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[ CAS No. 32779-36-5 ]

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CAS No. :32779-36-5 MDL No. :MFCD00483232
Formula : C4H2BrClN2 Boiling Point : 291°C at 760 mmHg
Linear Structure Formula :- InChI Key :N/A
M.W :193.43 g/mol Pubchem ID :606665
Synonyms :

Safety of [ 32779-36-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P264-P271-P280-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P403+P233-P405-P501 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 32779-36-5 ]

  • Upstream synthesis route of [ 32779-36-5 ]
  • Downstream synthetic route of [ 32779-36-5 ]

[ 32779-36-5 ] Synthesis Path-Upstream   1~42

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Reference: [1] Acta Chemica Scandinavica, 1997, vol. 51, # 3, p. 302 - 306
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Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 10033 - 10046
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YieldReaction ConditionsOperation in experiment
75% at 50℃; for 3 h; Step 1:
Synthesis of 5-bromo-2-(methylthio)pyrimidine
To a stirred solution of 5-bromo-2-chloropyrimidine (0.3 g, 1.563 mmol) in DMF (10 mL) was added methyl mercaptan (0.1 mL, 1.563 mmol) at room temperature and heat at 50° C. for 3 h.
Completion of reaction was monitored by TLC.
Reaction mixture was quenched by addition of water, extracted with EtOAc.
Organic portions were combined, dried over Na2SO4, evaporated under reduced pressure to obtain crude which was purified by column chromatography using silica gel (100-200 mesh); eluent 5percent ethyl acetate/hexane to obtain pure product 5-bromo-2-(methylthio)pyrimidine (0.240 g, 75percent) as white solid.
MS: 205.1[M++1]
Reference: [1] Patent: US2017/291910, 2017, A1, . Location in patent: Paragraph 0496-0498
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 23, p. 7046 - 7049
[2] Patent: WO2006/4532, 2006, A1, . Location in patent: Page/Page column 23-24
[3] Patent: EP1956009, 2008, A1, . Location in patent: Page/Page column 59
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YieldReaction ConditionsOperation in experiment
75% With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline for 4 h; Heating / reflux Phosphorus oxychloride (225 mL, 2.4 mol, 1.4 equiv) was added to a mixture of 5-bromo-2-hydroxypyrimidine (30 g, 0.17 mol) and dimethylaniline (7.5 mL) and the solution heated at reflux under N2 for 4 h.
The dark brown reaction mixture was cooled, poured over ice, and extracted with ether.
The organic phase was washed with bicarbonate solution, dried (Na2SO4), and concentrated to afford 5-bromo-3-chloropyrimidine 3d (25 g, 75percent) [Goodby, J. W.; Hird, M.; Lewis, R. A.; Toyne, K. J. J. Chem. Soc., Chem. Commun. 1996, 2719].
61.41% at 100℃; for 3 h; Inert atmosphere To a stirred solution of 5-bromopyrimidin-2-ol (1.0 g, 1.0 eq) in POOl3 (1 mL) dimethylaniline (0.21 g, 0.3 eq) was added under nitrogen atmosphere. Then, thereaction mixture was refluxed at 100 00 for 3 h. After cooling, the reaction mixture was basified with saturated sodium carbonate solution and extracted with ethyl acetate. Organic layer was then separated and dried over Na2SO4 and concentrated to get the crude which was then subjected to the combiflash-12 g silica to isolate the title product as an off white solid (0.67 g, 61.41percent).1H NMR: (DMSO-d6, 300MHz) 69.00-9.01(d, 2H).
61.41% at 100℃; for 3 h; Inert atmosphere To a stirred solution of 5-bromopyrimidin-2-ol (1.0 g, 1.0 eq) in P0013 (1 mL) dimethylaniline (0.21 g, 0.3 eq) was added under nitrogen atmosphere. Then, the reaction mixture was refluxed at 1 00 00 for 3 h. After cooling, the reaction mixturewas basified with saturated sodium carbonate solution and extracted with ethyl acetate. The organic layer was then separated and dried over Na2S04 and concentrated to get a crude which was then subjected to the combiflash-12 g silica and isolated the title product as an off white solid (0.67 g, 61 .41 percent).1H NMR: (DMS0- d6, 300MHz) 6 9.00-9.01 (d, 2H).
56% for 3 h; Heating / reflux Preparation of 5-Bromo-2-chloro-pyrimidine
2-Pyrimidinol hydrochloride (13.26 g, 100 mmol) is dissolved in 2N NaOH (50 ml) and bromine (17.98 g, 112.5 mmol) is added over 15 min.
The mixture is stirred for 45 min at r.t. and then concentrated in vacuo to yield a brownish solid.
The solid is suspended in phosphorus oxychloride (125 ml), N,N-dimethylaniline (9.35 g, 77 mmol) added and the mixture is heated to reflux for 3 h.
After cooling the reaction mixture is poured slowly under stirring onto 1 L ice water and the resulting mixture is extracted with diethyl ether (3*200 ml).
The extract is washed with brine, dried over MgSO4 and concentrated in vacuo yielding 5-bromo-2-chloro-pyrimidine as a pale yellow solid.
Yield 10.85 g (56percent)
1H-NMR (300 MHz, CDCl3): 8.70 (s, 2H)

Reference: [1] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 4, p. 1077 - 1081
[2] Patent: US2004/14775, 2004, A1, . Location in patent: Page/Page column 24; 30-31
[3] Journal of Organic Chemistry, 2002, vol. 67, # 18, p. 6550 - 6552
[4] Patent: WO2014/202580, 2014, A1, . Location in patent: Page/Page column 111
[5] Patent: WO2014/202528, 2014, A1, . Location in patent: Page/Page column 105
[6] Patent: US2005/222228, 2005, A1, . Location in patent: Page/Page column 15
[7] Chemical Communications, 1996, # 24, p. 2719 - 2720
[8] Angewandte Chemie - International Edition, 1999, vol. 38, # 5, p. 659 - 661
[9] Molecular Crystals and Liquid Crystals Science and Technology Section A: Molecular Crystals and Liquid Crystals, 2001, vol. 368, p. 279 - 292
[10] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 467 - 474
[11] Patent: US2009/253708, 2009, A1, . Location in patent: Page/Page column 15
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YieldReaction ConditionsOperation in experiment
80% at 0 - 120℃; for 4.16667 h; Synthesis of Compound 11-2 (0399) Compound 11-1 (5.0 g, 2.86 mmol) was added portionwise to POCl3 (15 mL) at 0° C. during 10 min. The reaction mixture was stirred at 120° C. for 4 h, then cooled to room temperature and added to ice-water (100 mL). Sat. Na2CO3 was added to adjust pH=7 and extracted with ethyl acetate (200 mL×4). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford 11-2, which was used in the next step without further purification (4.50 g, 80percent).
