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Product Details of [ 3934-20-1 ]

CAS No. :3934-20-1 MDL No. :MFCD00006061
Formula : C4H2Cl2N2 Boiling Point : -
Linear Structure Formula :- InChI Key :BTTNYQZNBZNDOR-UHFFFAOYSA-N
M.W : 148.98 Pubchem ID :77531
Synonyms :

Calculated chemistry of [ 3934-20-1 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 32.05
TPSA : 25.78 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.7 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.68
Log Po/w (XLOGP3) : 2.13
Log Po/w (WLOGP) : 1.78
Log Po/w (MLOGP) : 0.81
Log Po/w (SILICOS-IT) : 2.34
Consensus Log Po/w : 1.75

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.66
Solubility : 0.326 mg/ml ; 0.00218 mol/l
Class : Soluble
Log S (Ali) : -2.3
Solubility : 0.742 mg/ml ; 0.00498 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.87
Solubility : 0.203 mg/ml ; 0.00136 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.47

Safety of [ 3934-20-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 3934-20-1 ]

* 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.

  • Upstream synthesis route of [ 3934-20-1 ]
  • Downstream synthetic route of [ 3934-20-1 ]

[ 3934-20-1 ] Synthesis Path-Upstream   1~80

  • 1
  • [ 3934-20-1 ]
  • [ 7461-50-9 ]
  • [ 3993-78-0 ]
YieldReaction ConditionsOperation in experiment
69% With ammonium hydroxide In water at 20℃; To 2,4-Dichloropyrimidine (1.0 g, 6.7 mmol) was added 28 percent w/v ammonium hydroxide solution (20 mL). The mixture was stirred overnight at ambient temperature then concentrated in vacuo. The residue was dry loaded and purified by FCC eluting with 2-10 percent EtOH in CHCI3 to afford 2-amino-4-chloropyrimidine and 2-chloro-4-aminopyrimidine. Yield: 2-amino-4-chloropyrimidine 200 mg, 23 percent; 2-chloro-4-aminopyrimidine 600 mg, 69 percent.
23% With ammonia In water at 20℃; for 5 h; Example 1 : 2-Amino-4-chloropyrimidine (2) and 4-amino-2-chloropyrimidine (3) A suspension of 2,4-dichloropyrimidine (7.45 g, 50.0 mmol) in ammonium hydroxide (25percent, 125 mL) is stirred at room temperature for 5 h. The appearance of the insoluble material changes from "salt-like" to "snow-like". The precipitate is collected by filtration and dried in vacuo. The crude material is redissolved in MeOHiCH2CI2 (1 :1), adsorbed on SiO2 and purified by column chromatography (gradient cyclohexane:ethyl acetate from 5:1 to 1 :1) to yield 1.48 g (23percent) of 2 and 1.73 g (26percent) of 3 (TLC cyclohexane:ethyl acetate 3:1 , Rf (2)=0.45, Rf (3)=0.32). ESI-MS m/z 129.8 [M+H]+.
Reference: [1] Patent: WO2010/20556, 2010, A1, . Location in patent: Page/Page column 62
[2] Journal of the American Chemical Society, 2003, vol. 125, # 33, p. 9970 - 9982
[3] Tetrahedron, 2010, vol. 66, # 6, p. 1280 - 1288
[4] Patent: WO2006/114409, 2006, A1, . Location in patent: Page/Page column 18
[5] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 14, p. 1973 - 1978
[6] Chemische Berichte, 1905, vol. 38, p. 1690
[7] Chemische Berichte, 1905, vol. 38, p. 1690
[8] Journal of the American Chemical Society, 1930, vol. 52, p. 1152,1156; vgl. H 24 80
[9] Heterocycles, 2000, vol. 53, # 7, p. 1489 - 1498
[10] Patent: US2007/238737, 2007, A1, . Location in patent: Page/Page column 11
[11] Letters in Organic Chemistry, 2011, vol. 8, # 8, p. 545 - 548
[12] Archiv der Pharmazie, 2014, vol. 347, # 2, p. 77 - 88
[13] Patent: CN106317147, 2017, A, . Location in patent: Paragraph 0062; 0063; 0064; 0065; 0066; 0067
[14] Patent: US2007/37974, 2007, A1, . Location in patent: Page/Page column 10
  • 2
  • [ 3934-20-1 ]
  • [ 3993-78-0 ]
Reference: [1] Journal of the American Chemical Society, 1930, vol. 52, p. 1152,1156; vgl. H 24 80
[2] Patent: WO2008/70740, 2008, A1, . Location in patent: Page/Page column 201
  • 3
  • [ 3934-20-1 ]
  • [ 7664-41-7 ]
  • [ 7461-50-9 ]
  • [ 3993-78-0 ]
Reference: [1] Chemische Berichte, 1905, vol. 38, p. 1690
  • 4
  • [ 3934-20-1 ]
  • [ 676-58-4 ]
  • [ 13036-57-2 ]
YieldReaction ConditionsOperation in experiment
50% at 0℃; for 8 h; Example 1.1.26: (4-methylpyrimidin-2-yl)methanamine; MeMgCl (3M solution in THF, 4.47 mL, 13.42 mmol) was added dropwise to a stirred solution of the 2,4-dichloropyrimidine (2 g, 13.42 mmol) and Fe(acac)3 (1.37 g, 3.9 mmol) in THF (40 mL) under argon at 0 0C and the resulting reaction mixture was stirred at 0 0C for 8 h. The reaction mixture was diluted with water and extracted with EtOAc. Evaporation of the organic phase followed by column chromatography on a silica gel (eluting with 25percent EtOAc/hexanes) to afford 2-chloro-4-methylpyrimidine in 50percent yield.
Reference: [1] Patent: WO2009/42694, 2009, A1, . Location in patent: Page/Page column 83
  • 5
  • [ 3934-20-1 ]
  • [ 75-16-1 ]
  • [ 13036-57-2 ]
Reference: [1] Journal of Organic Chemistry, 2004, vol. 69, # 11, p. 3943 - 3949
  • 6
  • [ 3934-20-1 ]
  • [ 75-24-1 ]
  • [ 13036-57-2 ]
Reference: [1] Acta Chemica Scandinavica, 1997, vol. 51, # 3, p. 302 - 306
  • 7
  • [ 3934-20-1 ]
  • [ 7461-50-9 ]
  • [ 3993-78-0 ]
YieldReaction ConditionsOperation in experiment
69% With ammonium hydroxide In water at 20℃; To 2,4-Dichloropyrimidine (1.0 g, 6.7 mmol) was added 28 percent w/v ammonium hydroxide solution (20 mL). The mixture was stirred overnight at ambient temperature then concentrated in vacuo. The residue was dry loaded and purified by FCC eluting with 2-10 percent EtOH in CHCI3 to afford 2-amino-4-chloropyrimidine and 2-chloro-4-aminopyrimidine. Yield: 2-amino-4-chloropyrimidine 200 mg, 23 percent; 2-chloro-4-aminopyrimidine 600 mg, 69 percent.
23% With ammonia In water at 20℃; for 5 h; Example 1 : 2-Amino-4-chloropyrimidine (2) and 4-amino-2-chloropyrimidine (3) A suspension of 2,4-dichloropyrimidine (7.45 g, 50.0 mmol) in ammonium hydroxide (25percent, 125 mL) is stirred at room temperature for 5 h. The appearance of the insoluble material changes from "salt-like" to "snow-like". The precipitate is collected by filtration and dried in vacuo. The crude material is redissolved in MeOHiCH2CI2 (1 :1), adsorbed on SiO2 and purified by column chromatography (gradient cyclohexane:ethyl acetate from 5:1 to 1 :1) to yield 1.48 g (23percent) of 2 and 1.73 g (26percent) of 3 (TLC cyclohexane:ethyl acetate 3:1 , Rf (2)=0.45, Rf (3)=0.32). ESI-MS m/z 129.8 [M+H]+.
Reference: [1] Patent: WO2010/20556, 2010, A1, . Location in patent: Page/Page column 62
[2] Journal of the American Chemical Society, 2003, vol. 125, # 33, p. 9970 - 9982
[3] Tetrahedron, 2010, vol. 66, # 6, p. 1280 - 1288
[4] Patent: WO2006/114409, 2006, A1, . Location in patent: Page/Page column 18
[5] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 14, p. 1973 - 1978
[6] Chemische Berichte, 1905, vol. 38, p. 1690
[7] Chemische Berichte, 1905, vol. 38, p. 1690
[8] Journal of the American Chemical Society, 1930, vol. 52, p. 1152,1156; vgl. H 24 80
[9] Heterocycles, 2000, vol. 53, # 7, p. 1489 - 1498
[10] Patent: US2007/238737, 2007, A1, . Location in patent: Page/Page column 11
[11] Letters in Organic Chemistry, 2011, vol. 8, # 8, p. 545 - 548
[12] Archiv der Pharmazie, 2014, vol. 347, # 2, p. 77 - 88
[13] Patent: CN106317147, 2017, A, . Location in patent: Paragraph 0062; 0063; 0064; 0065; 0066; 0067
[14] Patent: US2007/37974, 2007, A1, . Location in patent: Page/Page column 10
  • 8
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  • [ 7461-50-9 ]
YieldReaction ConditionsOperation in experiment
57% With ammonia In water; isopropyl alcohol at 100℃; for 18 h; sealed tube To a suspension of 2,4-dichloropyrimidine (2.0 g, 13 mmol) in isopropanol (20 mL) was added ammonium hydroxide 28-30percent (50 mL, 1385 mmol). The suspension went into solution immediately. The resulting solution was heated at 100 0C in a sealed tube for 18 h. The mixture was brought to RT, extracted with DCM and the combined organics were <n="87"/>dried over MgSO4, filtered, and concentrated to afford an off-white solid as 2- chloropyrimidin-4-amine (1.7 g, 57percent yield). MS m/z: 130.0 (M+l).
57% With ammonium hydroxide In isopropyl alcohol at 100℃; for 18 h; Sealed tube Step 1:
2-Chloropyrimidin-4-amine
To a suspension of 2,4-dichloropyrimidine (2.0 g, 13 mmol) in isopropanol (20 mL) was added ammonium hydroxide 28-30percent (50 mL, 1385 mmol).
The suspension went into solution immediately.
The resulting solution was heated at 100° C. in a sealed tube for 18 h.
The mixture was brought to RT, extracted with DCM and the combined organics were dried over MgSO4, filtered, and concentrated to afford an off-white solid as 2-chloropyrimidin-4-amine (1.7 g, 57percent yield). MS m/z: 130.0 (M+1).
Reference: [1] Patent: WO2009/64418, 2009, A1, . Location in patent: Page/Page column 84-85
[2] Patent: US2010/120774, 2010, A1, . Location in patent: Page/Page column 37
[3] Angewandte Chemie - International Edition, 2018, vol. 57, # 34, p. 11035 - 11039[4] Angew. Chem., 2018, vol. 130, # 34, p. 11201 - 11205,5
[5] Patent: WO2005/49616, 2005, A1, . Location in patent: Page/Page column 79-80
  • 9
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  • [ 3993-78-0 ]
Reference: [1] Chemische Berichte, 1905, vol. 38, p. 1690
  • 10
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  • [ 156-81-0 ]
Reference: [1] Journal of the Chemical Society, 1948, p. 2240,2246
[2] Journal of the Society of Chemical Industry, London, 1950, vol. 69, p. 353
  • 11
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  • [ 7664-41-7 ]
  • [ 7758-99-8 ]
  • [ 108-95-2 ]
  • [ 156-81-0 ]
Reference: [1] Journal of the Society of Chemical Industry, London, 1950, vol. 69, p. 353
  • 12
  • [ 66-22-8 ]
  • [ 3934-20-1 ]
YieldReaction ConditionsOperation in experiment
72.3% at 110℃; for 3.5 h; Inert atmosphere In a 500 ml, two-necked, round-bottom flask equipped with a condenser, uracil (100 g, 0.82 mol) was dissolved in phosphorous oxychloride (400 ml). The solution was refluxed with stirring for 3.5 h at 110 °C. The residual phosphorous oxychloride was removed in vacuo at 50 °C and the remaining oil was poured into 50 g of ice, followed by extraction with chloroform (3 * 50 ml). The combined organic extract was washed with dilute sodium carbonate solution and dried over anhydrous sodium sulfate. 2,4-Dichloropyrimidine was obtained by removal of the solvent.
80 g at 0℃; for 4 h; Reflux To a mixture of Ν,Ν-dimethyl aniline (140 gm) and uracil (100 gm) was added phosphorous oxychloride (342 gm) slowly at 0°C. The contents were then heated to reflux and maintained for 4 hours. The solution was then cooled to room temperature, then transferred into ice water and stirred for 1 hour. The resulting precipitate was filtered and washed with water. The solid thus obtained was recrystallized from hexane to give 80 gm of 2,4-dichloro pyrimidine.
80 g at 0℃; for 4 h; Reflux Preparative Example 1 Preparation of 2,4-dichloro pyrimidine [0078] To a mixture of N,N-dimethyl aniline (140 gm) and uracil (100 gm) was added phosphorous oxychloride (342 gm) slowly at 0° C. The contents were then heated to reflux and maintained for 4 hours. The solution was then cooled to room temperature, then transferred in to ice water and stirred for 1 hour. The resulting precipitate was filtered and washed with water. The solid thus obtained was recrystallized from hexane to give 80 gm of 2,4-dichloro pyrimidine.
80 g at 0℃; for 4 h; Reflux Step-I:
Preparation of 2,4-dichloro pyrimidine
To a mixture of N,N-dimethyl aniline (140 gm) and uracil (100 gm) was added phosphorous oxychloride (342 gm) slowly at 0° C.
The contents were then heated to reflux and maintained for 4 hours.
The solution was then cooled to room temperature, then transferred into ice water and stirred for 1 hour.
The resulting precipitate was filtered and washed with water.
The solid thus obtained was recrystallized from hexane to give 80 gm of 2,4-dichloro pyrimidine.

Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 2, p. 435 - 448
[2] ChemMedChem, 2014, vol. 9, # 11, p. 2516 - 2527
[3] Polyhedron, 2014, vol. 81, p. 316 - 322
[4] Dalton Transactions, 2012, vol. 41, # 8, p. 2477 - 2485
[5] Chemische Berichte, 1905, vol. 38, p. 1690
[6] Journal of the Chemical Society, 1951, p. 1565,1568[7] Journal of the Chemical Society, 1953, p. 1646
[8] Journal of the Chemical Society, 1951, p. 1218,1221
[9] Journal of the American Chemical Society, 1930, vol. 52, p. 1152,1156; vgl. H 24 80
[10] Yakugaku Zasshi, 1950, vol. 70, p. 137[11] Chem.Abstr., 1950, p. 5886
[12] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 6, p. 1831 - 1835
[13] Tetrahedron Letters, 1997, vol. 38, # 7, p. 1111 - 1114
[14] Tetrahedron, 2009, vol. 65, # 1, p. 247 - 252
[15] Patent: WO2012/147091, 2012, A2, . Location in patent: Page/Page column 7
[16] Patent: WO2013/38425, 2013, A1, . Location in patent: Page/Page column 7; 8
[17] Heterocycles, 2012, vol. 86, # 2, p. 1583 - 1590
[18] Patent: US2014/228385, 2014, A1, . Location in patent: Paragraph 0078
[19] Patent: US2014/350038, 2014, A1, . Location in patent: Paragraph 0080; 0081
  • 13
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Reference: [1] Journal of Organic Chemistry, 2011, vol. 76, # 10, p. 4149 - 4153
[2] Phosphorus, Sulfur and Silicon and the Related Elements, 2008, vol. 183, # 4, p. 986 - 991
  • 14
  • [ 138918-23-7 ]
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  • [ 138918-24-8 ]
Reference: [1] Patent: US5298480, 1994, A,
[2] Patent: EP457581, 1991, A1,
  • 15
  • [ 49844-90-8 ]
  • [ 3934-20-1 ]
Reference: [1] Tetrahedron Letters, 2010, vol. 51, # 35, p. 4609 - 4611
  • 16
  • [ 68-12-2 ]
  • [ 66-22-8 ]
  • [ 3934-20-1 ]
  • [ 871254-61-4 ]
Reference: [1] Patent: CN108467368, 2018, A, . Location in patent: Paragraph 0014; 0015
  • 17
  • [ 1336-21-6 ]
  • [ 166752-02-9 ]
  • [ 3934-20-1 ]
Reference: [1] Patent: US6043248, 2000, A,
[2] Patent: US5981537, 1999, A,
  • 18
  • [ 3724-43-4 ]
  • [ 109-77-3 ]
  • [ 3934-20-1 ]
  • [ 16849-88-0 ]
Reference: [1] Organic Process Research and Development, 2012, vol. 16, # 1, p. 57 - 60
  • 19
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  • [ 3934-20-1 ]
Reference: [1] Il Farmaco; edizione scientifica, 1988, vol. 43, # 3, p. 277 - 291
  • 20
  • [ 141-90-2 ]
  • [ 3934-20-1 ]
Reference: [1] Journal of Biological Chemistry, 1907, vol. 2, p. 114[2] Chem. Zentralbl., 1906, vol. 77, # II, p. 1508
  • 21
  • [ 15493-07-9 ]
  • [ 66-22-8 ]
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Reference: [1] Journal of the Chemical Society, 1957, p. 323,325
  • 22
  • [ 141-90-2 ]
  • [ 10026-13-8 ]
  • [ 3934-20-1 ]
Reference: [1] Journal of Biological Chemistry, 1907, vol. 2, p. 114[2] Chem. Zentralbl., 1906, vol. 77, # II, p. 1508
  • 23
  • [ 3934-20-1 ]
  • [ 3289-47-2 ]
  • [ 155-90-8 ]
Reference: [1] Journal of the American Chemical Society, 1930, vol. 52, p. 1152,1156; vgl. H 24 80
[2] Journal of the American Chemical Society, 1934, vol. 56, p. 190,192
[3] Zhurnal Obshchei Khimii, 1957, vol. 27, p. 2113;engl.Ausg. S.2170
  • 24
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  • [ 124-41-4 ]
  • [ 3289-47-2 ]
  • [ 155-90-8 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 149 - 153
[2] Letters in Organic Chemistry, 2011, vol. 8, # 8, p. 545 - 548
  • 25
  • [ 3934-20-1 ]
  • [ 124-41-4 ]
  • [ 22536-63-6 ]
YieldReaction ConditionsOperation in experiment
98% at 0 - 20℃; [0170j To a solution of 2,4-dichloropyrimidine (41.8 g, 280 mmol) in methanol (900 mL)was added a solution of CH3ONa (15.2 g, 280 mmol) in 100 mL methanol at 0 °C. The mixturewas stirred at rt for overnight. The mixture was concentrated under reduce pressure to give awhite solid, which was diluted with water (400mL) and extracted with ethyl acetate (500 mL x3). The combined organic layer was washed with brine, dried, concentrated to give 2-chloro-4-methoxypyrimidine (40 g, yield: 98percent) as white solid. ESI-MS (M+H): 145.0. ‘H NMR (400 MHz, CDC13) (5: 8.30 (d, J= 5.6 Hz ,1H), 6.68 (s, J= 5.6 Hz ,1H), 4.02 (s, 3H).
82% at 0℃; for 2 h; To a solution of 2,4-dichloropyrimidine (7.5 g, 50 mmol,) in MeOH (80 mL) was added dropwise into a solution of NaOMe (2.84 g, 52.5 mmol) in MeOH (20 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was concentrated in vacuo to give crude product. The crude product was poured into 150 mL of water. The aqueous phase was extracted with EtOAc (100 mL). The organic layer was dried with Na2SO4and concentrated in vacuum to give 2-chloro-4-methoxypyrimidine (5.9 g, yield: 82percent) as a light yellow solid. ESI-MS (M+H)+: 145.0.1H NMR (400 MHz, CDCl3) δ: 8.27 (d, J = 6.0 Hz, 1H), 6.65 (d, J = 6.0 Hz, 1H), 3.99 (s, 3H).
9.7 g at 20℃; for 14 h; Preparative Example 2 Preparation of 2-chloro-4-methoxypyrimidine [0079] To a solution of 2,4-dichloro pyrimidine (20 gm) in methanol (200 ml) was added sodium methoxide (8.7 gm) at 0 to 5° C. The resulting mixture was stirred for 14 hours at room temperature and then concentrated under reduced pressure to obtain a residual mass. The residual mass obtained was extracted with ethyl acetate and water. The combined organic layers were washed with water and sodium chloride solution, and then concentrated under vacuum to obtain a crude solid. The crude solid obtained was dissolved in hexane (40 ml) at 0 to 5° C. and stirred for 1 hour. The solid obtained was collected by filtration and then dried to obtain 9.7 gm of 2-chloro-4-methoxypyrimidine.
9.7 g at 0 - 35℃; for 14 h; Step-II:
Preparation of 2-chloro-4-methoxypyrimidine
To a solution of 2,4-dichloro pyrimidine (20 gm) in methanol (200 ml) was added sodium methoxide (8.7 gm) at 0 to 5° C.
The resulting mixture was stirred for 14 hours at room temperature and then concentrated under reduced pressure to obtain a residual mass.
The residual mass obtained was extracted with ethyl acetate and water.
The combined organic layers were washed with water and sodium chloride solution, and then concentrated under vacuum to obtain a crude solid.
The crude solid obtained was dissolved in hexane (40 ml) at 0 to 5° C. and stirred for 1 hour.
The solid obtained was collected by filtration and then dried to obtain 9.7 gm of 2-chloro-4-methoxypyrimidine.

