General procedure: To an oven-dried microwave vial was added <strong>[113853-16-0]ethyl 2-amino-1,3-oxazole-5-carboxylate</strong> (546 mg, 3.50 mmol), Cs2CO3 (2279 mg, 6.99 mmol), Pd2(dba)3 (80 mg, 0.09 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (152 mg, 0.26 mmol) and the vial was capped and purged with nitrogen. 2,4-Dichloropyridine (0.378 mL, 3.50 mmol) was added via syringe, followed by 1,4-dioxane (18 mL) (degassed) and the reaction mixture was heated to 160 C for 1 h under microwave irradiation. CH2Cl2 (40 mL) was added to the crude reaction mixture together with silica (5 g). The solvents were removed under reduced pressure and the crude product was purified by flash silica chromatography with CH2Cl2 (containing 1% methanolic ammonia) as eluent.The resulting brown solid was triturated with Et2O to give ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (626 mg, 67%) as a pale yellow solid, which was collected by filtration and dried under vacuum.
6.01.33.01 2-Methyl-4-pyrimidin-2-yl-piperazine-1-carboxylic acid tert-butyl ester 100 mg 2-chloro-pyrimidine was added to 175 mg 2-Methyl-piperazine-1-carboxylic acid tert-butyl ester and this mixture was stirred for 2 h at 120 C. to give 240 mg of the desired compound. Rt: 1.31 min (method B), (M+H)+: 279 By using the same synthesis strategy as for 2-methyl-4-pyrimidin-2-yl-piperazine-1-carboxylic acid tert-butyl ester the following compound was obtained:
240 mg
at 120℃; for 2h;
2-Methyl-4-pyrimidin-2-yl-piperazine- 1 -carboxylic acid tert-butyl ester 100 mg 2-chloro-pyrimidine was added to 175 mg 2-Methyl-piperazine-l -carboxylic acid tert- butyl ester and this mixture was stirred for 2 h at 120 C to give 240 mg of the desired compound. Rt: 1.31 min (method B), (M+H)+: 279
To a solution of diethylmalonate (6.65 mL, 43.65 mmol) in DMF (30 mL) at -78 C,was added NaH (1.76 g, 52.38 mmol, 60% dispersion in mineral oil). The reaction was stirredfor 10 min at -78 C, warmed to room temperature and 2-chloropyrimidine (1.0 g, 8.73 mmol)in DMF (3 mL) was added. The reaction mixture was heated to 80 C for 72 hours, then to120 C for 18 hours, and upon completion was cooled to room temperature. The solution was15 quenched by addition of IN HCl, neutralized with saturated aqueous NaHC03 and extractedwith EtOAc (3X). The combined organics were dried over Na2S04, filtered, concentrated andpurified by flash chromatography on silica gel (0-1 00% EtOAc in hexanes) to give the titlecompound as a yellow-orange oil (1.34 g, 92%). MS 167 (MH+).
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; for 18h;Schlenk technique; Inert atmosphere; Heating;
General procedure: To a Schlenk tube charged with Pd2(dba)3 source (1 mol %) and Xantphos (1.5 mol %) was added aniline (1 mmol) and NaOtBu(1 mmol). 2-Chloropyrimidine (0.5 mmol) was added to this mixture. The tube was evacuated and backfilled with Ar three times. Toluene (1 mL / mmol aniline) was then added via syringe.The mixture was heated to 90 C. Once deemed complete (TLC) the reaction mixture was cooled, filtered through a pad of Celite, washed with EtOAc (20 mL) and diluted with water (50mL). The product was extracted with EtOAc (3 x 50 mL). The organic layers were combined, washed with brine (50 mL), dried over MgSO4 and concentrated under reduced pressure. The product was then purified using column chromatography (hexane: ethyl acetate 20-70%).