Reference: [1] Patent: US9138427, 2015, B2, . Location in patent: Page/Page column 289
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5849 - 5853
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YieldReaction ConditionsOperation 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
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Reference: [1] Journal of Organic Chemistry, 2008, vol. 73, # 23, p. 9326 - 9333
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Reference: [1] Patent: WO2004/50640, 2004, A1, . Location in patent: Page 22
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YieldReaction ConditionsOperation in experiment
100% for 72 h; Reflux 40percent Aqueous methylamine solution (35 ml) and methanol (20 ml) were added to 5-bromo-2-chloropyrimidine (3 g, 15.5 mmol) and the resulting mixture was heated to reflux for 3 days. The mixture was cooled, then the solvent was evaporated under reduced pressure, the residue was partitioned with methylene chloride and 1 M sodium hydroxide, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.0 g, 100percent) as a white solid.1H-NMR (CDCl3) δ: 2.98 (3H, d, J=5.12 Hz), 5.16 (1H, brs), 8.29 (2H, s).
98% With potassium carbonate In tetrahydrofuran; water; <i>tert</i>-butyl alcohol at 150℃; for 0.25 h; microwave 5-bromo-2-chloropyrimidine (2.00 g, 10.34 mmol), methylamine (41 percent in water, 2.00 mL, 23.78 mmol) and potassium carbonate (1.43 g, 10.34 mmol) in tert-butanol (4 mL)/THF (4 mL) are stirred for 15 min at 1500C in a microwave reactor. The crude mixture is diluted with DCM, the organic phase is washed with semi-saturated potassium carbonate solution and water, dried, filtered and evaporated down. Yield: 1.90 g (98 percent).
93%
Stage #1: at 115℃; for 48 h; Sealed vessel
Stage #2: With sodium hydroxide In dichloromethane; water
[0238] Methylamine (2.0 M in methanol, 4O mL, 80 mmol) was added to 5- bromo-2-chloropyrirnidine (5.6 g, 29.0 mmol) in a sealable reaction vessel. After allowing to vent for a few minutes, the vessel was sealed, placed behind a safety shield and heated in a 115 0C oil bath for 48 hours. Upon cooling the volatiles were removed in vacuo. The material was dissolved in CH2Cl2 (200 mL) and washed with IM NaOH (4O mL). The aqueous layer was extracted further with CH2Cb (2x50 mL). The combined organics were dried over MgSO4, filtered and concentrated yielding an off white solid (5.1 g, 93percent). LCMS (m/z): 188.0/190.0 (MH+).
93%
Stage #1: at 115℃; for 48 h; Sealed tube
Stage #2: With sodium hydroxide In dichloromethane; water
Synthesis -Aminomethyl-5-bromopyrimidine[0083] Methylamine (2.0 M in methanol, 40 mL, 80 mmol) was added to 5-bromo-2- chloropyrimidine (5.6 g, 29.0 mmol) in a sealable reaction vessel. After allowing to vent for a few minutes, the vessel was sealed, placed behind a safety shield and heated in a 115 °C oil bath for 48 hours. Upon cooling the volatiles were removed in vacuo. The material was dissolved in CH2C12 (200 mL) and washed with 1M NaOH (40 mL). The aqueous layer was extracted further with CH2C12 (2x50 mL). The combined organics were dried over MgSC>4, filtered and concentrated yielding an off white solid (5.1 g, 93percent). LCMS (m/z):188.0/190.0 (MH ).
90% at 60℃; for 6 h; To 5-bromo-2-chloropyrimidine (2g, 10.34mmol) was added 1 M methylamine solution in THF (20ml). The contents were stirred at 6O0C for 6h after which TLC confirmed the absence of the reactant. The contents were allowed to cool down. The volatiles were evaporated under reduced pressure and the residue was subjected to flash chromatography (hexane/ethyl acetate) to get (5-bromo-pyrimidin- 2-yl)-methyl-amine (1.75g, 90percent). This material was taken through Stage C (as described above) to get methyl-[5-(4,4,5,5,-tetramethyl-[1 ,3,2]dioxaborolan-2- yl]amine.

Reference: [1] Patent: US2010/130492, 2010, A1, . Location in patent: Page/Page column 93
[2] Patent: WO2010/12747, 2010, A1, . Location in patent: Page/Page column 16-17
[3] Patent: WO2007/84786, 2007, A1, . Location in patent: Page/Page column 90
[4] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 1, p. 34 - 38
[5] Patent: WO2012/109423, 2012, A1, . Location in patent: Page/Page column 18
[6] Patent: WO2009/93981, 2009, A1, . Location in patent: Page/Page column 105
[7] Patent: WO2006/79791, 2006, A1, . Location in patent: Page/Page column 42
[8] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 10033 - 10046
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Reference: [1] Patent: WO2006/44823, 2006, A2, . Location in patent: Page/Page column 197
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Reference: [1] Patent: US5371224, 1994, A,
[2] Patent: US5371224, 1994, A,
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  • [ 124-40-3 ]
  • [ 38696-21-8 ]
YieldReaction ConditionsOperation in experiment
86% at 20℃; Inert atmosphere To a solution of 5-bromo-2-chloropyrimidine (2 g, 10.34 mmol) and dimethylamine (5 ml, 10.00 mmol) in tetrahydrofuran (2 ml_) was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel chromatography 5percentEtOAc/PE) to give 5-bromo-N,N-dimethylpyrimidin-2-amine (1 .9 g, 8.93 mmol, 86 percent yield) as a white solid. LCMS: [M+H] 202.
