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Product Details of [ 14432-12-3 ]

CAS No. :14432-12-3 MDL No. :MFCD00060089
Formula : C5H5ClN2 Boiling Point : -
Linear Structure Formula :- InChI Key :BLBDTBCGPHPIJK-UHFFFAOYSA-N
M.W :128.56 Pubchem ID :84432
Synonyms :

Calculated chemistry of [ 14432-12-3 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 33.65
TPSA : 38.91 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.28 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.16
Log Po/w (XLOGP3) : 1.13
Log Po/w (WLOGP) : 1.33
Log Po/w (MLOGP) : 0.4
Log Po/w (SILICOS-IT) : 1.37
Consensus Log Po/w : 1.08

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.9
Solubility : 1.6 mg/ml ; 0.0125 mol/l
Class : Very soluble
Log S (Ali) : -1.54
Solubility : 3.7 mg/ml ; 0.0288 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.24
Solubility : 0.735 mg/ml ; 0.00571 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.41

Safety of [ 14432-12-3 ]

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 [ 14432-12-3 ]

* 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 [ 14432-12-3 ]
  • Downstream synthetic route of [ 14432-12-3 ]

[ 14432-12-3 ] Synthesis Path-Upstream   1~66

  • 1
  • [ 14432-12-3 ]
  • [ 2770-01-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
  • 2
  • [ 14432-12-3 ]
  • [ 3243-24-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
  • 3
  • [ 26452-80-2 ]
  • [ 19798-80-2 ]
  • [ 14432-12-3 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
[2] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 285,291
[3] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
[4] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 285,291
  • 4
  • [ 26452-80-2 ]
  • [ 19798-80-2 ]
  • [ 14432-12-3 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
  • 5
  • [ 14432-12-3 ]
  • [ 73583-37-6 ]
YieldReaction ConditionsOperation in experiment
96% With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 0 - 20℃; for 16 h; General procedure: To a mixture of copper source (1.2 eq., CuBr2 for 4b, CuCl2 for 4c, CuI for 4d)in acetonitrile (0.4M) was slowly added tBuONO (1.5 eq.). The mixture was stirred for15 min and then cooled to 0°C. A solution of 2-chloro-4-aminopyridine 3 (1.0 eq.) inacetonitrile (0.5M) was slowly added. The mixture was stirred for 1h at 0°C and thenallowed to warm to r.t. for 16h. After concentration in vacuo, aq. 15percent ammonia solution (1.3 mL/mmol) was added, and the aqueous layer was extracted withdichloromethane (10 mL/mmol; 3x). The combined organic layers were washed withbrine, dried (Na2SO4), filtered and carefully concentrated under reduced pressure(CAUTION: volatile products) to give the crude 4b-d, which was used in the next stepwithout purification.
52%
Stage #1: With hydrogen bromide; bromine In water at 0℃; for 0.166667 h;
Stage #2: With sodium nitrite In water at -10 - 20℃; for 2.16667 h;
Stage #3: With sodium sulfite In water at 5℃;
Step a:
Preparation of 2-chloro-4-bromopyridine
81.5 mL of an aqueous solution of 48percent strength hydrobromic acid are added, at 0° C., to 8.9 g (69.2 mmol) of 2-chloro-4-aminopyridine. 33.4 g (208.75 mmol) of molecular bromine are then added over a period of 10 minutes.
The solution is cooled to -10° C. and a solution of 10.65 g (154 mmol) of sodium nitrite in 20 mL of water is poured in over a period of 30 minutes.
The solution is stirred for a further 10 minutes at -10° C., then for 1 h30 at ambient temperature.
The solution is cooled to 5° C. and a saturated aqueous sodium sulfite solution is added until the reaction medium loses colour.
The reaction medium is basified with the assistance of a 35percent strength aqueous sodium hydroxide solution.