Reference: [1] Patent: WO2015/89337, 2015, A1, . Location in patent: Paragraph 0170
[2] Organic Letters, 2006, vol. 8, # 16, p. 3513 - 3516
[3] Patent: WO2018/191577, 2018, A1, . Location in patent: Page/Page column 56; 60; 61
[4] Tetrahedron, 1997, vol. 53, # 34, p. 11595 - 11626
[5] Chemical and Pharmaceutical Bulletin, 1959, vol. 7, p. 297
[6] Journal of the Chemical Society, 1955, p. 855,859
[7] Il Farmaco; edizione scientifica, 1988, vol. 43, # 3, p. 277 - 291
[8] Patent: WO2009/42694, 2009, A1, . Location in patent: Page/Page column 82-83
[9] Patent: EP2287173, 2011, A1, . Location in patent: Page/Page column 58
[10] Patent: WO2012/147091, 2012, A2, . Location in patent: Page/Page column 8-9
[11] Patent: US2014/228385, 2014, A1, . Location in patent: Paragraph 0079
[12] Patent: US2014/350038, 2014, A1, . Location in patent: Paragraph 0082
  • 26
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  • [ 22536-63-6 ]
YieldReaction ConditionsOperation in experiment
85% With sodium methylate In methanol at 0 - 20℃; To a well stirred solution of 2,4-dichloropyrimidine 5 (15 g,0.1 mol, 1 equiv) in 35 ml of MeOH was added 70 ml of MeOH containingMeONa (2.3 g, 0.1 mol, 1 equiv) at 0 C. Then, the reactionmixture was stirred at room temperature for overnight. After removalof the solvent under reduced pressure, appropriate amountof water was added, and then extracted with ethyl acetate(3 30 ml). The organic phase was dried over anhydrous Na2SO4,filtered, concentrated under reduced pressure to give crude product(6) as a white-yellow powder, which was pure enough to beused in the next step. Yield: 85percent, Mp: 53–55 C, 1H NMR(400 MHz, DMSO-d6) d ppm: 3.94 (s, 3H, –OCH3), 7.01 (d, 1H,J = 5.7 Hz, Pyrm-H), 8.46 (d, 1H, J = 5.7 Hz, Pyrm-H); ESI-MS:145.1 [M+H]+, 147.1[M+3]+. C5H5ClN2O [144.56].
Reference: [1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 23, p. 7398 - 7405
[2] Patent: US6455528, 2002, B1,
  • 27
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  • [ 865-33-8 ]
  • [ 22536-63-6 ]
YieldReaction ConditionsOperation in experiment
57% at 0 - 20℃; A solution of 2,4-dichloropyrimidine (30 g, 0.201 mol) was dissolved in methanol (300 mL) at 0 & lt; 0 & gt; C under stirred conditions,Potassium potassium methoxide (13 g, 0.24 mol) was added and the reaction was allowed to warm to room temperature and stirred overnight. Add appropriate amount of water, extracted with dichloromethane 3 times,The organic phase was combined and washed with saturated brine. The organic phase was dried and the crude dichloromethane was distilled off to give the crude product. N-hexane was added and stirred at 0 ° C for 1 hour to give 16.5 g of compound 2 in 57percent yield.
Reference: [1] Patent: CN106749203, 2017, A, . Location in patent: Paragraph 0123; 0124; 0125; 0126
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  • [ 124-41-4 ]
  • [ 22536-63-6 ]
YieldReaction ConditionsOperation in experiment
9.7 g at 0 - 35℃; for 14 h; To a solution of 2,4-dichloro pyrimidine (20 gm) in methanol (200 ml) was added sodium methoxide (8.7 gm) at 0 to 5°C. The resulting mixture was stirred for 14 hours at room temperature and then concentrated under reduced pressure to obtain a residual mass. The residual mass obtained was extracted with ethyl acetate and water. The combined organic layers were washed with water and sodium chloride solution, and then concentrated under vacuum to obtain a crude solid. The crude solid obtained was dissolved in hexane (40 ml) at 0 to 5°C and stirred for 1 hour. The solid obtained was collected by filtration and then dried to obtain 9.7 gm of 2-chloro-4-methoxypyrimidine.
Reference: [1] Patent: WO2013/38425, 2013, A1, . Location in patent: Page/Page column 8
  • 29
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  • [ 124-41-4 ]
  • [ 22536-63-6 ]
  • [ 51421-99-9 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 1499 - 1506
[2] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 1499 - 1506
  • 30
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  • [ 3551-55-1 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 149 - 153
  • 31
  • [ 67-56-1 ]
  • [ 3934-20-1 ]
  • [ 22536-63-6 ]
Reference: [1] Journal of Materials Chemistry A, 2014, vol. 2, # 15, p. 5418 - 5426
  • 32
  • [ 3934-20-1 ]
  • [ 5188-07-8 ]
  • [ 49844-93-1 ]
YieldReaction ConditionsOperation in experiment
52% at -10 - 20℃; for 5 h; To a solution of ethyl 2,4-dichloropyrimidine (20.0 g, 0.13 mol) in 150 mL of anhydrous tetrahydrofurane was added sodium thiomethoxide (49.30mL, 0.15 mol) at -10 °C. The reaction mixture was allowed to warm up to room temperature and then stirred for 5 hours with monitoring a reaction with LC-MS or thin layer chromatography (TLC). The reaction mixture was diluted with ethyl acetate and washed with brine (x2). The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting solid was slurrified with diethyl ether and then collected by filtration to afford the desired intermediate 10 as a white solid (11.2 g, 52 percent
33% at 20℃; To a solution of 2,4-dichloropyrimidine (1 g, 6.71 mmol) in THF (12 mL) was added sodium thiomethoxide (565 mg, 8.05 mmol) and the resulting suspension was stirred at ambient temperature overnight.
After TLC and MS showed completion of reaction, the mixture was quenched with water, extracted with EtOAc (2*25 mL), dried over anhydrous Na2SO4, filtered and evaporated to dryness.
The resulting residue was purified by column chromatography on an ISCO® chromatography system (SiO2 column:
hexanes/EtOAc 0 to 20percent gradient elution) to afford the title compound as yellow solid (348 g, 33percent yield).
Reference: [1] Journal of Heterocyclic Chemistry, 2007, vol. 44, # 4, p. 967 - 971
[2] Organic Letters, 2016, vol. 18, # 9, p. 2180 - 2183
[3] Patent: WO2013/109882, 2013, A1, . Location in patent: Page/Page column 63
[4] Patent: US2016/83365, 2016, A1, . Location in patent: Paragraph 0841-0843
[5] Journal of Organic Chemistry, 2017, vol. 82, # 5, p. 2664 - 2671
  • 33
  • [ 3934-20-1 ]
  • [ 3289-47-2 ]
  • [ 155-90-8 ]
Reference: [1] Journal of the American Chemical Society, 1930, vol. 52, p. 1152,1156; vgl. H 24 80
[2] Journal of the American Chemical Society, 1934, vol. 56, p. 190,192
[3] Zhurnal Obshchei Khimii, 1957, vol. 27, p. 2113;engl.Ausg. S.2170
  • 34
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  • [ 155-90-8 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 149 - 153
[2] Letters in Organic Chemistry, 2011, vol. 8, # 8, p. 545 - 548
  • 35
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  • [ 141-52-6 ]
  • [ 3551-55-1 ]
Reference: [1] Journal of the American Chemical Society, 1980, vol. 102, p. 916
  • 36
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  • [ 3551-55-1 ]
Reference: [1] Patent: US2003/147845, 2003, A1,
  • 37
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  • [ 124-41-4 ]
  • [ 3551-55-1 ]
Reference: [1] Journal of the American Chemical Society, 1930, vol. 52, p. 2001,2006
  • 38
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  • [ 124-41-4 ]
  • [ 22536-63-6 ]
  • [ 3551-55-1 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 149 - 153
  • 39
  • [ 3934-20-1 ]
  • [ 5188-07-8 ]
  • [ 5909-26-2 ]
Reference: [1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 18, p. 3237 - 3239
  • 40
  • [ 3934-20-1 ]
  • [ 74-89-5 ]
  • [ 31058-81-8 ]
  • [ 23631-02-9 ]
YieldReaction ConditionsOperation in experiment
55% at 20℃; for 2 h; Step B:
Synthesis of (2-chloro-pyrimidin-4-yl)-dimethyl-amine.
To a solution of 2,4-dichloro-pyrimidine (15.0 g, 10.15 mmol) in THF (150 mL) was added 50percent aqueous MeNH2 (22.7 g, 25.2 mmol).
The mixture was stirred at ambient temperature for 2 hr.
The solution was poured into saturated aqueous NaHCO3 and the aqueous layer was extracted with CHCl3 (three times).
The combined organic layer was dried over MgSO4, filtrated, concentrated, and purified by flash chromatography (NH-silica, 20percent EtOAc in hexane) to give (2-chloro-pyrimidin-4-yl)-dimethyl-amine (8.66 g, 55 percent) as a white solid and (4-chloro-pyrimidin-2-yl)-dimethyl-amine (0.87 g, 6percent) as a white solid.
Reference: [1] Patent: EP1464335, 2004, A2, . Location in patent: Page/Page column 172
  • 41
  • [ 3934-20-1 ]
  • [ 124-40-3 ]
  • [ 31058-81-8 ]
  • [ 23631-02-9 ]
Reference: [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1089 - 1104
[2] Patent: WO2005/95357, 2005, A2, . Location in patent: Page/Page column 136
  • 42
  • [ 3934-20-1 ]
  • [ 38111-44-3 ]
  • [ 13036-50-5 ]
YieldReaction ConditionsOperation in experiment
64% at 50℃; To a solution of 2,4-dichloropyrimidine (149 mg, 1 mmol) in THF (5 mL), tetrakis(triphenylphosphine) palladium (23 mg, 2 mol percent) and 0.5M solution of phenylzinc bromide (2.1 mL, 1.05 mmol) in THF were added. The reaction mixture was stirred at 50° C. for overnight. Then it was added saturated ammonium chloride solution and extracted with EtOAc twice. The organic layers were combined, washed with water and dried (MgSO4). Evaporation of solvent gave a yellow residue which was purified by Prep. HPLC to afford a yellowish oil as 2-chloro-4-phenyl-pyrimidine.
Reference: [1] Patent: US2008/107625, 2008, A1, . Location in patent: Page/Page column 64
[2] Patent: US2006/183694, 2006, A1, . Location in patent: Page/Page column 76
[3] Patent: WO2003/99274, 2003, A1, . Location in patent: Page 442
[4] Patent: US2007/99825, 2007, A1, . Location in patent: Page/Page column 65
[5] Patent: US2008/107623, 2008, A1, . Location in patent: Page/Page column 60
[6] Patent: US2008/107624, 2008, A1, . Location in patent: Page/Page column 63
  • 43
  • [ 3934-20-1 ]
  • [ 98-80-6 ]
  • [ 13036-50-5 ]
YieldReaction ConditionsOperation in experiment
87% With tetrabutylammomium bromide; sodium carbonate In ethanol; water at 70℃; for 10 h; General procedure: Azaheteroaryl halide (1 mmol), catalyst (0.005-0.05 mol percent) and 1M aq. Na2CO3 (1.1 mL) were stirred in a mixture of H2O-EtOH(1:2, 5 mL). The arylboronic acid (1.1 mmol) was added to the above mixture and stirring was continued for required time at 60 °C. After the requisite time, reaction mixture was diluted with ethyl acetate and the catalyst was separated by centrifugation. The centrifugate was dried over anhydrous sodium sulphate and evaporated. Then the product was analyzed by GC-MS or LC-MS.The solution was concentrated and chromatographed on a silicagel column with n-hexane-ethyl acetate (4:1) as the eluting solvent to give the coupled product. The product was confirmed by 1H and 13C NMR spectral analysis. The used catalyst was washed with water, ethanol and dichloromethane, and dried under vacuum before reuse.
86% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; toluene for 4 h; Inert atmosphere; Reflux comprising the compound B-12 (10g, 67.1mmol) was added to a round bottom flask the compound Β-11 (9. 8g, 80. 5mmol) and Pd (PPh3)4 (2. 33g, 2.01mmol) , and the round-bottom flask filled with argon. To this was added toluene (240mL), ethanol (120mL) and 2Μ K2C03 (120mL), and the mixture was stirred at reflux for 4 hours. Cooled at room temperature, after extraction with EA and washed with water, drying the resulting organic layer to give compound B-13 (11g, 86percent) was purified by column chromatography on silica.
86% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; toluene for 4 h; Inert atmosphere; Reflux A round bottom flask containing 10 g (67.1 mmol) of the compound B-12 was charged with 9.8 g (80.5 mmol) of the compound B-11 and 2.33 g (2.01 mmol) of Pd(PPh3)4 was charged and filled with argon gas. 240 mL of toluene, 120 mL of ethanol and 120 mL of 2M K2CO3 were added and the mixture was refluxed and stirred for 4 hours. Cooled to room temperature, extracted with EA and washed with water. The obtained organic layer was dried and purified by silica column to obtain 11 g (86percent) of Compound B-13.
83% With sodium carbonate In ethanol; toluene at 70℃; for 3 h; Preparation of Compound 2-6 [130] After 2,4-dichloropyrimidine (15 g, 100 mmol), phenyl boronic acid (12.28 g, 100 mL), Tetrakis(triphenylphosphine)palladium (5.82 g, 5 mmol), sodium carbonate (25.61 g, 240 mmol) and ethanol (200 mL) were dissolved in toluen (500 mL), the mixture was stirred under reflux for 3 hours at 70 . After extracting with EA/H2O, drying an organic layer with MgSO4, and removing a solvent by the rotary type evaporator, Compound 2-6 (16 g, 83percent) was obtained via column separation.
70% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,4-dioxane; water; N,N-dimethyl-formamide at 80℃; for 10 h; Inert atmosphere A mixture of 2,4-dichloroprymidine 5 (1.00g, 6.7mmol), phenylboronic acid (0.99g, 8.1mmol), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.51g, 0.7mmol) and sodium carbonate (2.13g, 20.1mmol) in DMF/1,4-dioxane/water (4:2:1, 10mL) was degassed with nitrogen and stirred at 80°C for 10h. After completion of the reaction, the reaction mixture was diluted with dichloromethane (50ml), washed with brine (30mL×3), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography (ethyl acetate/petroleum ether) on silica gel to give 8h as a white solid (70percent): mp 87.7–88.2°C; 1H NMR (400MHz, CDCl3) δ: 8.65 (d, J=5.3Hz, 1H), 8.11 (dd, J=8.1, 1.9Hz, 2H), 7.66 (d, J=5.3Hz, 1H), 7.58–7.51 (m, 3H).
64% With sodium carbonate In 1,2-dimethoxyethane at 95℃; for 20 h; Inert atmosphere To a mixture of 2,4-dichloropyrimidine (90) (50 mg, 0.336 mmol), phenylboronic acid (41 mg, 0.336 mmol), sodium carbonate (110 mg in 0.5 niL water) and DME (2.5 niL) was added palladium acetate (3.8 mg, 0.0168 mmol) and triphenylphosphine (8.8 mg, 0.0336 mmol). The reaction mixture was heated at 950C for 20 h. Solvent was removed under reduced pressure and the residue taken up into dichloromethane (20 mL), washed with water (3 x 5 mL), dried over MgSO4, and concentrated to give a residue which was purified by preparatory TLC (hexane:EtOAc, 8:2) to yield 41 mg (64percent) of 91. 1H NMR (500 MHz, CDCl3): δ 8.63 (d, J = 5.2 Hz, IH), 8.06-8.11 (m, 2H), 7.64 (d, J = 5.3 Hz, IH), 7.47-7.57 (m, 3H); 13C NMR (166 MHz, CDCl3): δ 167.2, 161.9, 159.8, 135.1, 131.9, 129.1, 127.4, 115.2.
55% With potassium carbonate In N,N-dimethyl-formamide; toluene at 185℃; for 0.166667 h; Microwave irradiation j00469j To a stirred solution of 2,4-dichloropyrimidine (0.200 g, 1.34 mmol, 1 equiv) in mixture of toluene and DMF (1.8/0.2 ml) was added K2C03 (0.557 g, 4.03 mmol, 1 equiv), and phenylboronic acid (0.196 g, 1.61 mmol, 1.2 equiv). The reaction mixture was irradiated in the microwave (185 °C, 10 mm), diluted with EtOAc, washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude brown oil was purified by chromatography on Si02 (EtOAc/hex, 1:10 to 3:7) to give a 0.140 g (55percent yield) of the desired product as a white solid.
47% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water; acetonitrile at 90℃; for 18 h; Inert atmosphere 2-Chloro-4-phenylpyrimidine 2,4-Dichloropyrimidine (5 g, 33.57 mmol) was dissolved in acetonitrile (60 ml) prior to the addition of water (15 ml). To this was added phenylboronic acid (4.09 g, 33.57 mmol) and sodium carbonate (14.23 g, 134.28 mmol). The reaction mixture was degassed for 10 min by bubbling nitrogen through it before addition of Pd(PPh3)4 (354 mg, 0.34 mmol). The reaction mixture was stirred under nitrogen at 90 °C for 18 h. The reaction mixture was then filtered through celite and the filtrate collected. The solvent was removed in vacuo and the crude material was purified by column chromatography, eluting 10-15percent ethyl acetate/petroleum spirits to give the title compound as a colourless solid (2.98 g, 47percent). LRMS [M+H]+ 191 .1 m/z; 1 H NMR (400 MHz, CDCI3) δ 8.62 (d, J= 5.3 Hz, 1 H), 8.16 - 7.99 (m, 2H), 7.63 (d, J = 5.3 Hz, 1 H), 7.50 (qdd, J = 6.0, 3.2, 1 .4 Hz, 3H).
41% With sodium carbonate In 1,2-dimethoxyethane; ethanol; water at 125℃; for 0.5 h; Microwave irradiation To a mixture of 2,4-dichloropyrimidine (1.47g, 9.8mmol), benzene boronic acid (Ig, 8.2mmol), Na2CO3 (2.61g, 24.6mmol) in a mixture of DME (15ml), EtOH (2ml) and water (3ml) was added Pd(PPh3)4 (190mg, 0.16mmol) and the resulting mixture heated in a microwave at 125°C for 30 min. The reaction was repeated on same scale. The reaction mixtures were combined and diluted with water and extracted with EtOAc (x 2). The EtOAc layers were combined and washed with sat. NaCl, dried over MgSO45 filtered and evaporated. The residue was purified by MPLC (Biotage Horizon: FLASH 40+M) eluent: 100percent Hexanes (180ml), gradient rising from 100percent Hexanes to 10percent EtOAc in Hexanes (900ml), then 10percent EtOAc in Hexanes (500ml) to give 1.3g of the title compound (41percent) as a white solid. 1H NMR (CDCl3): 7.54 (m, 3H), 7.76 (s, 1H)5 8.08 (m, 2H)3 9.04 (s. 1H).
34%
Stage #1: With sodium carbonate In water for 0.25 h; Inert atmosphere
Stage #2: With tetrakis(triphenylphosphine) palladium(0) In waterInert atmosphere
General procedure: A mixture of 2,4-dichloropyrimidine (6.71 mmol), ary-boronic acid (6.71 mmol). DMF or dioxane (10 ml) was added to the above mixture followed by aqueous sodium carbonate (2 M, 6 ml,). The reaction mixture was degassed with argon for 15 min. Pd(PPh3)4 (50 mg, 0.17 mmol) was added and again degassed 5 min. The reaction mixture was maintained at rt for 12 h. The mixture was subsequently filtered and the remaining solid was washed with EtOAc. The filtrate was washed again with water and brine. The organic layer was separated, dried with anhydrous Na2SO4 and filtered. The organic layer was purified by silica gel column chromatography to give the desired product.
0.45 g With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In 1,4-dioxane; water at 20 - 110℃; for 14 h; A solution of 2,4-dichloropyrimidine (1.OOg, 6.71 mmol), phenylboronic acid (0.90g, 7.38 mmol) in 1,4-dioxane:water (8:2; 15 ml) was stirred at rt. The reaction mixture was degassed for 15 mm before addition of Cs2CO3 (6.56 g, 20.13 mmol) and Pd(PPh3)4 (0.39g, 0.335 mmol). The reaction mixture was heated at 110°C for 14 h. The resulting reaction mixture was cooled to rt and poured into saturated NaHCO3 solution (40 ml). The obtained mixture was extracted with EtOAc (2 x 25 ml). The combined organic phase was washed with brine solution (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (8percent EtOAc in hexane) yielding 2-chloro-4-phenylpyrimidine (0.45g, 2.37 mmol). LCMS: Method C, 2.23 mi MS: ES+ 191.57; ‘H NMR (400 MHz, CDC13) ppm 8.67 (d, J=5.2 Hz, 1 H), 8.11 - 8.13 (m, 2 H), 7.68 (d, J=5.6 Hz, 1 H), 7.54 - 7.58 (m, 3 H).