3.2 g at 20℃; for 1 h; A mixture of 22.5 ml (45.5 mmol) solution of dimethylamine in THF, 3.0 g (15.5 mmol) 2-chloro-5-bromo-pyrimidine and ACN are stirred at RT for 1 h. The solvent is evaporated, water is added and the mixture is extracted with EtOAc. The organic phases are pooled, dried and evaporated yielding 3.2 g 5-bromo-N,N-dimethyl- pyrimidin-2-amine .
Reference: [1] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 1, p. 34 - 38
[2] Patent: WO2017/98440, 2017, A1, . Location in patent: Page/Page column 212
[3] Patent: WO2017/194453, 2017, A1, . Location in patent: Page/Page column 46
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Reference: [1] Patent: US2004/82586, 2004, A1,
[2] Patent: WO2014/100695, 2014, A1, . Location in patent: Paragraph 00373
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YieldReaction ConditionsOperation in experiment
86%
Stage #1: With dichloro bis(acetonitrile) palladium(II); sodium carbonate In ethanol; water at 45℃; for 0.5 h;
General procedure: Catalyst (2 molpercent), aryl halide (1 equiv.) and Na2CO3 (1.1 equiv.) were stirred in H2O (5 mL) taken in the round bottom flask. The aryl boronic acid (1.1 equiv.) was added to the stirring solution. Stirring was continued for required time at 45 °C. After the requisite time, the reaction mixture was diluted with water and the product was extracted with ethyl acetate. The ethyl acetate extract was passed through celite bed and then analyzed by GC. Authentic samples of both reactant and product were used to verify the retention time and to confirm the product formation. The ethyl acetate extract was concentrated and chromatographed on a silica gel column using hexane and ethylacetate as eluent to afford coupled product. The products are characterized by NMR, GC MS and UPLC analyses.
Reference: [1] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 4, p. 1077 - 1081
[2] Journal of Molecular Catalysis A: Chemical, 2013, vol. 371, p. 118 - 124
[3] European Journal of Medicinal Chemistry, 2018, vol. 150, p. 30 - 38
[4] Patent: WO2004/22556, 2004, A1, . Location in patent: Page 16-17
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Reference: [1] Organic Letters, 2008, vol. 10, # 17, p. 3745 - 3748
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Reference: [1] Chemical Communications, 2016, vol. 52, # 11, p. 2326 - 2329
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Reference: [1] Acta Chemica Scandinavica, 1989, vol. 43, # 1, p. 62 - 68
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Reference: [1] Angewandte Chemie - International Edition, 2017, vol. 56, # 6, p. 1581 - 1585[2] Angew. Chem., 2017, vol. 129, # 6, p. 1603 - 1607,5
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Reference: [1] Journal of the American Chemical Society, 2015, vol. 137, # 33, p. 10480 - 10483
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YieldReaction ConditionsOperation in experiment
99% With 1,4-diaza-bicyclo[2.2.2]octane In water; dimethyl sulfoxide at 20℃; for 18 h; Preparation 63 5-Bromo-pyrimidine-2-carbonitrile A solution of 5-bromo-2-chloropyrimidine (10g, 51.8mmol) in dimethylsulfoxide (26ML)-WAS-ADDED TO : A MIXTURE, of sodium cyandie (2.59g, 51.8mmol) and triethylenediamine (1. 2g, 10. 4mmol) in dimethylsulfoxide (14mL) and water (28ML). THE RESULTING mixture was stirred for 18 hours at ROOM TEMPERATURE. THE ; mixture was-then diluted with water (130MOLY and extracted with diethyl ether (3x150mL) the combined organic solutions were dried over sodium sulfate and concentrated in vacuo to give a pale yellow solid. Re-crystallisation of the solid from hot dichloromethane afforded the title product in 99percent yield, 9.4g. 1HNMR (CDCL3, 400MHZ) No.: 8.84 (S, 2H).
88% at 20℃; Example 50; 2-Benzoyl-pyrimidine-5-carboxylic acid morpholin-4-ylamide; <n="95"/>Step 1 : 5-Bromo-2-chloropyrimidine (7.51 g, 38.83 mmol) is dissolved in DMSO (20 niL) is added to a mixture of NaCN (1.9 g, 38.83 mmol) and l,4-diazabicyclo[2,2,2]octane (0.87 g, 7.77 mmol) in DMSO (10 mL) and water (20 mL). The mixture is stirred at rt overnight, and then water (100 mL) is added. The mixture is extracted with ether (3x100 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo to afford 5
bromo-pyrimidine-2-carbonitrile (6.28 g, 88percent) as a solid. MS: 184 (M+H).
Reference: [1] Patent: WO2005/28452, 2005, A1, . Location in patent: Page/Page column 87
[2] Patent: WO2008/121670, 2008, A1, . Location in patent: Page/Page column 93-94
[3] Patent: WO2008/57336, 2008, A2, . Location in patent: Page/Page column 44
[4] Patent: WO2004/56369, 2004, A1, . Location in patent: Page/Page column 20
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YieldReaction ConditionsOperation in experiment
76% With 1,4-diaza-bicyclo[2.2.2]octane In water; dimethyl sulfoxide at 20℃; To a solution of NaCN (0.849 g, 17.32 mmol) and DABCO (0.390 g, 3.48 mmol) in a mixture of DMSO (4 ml) and H2O (9 ml) was added a solution of 5-bromo-2-chloropyrimidine (3.05 g, 15.75 mmol) in DMSO (9 ml).
The solution was stirred at room temperature overnight, and then diluted with water, and extracted with EtOAc.
The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give 5-bromopyrimidine-2-carbonitrile (2.327 g, 12.01 mmol, 76percent yield, 1H NMR (CDCl3 500 MHz): δ 8.94 (s, 2H)).
Reference: [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 2, p. 568 - 583
[2] Patent: US2014/107335, 2014, A1, . Location in patent: Paragraph 0170; 0171
[3] Patent: US2009/253708, 2009, A1, . Location in patent: Page/Page column 15
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YieldReaction ConditionsOperation in experiment
84% With 1,4-diaza-bicyclo[2.2.2]octane In water; dimethyl sulfoxide at 20℃; A mixture of 5-bromo-2- chloropynmidine (20 g, 1 03.40 mmol, 1 .00 equiv), 1 , 4-diaza-bicyclo[2.2.2]octane (2.32 g), and potassium carbon itri le (6.72 g, 1 03.20 mmol, 1 .00 equiv) in water (54 2 mL) and DMSO (80 mL) was stirred overnight at rt. Water (50 mL) was then added and the resulting solution was extracted with 3 100 mL of ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1 6 g (84percent) of 5-bromopynmidine-2-carbonitri le as a yellow solid. 1HNMR (300 MHz, CDCl3) δ 8.94 (s, 2H).