tert-butyl ((cis)-4-(pyrimidin-2-ylamino)cyclohexyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In N,N-dimethyl-formamide; at 150℃; for 0.333333h;Microwave irradiation;
As shown in step 5-i of Scheme 5, a mixture of tert-butyl ((cis)-4-aminocyclohexyl)carbamate (compound 1009, 490 mg, 2.3 mmol), 2-chloropyrimidine (262 mg, 2.3 mmol) and TEA (463 mg, 6374, 4.6 mmol) in DMF (10 mL) was subjected to microwave irradiation for 20 minutes at 150 C. The reaction mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0 to 50% EtOAc/hexanes gradient) to provide tert-butyl ((cis)-4-(pyrimidin-2-ylamino)cyclohexyl)carbamate (compound 1010) as a white solid: 1H-NMR (300 MHz, CDCl3) delta 8.28 (d, J=4.8 Hz, 2H), 6.53 (t, J=4.8 Hz, 1H), 5.12 (s, 1H), 4.56 (s, 1H), 3.99 (dq, J=7.0, 3.5 Hz, 1H), 3.65 (s, 1H), 1.83 (tq, J=10.2, 3.6 Hz, 5H), 1.66 (s, 8H), 8.13-7.91 (m, 3H), 1.47 (s, 9H).
With triethylamine; In N,N-dimethyl-formamide; at 150℃; for 0.333333h;Microwave irradiation;
As shown in step 5-i of Scheme 5, a mixture of /er/-butyl ((c/.s)-4- aminocyclohexyl)carbamate (compound 1009, 490 mg, 2.3 mmol), 2- chloropyrimidine (262 mg, 2.3 mmol) and TEA (463 mg, 637pL, 4.6 mmol) in DMF (10 mL) was subjected to microwave irradiation for 20 minutes at l50C. The reaction mixture was diluted with EtOAc, washed with H20, dried over Na2S04, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0 to 50 % EtO Ac/hexanes gradient) to provide /cvV-butyl ((cis) - (pyrimidin-2-ylamino)cyclohexyl)carbamate (compound 1010) as a white solid: 1H- NMR (300 MHz, CDCl3) d 8.28 (d, J= 4.8 Hz, 2H), 6.53 (t, J= 4.8 Hz, 1H), 5.12 (s, 1H), 4.56 (s, 1H), 3.99 (dq, j= 7.0, 3.5 Hz, 1H), 3.65 (s, 1H), 1.83 (tq, j= 10.2, 3.6 Hz, 5H), 1.66 (s, 8H), 8.13-7.91 (m, 3H), 1.47 (s, 9H).
tert-butyl 3,3-dimethyl-4-(pyrimidin-2-yl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium fluoride; triethylamine; In N,N-dimethyl-formamide; at 80 - 140℃; for 25h;Inert atmosphere; Microwave irradiation;
Tert-butyl 3,3-dimethylpiperazine-1-carboxylate (CAS 259808-67-8, 300 mg, 1.40 mmol), 2- chloropyrimidine (CAS 1722-12-9, 240 mg, 2.10 mmol), potassium fluoride (122 mg, 2.10 mmol) and TEA (0.389 mL, 2.80 mmol) were dissolved in DMF (3 mL). After flushing with argon, the solution was heated in a microwave reactor for 3 h at 80C, 6h at 100C, 6 h at 120C and 10 h at 140C.After cooling to rt the crude mixture was extracted with EtOAc (2x10mL) and water. The combined organic phases were washed with 1M HCI (aq), dried over Mg504 and evaporated to give crude tert-butyl 3,3-dimethyl-4-(pyrimidin-2-yl)piperazine-1- carboxylate.
With C37H44ClN2O3PPd; caesium carbonate; In water; at 100℃; for 12h;Schlenk technique; Inert atmosphere;
General procedure: In a Schlenk tube, a mixture of the required amount of catalyst, plus the aryl chloride (1.0 mmol), aryl boronic acid (1.5 mmol) and the selected base (2.0 mmol) in water was evacuated and charged with nitrogen. The reaction mixture was heated at 100°C for 12 h. After cooling, the mixture was extracted with CH2Cl2 and the extract was evaporated. The resulting residue was purified by flash chromatography on silica gel using a mixture of CH2Cl2/ethyl acetate (5/1) as eluent. The known products 5, 6a [17,18], 6b [22], 6c [23], 6e [24], 6g [19], 6h [25] and 7a [26] were characterized by comparison of data with those in the literature. The products 6d, 6f and 7b?h were new compounds and characterized by elemental analysis, MS, 1H and 13C NMR.