Reference: [1] Journal of Organometallic Chemistry, 2018, vol. 862, p. 76 - 85
[2] Patent: CN103819455, 2016, B, . Location in patent: Paragraph 0067; 0084; 0085
[3] Patent: KR2015/34146, 2015, A, . Location in patent: Paragraph 0059; 0076; 0077
[4] Tetrahedron Letters, 2006, vol. 47, # 26, p. 4415 - 4418
[5] Patent: WO2011/93609, 2011, A1, . Location in patent: Page/Page column 19
[6] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 3, p. 490 - 494
[7] Bioorganic Chemistry, 2018, vol. 78, p. 393 - 405
[8] Tetrahedron Letters, 2010, vol. 51, # 25, p. 3259 - 3262
[9] Patent: WO2011/22440, 2011, A2, . Location in patent: Page/Page column 167
[10] Journal of Medicinal Chemistry, 2014, vol. 57, # 4, p. 1208 - 1224
[11] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 4, p. 1077 - 1081
[12] Archives of Pharmacal Research, 2018, vol. 41, # 3, p. 251 - 258
[13] Patent: WO2017/49295, 2017, A1, . Location in patent: Paragraph 00469
[14] Synthesis, 2010, # 16, p. 2721 - 2724
[15] Patent: WO2015/172196, 2015, A1, . Location in patent: Paragraph 00186
[16] Patent: WO2011/25774, 2011, A1, . Location in patent: Page/Page column 46-47
[17] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 20, p. 4749 - 4754
[18] Patent: WO2006/66885, 2006, A1, . Location in patent: Page/Page column 74-75
[19] Patent: WO2004/80981, 2004, A1, . Location in patent: Page 64; 65
[20] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5206 - 5209
[21] Journal of Medicinal Chemistry, 2014, vol. 57, # 24, p. 10443 - 10454
[22] Patent: KR2016/108281, 2016, A, . Location in patent: Paragraph 0700-0702
[23] Patent: WO2017/103614, 2017, A1, . Location in patent: Page/Page column 54
[24] Patent: KR2015/111825, 2015, A, . Location in patent: Paragraph 0700-0702
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  • [ 98-80-6 ]
  • [ 13036-50-5 ]
  • [ 25095-48-1 ]
Reference: [1] Heterocycles, 2000, vol. 53, # 7, p. 1489 - 1498
  • 45
  • [ 3934-20-1 ]
  • [ 960-16-7 ]
  • [ 13036-50-5 ]
Reference: [1] Acta Chemica Scandinavica, 1989, vol. 43, # 1, p. 62 - 68
  • 46
  • [ 3934-20-1 ]
  • [ 591-51-5 ]
  • [ 26032-72-4 ]
Reference: [1] Journal of Chemical Research, 2006, # 12, p. 785 - 787
  • 47
  • [ 557-21-1 ]
  • [ 3934-20-1 ]
  • [ 75833-38-4 ]
Reference: [1] Patent: WO2010/36632, 2010, A1, . Location in patent: Page/Page column 220; 221
  • 48
  • [ 3934-20-1 ]
  • [ 74-89-5 ]
  • [ 66131-68-8 ]
YieldReaction ConditionsOperation in experiment
58% at -40 - 0℃; for 4 h; 2-Chloro-N-methylpyrimidin-4-amine (18)[00413] To a solution of 2,4-dichloropyrimidine (5.0 g, 33.79 mmol) in anhydrous THF (50 mL) was slowly added 2.0 M methylamine solution in THF (42.2 mL, 84.48 mmol) at -40 °C. The reaction mixture was stirred at 0 °C for 4 h and partitioned between CHCl3/2- propanol (4/1) and water. The organic layer was dried over anhydrous sodium sulfate, filtered through a pad of CELITE, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (100percent dichloromethane) to afford 2-chloro-N- methylpyrimidin-4-amine (2.8 g, 58percent yield) as a white solid. Rt = 1.15 min;1H NMR 600 MHz (DMSO-d6) 8.02 (s, 1H), 6.22 (m, 1H), 2.86 (d, J = 4.8 Hz, 3H) ppm; MS m/z: 144.12 [M+1].
27% at 20℃; for 3 h; 2,4-Dichloropyrimidine (104, 500 mg, 3.30 mmol) was dissolved in methanol (5 mL) having 2.0 M monomethylamine dissolved therein, stirred at room temperature for 3 hours. Then, the methanol solvent was removed under reduced pressure and water was added to the reaction mixture. Organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-chloro-4-(N-monomethylamino)pyrimidine (106b, 128 mg, 27percent) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 3.01 (d, J=5.2 Hz, 3H), 5.97 (brs, 1H), 6.55 (d, J=5.2, 1H), 8.16 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 28.3, 109.6, 159.0, 162.9.
Reference: [1] Patent: WO2016/23014, 2016, A2, . Location in patent: Paragraph 00412-00413
[2] Patent: US2010/261727, 2010, A1, . Location in patent: Page/Page column 30
[3] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 13, p. 3510 - 3513
[4] Patent: WO2009/97474, 2009, A1, . Location in patent: Page/Page column 26-27
[5] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 5, p. 1349 - 1356
[6] Archiv der Pharmazie, 2014, vol. 347, # 2, p. 77 - 88
  • 49
  • [ 3934-20-1 ]
  • [ 593-51-1 ]
  • [ 66131-68-8 ]
YieldReaction ConditionsOperation in experiment
63% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18 h; Into a 50-mL round-bottom flask, was placed 2,4-dichloropyrimidine (1.1 g, 7.38 mmol, 1.00 equiv.), methanamine hydrochloride (498 mg, 7.38 mmol, 1.00 equiv.), potassium carbonate (3.07 g, 22.21 mmol, 3.00 equiv.), N,N-dimethylformamide (10 mL). The resulting solution was stirred for 18 h at 20 °C. The resulting solution was diluted with 60 mL of H2O. The resulting solution was extracted with 3x80 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x100 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/2). This resulted in 0.67 g (63percent) of 2-chloro-N- methylpyrimidin-4-amine as a white solid.
Reference: [1] Patent: WO2017/181177, 2017, A1, . Location in patent: Paragraph 0448-0450
  • 50
  • [ 3934-20-1 ]
  • [ 3921-01-5 ]
Reference: [1] Journal of Organic Chemistry, 2001, vol. 66, # 21, p. 7125 - 7128
  • 51
  • [ 3934-20-1 ]
  • [ 124-41-4 ]
  • [ 22536-63-6 ]
  • [ 51421-99-9 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 1499 - 1506
[2] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 1499 - 1506
  • 52
  • [ 3934-20-1 ]
  • [ 108-95-2 ]
  • [ 18214-00-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 9, p. 2284 - 2288
  • 53
  • [ 123-75-1 ]
  • [ 3934-20-1 ]
  • [ 35691-20-4 ]
YieldReaction ConditionsOperation in experiment
75% With triethylamine In ethanol at 20℃; for 0.25 h; General procedure: To a solution of absolute ethanol (5 mL) and dichlorodiazine (3.36 mmol) in a 50mL round-bottom flaskwas added triethylamine (5.03 mmol), followed by the amine (5.03 mmol). The mixture was stirred either under reflux of ethanol (for dichloropyridazine and for dichloropyrazine) or at room temperature (for dichloropyrimidines). The reaction was monitored by GC. Once the starting dichlorodiazinewas completely consumed, the mixture was poured into a saturated NH4Cl solution (20 mL), then extracted with CH2Cl2 (320 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under vacuum. The crude solid was triturated in petroleum ether, filtered through a Buchner to afford the pure product.
70% at 20℃; for 12 h; General procedure: To a stirred solution of 2,4-dichloropyrimidine in EtOH was added a solution of the corresponding amine (1.2 equiv) in EtOH. After stirring for 12 h at the same temperature, the reaction mixture was concentrated in vacuo. The residue was quenched with H2O and then extracted with EtOAc. The combined organic layers were dried over MgSO4 and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel.
Reference: [1] Organic Letters, 2018, vol. 20, # 2, p. 473 - 476
[2] Tetrahedron, 2015, vol. 71, # 29, p. 4859 - 4867
[3] Bioorganic and Medicinal Chemistry Letters, 2018,
[4] European Journal of Medicinal Chemistry, 1991, vol. 26, # 7, p. 729 - 733
[5] Patent: WO2009/29617, 2009, A1, . Location in patent: Page/Page column 86-87
  • 54
  • [ 123-75-1 ]
  • [ 3934-20-1 ]
  • [ 35691-20-4 ]
  • [ 33852-01-6 ]
Reference: [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1089 - 1104
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 1998, vol. 41, # 7, p. 577 - 584
  • 55
  • [ 3934-20-1 ]
  • [ 100-51-6 ]
  • [ 108381-28-8 ]
YieldReaction ConditionsOperation in experiment
75%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran for 0.5 h; Reflux
Stage #2: at -78℃; for 1 h;
Step 1. A mixture formed by 2.26 g (20.1 mmol, 1 equiv.) of potass tert-butoxide and 4.3 g (40.2 mmol, 2 equiv.) of compound phenylmethanol in 10 ml of THF was heated under reflux temperature for half an hour. The reaction mixture was cooled down to 0 0C and slowly added drop-wise to 3 g (20.1 mmol, 1 equiv.) of 2,4-dichloropyrimidine dissolved in 15 ml of N,N- dimethyl formamide, maintaining the temperature below -78 0C. After stirring for one hour, it was left to reach room temperature. The mixture was added drop-wise to 100 ml of cold water, obtaining white solid 4-(benzyloxy)-2-chloropyrimidine (3.3 g, 75percent). The compound was determination by LC-MS (LC-MS (m/z) =222.0 [M+H]+)
24%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 1 - 2℃; for 0.5 h;
Stage #2: at 1 - 2℃; for 3.5 h;
To a cooled (1-2° C.) suspension of sodium hydride (60percent in mineral oil) (1.5 equiv) in 250 ml THF, benzyl alcohol (1.0 equiv.) was added dropwise and the mixture stirred 30 min under N2.
This suspension was then added in small portions (via syringe, over 1 hr) to a solution of 2,4-dichloropyrimidine (1.5 equiv.) in THF also at 1-2° C. (internal thermometer).
The resulting mixture (0.06 M) was stirred at temp <2° C. for 2.5 hrs, then quenched with NH4Cl(sat.) and extracted with EtOAc.
Upon separation, the organic layer was washed with NaCl(sat.), dried over Na2SO4, concentrated and purified by silica gel chromatography (hexanes/DCM eluant) to yield 4-(benzyloxy)-2-chloropyrimidine (24percent). LC/MS=221.0 (M+H), LC=3.93 min.
Reference: [1] Organic Letters, 2017, vol. 19, # 7, p. 1854 - 1857
[2] Chemistry - A European Journal, 2017, vol. 23, # 58, p. 14563 - 14575
[3] Patent: WO2011/19405, 2011, A1, . Location in patent: Page/Page column 107
[4] Patent: US2011/195980, 2011, A1, . Location in patent: Page/Page column 28
[5] Patent: EP1564212, 2005, A1, . Location in patent: Page 13
  • 56
  • [ 3934-20-1 ]
  • [ 108381-28-8 ]
Reference: [1] Tetrahedron, 1992, vol. 48, # 37, p. 8117 - 8126
[2] Patent: WO2011/22440, 2011, A2, . Location in patent: Page/Page column 169
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 4, p. 1208 - 1224
  • 57
  • [ 110-91-8 ]
  • [ 3934-20-1 ]
  • [ 62968-37-0 ]
YieldReaction ConditionsOperation in experiment
90% With triethylamine In ethanol at 0℃; for 3 h; To a cooled (0° C.) suspension of 2,4-dichloropyrimidine (20)(1.0 g, 6.7 mmol) in ethanol (20 ml), which was stirred under an inert atmosphere, was added triethylamine (1.4 ml, 10.1 mmol) and then morpholine (0.59 ml, 6.7 mmol). The mixture was maintained at this temperature for 3 hours whereupon it was concentrated in vacuo, diluted with NaOH (20 ml, 1M) and extracted with EtOAc (3.x.20 ml). The organic extracts were combined, dried (Na2SO4), filtered and concentrated in vacuo to give a colorless solid. The crude residue was re-crystallised using EtOAc/Hexanes to give the title compound (1.21 g, 90percent) as a colourless solid which required no further purification. m/z (LC-MS, ESP): 200 [M+H]+, R/T=3.26 mins
84% With triethylamine In ethanol at 20℃; for 0.25 h; General procedure: To a solution of absolute ethanol (5 mL) and dichlorodiazine (3.36 mmol) in a 50mL round-bottom flaskwas added triethylamine (5.03 mmol), followed by the amine (5.03 mmol). The mixture was stirred either under reflux of ethanol (for dichloropyridazine and for dichloropyrazine) or at room temperature (for dichloropyrimidines). The reaction was monitored by GC. Once the starting dichlorodiazinewas completely consumed, the mixture was poured into a saturated NH4Cl solution (20 mL), then extracted with CH2Cl2 (320 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under vacuum. The crude solid was triturated in petroleum ether, filtered through a Buchner to afford the pure product.
70% With triethylamine In tetrahydrofuran at 20℃; for 3 h; A solution of 2,4-dichloropyrimidine (1.00 g, 6.71 mmol) and morpholine (0.59 mL, 6.81 mmol) in THF (25 mL) was charged with triethylamine (1 ,4 mL, 10.0 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was evaporated to dryness, the residue was taken up in CH2Cl2, and the organic layer was washed with water followed by brine; dried over sodium sulphate, filtered and concentrated. The residue was purified by combi-flash companion (silica gel, CH3OH/CH2CI2) to provide 4-(2-chloropyrimidm-4-yl)morpholine 417c (1.0 g, 70percent) as a white solid. 1H NMR (300 MHz, CDCI3): δ 8.17 (d, J = 5 , 1 Hz, 1H), 6,53 (d, J = 5.1 Hz, I I I). 3.81 (t, ./ 4.5 Hz, 41 1 ). 3.75 (t, J =4.5 Hz, 4H); ESI+APCI MS m/z 200 [M + i | . A solution of 2-(5 -chloro-2,4-dimethoxyphenyl)-7-(piperazin-1-yl)imidazo[1 ,2-a]pyridine 301 (250 mg, 0.67 mmol) and NN-diisopropylethylamine (0.5 mL, 2.87 mmol) in DMF (7.5 mL) was charged with 4-(2-chloropyrimidin-4-yl)morpholine 417c (238 mg, 1.34 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature, suspended in water and stirred for 1 h. The precipitate was collected by filtration; the solid obtained was washed with water, dried under reduced pressure and purified by combi-flash companion (silica gel, CH3OH/CH2CI2). The product obtained was further triturated with methanol and filtered. The solids were washed with hexanes and dried to provide 4-(2-(4-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[1,2-a]pyridin-7-yl)piperazin-1-yl)pyrimidin-4-yl)morpholine 418c (20 mg, 5percent) as an off-white solid. I NMR (300 MHz, DMSO- 6): 0 8.34 (d, ./ 10.0 Hz, i l l). 8.16 (s, I I I). 8.03 (s, ), 7.94 (d, J = 8.0 Hz, 1H), 6.87 (s, 1 H), 6.85 (s, 1 H), 6.71 (s, 1 H), 6.12 (d, J = 7,6 Hz, 4.01 (s, 3H), 3.93 (s, 3H), 3 ,82 (br s, 4H), 3.65 (br s, 4H), 3.53 (br s, All), 3,28 (br s, 4H); HPLC (Method 6) 97.4percent (AUC), R = 1 1 .89 mm.; ESI+APCI MS m/z 536 [M + H]+
55% at 20℃; for 12 h; General procedure: To a stirred solution of 2,4-dichloropyrimidine in EtOH was added a solution of the corresponding amine (1.2 equiv) in EtOH. After stirring for 12 h at the same temperature, the reaction mixture was concentrated in vacuo. The residue was quenched with H2O and then extracted with EtOAc. The combined organic layers were dried over MgSO4 and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel.
36% With N-ethyl-N,N-diisopropylamine In ethanol at 0 - 20℃; A stirred solution of 2,4-dichloropyrimidine (5.00g, 36.5mmol) and diisopropylethylamine (14.0ml, 80.4mmol) in EtOH (60ml) at 0°C was treated with morpholine (3.18ml, 36.5mmol) and allowed to warm to ambient temperature overnight. The solution was poured into brine and extracted with DCM. The organics were dried (MgS04), filtered and evaporated. The residue was purified by column chromatography (Si02, 5percent EtOH in DCM) to afford the title compound IIIc as a white solid (1.3g, 36percent). XH NMR (300 MHz, DMSO-d6) δ 8.10 (d, J = 6.2 Hz, 1H), 6.83 (d, J = 6.2 Hz, 1H), 3.72 - 3.49 (m, 8H).
36% With N-ethyl-N,N-diisopropylamine In ethanol at 0 - 20℃; [0108] A stirred solution of 2,4-dichloropyrimidine (5.00g, 36.5mmol) and diisopropylethylamine (14.0ml, 80.4mmol)in EtOH (60ml) at 0°C was treated with morpholine (3.18ml, 36.5mmol) and allowed to warm to ambient temperatureovernight. The solution was poured into brine and extracted with DCM. The organics were dried (MgSO4), filtered andevaporated. The residue was purified by column chromatography (SiO2, 5percent EtOH in DCM) to afford the title compoundIVc as a white solid (1.3g, 36percent). 1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J = 6.2 Hz, 1H), 6.83 (d, J = 6.2 Hz, 1H), 3.72- 3.49 (m, 8H).