The aqueous basic phase is extracted twice with diethyl oxide.
The organic phases are combined, dried over magnesium sulfate, filtered and concentrated.
The resultant yellow oil (13 g) is chromatographed on silica gel (eluent: 1/9 ethyl acetate/heptane).
Yield: 52percent (slightly coloured oil)
1H NMR (CDCl3): 8.25 (doublet, 1H, J=5 Hz); 7.55 (singlet, 1H); 7.4 (doublet, 1H, J=5 Hz)
Reference: [1] Journal of Organic Chemistry, 2006, vol. 71, # 22, p. 8602 - 8609
[2] Synlett, 2016, vol. 27, # 1, p. 67 - 69
[3] Patent: US2006/89364, 2006, A1, . Location in patent: Page/Page column 22
[4] Roczniki Chemii, 1955, vol. 29, p. 1019,1025[5] Chem.Abstr., 1956, p. 12045
[6] Journal of Organic Chemistry, 2006, vol. 71, # 22, p. 8610 - 8613
  • 6
  • [ 14432-12-3 ]
  • [ 153034-86-7 ]
YieldReaction ConditionsOperation in experiment
63%
Stage #1: With hydrogenchloride In water at 0℃;
Stage #2: With sodium nitrite In water at -10℃; for 0.666667 h;
To a ice-cooled solution of 4-amino-2-chloro-pyridine (8.09g, 63 mmol, 1eq) in water [(150ML)] was added concentrated 98percent HCl whilst maintaining the reaction at [0°C A] solution of sodium nitrite (5.65g, [82MMOL,] 1.3eq) in water [(50ML)] was added slowly [AT-10°C.] The mixture was stirred at-10°C [FOR 40 MIN] and a solution of potassium iodide (12.55g, 75. [6MMOL,] 1.2eq) in water [(50ML)] was added. The resulting mixture was stirred at [0°C] overnight. After treatment with [NAOH] 35percent, and extraction with ethyl acetate, the organic phases were combined and dried over [NA2SO4.] The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (eluent : CH2CI2 then [CH2CL2/CH30H] 99/1) to give the title compound as an orange solid (9.5g, 63percent) ;'H NMR (300 MHz, CDCl3) [6] : 7.99 (d, [1H),] 7.68 (s, 1H), 7.52 (d, 1H) ; (GC-MS) m/z: 239.
63%
Stage #1: With hydrogenchloride; sodium nitrite In water at -10℃; for 0.666667 h;
Stage #2: With potassium iodide In water at 0℃;
To a solution of 4-amino-2-chloro-pyridine (8.09g, 63 mmol, [1EQ)] in water [(150ML)] cooled to [0°C] was added concentrated 98percent HCI. A solution of sodium nitrite (5.65g, [82MMOL,] 1.3eq) in water (50mL) was added slowly at-10°C and the mixture was stirred at this temperature for 40 min. A solution of potassium iodide [(12.] 55g, 75. [6MMOL,] 1.2eq) in water (50mL) was added and the resulting mixture was stirred at [0°C] overnight. After treatment with NaOH (35percent) and extraction with ethyl acetate, the organic phases were combined and dried over [NA2SO4.] The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (eluent : CH2CI2 then [CH2CI2/CH30H] 99: 1) to give the title compound as an orange solid (9.5g, 63percent) [; 1H] NMR (300 MHz, [CD13)] [8] ppm: 7.99 (1H, d), 7.68 (1H, s), 7.52 (1H, d); (GC-MS) m/z: 239.
34% With copper(l) iodide; tert.-butylnitrite In acetonitrile at 0 - 20℃; for 16 h; General procedure: To a mixture of copper source (1.2 eq., CuBr2 for 4b, CuCl2 for 4c, CuI for 4d)in acetonitrile (0.4M) was slowly added tBuONO (1.5 eq.). The mixture was stirred for15 min and then cooled to 0°C. A solution of 2-chloro-4-aminopyridine 3 (1.0 eq.) inacetonitrile (0.5M) was slowly added. The mixture was stirred for 1h at 0°C and thenallowed to warm to r.t. for 16h. After concentration in vacuo, aq. 15percent ammonia solution (1.3 mL/mmol) was added, and the aqueous layer was extracted withdichloromethane (10 mL/mmol; 3x). The combined organic layers were washed withbrine, dried (Na2SO4), filtered and carefully concentrated under reduced pressure(CAUTION: volatile products) to give the crude 4b-d, which was used in the next stepwithout purification.
Reference: [1] Patent: WO2004/13125, 2004, A1, . Location in patent: Page 18