Reference: [1] Patent: WO2013/127267, 2013, A1, . Location in patent: Page/Page column 98
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 3, p. 529 - 541
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Reference: [1] Patent: US2015/31673, 2015, A1, . Location in patent: Paragraph 0394
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Reference: [1] Heterocycles, 2011, vol. 83, # 5, p. 1145 - 1151
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YieldReaction ConditionsOperation in experiment
60% at 70℃; Synthesis of Compound 11-3 (0400) To a solution of 11-2 (2.0 g, 10 mmol) in methanol (15 mL) was added CH3ONa (2.16 g, 40 mmol). The resulting mixture was stirred at 70° C. overnight. Methanol was evaporated in vacuum. Water (10 mL) was added carefully to the residue and the mixture was extracted with ethyl acetate (300 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford 11-3 as a yellow solid (1.17 g, 60percent).
1.17 g at 70℃; To a solution of 24-2 (2.0 g, 10 mmol) in methanol (15 ml) was added CH3ONa (2.16 g, 40 mmol). The resulting mixture was stirred at 70 °C overnight. Methanol was evaporated in vacuum. Water (10 ml) was added carefully to the residue and the mixture was extracted with ethyl acetate (300 ml x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford 24-3 as a yellow solid (1.17 g, 60percent yield).
Reference: [1] Patent: US9138427, 2015, B2, . Location in patent: Page/Page column 289-290
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5849 - 5853
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Reference: [1] Journal of Medicinal Chemistry, 2010, vol. 53, # 1, p. 77 - 105
[2] Patent: WO2012/177603, 2012, A2, . Location in patent: Page/Page column 74
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Reference: [1] Patent: WO2016/30443, 2016, A1, . Location in patent: Page/Page column 180
[2] Patent: WO2017/144637, 2017, A1, . Location in patent: Page/Page column 99; 100
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YieldReaction ConditionsOperation in experiment
18% With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2 h; A solution of 1.00 g (5.17 mmol) of 5-bromo-2-chloropyrimidine and 551 μl (6.20 mmol) of dimethyl disulfide in 26 ml of tetrahydrofuran was cooled to -78° C. and 1.89 ml (5.17 mmol) of 2.73 N n-butyl lithium/n-hexane solution was added thereto, and the reaction solution was stirred for 2 hours.
After completion of the reaction, saturated ammonium chloride aqueous solution was added to the reaction solution and the reaction solution was extracted with ethyl acetate.
The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.
The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=90/10 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 149 mg of the title compound as a white solid (yield: 18percent).
1H-NMR spectrum (500 MHz, CDCl3) δ ppm: 8.49 (2H, s), 2.54 (3H, s).
Reference: [1] Patent: US2013/109653, 2013, A1, . Location in patent: Paragraph 0831-0833
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YieldReaction ConditionsOperation in experiment
84%
Stage #1: With hydrogen iodide; sodium iodide In chloroform; water at 0 - 20℃; for 20 h;
Stage #2: With sodium hydroxide In chloroform; water for 0.166667 h;
Preparation of 5-Bromo-2-iodo-pyrimidine
To a suspension of 5-bromo-2-chloro-pyrimidine (5.80 g, 30 mmol) and sodium iodide (7.5 g, 50 mmol) in chloroform (20 ml) a Hydroiodic acid (57 wt. percent) (2.85 g, 25.6 mmol) is added at 0° C.
After removing the cooling the reaction mixture is stirred for 20 h at r.t. and then poured into a mixture of 200 ml ice water and 30 ml 10N NaOH. Chloroform (150 ml) is added and the mixture is stirred for 10 min.
The organic phase is separated, the aqueous layer is extracted with chloroform (2*100 ml) and the combined organic phases dried over MgSO4 and concentrated in vacuo to yielding 5-bromo-2-iodo-pyrimidine as a pale yellow solid.
Yield 6.29 g (84percent)
MS: M=284.8 (ESI+)
1H-NMR (300 MHz, CDCl3): 8.54 (s, 2H) 7.56(d, J=16.4 Hz, 1H), 7.59-7.66(m, 4H).
81%
Stage #1: With hydrogen iodide; sodium iodide In dichloromethane at 20 - 50℃; for 5 h;
Stage #2: With sodium hydrogencarbonate In dichloromethane; water
Preparation of Compound A8:To a solution of compound A7 (50 g, 0.26 mol) in DCM (300 mL) was added NaI (80 g, 0.52 mol) at room temperature, then HI (75 g, 0.52 mol) was added. After stirred at 50° C. for 5 h, the mixture was poured into ice water and carefully neutralized by addition of solid sodium bicarbonate until mixture became colorless. Then the mixture was extracted with DCM (2.x.200 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford compound A8 (60 g, yield: 81percent) as white solid.1H NMR (400 MHz, CDCl3): δ: 8.54 (s, 2H).