Reference: [1] Patent: US2006/199804, 2006, A1, . Location in patent: Page/Page column 27
[2] Tetrahedron, 2015, vol. 71, # 29, p. 4859 - 4867
[3] Organic Letters, 2018, vol. 20, # 2, p. 473 - 476
[4] Patent: WO2017/58503, 2017, A1, . Location in patent: Page/Page column 419-421
[5] European Journal of Medicinal Chemistry, 1991, vol. 26, # 7, p. 729 - 733
[6] Bioorganic and Medicinal Chemistry Letters, 2018,
[7] Patent: WO2015/144614, 2015, A1, . Location in patent: Page/Page column 40
[8] Patent: EP3144307, 2017, A1, . Location in patent: Paragraph 0108
[9] Patent: US2006/199804, 2006, A1, . Location in patent: Page/Page column 34
[10] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 9, p. 2284 - 2288
  • 58
  • [ 110-91-8 ]
  • [ 3934-20-1 ]
  • [ 62968-37-0 ]
  • [ 24192-96-9 ]
YieldReaction ConditionsOperation in experiment
7% With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 0 - 20℃; A solution of 2,4-dichloropyrimidine (0.500g, 3.36mmol) and N,N-diisopropylethylamine (0.818mL, 4.70mmol) in isopropanol (5mL) was stirred at 0°C. Morpholine (0.319mL, 3.69mmol) was added dropwise and the solution continued to stir at 0°C for 30min, and then room temperature for 12h. The reaction mixture was concentrated under reduced pressure and then partitioned between ethyl acetate and water. The organic layer was extracted three times, washed with brine, dried over sodium sulfate, and concentrated to dryness. The products were purified by silica column chromatography in hexanes and ethyl acetate to afford 4-(4-chloropyrimidin-2-yl)morpholine and 4-(2-chloropyrimidin-4-yl)morpholine in 7percent and 92percent yields, respectively. (0058) 4-(4-chloropyrimidin-2-yl)morpholine (15). (White solid, Yield: 7percent). 1H NMR (500MHz, CDCl3) δ ppm 3.74 (m, 4H), 3.81 (m, 4H), 6.53 (d, J=4.9Hz, 1H), 8.16 (d, J=4.9Hz, 1H). LCMS found 200.0, [M+H]+. (0059) 4-(2-chloropyrimidin-4-yl)morpholine (16). (White solid, Yield: 92percent). 1H NMR (500MHz, CDCl3) δ ppm 3.64 (br. s, 4H), 3.77 (m, 4H), 6.38 (d, J=5.9Hz, 1H), 8.07 (d, J=6.3Hz, 1H). LCMS found 200.0, [M+H]+.
Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 141, p. 446 - 459
[2] New Journal of Chemistry, 2014, vol. 38, # 10, p. 5087 - 5095
[3] Organic Process Research and Development, 2012, vol. 16, # 11, p. 1770 - 1782
  • 59
  • [ 3934-20-1 ]
  • [ 262353-34-4 ]
Reference: [1] Journal of Organic Chemistry, 2001, vol. 66, # 21, p. 7125 - 7128
[2] Tetrahedron, 2000, vol. 56, # 2, p. 265 - 273
[3] Tetrahedron, 2008, vol. 64, # 12, p. 2783 - 2791
[4] Patent: WO2013/178816, 2013, A1, . Location in patent: Paragraph 00152; 00153
  • 60
  • [ 3934-20-1 ]
  • [ 1692-25-7 ]
  • [ 483324-01-2 ]
YieldReaction ConditionsOperation in experiment
74.6% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 90℃; for 4 h; Inert atmosphere; Green chemistry In a 250 mL three-necked flask,2,4-dichloropyrimidine (5.0 g, 33.56 mmol)Dissolved in 1,4-dioxaneAnd water (4: 1, 50 mL) A solution of 3-boronic acid pyridine (4.95 g, 40.27 mmol),Potassium carbonate (9.28 g, 67.12 mmol)And Pd (dppf) Cl2 (2.45 g, 3.36 mmol);The system was replaced with argon three times,Gradually heated to 90 ° C,Reaction for 4 hours;After the reaction, the system was concentrated under reduced pressure to remove most of the solvent,Ethyl acetate (150 mL)And water (100 mL),Extraction and separation,The aqueous phase was then extracted with ethyl acetate (80 mL)The organic phases were combined,Re-water (80 mL x 2) and saturateWashed with brine (80 mL x 2)Liquid separation,The organic phase was dried over anhydrous sodium sulfate for 3 hours,Filtration and concentration,Crude;The crude product was added petroleum ether (32 mL)And ethyl acetate (6 mL) were stirred for 1 hour,filter,Dried in vacuo to give 4.8 g of 2-chloro-4- (3-pyridyl) pyrimidine,The yield was 74.6percentPurity HPLC was greater than 95percent.
73% With sodium carbonate In tetrahydrofuran; water for 16 h; Heating; Reflux; Inert atmosphere Example 11 Preparation of 2-chloro-4-(pyridin-3-yl)pyrimidine[00106] Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of pyridin-3-ylboronic acid (4.42 g, 36.0 mmol, 1.00 equiv) in THF/H2O (30 mL), a solution of 2,4-dichloropyrimidine (5.40 g, 36.2 mmol, 1.00 equiv) in THF/H2O (30 mL), Na2CO3 (11.5 g, 108 mmol, 3.00 equiv) and PdCl2(PPh3)2 (1.80 g, 2.57 mmol, 0.06 equiv). The resulting solution was heated to reflux for 16 hrs in an oil bath. The reaction mixture was cooled and quenched by the addition of 100 mL of water. The resulting solution was extracted with 5x200 mL of ethyl acetate. The organic layers were combined, washed with 3x200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1: 1). This resulted in 5 g (73percent) of 2-chloro-4-(pyridin-3-yl)pyrimidine as a yellow solid.
52% With bis-triphenylphosphine-palladium(II) chloride In 1,4-dioxane for 14 h; Reflux; Inert atmosphere General procedure: To a solution of 2,4-dichloro-5-methylpyrimidine (500 mg, 3.1 mmol) and 4-trifluoromethoxylphenylboronic acid (644 mg, 3.1 mmol) in dioxane (15 mL), Pd(PPh3)2Cl2 (215 mg, 0.3 mmol) and 2M Na2CO3 (920 mg, 8.7 mmol) were added. The mixture was stirred at reflux for 14 h under N2 atmosphere. The reaction mixture was cooled to room temperature and filtrated. The filtrate was diluted with H2O (100 mL) and then extracted with EtOAc, and the organic layer was dried over anhydrous Na2SO4, After filtration, the filtrate was evaporation and purified by chromatography (petroleum ether/ EtOAc, 5:1) to give the product as oil (700 mg, 73 percent).
Reference: [1] Patent: CN106243083, 2016, A, . Location in patent: Paragraph 0037-0039; 0044-0046; 0051-0053
[2] Patent: WO2011/8788, 2011, A1, . Location in patent: Page/Page column 28-29
[3] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 15, p. 3259 - 3263
[4] Patent: US2004/122237, 2004, A1, . Location in patent: Page 179
[5] Patent: WO2013/66839, 2013, A2, . Location in patent: Page/Page column 31
[6] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 18, p. 5029 - 5036
  • 61
  • [ 626-55-1 ]
  • [ 3934-20-1 ]
  • [ 483324-01-2 ]
Reference: [1] Journal of the Chemical Society. Perkin Transactions 1, 2002, # 16, p. 1847 - 1849
  • 62
  • [ 220565-63-9 ]
  • [ 3934-20-1 ]
  • [ 483324-01-2 ]
Reference: [1] Patent: US2006/149061, 2006, A1, . Location in patent: Page/Page column 7
  • 63
  • [ 3934-20-1 ]
  • [ 4334-88-7 ]
  • [ 499195-60-7 ]
YieldReaction ConditionsOperation in experiment
60% With sodium carbonate In toluene at 75 - 100℃; Example 1 - Synthesis of Compound 3; A mixture of 4-ethoxycarbonylphenyl boronic acid (23.11 g, 119 mmol), 2,4- dichloropyrimidine (16.90 g, 113 mmol), toluene (230 mL) and aqueous sodium carbonate (2 M, 56 mL) was stirred vigorously and nitrogen was bubbled through the suspension for 15 minutes. Tetrakis(triphenylphosphine)palladium[0] (2.61 g, 2.26 mmol) was added. Nitrogen was bubbled through for another 10 min., the mixture was heated to 100°C, then at 75°C overnight. The mixture was cooled, diluted with ethyl acetate (200 mL), water (100 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (100 ml) and the two organic extracts were combined. The organics were washed with brine, filtered through sodium sulfate, <n="58"/>concentrated, and the resultant solid was triturated with methanol (100 niL) and filtered. The solids were washed with methanol (2 x 30 mL) and air dried. This material was dissolved in acetonitrile (150 mL) and dichloromethane (200 mL), stirred with MP.TMT Pd-scavenging resin (Agronaut part number 800471) (7.5 g) over 2 days. The solution was filtered, the solids were washed with dichloromethane (2 x 100 mL), and the filtrate concentrated to give ethyl 4-(2-chloropyrimidin-4-yl)benzoate as anoff-white solid (17.73 g, 60percent) - additional washing with dichloromethane yielded a further 1.38 g and 0.5 g of product. 1H NMR (300 MHz, J6-DMSO) δ 8.89 (IH, d, J= 5.0 Hz); 8.32 (2H, d, J= 8.7 Hz); 8.22 (IH, d, J= 5.5 Hz); 8.12 (2H, d, J= 8.7 Hz); 4.35 (2H, q, J= 7.1 Hz); 1.34 (3H, t, J= 7.1 Hz); LC-ESI-MS (method B): rt 7.3 min.; m/z 263.0 / 265.0 [M+H]+.
37%
Stage #1: With bis-triphenylphosphine-palladium(II) chloride In N,N-dimethyl-formamide at 90℃; for 1 h;
Stage #2: at 90℃; for 0.5 h;
Stage #3: With potassium hydrogencarbonate In water; N,N-dimethyl-formamide at 90℃; for 0.5 h;
Ester 1 : Preparation of Ethyl 4-(2-chloropyrimidin-4-yl)benzoate. To a solution of 2,4-dichloropyrimidine [70 g, 470 mmol] in DMF [600 mL] was added (PPh3)2PdCl2 [9.9 g, 14 mmol] and mixture was heated to 90°C for 1 h. To this, (4-(ethoxycarbonyl)phenyl)boronic acid [91 g, 470 mmol] was added and mixture was heated to 90°C for additional 0.5 h. A solution of potassium bicarbonate [282 g, 2.8 mol] in 200 mL of water was added to reaction mixture and stirred for 0.5 h at 90°C. After completion of reaction, mixture was quanched in ice cooled water [500 mL]. The off white solid obtained was filtered, washed with water and dried under vacuum to get title compound. [45 g, 37percent].
Reference: [1] Patent: WO2008/109943, 2008, A1, . Location in patent: Page/Page column 56-57
[2] Patent: WO2015/19365, 2015, A1, . Location in patent: Page/Page column 17; 18
  • 64
  • [ 67-56-1 ]
  • [ 3934-20-1 ]
  • [ 163271-07-6 ]
  • [ 75-09-2 ]
  • [ 163271-08-7 ]
Reference: [1] Patent: US5502063, 1996, A,
  • 65
  • [ 120-72-9 ]
  • [ 3934-20-1 ]
  • [ 945016-63-7 ]
YieldReaction ConditionsOperation in experiment
79% at 110℃; for 3 h; Inert atmosphere 3-(2-chloropyrimidin-4-yl)-1H-indole (1 g, 4.37 mmol), 2-(difluoromethoxy)-4-fluoro-5-nitroaniline (810 mg, 4.37mmol) and p-toluenesulfonic acid (750 mg, 4.37 mmol) were dissolved in 2-pentanol (40 mL), and then the reactionsolution was heated at 110 °C for 3 hours. After LCMS showed completion of the reaction, the reaction solution wascooled to room temperature naturally, and a dark solid was precipitated. The solid was filtered, and the filter cake waswashed with methanol and methyl tert-butyl ether to obtain 3-(2-chloropyrimidin-4-yl)-1H-indole (1.3 g, 79percent).
49%
Stage #1: With aluminum (III) chloride In dichloromethane at 20℃; for 0.333333 h; Inert atmosphere
Stage #2: at 20℃; for 10 h;
Partially added to a solution of compound 1 (21 g, 0.14 mol) in dichloromethane (500 mL) under N2.AlCl3 (22.5 g, 0.17 mol) was added over 10 minutes.After the resulting suspension was stirred at room temperature for 10 minutes, the reaction system was substantially clear.Compound 2 (16.5 g, 0.14 mol) was added portionwise to the above reaction mixture at room temperature, and was added over 10 minutes.The resulting brown suspension was stirred overnight at room temperature; the reaction was monitored by TLC, and after the consumption of Compound 1 was completed, the reaction solution was poured into ice water with stirring.This system was extracted 3 times with EtOAc (300 mL).The organic phases were combined and washed with brine (200 mL) twice.After drying over sodium sulfate, it was concentrated under reduced pressure to yield 38g of brown crude.The crude product was purified by silica gel column chromatography (eluent n-hexane:EtOAc = 5:1 to 3:1).16 g of the title compound 3 were obtained as a yellow solid, yield 49percent.
46%
Stage #1: With methylmagnesium bromide In diethyl ether; 1,2-dichloro-ethane at 0℃; for 0.416667 h; Inert atmosphere
Stage #2: at 0 - 20℃; for 16 h; Inert atmosphere
CH3MgBr (3M in diethyl ether, 22.68 mL, 68.03 mmol) was added dropwise over a period of 10 minutes to a stirred solution of 1H-indole (7.97 g, 68.03 mmol) in 1,2-dichloroethane (250 mL) at 0°C under an atmosphere of N2. The resulting solution was stirred for 15 minutes and then 2,4-dichloropyrimidine (15.00 g, 100.69 mmol) was added in one portion. The resulting solution was allowed to warm to r.t. and was stirred for a further 16h. The reaction was quenched by the addition of CH3OH (25 mL) then the mixture was concentrated in vacuo and absorbed onto silica. Purification by FCC, eluting with 0-20percent CH3OH in CH2Cl2 gave the title compound (7.17 g, 46percent) as a yellow solid; 1H NMR: 7.20-7.28 (2H, m), 7.49-7.53 (1H, m), 7.91 (1H, d), 8.42 (1H, dd), 8.50 (1H, d), 8.53 (1H, d), 12.06 (1H, s); m/z: ES+ MH+ 230.
46%
Stage #1: With methylmagnesium bromide In diethyl ether; 1,2-dichloro-ethane at 0 - 20℃; for 0.25 h; Inert atmosphere
Stage #2: at 20℃; for 16 h;
In a period of 10 minutes at 0 in N2atmosphere, CH. 3MgBr2 (3M, in diethyl ether, 22.68mL,68.03mmol) was added dropwise to 1-H- indole (7.97g, 68.03mmol) in 1,2-dichloroethane (250 mL) stirred solutionwas.The resulting solution was stirred for 15 minutes and then 2,4-dichloropyrimidine (15.00 g, 100.69 mmol) was added in one portion.Letthe resulting solution was allowed to warm to room temperature and stirred for 16 hours.By addition of CH. 3OH (25 mL) quenched the reaction and then the mixture feedline concentrated in vacuo, adsorbed onto silica gel.FCC purification using, for use in CH2CI20-20percent of CH. 3for OH washoff to give the title compound (7.17g, 46percent) as a yellow solid.m / z: 229
34%
Stage #1: With ethylmagnesium bromide In 1,2-dichloro-ethane at 0℃; Inert atmosphere
Stage #2: at 0 - 20℃;
Example 48 1. Synthesis of intermediate 048-2 The intermediate 048-1 (3.0 g, 25.6 mmol) as a raw material was dissolved in 50 mL of 1,2-dichloroethane (DCE) in 100 mL of a three-necked flask at room temperature under a nitrogen atmosphere. The reaction mixture was cooled to 0°C. Ethylmagnesium bromide (8.5 mL, 25.6 mmol) was added dropwisely to the reaction system. After the reaction was completed, the reaction was maintained at a constant temperature for 30 min and the intermediate 001-5 (5.4 g, 36.3 mmol) was added into the reaction system at 0°C. The reaction was carried out overnight at room temperature. After the reaction was completed, the reaction mixture was quenched by adding 100 mL of ice water. The mixture was extracted with 100 mL of methylene dichloride three times. The organic phases were combined, washed with 100 mL of saturated brine three times, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (EA/PE = 1:10- 1:5) to give 2.0 g of the intermediate 048-2 (34percent) as a yellow solid. LCMS: 229.0.
34%
Stage #1: With methylmagnesium bromide In 1,2-dichloro-ethane at 0℃; for 0.5 h; Inert atmosphere
Stage #2: at 0 - 20℃;
Under nitrogen protection, in a 100 ml (mL) three-neck flask at room temperature,Raw material 121-1 (3.0 g (g), 25.6 mmol (mmol)) was dissolved in 50 mLIn 1,2-dichloroethane (DCE), the mixture is reduced to 0°C,Methylmagnesium bromide (8.5 mL, 25.6 mmol) was added dropwise to the reaction system at 0 °C,After the addition, the reaction was continued at a constant temperature for 30 minutes (min), and 121-2 (5.4 g, 36.3 mmol) was added at 0°C.It was added to the reaction system, and the reaction was warmed to room temperature overnight.After the reaction is complete, 100 ml of ice water is added to the reaction mixture to quench the reaction.The mixture is extracted 3 times with 100 mL of dichloromethane and the organic phase is combined with 100It was washed 3 times with saturated brine, dried over anhydrous sodium sulfate and concentrated.The crude product was purified by silica gel column chromatography (ethyl acetate (EA)/petroleum ether (PE)=1:10-1:5).2.0 g of product 121-3 (34percent) was obtained as a yellow solid.
25% With iron(III) chloride In 1,2-dimethoxyethane at 60℃; Inert atmosphere A mixture of 2,4-dichloropyrimidine (17.9 g, 1.1 eq) was added to a round bottom flask, 100 ml of ethylene glycol dimethyl ether and anhydrous ferric chloride (21.1 g, 1.2 eq) were added, After the addition of nitrogen, the temperature was raised to 60 ° C, and 1H-indole (12.7 g, 1 eq) was added dropwise. The reaction was continued, After the TLC test reaction was complete, the system was reduced to room temperature, 150 ml of water was added, no solid precipitated, extracted with the same amount of ethyl acetate three times, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give intermediate 3- (2- Chloropyrimidin-4-yl) -1H-indole (8.8 g, yield 25percent).
23.8%
Stage #1: With methylmagnesium bromide In 1,2-dichloro-ethane at -5 - 20℃; for 0.5 h; Inert atmosphere
Stage #2: at 0 - 20℃; for 16 h;
Under nitrogen atmosphere, compound A2 (150 g) was sequentially added to a 3 L three-necked flask.1.28 mol) and dry dichloroethane (1.5 L) were dissolved by magnetic stirring. Ice salt bath cooling to 0 °C,Methylmagnesium bromide (640 mL, 3M) was slowly added dropwise.Dropping process control temperature -5 ~ 5 °C, after the completion of dropping, to room temperature and continue the reaction 0.5h.The reaction solution was cooled to 0° C. and Compound A1 (267 g, 1.79 mol) was added dropwise.Warm to room temperature and react for 16 h. After the reaction is completed, the reaction solution is poured into ice water (2.5 L) to quench it.Dichloromethane (300mL*3) was added for extraction.The organic layers were combined, washed with saturated brine (300 mL*3), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (PE/EA=10/1 to PE/EA=4/1) to give Compound A3 (70.0 g). ,23.8percent).
19 g
Stage #1: With methylmagnesium bromide In tetrahydrofuran; diethyl ether at 0℃; for 1.16667 h; Inert atmosphere
Stage #2: at 20℃; for 21 h; Reflux
Methylmagnesium bromide (3 M in diethyl ether) (100 mL) was added dropwise over a period of 10 mm to a stirred solution of 1H- indole (35.2 g) in THF (500 mL) at 0 °C under nitrogen. The resulting solution was stirred for 60 mm. 2,4-Dichloropyrimidine (44.7 g) was added in one portion. The resulting solution was heated at reflux for 5 hours and stirred at ambient temperature for 16 h. The reaction was quenched by the addition of water (400 mL) and EtOAc (500 mL). The organic layer was evaporated to dryness and purified by flash silica chromatography. Pure fractions were evaporated to dryness. 3-(2- chloropyrimidin-4-yl)-1H-indole (compound 3, 19 g) as a yellow solid.