With potassium carbonate; In dimethyl sulfoxide; acetone; at 110℃; for 16h;
2-chloropyrimidine (1.98 g, 17.3 mmol, 1.1 eq.) and potassium carbonate (2.6 g, 18.8 mmol, 1.2 eq) were added to a solution of <strong>[121219-03-2]4-bromo-3-fluorophenol</strong> (3.0 g, 15.7 mmol, 1.0 eq.) in acetone (30 mL) and dimethyl sulfoxide (10 mL) was added. The reaction was stirred at 110 C. for 16 hours. After cooled to room temperature, water (100 mL) was added, and then extracted with ethyl acetate (100 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, and the filtrate was concentrated to spin dry, the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to give the title compound (930 mg, yield: 22%).
With bis-triphenylphosphine-palladium(II) chloride; cesium fluoride; In 1,2-dimethoxyethane; water; at 130 - 140℃; for 1h;Sealed tube;
A mixture of 2-chloropyrimidine (572.5 mg, 5.0 mmol), <strong>[871126-22-6](2-fluoro-4-formylphenyl)boronic acid</strong> (839.5 mg, 5.0 mmol), CsF (1.52 g, 10 mmol) and Pd(PPh3)2Cl2 (350 mg, 0.5 mmol) in DME/H20 (1:1, 20 mL) was heated in a sealed tube at 130-140 C (oil bath) for lh. It underwent changes from a suspension to a near solution and back to a suspension. After cooling to room temperature, the reaction was diluted with ethyl acetate (50 mL) and vacuum filtered. The solid was washed with ethyl acetate (5mL). The filtrate was extracted with ethyl acetate (100 mL). The organic layer was washed with water (30 mL), brine (30 mL) and dried over anhydrous sodium sulfate. Removal of solvent in vacuo afforded the crude as a light brown solid. It was purified by flash column (silica gel, hexane/ethyl acetate, 3: 1, v/v) to obtain the intermediate 1 as a white solid (0.7 g, 69% yield).
2-(5-methyl-3-nitro-1H-pyrazol-1-yl)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
539 mg
With potassium carbonate; In acetonitrile; at 90℃; for 12h;
5-methyl-3-nitro -1H- pyrazole (450 mg of) in 30mLacetonitrile and carbonatePotassium (733 mg) and 2-chloropyrimidine (608 mg of the),and the mixture was stirred at 90 12 smallTime. The mixture was concentrated under reduced pressure,the residue was mixed with water and extracted with ethyl acetate, withThe organic phase was dried over sodium sulfate, filteredand concentrated under reduced pressure. The crude product was stirred inn-hexane,Suction filtered and dried under reducedpressure. To give 539mg of the title compound
1-(tert-butyl) 3-methyl 2-(pyrimidin-2-yl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
A 3-neck 200 mL round bottom flask fitted witha reflux condenser and stir bar was charged with t-butyl methyl malonate (8.86 mL, 52.4 mmol) followedby dry DMF (43.7 mL). The atmosphere was exchanged for nitrogen and sodium hydride (60percentdispersion in mineral oil, 2110 mg, 52.8 mmol) was added portion-wise at 25 °C . After bubbling wascomplete (15 min), the 2-chloropyrimidine (2.5 g, 21.83 mmol) was added. The reaction turned orangeupon addition and was heated to 80 °C for 16 h. The reaction was cooled to 25 °C and quenched via theaddition of saturated ammonium chloride (50 mL) and diluted with EtOAc (50 mL). The layers wereseparated and the aq. phase was further extracted with EtOAc (3 x 50 mL). The organic phase was dried(MgSO4) and concentrated. The crude material was purified via column chromatography to provide theproduct (2.97 g, 54percent). 1H NMR (400 MHz, CDCl3) delta 8.78-8.77 (d, J = 4.7 Hz, 2H), 7.28-7.26 (m, 1H), 5.07 (s, 1H), 3.84 (s, 3H), 1.51(s, 9H).13C NMR (101 MHz, CDCl3) delta 167.37, 165.59, 163.81, 157.47, 119.77, 82.92, 62.63, 52.69, 27.90.LRMS (ESI) m/z: calc?d for C12H16N2O4 [M+H] 253.12, found 253.23
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In water; N,N-dimethyl-formamide; at 110℃;Inert atmosphere;