81% With hydrogen iodide; sodium iodide In dichloromethane at 20 - 50℃; for 5 h; Example A7 A8 A9 A10 [0412] Preparation of compound A8: To a solution of compound A7 (50 g, 0.26 mol) in DCM (300 mL) was added Nal (80 g, 0.52 mol) at room temperature, then HI (75 g, 0.52 mol) was added. After stirred at 50°C for 5h, the mixture was poured into ice water and carefully neutralized by addition of solid sodium bicarbonate until mixture became colorless. Then the mixture was extracted with DCM (2 x 200 mL). The organic layer was dried over Na2S04, filtered and concentrated to afford compound A8 (60 g, yield: 81percent) as white solid. [0413] 1H NMR (400 MHz, CDC13): δ: 8.54 (s, 2H). [0414] Preparation of compound A9: To the solution of compound A8 (50 g, 0.18 mol) in THF (300 mL) was added Pd(PPh3)4 (11.5 g, 0.01 mol), followed by addition of a solution of zinc reagent 3 (freshly prepared from iodomethyl 2,2-dimethylpropanoate) in THF (500 ml, 0.36 mol) and stirred at room temperature for 12h. Then ice water was added and the mixture was extracted with ethyl acetate (2 x 200 mL). The organic layer was dried over Na2S04, filtered and concentrated to afford crude product. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate = 10: 1) to afford the compound A9 (41 g, yield: 85percent) as yellow solid. [0415] 1H NMR (400 MHz, CDC13): δ: 8.75 (s, 2H), 5.26(s, 2H), 5.06 (s, 1H), 1.28 (s, 9H). [0416] Preparation of compound A10: To a stirred solution of compound A9 (15.0 g, 54.9 mmol) in dioxane (100 mL) was added bis(pinacolato)diboron (17.0 g, 65.4 mmol) under nitrogen, followed by Pd(dppf)Cl2 (2.20 g, 2.72 mmol) and KOAc (16 g, 163 mmol). The reaction mixture was heated at 85°C for 3h. The black suspension was cooled to room temperature, filtered, concentrated to afford crude product. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate = 15: 1) to afford compound A10 (15.4 g) as white solid, contaminated with pinacol derivatives. [0417] 1H NMR (400 MHz, CDC13): δ: 8.97 (s, 2H), 5.30 (s, 2H), 1.35 (s, 9H), 1.28 (s, 9H). [0418] Preparation of compound All: To a solution of compound A10 (15.6 g, 48.7 mmol) in MeOH (100 mL) was added H202 (16.0 g, 140 mmol). The mixture was stirred at room temperature for 12 h. 2N sodium thiosulphate (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL) The aqueous phase was adjusted pH to 4- 5 with 2N HCl; then the mixture was extracted with ethyl acetate (2 x 200 mL). The organic layer was dried over a2S04, filtered and concentrated to get compound All (9.4 g, yield: 82percent in two steps). [0419] 1H NMR (400 MHz, DMSO-i): δ: 10.48 (s, 1H), 8.31 (s, 2H), 5.1 1 (s, 2H), 1.21 (s, 9H). [0420] Preparation of compound A12: To a solution of compound All (10 g, 30 mmol) in MeOH (200 mL) was added MeONa (50 ml, 1M in MeOH). After stirred at room temperature for 12 h, the mixture was poured into water and extracted with ethyl acetate (2 x 200 mL). The organic layer was dried over a2S04, filtered and concentrated to afford the compound A12 (7.3 g, yield: 98percent) as white solid. [0421] 1H NMR (300 MHz, CDC13): δ: 8.43 (s, 2H), 7.35 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.09 (s, 2H), 4.78 (s, 2H).
Reference: [1] Angewandte Chemie - International Edition, 1999, vol. 38, # 5, p. 659 - 661
[2] Patent: US2005/222228, 2005, A1, . Location in patent: Page/Page column 15-16
[3] Chemical Communications, 1996, # 24, p. 2719 - 2720
[4] Patent: US2012/238751, 2012, A1, . Location in patent: Page/Page column 30
[5] Patent: WO2014/43272, 2014, A1, . Location in patent: Paragraph 0411; 0412; 0413
[6] Journal of Organic Chemistry, 2002, vol. 67, # 18, p. 6550 - 6552
[7] Molecular Crystals and Liquid Crystals Science and Technology Section A: Molecular Crystals and Liquid Crystals, 2001, vol. 368, p. 279 - 292
[8] Patent: US2006/194801, 2006, A1, . Location in patent: Page/Page column 37
[9] Patent: EP2258697, 2010, A1, . Location in patent: Page/Page column 122
[10] Patent: WO2015/138895, 2015, A1, . Location in patent: Paragraph 000295
  • 31
  • [ 32779-36-5 ]
  • [ 108-95-2 ]
  • [ 257280-25-4 ]
Reference: [1] Patent: US2002/156081, 2002, A1,
[2] Patent: US6921763, 2005, B2,
  • 32
  • [ 123-30-8 ]
  • [ 32779-36-5 ]
  • [ 76660-37-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2357 - 2360
  • 33
  • [ 288-13-1 ]
  • [ 32779-36-5 ]
  • [ 883230-94-2 ]
YieldReaction ConditionsOperation in experiment
440 mg With caesium carbonate In N,N-dimethyl acetamide at 120℃; for 0.5 h; 1st Step
Pyrazole (130 mg) and cesium carbonate (610 mg) were added to a DMAc (10 ml) solution containing 5-bromo-2-chloropyrimidine (300 mg), followed by stirring at 120° C. for 0.5 hours.
The reaction mixture was adjusted to room temperature and water was added to the mixture.
Next, the organic layers were collected, washed with saturated saline, and dried over anhydrous sodium sulfate.
The solvent was distilled away under reduced pressure and a yellow solid of 5-bromo-2-(pyrazol-1-yl)pyrimidine (440 mg) was thus obtained.
MS (ESI m/z): 226 (M+H)
Reference: [1] RSC Advances, 2015, vol. 5, # 100, p. 82097 - 82111
[2] Patent: WO2006/38100, 2006, A1, . Location in patent: Page/Page column 84
[3] Patent: US2014/309225, 2014, A1, . Location in patent: Paragraph 0901; 0902; 0903; 0904
  • 34
  • [ 1116-98-9 ]
  • [ 32779-36-5 ]
  • [ 831203-15-7 ]
YieldReaction ConditionsOperation in experiment
45%
Stage #1: With sodium hydride In dimethyl sulfoxide at 20℃; for 1 h; Inert atmosphere
Stage #2: at 20℃; for 8 h; Inert atmosphere
Stage #3: With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 16 h;
To a suspension of sodium hydride (53 mg (60percent oil suspension), 1.34 mmol) in DMSO (2 ml) at room temperature under a nitrogen atmosphere was added tert-butyl cyanoacetate (197 mg, 39 mmol) in DMSO (1 ml) was added dropwise over 15 minutes and then stirred at room temperature for 1 hour.5-Bromo-2-chloropyrimidine (100 mg, 0.52 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 8 hours. Next, a saturated aqueous solution of ammonium chloride was added to the reaction system, extracted with ethyl acetate, washed with water, and then concentrated under reduced pressure to obtain a crude product.Subsequently, trifluoroacetic acid (1.8 ml) was added to a solution of the dried crude product in dichloromethane (2.3 ml) at 0 ° C., and the mixture was stirred for 1 hour and then allowed to warm to room temperature and stirred for 15 hours did.The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered and concentrated under reduced pressure to obtain a crude product of (5-bromopyrimidin-2-yl) acetonitrile.The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain (5-bromopyrimidin-2-yl) acetonitrile. Yield 46 mg, yield 45percent, white solid.