Reference: [1] Patent: EP3205650, 2017, A1, . Location in patent: Paragraph 0106; 0512; 0513
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 17, p. 7025 - 7048
[3] Patent: CN105153122, 2018, B, . Location in patent: Paragraph 0034; 0117; 0118; 0119; 0120
[4] Patent: WO2013/14448, 2013, A1, . Location in patent: Page/Page column 139
[5] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8249 - 8267
[6] Patent: CN106995435, 2017, A, . Location in patent: Paragraph 0301-0304
[7] Patent: EP3216786, 2017, A1, . Location in patent: Paragraph 0328-0330
[8] Patent: CN106478605, 2017, A, . Location in patent: Paragraph 0078; 0079; 0080; 0081
[9] Patent: CN106995437, 2017, A, . Location in patent: Paragraph 0125; 0127-0129
[10] Patent: CN107973783, 2018, A, . Location in patent: Paragraph 0049; 0051; 0052
[11] Patent: WO2017/117070, 2017, A1, . Location in patent: Paragraph 00101
[12] Patent: CN108503627, 2018, A, . Location in patent: Paragraph 0084; 0085; 0086
  • 66
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YieldReaction ConditionsOperation in experiment
95% With triethylamine In N,N-dimethyl-formamide at 20℃; Weigh 2,4-dichloropyrimidine (2.0 g, 13.43 mmol),Dissolved in DMF (15 mL), followed by triethylamine (TEA) (2.72 g, 26.85 mmol).1-Boc piperazine (2.75 g, 14.77 mmol), stirred at room temperature overnight.A white solid precipitated in the reaction solution, and the reaction was completed by TLC.The reaction solution was poured into 200 mL of ice water, and a large amount of white solid precipitated.Filter and dry to give a white solid C-2 (3.8 g, 13.43 mmol)
90% With triethylamine In N,N-dimethyl-formamide at 20℃; for 4 h; (1)
Tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate
A mixture of 2,4-dichloropyrimidine (1.00 g, 6.71 mmol), tert-butyl piperazine-1-carboxylate (1.37 g, 7.38 mmol), triethylamine (1.40 ml, 10.1 mmol) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 4 hours.
The reaction was poured into water and extracted with ethyl acetate.
The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
To the residue was added diethylether and separated by filtration to obtain the title compound (1.80 g, 90percent) as a solid.
1H NMR (CDCl3) δ: 1.49 (9H, s), 3.47-3.58 (4H, m), 3.60-3.71 (4H, m), 6.40 (1H, d, J=6.2 Hz), 8.07 (1H, d, J=6.2 Hz).
90% With triethylamine In N,N-dimethyl-formamide at 20℃; for 4 h; A mixture of 2,4-dichloropyrimidine (1.00g, 6.71mmol), N-Boc-piperazine (1.37g, 7.38mmol), triethylamine (1.40mL, 10.1mmol), and DMF (10mL) was stirred at room temperature for 4.0h. The mixture was diluted with water, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was triturated with Et2O to give 7 (1.80 g, 90percent) as a colorless powder. 1H NMR (300MHz, CDCl3) δ: 1.49 (9H, s), 3.47–3.58 (4H, m), 3.60–3.71 (4H, m), 6.40 (1H, d, J=6.2Hz), 8.07 (1H, d, J=6.2Hz). MS (ESI): m/z 299 [M+H]+.
51% With triethylamine In N,N-dimethyl-formamide at 20℃; for 16 h; A solution of 2,4-dichloropyrimidine (500 mg, 3.35 mmol) and tert-butyl piperazine-1-carboxylate (685 mg, 3.67 mmol) in DMF (5 mL) was charged with triethylamine (0.7 mL, 5.02 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction suspended in water, the solids formed were collected by filtration, washed with water, dried under reduced pressure. The crude material was purified by combi-flash companion (silica gel, CH3OH/CH2CI2) to provide tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate 417d (510 mg, 51percent) as a white solid. 1H NMR (400 MHz, CDC13): δ 8.06 (d, ./ 6.0 Hz, 1H), 6,40 (d, ./ 6.0 Hz, 1H), 3.65 (br s, 4H), 3.52 (br s, 4H), 1 .49 (s, 9H); ESI+APCI MS m/z 299 [M + Hf . A solution of 2-(5-chloro-2,4-dimethoxyphenyl)-7-(piperazin-1-yl)imidazo[l ,2-a]pyridine 301 (150 mg, 0.40 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.72 mmol) in DMF (3 mL) was charged with tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate 417d (243 mg, 0.81 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature, suspended in water and stirred for 1 h. The precipitate was collected by filtration, washed with water, dried under reduced pressure. The solid obtained was purified by combi-fiash companion (silica gel, CH3OH/CH2Cl2) to provide tert-butyl 4-(2-(4-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-yl)piperazin-1-yl)pyrimidin-4-yl)piperazine-1-carboxylate 418d (70 mg, 39percent) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): 6 8.34 (d,J = 7.6 Hz, 1H), 8.1 7 (s, i l l). 8.03 (s, IH), 7.93 (d. ./ 6.0 Hz, 1H), 6.87 (s, 1 H), 6.85 is. 1 H), 6.71 (s, 1 H), 6.12 (d. ./ 6.0 Hz, IH), 4.01 (s, 3H), 3.93 (s, 3H), 3.82 (br s, 4H), 3.56 (br s, 4H), 3.40 (br s, 4H), 3.27 (br s, 4H), 1.42 (s, 9H); ESI+APCI MS m/z 635 [M + H . A solution of ter -butyl 4-(2-(4-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-yl)piperazin-1-yl)pyrimidin-4-yl)piperazine-l-carboxylate 418d (90 mg, 0, 14 mmol) in 2,2,2-trifluoroethanol (3 mL) was charged with trimethylsilyl chloride (0.2 rnL) at 0 °C. The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was evaporated to dryness to provide 2-(5-chloro-2,4-dimethoxyphenyl)-7-(4-(4-(piperazin-1-yl)pyrimidin-2-yi)piperazin-1-yl)imidazo| l,2-o]pyridine dihydrochloride 418e (80 mg, 93percent) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.97 (br s, IH), 9.55 (br s, 2H), 8,60 (d, ./ 10.0 Hz, IH), 8.30 (s, IH), 8.10 (s, IH), 8,01 (d, J= 9.2 Hz, IH), 7.35 (dd, J= 2,8 Hz, J= 10.4 Hz, IH), 6.98 (s, IH), 6.80 (d, J= 2.0 Hz, IH), 6,59 (s, IH), 4.06 (s, 3H), 3.99 (br s, 1 IH), 3.71 (br s, 4H), 3.21 (br s, 4H); HPLC (Method 1) 91.7percent (AUC), iR = 10.95 mm.; ESI+APCI MS m/z 535 [M + 1 1 ]
45% With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 0 - 10℃; for 15 h; Inert atmosphere Method B: t-butyl 4-(2-chloropyhmidin-4-yl)piperazine-1 -carboxylate. To a mixture of 2,4-dichloropyrimidine (2Og, 0.135mol, 1 eq.) and DIPEA (26g, 0.203mol, 1.5eq) in /-PrOH (40OmL) was added tert-butyl piperazine-1- carboxylate (27g, 0.148mol, 1.1 eq) by portions at 0 0C, and the resulting reaction was stirred overnight (about 15 hrs) at 10 0C. A lot of white solid precipitated and TLC showed that there was still a little 2,4-dichloropyrimidine. The solid was filtered and recrystallized from DCM to afford the title product (18g, 45percent yield) as a white solid. 1H NMR (300 MHz, CDCI3): 8.08 (d, J = 6.2 Hz, 1 H), 6.41 (d, J = 6.2 Hz, 1 H), 3.67 (s, 4H), 3.56-3.41 (m, 4H), 1.48 (s, 9H). t-butyl 4-(2-(neopentylamino)pyhmidin-4-yl)piperazine-1 -carboxylate. A solution of tert-butyl 4-(2-chloropyhmidin-4-yl)piperazine-1 -carboxylate -->(300mg, 1 mmol) 2,2-dimethylpropan-1-amine (131 mg, 1.5mmol) and DIPEA (259mg, 2mmol) in pentan-1-ol (15mL) was stirred at reflux for 18 hrs. The solvent was removed under reduced pressure and the residue was purified by column chromatography (100percent ethyl acetate) to afford the desired product. 1H NMR (300 MHz, CDCI3): 7.88 (d, J = 5.7 Hz, 1 H), 5.84 (d, J = 6.3 Hz, 1 H), 4.97 (br s, 1 H), 3.58 (m, 4H), 3.50 (m, 4H), 3.21 (d, J = 6.3 Hz, 2H), 1.48 (s, 9H), 0.96 (s, 9H). N-neopentyl-4-(piperazin-1-yl)pyhmidin-2-amine dihydrochlohde. t-butyl 4-(2-(neopentylamino)pyhmidin-4-yl)piperazine-1 -carboxylate obtained from the previous stey was dissolved in MeOH (4ml_) and 7N HCI / Et2O solution (2OmL) was added. The resulting solution was stirred at ambient temperature for 18 hrs. The solvent was concentrated to give the desired product as a yellow solid (130mg, 40percent yield in two steps). 1H NMR (300 MHz, CD3OD): 7.84 (d, J = 7.2 Hz, 1 H), 6.56 (d, J = 7.2 Hz, 1 H), 4.27 (br s, 2H), 4.02 (br s, 2H), 3.40 (br s, 4H), 3.33 (br s, 2H), 1.01 (s, 9H); LC-MS, m/z = 250.2 [M+H]+, tR = 0.8 min; HPLC: 99percent (214 nm), 98percent (254 nm), tR = 4.7 min.
40% With sodium hydrogencarbonate In ethanol for 1.5 h; Heating / reflux (1)
Tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate
To a solution of 2,4-dichloropyrimidine (50.0 g, 0.338 mol) in ethanol (500 ml) was added tert-butyl piperazine-1-carboxylate (62.8 g, 0.338 mol) and sodium hydrogencarbonate (56.8 g, 0.676 mol) and heated under reflux for 1.5 hours.
The reaction was filtered and the filtrate was concentrated.
To the residue was added methylene chloride and water followed by extracted.
The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the title compound (40.0 g, 40percent).
1H NMR (CDCl3) δ: 1.49 (9H, s), 3.46-3.53 (4H, m), 3.62-3.69 (4H, m), 6.40 (1H, d, J=6.4 Hz), 8.06 (1H, d, J=6.4 Hz).