To a degassed souton of DMF:H20 (10:1 raUo) (0.3 M), under an atmosphere of nitrogen, was added the pnaco ester (1 mmo), 2-bromopyrdne or 2-choropyrmdne (1 .5 eq.), and Cs2CO3 (4.4 eq.). The whoe mxture was degassed once agan and then Pd(PPh3)4 (5mo%) was added. The resutng souton was heated to 110C overnght. The sovent was removed in vacuo to give a dark gummy residue, which was taken up nto EtOAc and H20, then acdfied with 2 M HC to pH 2. The organic ayer was separated and the aqueous ayer was further extracted with EtOAc (2x). The combined organic ayers were dried over MgSO4 and concentrated in vacuo to gve a back ofly residue. The residue was dry oaded ontosWca ge in vacuo then purfied by flash coumn chromatography, eutng with 10-30% EtOAc/petroeum benzne and 1% acetic acid to afford the tWe compound.The foHowng compounds were made by Suzuk CoupUng F:CO2HP7BiOff-whte scUd (79%) yed). 1H NMR (400 MHz,DM80) 6 8.99 (t, J = 1.5 Hz, 1 H), 8.95 (d, J = 4.9Hz, 2H), 8.61 (d, J= 7.9 Hz, 1H), 8.09 (d, J 7.7 Hz,1 H), 7.68 (d, J = 7.8 Hz, 1 H), 7.50 (t, J = 4.9 Hz, 1 H).LCMS B rt2.96 mn, m/z201.1 [M + H].
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 2-methyltetrahydrofuran; water; at 100℃; for 15h;
Step 2: A stirred mixture of A-22.3 (25.0 g, 95.4 mmol), A-22.4 (12.0 g, 104.9 mmol), Pd(dppf)CI2-DCM (7.78 g, 9.54 mmol) and sodium carbonate (40.4 g, 381 .5 mmol) in 2-methyl tetrahydrofuran (300 mL) and water (150 mL) is heated at 100°C for 15 h. The reaction is cooled to RT and quenched with water and EA and filtered through a pad of celite. The layers are separated, the organic layer is dried, filtered and concentrated. The residue is purified by flash column chromatography on silica gel (EA hexane = 1 :4) to provide 15.0 g of A-22.5. ESI- MS: 215 [M+H]+; HPLC (Rt): 1 .42 min (method K)
15 g
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 2-methyltetrahydrofuran; water; at 100℃; for 15h;
A stirred mixture of A-23.3 (25.0 g, 95.4 mmol), A-23.4 (12.0 g, 105 mmol), Pd(dppf)Cl2DCM (7.78 g, 9.54 mmol) and sodium carbonate (40.4 g, 382 mmol) in 2-methyl tetrahydrofuran (300 mL) and water (150 mL) is heated at 100°C for 15 h. The reaction is cooled to RT and quenched with water and EA and filtered through a pad of celite. The layersare separated, the organic layer is dried, filtered and concentrated. The residue is purified by flash column chromatography on silica gel (EAlhexane = 1:4) to provide 15.0 g of A-23.5. ESIMS: 215 [M+H] HPLC (Rt): 1.42 mm (method G)
6-chloro-1-(pyrimidin-2-yl)-1H-indole-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With sodium hydride; In N,N-dimethyl-formamide; at 20 - 120℃; for 18.5h;
6-Chloro-1H-indole-3-carboxylic acid (1.0 g)Of DMF (30 mL)60% sodium hydride (450 mg) was added to the solution,After stirring at room temperature for 30 minutes,2-Chloropyrimidine (644 mg) was added,And the mixture was stirred at 120 C. for 18 hours.After cooling the reaction solution to room temperature, water (100 mL) and ethyl acetate (100 mL) were added and the mixture was extracted with ethyl acetate. The obtained aqueous layer was made acidic with concentrated hydrochloric acid,After stirring at room temperature for 30 minutes, the obtained solid was collected by filtration,By washing with water,1.2 g (yield 89%) of 6-chloro-1- (pyrimidin-2-yl) -1H-indole-3-carboxylic acid was obtained
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; toluene; at 100℃; for 22h;Inert atmosphere;
7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole (500 mg),2-Chloropyrimidine (353 mg),Potassium carbonate (573 mg),, And tetrakis (triphenylphosphine) palladium (0) (36 mg) in a nitrogen atmosphere,Toluene (60 mL) / water (10 mL) was added,And the mixture was stirred at 100 C. for 22 hours.After cooling the reaction solution to room temperature, dichloromethane (100 mL) and water (100 mL) were added, the mixture was extracted with dichloromethane and washed with saturated brine. The organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (hexane-ethyl acetate)7- (pyrimidin-2-yl) -1 H-indole220 mg (yield 55%) was obtained.