Reference: [1] Patent: JP2017/178911, 2017, A, . Location in patent: Paragraph 0152; 0153
  • 35
  • [ 5419-55-6 ]
  • [ 32779-36-5 ]
  • [ 1003845-06-4 ]
YieldReaction ConditionsOperation in experiment
73.3% With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 4 h; Step 1:
Synthesis of 2-chloropyrimidin-5-yl-5-boronic acid
To a stirred solution of 5-bromo-2-chloropyrimidine (1.0 g, 5.170 mmol) in mixture of THF:Toluene (25 mL, 4:1) was added n-BuLi (1.6M in Hexane) (3.87 mL, 5.61 mmol) dropwise at -78° C.
And allowed to stir at -78° C. for 4 h.
On completion, Reaction mass diluted with water and stirred at RT for 1 h, extracted with Diethyl ether.
Then acidify using 1N HCl up to pH 2-3and extracted with EtOAc.
Organic portions were combined, dried over Na2SO4, evaporated under reduced pressure to give 2-chloropyrimidin-5-yl-5-boronic acid (0.6 g, 73.3percent) as white solid.
MS: 159.3[M++1]
51% With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 1.75 h; 34). Synthesis of 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine; To a solution of 5-bromo-2-chloro-pyrimidine (10 mmol, 1.93 g) and triisopropyl borate (12 mmol, 2.8 ml.) in toluene (16 ml) and THF (4 mi_) is added n-buty. lithium \\r, hexane (1.58 M, 12 mmol, 7.6 mL) dropwise at -78 0C over 45 min and stirred at -78 0C for 1 hour. The mixture is warmed to -20 0C, then added aq. hydrogen chloride (1M, 20 mL). The mixture is warmed to room temperature. The precipitate is collected and washed with hexane to give a colorless powder (808 mg, 51percent). A mixture of the powder (3.63 mmol, 575 mg), pinacol (3.81 mmol, 450 mg) and MgSO4 (18.15 mmol, 2.2 g) in toluene (10 mL) is <n="192"/>stirred at room temperature for 15 hour. The mixture is filtrated and the solution is concentrated under reduced pressure. The resultant solid is washed with water to give 2- chloro-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrimidine (875 mg, quant); ESI-MS m/z: 159 [M+1-pinacol]\\ Retention time 1.75 min (condition A).
Reference: [1] Patent: US2017/291910, 2017, A1, . Location in patent: Paragraph 0508-0510
[2] Patent: WO2008/9435, 2008, A1, . Location in patent: Page/Page column 189-190
[3] Patent: WO2011/84402, 2011, A1, . Location in patent: Page/Page column 153
  • 36
  • [ 32779-36-5 ]
  • [ 1003845-06-4 ]
YieldReaction ConditionsOperation in experiment
51%
Stage #1: With n-butyllithium; Triisopropyl borate In tetrahydrofuran; hexane; toluene at -78 - -20℃; for 1.75 h;
Stage #2: With hydrogenchloride; water In tetrahydrofuran; hexane; toluene at -20℃;
Example 14; 1)
Synthesis of 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine
To a solution of 5-bromo-2-chloro-pyrimidine (10 mmol, 1.93 g) and triisopropyl borate (12 mmol, 2.8 mL) in toluene (16 mL) and THF (4 mL) is added n-butyl lithium in hexane (1.58 M, 12 mmol, 7.6 mL) dropwise at -78° C. over 45 min and stirred at -78° C. for 1 hour.
The mixture is warmed to -20° C., then added aqueous 1 M HCl (20 mL).
The mixture is warmed to room temperature.
The precipitate is collected and washed with hexane to give a colorless powder (808 mg, 51percent).
A mixture of the powder (3.63 mmol, 575 mg), pinacol (3.81 mmol, 450 mg) and MgSO4 (18.15 mmol, 2.2 g) in toluene (10 mL) is stirred at room temperature for 15 hour.
The mixture is filtrated and the solution is concentrated under reduced pressure.
The resultant solid is washed with water to give 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine (875 mg, quant); ESI-MS m/z: 159 [M+1-pinacol]+, Retention time 1.75 min (condition A).
Reference: [1] Applied Organometallic Chemistry, 2012, vol. 26, # 7, p. 330 - 334
[2] Patent: US2009/118287, 2009, A1, . Location in patent: Page/Page column 67-68
[3] Patent: US2009/136473, 2009, A1, . Location in patent: Page/Page column 37
  • 37
  • [ 61676-62-8 ]
  • [ 32779-36-5 ]
  • [ 1003845-08-6 ]
YieldReaction ConditionsOperation in experiment
65%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 5 h;
Synthesis of Intermediate 1-1 (0337) 1.93 g (10 mmol) of 5-bromo-2-chloropyrimidine was dissolved in 200 mL of THF, and then, at a temperature of −78° C., 4 mL (2.5M in hexane) of normal butyllithium was added thereto. At the same temperature about one hour thereafter, 2.0 mL (10 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added thereto. At room temperature, the result was stirred for about 5 hours, and then, water was added thereto and a washing process was performed three times thereon using diethylether (100 mL). A washed diethylether layer was dried by using MgSO4, and then, dried under reduced pressure, thereby obtaining a product. The product was separation-purified by silica gel column chromatography, thus preparing 1.56 g (Yield 65percent) of Intermediate 1-1.