Reference: [1] Patent: CN108503645, 2018, A, . Location in patent: Paragraph 0117-0119
[2] Patent: US2009/163508, 2009, A1, . Location in patent: Page/Page column 14
[3] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 4, p. 1468 - 1478
[4] Organic Letters, 2018, vol. 20, # 2, p. 473 - 476
[5] Patent: WO2017/58503, 2017, A1, . Location in patent: Page/Page column 419; 421; 422
[6] Patent: WO2009/152325, 2009, A1, . Location in patent: Page/Page column 68-69
[7] Patent: US2009/163508, 2009, A1, . Location in patent: Page/Page column 38
[8] Patent: US2012/295902, 2012, A1, . Location in patent: Paragraph 0422
[9] Patent: US2003/105106, 2003, A1,
  • 67
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  • [ 57260-71-6 ]
  • [ 221050-88-0 ]
  • [ 479691-42-4 ]
Reference: [1] Patent: US2005/176722, 2005, A1, . Location in patent: Page/Page column 20; 22
  • 68
  • [ 3934-20-1 ]
  • [ 53788-49-1 ]
  • [ 479691-42-4 ]
YieldReaction ConditionsOperation in experiment
73% at 110℃; A mixture of 2,4-dichloropyrimidine (50g, 336mmol), tert-butyl 4-methylpiperazine-1-carboxylate (67.2g, 336mmol), and toluene (500mL) was stirred at 110 °C overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane–EtOAc) to give 10 (109g, 73percent) as a colorless powder. 1H NMR (300MHz, CDCl3) δ: 1.49 (9H, s), 3.44–3.53 (4H, m), 3.75–3.84 (4H, m), 6.53 (1H, d, J=5.1Hz), 8.16 (1H, d, J=5.1Hz). MS (ESI): m/z 299 [M+H]+.
62% at 110℃; (2)
Tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate
A mixture of 4-methyltert-butyl piperazine-1-carboxylate (2.0 g, 9.98 mmol), 2,4-dichloropyrimidine (1.49 g, 9.98 mmol) and toluene (20 ml) was stirred at 110° C. overnight.
The reaction was poured into water and extracted with ethyl acetate.
The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound (1.83 g, 62percent) as a solid.
1H NMR (CDCl3) δ: 1.49 (9H, s), 3.44-3.53 (4H, m), 3.75-3.84 (4H, m), 6.53 (1H, d, J=5.1 Hz), 8.16 (1H, d, J=5.1 Hz).
Reference: [1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 4, p. 1468 - 1478
[2] Patent: US2009/163508, 2009, A1, . Location in patent: Page/Page column 20
[3] Patent: US2003/105106, 2003, A1,
  • 69
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  • [ 57260-71-6 ]
  • [ 221050-88-0 ]
  • [ 479691-42-4 ]
Reference: [1] Patent: US2005/176722, 2005, A1, . Location in patent: Page/Page column 20; 22
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  • [ 479691-42-4 ]
YieldReaction ConditionsOperation in experiment
6% With sodium hydrogencarbonate In ethanol for 1.5 h; Heating / reflux (1)
Tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate
To a solution of 2,4-dichloropyrimidine (50.0 g, 0.338 mol) in ethanol (500 ml) was added tert-butyl piperazine-1-carboxylate (62.8 g, 0.338 mol) and sodium hydrogencarbonate (56.8 g, 0.676 mol) and heated under reflux for 1.5 hours.
The reaction was filtered and the filtrate was concentrated.
To the residue was added methylene chloride and water followed by extracted.
The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the title compound (6.30 g, 6percent).
1H NMR (CDCl3) δ: 1.49 (9H, s), 3.45-3.52 (4H, m), 3.75-3.83 (4H, m), 6.53 (1H, d, J=4.8 Hz), 8.16 (1H, d, J=4.8 Hz).
Reference: [1] Patent: US2009/163508, 2009, A1, . Location in patent: Page/Page column 39
[2] Patent: US2010/331307, 2010, A1, . Location in patent: Page/Page column 26
  • 71
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  • [ 1376676-65-1 ]
  • [ 444731-75-3 ]
YieldReaction ConditionsOperation in experiment
81.6% With sodium hydrogencarbonate In tetrahydrofuran; ethanol for 20 h; Reflux Formula III (5 g, 0.029 mol)And sodium bicarbonate (7.2 g, 0.086 mol)Was added to THF (20 ml)And absolute ethanol (80 ml).2,4-dichloropyrimidine (12.8 g, 0.086 mol) was added at room temperature,Heated to reflux for 20 h.The reaction was cooled to room temperature,filter,The filter cake was washed with absolute ethanol (20 ml x 2).The filtrates were combined,After concentration under reduced pressure to dryness, isopropyl ether (60 ml)And toluene (30 ml) were mixed,Stirred at room temperature for 1 h,filter,The filter cake was dried to give pale yellow solid 7 (6.7 g, 81.6percent),
Reference: [1] Letters in Organic Chemistry, 2012, vol. 9, # 4, p. 276 - 279
[2] Patent: CN103373989, 2016, B, . Location in patent: Paragraph 0063; 0064
  • 72
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  • [ 75-04-7 ]
  • [ 86443-51-8 ]
Reference: [1] Patent: WO2005/95357, 2005, A2, . Location in patent: Page/Page column 131
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  • [ 75-04-7 ]
  • [ 86443-51-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 8, p. 2560 - 2563
  • 74
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  • [ 1765-93-1 ]
  • [ 85979-59-5 ]
YieldReaction ConditionsOperation in experiment
61% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; water; toluene at 55℃; for 12 h; To a stirred solution of 2,4-dichloropyrimidine (3.00 g, 20.1 mmol) in toluene (25 mL) was added 4-fluorophenylboronic acid (2.82 g, 20.1 mmol), potassium carbonate (8.32 g, 60.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.630 g, 0.545 mmol) and 1 : 1 (v/v) ethanol/water (36 mL). The mixture was heated at 55 °C for 12 hours and then concentrated. The residue was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2S04) and concentrated. The crude material was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford 2-chloro-4-(4-fluorophenyl)pyrimidine as a yellow solid (2.50 g, 61percent). To a stirred solution of this compound (1.27 g, 6.09 mmol) in N,N-dimethylformamide (8 mL) was added ethyl piperidine-4-carboxylate (0.959 g, 6.10 mmol) and cesium carbonate (2.10 g, 6.44 mmol). The mixture was heated at 100 °C for 12 hours and then concentrated. The residue was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2S04) and concentrated. The crude material was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford ethyl l-(4'-fluoro-[l, -biphenyl]-3-yl)piperidine-4-carboxylate as a yellow oil (1.60 g, 80percent>). To a stirred solution of this intermediate (1.60 g, 4.80 mmol) in 1 : 1 (v/v) methanol/water (20 mL) was added solid sodium hydroxide (0.968 g, 24.2 mmol). After 2 hours, the reaction was concentrated. The residue was dissolved in water, made acidic (pH ~6) with the addition of IN hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2S04) and concentrated to afford l-(4'-fluoro-[l, -biphenyl]-3-yl)piperidine-4-carboxylic acid as a white solid (1.40 g, 97percent). Using General Procedure D and Intermediate 5, this carboxylic acid was subjected to amide coupling to generate the title compound as a white solid (0.118 g, 27percent). FontWeight="Bold" FontSize="10" Η ΝΜΚ (500 MHz, CDC13) δ 8.37 (d, J= 5.0 Hz, 1H), 8.07-8.04 (m, 2H), 7.15 (t, J= 9.0 Hz, 2H), 6.89 (d, J= 10.0 Hz, 1H), 5.38 (s, 1H), 4.97-4.95 (m, 2H), 3.02-2.83 (m, 8H), 2.39-2.37 (m, 2H), 1.96-1.51 (m, 13H) ppm. 13C NMR (100 MHz, CDCI3) δ 174.1, 165.3, 163.3, 163.2, 161.7, 158.4, 133.8, 129.0, 128.9, 115.7, 115.5, 105.2, 59.4, 53.1, 47.6, 46.1, 44.6, 43.5, 39.3, 36.1, 28.9, 28.7, 25.1, 24.3, 24.2 ppm. Purity: >96percent (214 & 254 nm) LCMS; retention time: 1.44 min; (M+H+) 438.3.
Reference: [1] Patent: WO2014/43068, 2014, A1, . Location in patent: Page/Page column 188; 189
[2] Synthesis, 2010, # 16, p. 2721 - 2724
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  • [ 96042-30-7 ]
  • [ 57260-71-6 ]
  • [ 221050-89-1 ]
Reference: [1] Patent: US6262069, 2001, B1,
  • 76
  • [ 68-12-2 ]
  • [ 66-22-8 ]
  • [ 3934-20-1 ]
  • [ 871254-61-4 ]
Reference: [1] Patent: CN108467368, 2018, A, . Location in patent: Paragraph 0014; 0015
  • 77
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  • [ 25487-66-5 ]
  • [ 937271-47-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 1, p. 169 - 196
[2] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 7, p. 2404 - 2408
[3] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 9, p. 2284 - 2288
  • 78
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  • [ 603-76-9 ]
  • [ 1032452-86-0 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: With graphene supported FeCl3 In ethanol; butanone at 30 - 40℃; for 0.333333 h;
Stage #2: at 15 - 50℃; for 6 h;
1) 100 g of 2,4-dichloropyrimidine,(^ The graphene-supported? Lean catalyst prepared in Example 1 was placed in ethanol and methyl ethyl ketoneOf the mixed solution (500 ml, the volume ratio of ethanol to methyl ethyl ketone was 4: 1)In the 30-40 ° C stirring 20min;2) the temperature of the reaction system to 15 ° C, and then by adding 1-methyl-1H-indole, control the process of adding the reaction system temperature does not exceed 15 ° C;3) After 1-methyl-1H-indole was added dropwise, the temperature was raised to 30 ° C at a heating rate of 5 ° C / h and the incubation was carried out at 30 ° C for 3 h; then the temperature was raised to 5 ° C / h 40 ° C, 40 ° C insulation reaction 2h; the final 5 ° C / h heating rate to 50 ° C, 50 ° C insulation reaction lh;4) the end of the incubation reaction, cooling to room temperature, 0.5 micron microfiltration filter to remove the graphene-loaded FeCl3 catalyst, the filtrate at 40 ° C under reduced pressure to dry, and then add 600ml n-heptane to the system in 35- 40 ° C under the beating 6-8h, after the end of the filter,Dried to give 3- (2-chloropyrimidin-4-yl) -1-methylindole (yield 92percent, HPLC area normalized purity 99.3percent).
85%
Stage #1: With iron(III) chloride In Dimethyl ether at 10 - 35℃;
Stage #2: at 50℃;
Intermediate 7: 3-(2-chloropyrimidin-4-yl)-1-methylindole
To a 1 L three-neck flask, were added 40 g 2,4-dichloropyrimidine and 200 mL DME, after dissolved, cooled to 10 to 15°C, 45 g anhydrous FeCl3 was added in portions rapidly, the temperature was kept at or below 35°C, and the mixture was stirred for 15 min after each portion was added.
52.8 g 1-methylindole was added dropwise into the above reaction system, then the mixture was heated slowly to 50°C, stirred overnight, the reaction was monitored by TLC until it finished.
The reaction mixture was cooled to 5 to 10°C, about 300 mL methanol aqueous solution (1:2, v/v) was slowly added dropwise and large amount of viscous solid was precipitated.
The mixture was filtered, the filter cake was washed with methanol twice, after filtration, dried under reduced pressure at 50°C, yield 85percent.
81.5% With iron(III) chloride In 1,2-dimethoxyethane at 60℃; To a stirred solution 2,4-dichloropyrimidine (70.5 g, 463.76 mmol) in dimethoxyethane (900 mL) was added FeCl3 (77.16 g, 459.12 mmol) and 1-methyl indole (68.28 g) at 60°C. The resulting mixture was stirred overnight at 60°C. After cooling, a solid was precipitated by adding methanol (345 mL) and water (900 mL). The resulting slurry was stirred for 3h. The solid was collected by filtration, washed with CH3OH (1.38 L) and dried at 50°C overnight to give the title compound (138.7 g, 81.5percent) as a purple solid; 1H NMR (CDCl3) 3.89 (3H, s), 7.36-7.41 (3H, m), 7.49 (1H, s), 7.96 (1H, s), 8.34 (1H, s), 8.45 (1H, s); m/z: ES+ MH+ 244.05.
72% With aluminum (III) chloride In 1,2-dimethoxyethane at 60℃; for 3 h; Inert atmosphere N-methylindole (300 mg, 2.29 mmol), 2,4-dichloropyrimidine (340 mg, 2.30 mmol) and anhydrous aluminum trichloride (460 mg, 3.43 mmol) were dissolved in ethylene glycol dimethyl ether (12 mL). The reaction was heated to 60 °C in a nitrogen atmosphere and stirred for 3 hours. After the reaction was completed, the reaction solution was poured into an ice-water mixture (about 50 mL) and extracted with methyl tert-butyl ether (20 mL*3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to obtain the product 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (400 mg, 72percent).
71% With aluminum (III) chloride In 1,2-dichloro-ethane at 80℃; for 1.5 h; Intermediate 2a: 3-(2-chloropyrimidin-4-yl)-l-methyl-1H-indole (0131) (0132) To a 500mL single-necked flask were added 2,4-dichloropyrimidine (14.9 g, 100 mmol), 1-methyl-1H-indole (13 g, 100 mmol), 200 ml 1,2-dichloroethane and aluminium chloride (13.9 g, 120 mmol). The mixture was stirred at 80°C for 1.5 hours. The reaction mixture was cooled to room temperature in an ice bath. 120 ml methanol and 400 ml water were added to quench the reaction. A solid precipitated and was filtered. The filter cake was washed with methanol, and dried in vacuum to produce 17.2 g of a product with a yield of 71percent. MS m/z: 244 [M+1], 246. (0133) 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 5.5 Hz, 1H), 8.49 (s, 1H), 8.42 (dd, J = 7.0, 1.5 Hz, 1H), 7.81 (d, J = 5.5 Hz, 1H), 7.56 (dd, J = 7.0, 1.2 Hz, 1H), 7.33 7.26 (m, 2H), 3.90 (d, J = 5.2 Hz, 3H)
62%
Stage #1: With aluminum (III) chloride In 1,2-dimethoxyethane at 20℃; for 0.25 h;
Stage #2: at 80℃;
This compound was prepared by the procedure of Finlay et al. 11 A suspension of 2,4-dichloropyrimidine (5.0 g, 33.6 mmol) and aluminum chloride (1.83 mL, 33.6 mmol) in DME (1,2-dimethoxyethane)(50 mL) was stirred at ambient temperature for 15 min. To this was added 1-methylindole (4.29 mL, 33.6 mmol), and the mixture was heated at 80 °C for 2–4 h. The cooled reaction mixture was added dropwise to vigorously stirring water (300 mL) over 20 min. Upon complete addition, the mixture was stirred for 30 min, filteredand the solid washed with water (250 mL). The crude product was purified by flash silica chromatography, eluting with DCM. Pure fractions were evaporated to dryness to afford 3-(2-chloropyrimidin-4-yl)-1-methylindole (5.08 g, 62percent) as a white solid. m.p. 201°C dec. (acetonitrile/water);1H NMR (CDCl3) δ 8.45 (m, 2H), 8.35 (m, 1H),7.37–7.95 (m, 4H), 3.89 (s, 3H); MS calcd for C13H10ClN3 [M]+ 243.1; found: 244.1
61%
Stage #1: With aluminum (III) chloride In 1,2-dimethoxyethane at 10℃; for 0.25 h;
Stage #2: for 2 h; Reflux
To a stirred suspension of 2,4-dichloropyrimidine (2.637 g, 20.13 mmol) in dimethoxyethane (30 mL) was added aluminum trichloride (2.67 g, 20.134 mmol) at 10 °C. The mixture was stirred at 10 °C for 15 mins. 1 -methyl- lH-indole (3.0 g, 20.13 mmol) was added, and the mixture was heated under reflux for 2 h. The mixture was cooled to RT, poured into water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over sodium sulphate and concentrated to afford 3-(2-chloropyrimidin-4-yl)-l-methyl-lH-indole (3.0 g, 12.34 mmol, 61percent). LC/MS (ESI) m/z 244.3 [M+H]+.
49% With iron(III) chloride In 1,2-dimethoxyethane at 60℃; 2,4-dichloropyrimidine (3 g, 20.1 mmol) was dissolved in DME (50 ml) and heated to 60 °C. FeCl3 (2953 mg, 22.1 mmol) added followed by 1-methylindole (2642 mg, 20.1 mmol) and reaction stirred at 60 °C overnight. Cooled to r.t. and poured into ice water, stirred for 30 minutes and the resulting precipitate collected by filtration. Purified by column chromatography eluting with DCM to provide 2.4 g (49percent) of 3-(2-chloropyrimidin-4-yl)-1-methyl-indole. NMR and LC-MS conform to structure and match literature reports
47% With iron(III) chloride In 1,2-dimethoxyethane at 64℃; Inert atmosphere Under nitrogen, 100mL three-mouthed flask successively add 002-2 (1.3g, 8.73mmol), 13mL DME, FeCl3 (1.414g, 8.72mmol) and 001-5 (974mg, 7.43mmol). In an oil bath at 64 deg.C react overnight. After completion of the reaction, the reaction mixture was down to room temperature, filtered, the filter cake washed 3 times with 20mL of methanol, the organic phases were combined and concentrated to dryness, and driedto give 1.0g 005-1 (47percent), as a yellow solid.
47% With iron(III) chloride In 1,2-dimethoxyethane at 64℃; Inert atmosphere Example 6 1. Synthesis of intermediate 006-2 The intermediate 001-5 (1.3 g, 8.73 mmol), 13 mL of DME, FeCl3 (1.414 g, 8.72 mmol) and the intermediate 006-1 (974 mg, 7.43 mmol) were added sequentially to a 100 mL three-necked flask under nitrogen atmosphere, and the reaction mixture was in an oil bath at 64°C overnight. After the reaction was completed, the reaction mixture was cooled to room temperature and filtered. The filter cake was washed three times with 20 mL of methanol and the organic phases were combined, concentrated to dryness and 1.0 g of intermediate 006-2 (47percent) was obtained as a yellow solid. LCMS: 244.1.
46%
Stage #1: With methylmagnesium bromide In diethyl ether; 1,2-dichloro-ethane at 0℃; for 0.25 h; Inert atmosphere
Stage #2: at 20℃; for 16 h;
In 10 minutes at 0 ° CN2 atmosphere,CH3MgBr (3M in ether, 22.68 mL, 68.03 mmol)Was added dropwise to a solution of 1-methyl-indole (7.97 g, 68.03 mmol)In 1,2-dichloroethane (250 mL)In the stirred solution.The resulting solution was stirred for 15 minutes,And then 2,4-dichloropyrimidine (15.00 g, 100.69 mmol) was added in one portion.The resulting solution was allowed to warm to room temperature and stirred for an additional 16 hours.The reaction was quenched by the addition of CH3OH (25 mL)The mixture was then concentrated in vacuo to allow it to adsorb onto silica gel.Using FCC for purification,Eluting with 0-20percent CH3OH in CH2Cl2,The title compound was obtained as a yellow solid (7.17 g, 46percent).