Exemplified dye D-2-8a was synthesized in the same manner as exemplified dye D-1-1a, except that compound d-1-8 for exemplified dye D-1-1a was changed to compound d-37-4.
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 12h;
[1615] a mixture of <strong>[52222-73-8]4-(trifluoromethyl)-1H-pyrazole</strong> compound (1 g, 7.35 mmol), 2-chloropyrimidine (926 mg, 8.09 mmol) and K2CO3 (2.03 g, 14.7 mmol) in DMF(15 ml) was heated to 110 C for 12 hr. The mixture was added water (20 ml) and extracted with ethyl acetate (20 ml x 2), the organic phases were washed with brine (10 ml), dried over Na2SO4, filtered and concentrated. The residue was recrystallized by mtbe to give compound 410a (800 mg, yield: 50.8%) as yellow solid. 1H NMR (400mhz, CDCl3) delta 8.94 (s, 1h), 8.83 (d, 7 = 4.8 hz, 2h), 8.03 (s, 1h), 7.34 (t, 7 = 4.8 hz, 1h).
[1-hydroxy-3-(pyrimidin-2-ylamino)propane-1,1-diyl]bis(phosphonic acid)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
2-Chloropyrimidine (97mg, 0.85mmol) was added to a solution of 3 (pamidronic acid, 100mg, 0.43mmol) and K2CO3 (147mg, 1.06mmol) in water (3.5mL). The resulting reaction mixture was kept under reflux for 23h. The solvent was removed under reduced pressure and the reaction crude residue was washed with ethanol (3×10mL) at 70C. Ethanol was removed by filtration of the solid, obtaining a pale yellow product that was dissolved in water (2mL). The solution of the crude product was acidified until pH=1 by adding 4N HCl, the volume was reduced to 1mL obtaining a suspension that was kept at 5C for 48h, affording white crystals of 11, that were washed with cold water (2mL) and dried under vacuum. Yield: 95mg (71%). 1H NMR (500MHz, D2O, delta): 2.16-2.24 (m, 2H), 3.70 (t, 2H, J=7.3Hz), 6.86 (t, 1H, J=5.4Hz), 8.40 (d, 2H, J=5.4Hz). 31P NMR (202MHz, D2O, delta): 17.9 (s, 2P).
N-(pyrimidin-2-yl)pyrimidine-4,6-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
With sodium hydride; In N,N-dimethyl acetamide; mineral oil; at 70℃; for 2h;Inert atmosphere;
To the compound <strong>[2434-56-2]4,6-diaminopyrimidine</strong> 69a (110.0 mg, 1.0 mmol) at room temperature, sodium hydrogen (mineral oil dispersion 60%,120.0 mg, 5.0 mmol) was mixed with N,N-dimethylacetamide (10 mL), and 2-chloropyrimidine (114.0 mg,1.0 mmol), reacted at 70 C for 2 hours. After cooling to room temperature, the mixture was quenched with 10 mL of aq.The organic layer was washed with brine (30 mL). Dry the organic phase with anhydrous sodium sulfateDrying, filtering to remove the desiccant, and purifying the concentrate by flash column chromatography (dichloromethane / methanol = 10:1) to obtain the desired product N-(Pyrimidin-2-yl)<strong>[2434-56-2]pyrimidine-4,6-diamine</strong> 69b (47.0 mg, 0.20 mmol, white solid), yield: 25%.
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