Reference: [1] Patent: US2017/179408, 2017, A1, . Location in patent: Paragraph 0336-0337
[2] Patent: CN104788482, 2016, B, . Location in patent: Paragraph 0023
  • 38
  • [ 1195-66-0 ]
  • [ 32779-36-5 ]
  • [ 1003845-08-6 ]
Reference: [1] Patent: CN104788482, 2016, B, . Location in patent: Paragraph 0018
  • 39
  • [ 32779-36-5 ]
  • [ 57260-71-6 ]
  • [ 374930-88-8 ]
YieldReaction ConditionsOperation in experiment
88.7% With potassium carbonate In 1,4-dioxane at 110℃; for 12 h; To 1,4-dioxane (30 mL) were added tert-butyl piperazine-1-carboxylate (2.89 g, 15.51 mmol), 5-bromo-2-chloropyrimidine (2.00 g, 10.34 mmol) and potassium carbonate (2.86 g, 20.68 mmol) sequentially. The mixture was heated to 110 °C, after stirring for 12 hours, the reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as a pale yellow solid (3.15 g, 88.7percent).MS (ESI, pos. ion)m/z: 343.1 [M+H] and‘HNMR(400IVIHz, CDC13): (ppm) 8.29 (s, 2H), 3.83-3.66 (m, 4H), 3.56-3.41 (m, 4H), 1.48 (s, 9H).
87.7% With potassium carbonate In acetonitrile at 80℃; To a solution of commercially available S-bromo-2-chloropyrimidin (9.75 g, 50 mmol) in CH3CN (100 mL) was added compound i-Boc-piperazine (9.25 g, 50 mmol) and K2003 (13.8 g, 100 mmol). The reaction mixture was stirred at 80 00 overnight. Then, the reaction mixture was concentrated under vacuo andextracted with EA and washed with water, dried by Na2SO4 and concentrated under vacuo to give the KR-7 (15 g 87.7percent yield). ESI-MS (Mi-i): 343, 345calc. for C13H19BrN4O2: 342.1.
87.7% With potassium carbonate In acetonitrile at 80℃; Preparation of reagents Preparation of reagent KR-1 : 1 - e/t-Butoxycarbonyl-4-(5-bromopyrimidin-2- vQpiperazine To a solution of commercially available 5-bromo-2-chloropyrimidin (9.75 g, 50 mmol) in CH3CN (100 mL) was added compound 1 -Boc-piperazine (9.25 g, 50 mmol) and K2CO3 (13.8 g, 100 mmol). The reaction mixture was stirred at 80 °C overnight. Then, the reaction mixture was concentrated under vacuo and extracted with EA and washed with water, dried by Na2SO4 and concentrated under vacuo to give the KR-1 (15 g 87.7percent yield). ESI-MS (M+1 ): 343, 345 calc. for Ci3H19BrN4O2: 342.1.
84.5% With triethylamine In N,N-dimethyl-formamide at 80℃; for 14 h; To a stirred solution of 1-boc piperazine (10.42 g, 56.86 mmol, Symax fine chemicals) in dry DMF (100 mL), TEA (14.43 mL, 103.39 mmol) and 5-bromo-2-chloropyrimidine (10 g,51.69 mmol, Oakwood chemicals) were added at rt and the reaction mixture was stirred at80 °C for 14 h. The reaction mixture was cooled to rt and poured into water (100 mL). Theformed precipitate was filtered and washed with diethyl ether (50 mL) to afford the titleproduct. Yield: 84.5percent (15 g, off white solid). 1H NMR (400 MHz, DMSO-d6): 68.49(s, 2H),3.69 (t, J = 5.2 Hz, 4H), 3.40 (t, J = 5.1 Hz, 4H), 1.42 (5, 9H). LCMS: (Method A) 345.23 (M+2), Rt. 4.92 mm, 99.6percent (Max).
84.5% With triethylamine In N,N-dimethyl-formamide at 80℃; for 14 h; To a stirred solution of 1-boc piperazine (10.42 g, 56.86 mmol, Symax fine chemicals) in dry DMF (100 mL), TEA (14.43 mL, 103.39 mmol) and 5-bromo-2-chloropyrimidine (10 g, 51.69 mmol, Oakwood chemicals) were added at rt and the reaction mixture was stirred at 80 °C for 14 h. The reaction mixture was cooled to rt and poured into water (100 mL). The formed precipitate was filtered and washed with diethyl ether (50 mL) to afford the title product. Yield: 84.5percent (15 g, off white solid). 1H NMR (400 MHz, DMSO-d6): δ 8.49 (s, 2H), 3.69 (t, J = 5.2 Hz, 4H), 3.40 (t, J = 5.1 Hz, 4H), 1.42 (s, 9H). LCMS: (Method A) 345.23 (M +2), Rt. 4.92 min, 99.6percent (Max).
80% With potassium carbonate In 1,4-dioxane for 1.5 h; Reflux To a solution of 5-bromo-2-chloropyrimidine (50.0 g, 258 mmol) and 1-tert-butoxycarbonylpiperazine (72.2 g, 387 mmol) in 1,4-dioxane (500 mL) was added potassium carbonate (67.8 g, 491 mmol), and the mixture was stirred under reflux for 1.5 h. The reaction was cooled to RT, quenched by water (500 mL) and extracted with diethyl ether (1000 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified with silica gel chromatography (petroleum ether:ethyl acetate=8:1-4:1) to give the title compound (70.5 g, 80percent) as a white solid. MS (ES+) C13H19BrN4O2 requires: 342. found: 243 [M+H−100]+.
80% With potassium carbonate In 1,4-dioxane for 1.5 h; Reflux Step 4:
Synthesis of tert-butyl 4-(5-bromopyrimidin-2-yl) piperazine-1-carboxylate
To a solution of 5-bromo-2-chloropyrimidine (50.0 g, 258 mmol) and 1-tert-butoxycarbonylpiperazine (72.2 g, 387 mmol) in 1,4-dioxane (500 mL) was added potassium carbonate (67.8 g, 491 mmol), and the mixture was stirred under reflux for 1.5 h.
The mixture was diluted with water (500 mL) and extracted with diethyl ether (1000 mL*2).
The combined organic layers were dried over sodium sulfate, filtered and concentrated.
The residue was purified with silica gel chromatography (elute: hexane:ethyl acetate=8:1 to 4:1) to give tert-butyl 4-(5-bromopyrimidin-2-yl) piperazine-1-carboxylate (70.5 g, 80percent) as a white solid. MS (ES+) C13H19BrN4O2 requires: 342, found: 243 [M+H-100]+.