Reference: [1] Patent: CN106957304, 2017, A, . Location in patent: Paragraph 0013
[2] Patent: EP3181559, 2017, A1, . Location in patent: Paragraph 0048
[3] Patent: WO2013/14448, 2013, A1, . Location in patent: Page/Page column 160
[4] Patent: EP3205650, 2017, A1, . Location in patent: Paragraph 0119; 0120
[5] Patent: EP3181560, 2017, A1, . Location in patent: Paragraph 0131; 0132; 0133
[6] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8249 - 8267
[7] Journal of Chemical Research, 2015, vol. 39, # 6, p. 318 - 320
[8] Patent: WO2017/205459, 2017, A1, . Location in patent: Paragraph 0175
[9] Patent: WO2018/119441, 2018, A1, . Location in patent: Paragraph 00890; 00891
[10] Patent: CN105237515, 2016, A, . Location in patent: Paragraph 0185; 0186; 0187
[11] Patent: EP3216786, 2017, A1, . Location in patent: Paragraph 0097-0099
[12] Patent: CN107043369, 2017, A, . Location in patent: Paragraph 0403; 0404; 0405; 0406
[13] Patent: CN108503627, 2018, A, . Location in patent: Paragraph 0095; 0097; 0099
[14] Patent: CN108658943, 2018, A, . Location in patent: Paragraph 0017; 0021; 0023
[15] European Journal of Medicinal Chemistry, 2019, p. 367 - 380
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YieldReaction ConditionsOperation in experiment
42% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 14 h; To a solution of ethyl 3-methyl-iH-pyrazole-4-carbaldehyde (6.4 g, 58.0 mmol) in 60 mL of anhydrous N,N- dimethylformamide were added potassium carbonate (10.8 g, 77.8 mmol) and 2,4-dichloropyrimidine (8.64 g, 58.0 mmol) at room temperature. The resulting suspension was stirred for 14 hours at room temperature with monitoring a reaction with LC-MS or thin layer chromatography (TLC). The reaction mixture was diluted with ethyl acetate and washed with brine (x2). The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a mixture of heptanes and ethyl acetate to afford the desired intermediate 2 as a white solid (5.47 g, 42 percent); MS (ESI) m/z 223 [M+H]+, 1H NMR (300 MHz, CDCls) δ 10.06 (s, 1H), 9.04 (s, 1H), 8.70 (d, 1H, / = 5.4 Hz), 7.87 (1H, d, / = 5.4 Hz), 2.59 (s, 3H).
42% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 14 h; Preparation of 1-(2-chloropyrimidin-4-yl)-3-methyl-1H-pyrazole-4-carbaldehyde; Intermediate 1
To a solution of ethyl 3-methyl-1H-pyrazole-4-carbaldehyde (6.4 g, 58.0 mmol) in 60 mL of anhydrous N,N-dimethylformamide were added potassium carbonate (10.8 g, 77.8 mmol) and 2,4-dichloropyrimidine (8.64 g, 58.0 mmol) at room temperature.
The resulting suspension was stirred for 14 hours at room temperature with monitoring a reaction with LC-MS or thin layer chromatography (TLC).
The reaction mixture was diluted with ethyl acetate and washed with brine (*2).
The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo.
The resulting residue was purified by silica gel chromatography using a mixture of heptanes and ethyl acetate to afford the desired intermediate 1 as a white solid (5.47 g, 42percent); MS (ESI) m/z 223 [M+H]+, 1H NMR (300 MHz, CDCl3) δ 10.06 (s, 1H), 9.04 (s, 1H), 8.70 (d, 1H, J=5.4 Hz), 7.87 (1H, d, J=5.4 Hz), 2.59 (s, 3H).
Reference: [1] Patent: WO2013/109882, 2013, A1, . Location in patent: Page/Page column 55
[2] Patent: US2015/111883, 2015, A1, . Location in patent: Paragraph 0218; 0219
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 20, p. 4441 - 4446
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