78% With potassium carbonate In 1,4-dioxane at 20℃; for 4 h; Reflux To a solution of 5-bromo-2-chloro-pyrimidine (0.5 g, 2.58 mmol) in 1,4-dioxane (20 mL),tert-butyl piperazine-1-carboxylate (0.722 g, 3.88 mmol) and K2C03 (0.713 g, 5.17 mmol)were added at RT. The reaction mixture was refluxed for 4 h (TLC indicated complete consumption of starting material). The reaction mixture was brought toRT, diluted withwater (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts werewashed with water (2 x 40 mL), brine (1 x 40 mL), dried over Na2S04 and concentratedunder reduced pressure to give the residue. The residue was further purified by columnchromatography (100-200 silica gel, 15 g, 10percent EtOAc-Hexane) to afford tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-l-carboxylate (0.7 g, 78percent) as a white solid.1H NMR [400 MHz, CDCh]: J 8.29 (s, 2H), 3.75 (t, J = 4.8 Hz, 4H), 3.47 (t, J = 5.2 Hz,4H), 1.47 (s, 9H).LCMS: m/z: 287.44 [M-tBut.
76% With triethylamine In N,N-dimethyl-formamide at 90℃; for 8 h; To a stirred solution of 1-boc-piperazine (6.0 g, 31.5 mmol) in DMF (50 mL), triethyl amine (7 mL, 46.00 mmol) and 5-bromo-2-chloropyrimidine (6.3 g, 37.00 mmol) were added and the reaction mixture was stirred at 90 °C for 8 h. The reaction mixture was concentrated under reduced pressure. Water (50 mL) was added and the desired product was extracted with DCM (150 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (10percent EtOAc in pet ether) to afford the title compound. Yield: 76percent (7 g, white). 1H NMR (400 MHz, DMSO-d6): δ 8.46 (s, 2H), 3.68-3.67 (m, 4H), 3.39-3,37 (m, 4H), 1.40 (s, 9H). LCMS: (Method A) 289.0 (M+H), Rt. 5.19 min, 99.05percent (Max).
76% With triethylamine In N,N-dimethyl-formamide at 90℃; for 8 h; To a stirred solution of 1-boc-piperazine (6.0 g, 31.5 mmol) in DMF (50 mL), triethyl amine (7 mL, 46.00 mmol) and 5-bromo-2-chloropyrimidine (6.3 g, 37.00 mmol) were added and the reaction mixture was stirred at 90 °C for 8 h. The reaction mixture was concentrated under reduced pressure. Water (50 mL) was added and the desired product was extracted with DCM (150 mL). The organic layer was dried over Na2SO4and concentrated under reduced pressure. The crude product was purified by flash chromatography (10percent EtOAc in pet ether) to afford the title compound. Yield: 76percent (7 g, white). 1H NMR (400 MHz, DMSO-d6): 6 8.46 (s, 2H), 3.68-3.67 (m, 4H), 3.39-3,37 (m, 4H), 1.40 (s, 9H). LCMS: (Method A) 289.0 (M+H), Rt. 5.19 mm, 99.05percent (Max).

Reference: [1] Patent: WO2016/192657, 2016, A1, . Location in patent: Page/Page column 50
[2] Patent: WO2014/131855, 2014, A1, . Location in patent: Page/Page column 54; 55
[3] Patent: WO2016/20307, 2016, A1, . Location in patent: Page/Page column 44
[4] Journal of Medicinal Chemistry, 2016, vol. 59, # 19, p. 8967 - 9004
[5] Patent: WO2017/144633, 2017, A1, . Location in patent: Page/Page column 109
[6] Patent: WO2017/144639, 2017, A1, . Location in patent: Page/Page column 94
[7] Patent: US2015/111887, 2015, A1, . Location in patent: Paragraph 0282; 0283
[8] Patent: US2015/111857, 2015, A1, . Location in patent: Paragraph 0159; 0166; 0167
[9] Patent: WO2018/125961, 2018, A1, . Location in patent: Page/Page column 114; 115
[10] Patent: WO2016/30443, 2016, A1, . Location in patent: Page/Page column 129-130
[11] Patent: WO2017/144637, 2017, A1, . Location in patent: Page/Page column 65
[12] Patent: EP1956009, 2008, A1, . Location in patent: Page/Page column 98
[13] Patent: WO2010/94126, 2010, A1, . Location in patent: Page/Page column 75
[14] Patent: WO2011/54841, 2011, A1, . Location in patent: Page/Page column 47-48
[15] Patent: US2011/301143, 2011, A1, . Location in patent: Page/Page column 47
[16] Patent: US2012/208798, 2012, A1, . Location in patent: Page/Page column 20
  • 40
  • [ 557-20-0 ]
  • [ 32779-36-5 ]
  • [ 873331-73-8 ]
Reference: [1] Journal of Organic Chemistry, 2008, vol. 73, # 23, p. 9326 - 9333
  • 41
  • [ 4606-65-9 ]
  • [ 32779-36-5 ]
  • [ 1189973-29-2 ]
Reference: [1] Patent: WO2009/156966, 2009, A1, . Location in patent: Page/Page column 34
  • 42
  • [ 32779-36-5 ]
  • [ 109-85-3 ]
  • [ 886365-79-3 ]
YieldReaction ConditionsOperation in experiment
92.3% With potassium carbonate In acetonitrile at 100℃; for 6 h; To a solution of 5-bromo-2-chloropyrimidine (4 g, 20.68 mmol) in acetonitrile (40 mL) was added 2-methoxyethanamine (5.5 mL, 63 mmol) and potassium carbonate (14 g, 100 mmol) . The mixture was heated at 100 and stirred for 6 h. The reaction mixture was concentrated to remove solvent. The residue was diluted with water (30 mL) . The resulting mixture was extracted with DCM (50 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 9/1 to give a colorless oily product (4.43 g, 92.3) .[1798]MS (ESI, pos. ion) m/z: 233.2 [M+1]+.
Reference: [1] Patent: WO2016/615, 2016, A1, . Location in patent: Paragraph 00725
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