[2] Patent: WO2004/13135, 2004, A1, . Location in patent: Page 42-43
[3] Synlett, 2016, vol. 27, # 1, p. 67 - 69
[4] Roczniki Chemii, 1955, vol. 29, p. 1019,1025[5] Chem.Abstr., 1956, p. 12045
  • 7
  • [ 14432-12-3 ]
  • [ 17368-12-6 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: With sulfuric acid; sodium nitrite In water at 0 - 20℃; for 24 h;
Stage #2: With sodium hydroxide In water
In a recovery flask, 4-amino-2-chloropyridine (3.0 g, 23.3 mmol) was dissolved in 40percent sulfuric acid (50 g) . While the solution was stirred at 00C, sodium nitrite (1.93 g, 28.0 mmol) was added. The mixture was stirred at room temperature for 24 hours. After the reaction completed, the reaction <n="39"/>liquid was neutralized by adding an aqueous sodium hydroxide solution and an aqueous sodium hydrogencarbonate solution. The organic phase was extracted with ethyl acetate. The organic phase was then dried over magnesium sulfate, filtered, distilled to remove the solvent, and dried under reduced pressure to give 2-chloro-4-hydroxypyridine (light brown solid). The solid weighed 2.78 g, and the yield was 92percent. [0088]1H-NMR (270 MHz, DMSO-d6) ppm: 11.20 (s, IH, -OH), 8.09 (d, IH, J = 5.4 Hz, ArH), 6.81 (s, IH, ArH), 6.77 (d, IH, J = 2.2 Hz, ArH)
Reference: [1] Patent: WO2009/11447, 2009, A2, . Location in patent: Page/Page column 37-38
  • 8
  • [ 23056-36-2 ]
  • [ 14432-12-3 ]
Reference: [1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 1, p. 51 - 54
[2] Journal of the Chinese Chemical Society, 2003, vol. 50, # 2, p. 267 - 271
[3] Organic Letters, 2017, vol. 19, # 18, p. 4746 - 4749
[4] Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chemistry, 2016, vol. 46, # 10, p. 1499 - 1505
  • 9
  • [ 14432-16-7 ]
  • [ 14432-12-3 ]
Reference: [1] Tetrahedron, 1999, vol. 55, # 41, p. 11985 - 11996
[2] Journal of Chemical Research, Miniprint, 1997, # 6, p. 1359 - 1376
[3] Roczniki Chemii, 1955, vol. 29, p. 1019,1025[4] Chem.Abstr., 1956, p. 12045
[5] Journal fuer Praktische Chemie (Leipzig), 1988, vol. 330, # 1, p. 154 - 158
[6] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
  • 10
  • [ 14432-16-7 ]
  • [ 142-96-1 ]
  • [ 14432-12-3 ]
Reference: [1] Patent: US4808722, 1989, A,
  • 11
  • [ 2402-95-1 ]
  • [ 14432-12-3 ]
Reference: [1] Tetrahedron, 1999, vol. 55, # 41, p. 11985 - 11996
[2] Journal of Chemical Research, Miniprint, 1997, # 6, p. 1359 - 1376
[3] Roczniki Chemii, 1955, vol. 29, p. 1019,1025[4] Chem.Abstr., 1956, p. 12045
[5] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
  • 12
  • [ 109-09-1 ]
  • [ 14432-12-3 ]
Reference: [1] Tetrahedron, 1999, vol. 55, # 41, p. 11985 - 11996
[2] Journal of Chemical Research, Miniprint, 1997, # 6, p. 1359 - 1376
[3] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
  • 13
  • [ 26452-80-2 ]
  • [ 19798-80-2 ]
  • [ 14432-12-3 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
[2] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 285,291
[3] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
[4] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 285,291
  • 14
  • [ 70696-29-6 ]
  • [ 14432-12-3 ]
Reference: [1] Helvetica Chimica Acta, 1951, vol. 34, p. 496,499
  • 15
  • [ 1124-33-0 ]
  • [ 14432-12-3 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 285,291
  • 16
  • [ 626-03-9 ]
  • [ 14432-12-3 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
  • 17
  • [ 26452-80-2 ]
  • [ 19798-80-2 ]
  • [ 14432-12-3 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
  • 18
  • [ 14432-12-3 ]
  • [ 151-50-8 ]
  • [ 33252-30-1 ]
Reference: [1] Roczniki Chemii, 1955, vol. 29, p. 1019,1025[2] Chem.Abstr., 1956, p. 12045
  • 19
  • [ 14432-12-3 ]
  • [ 100367-39-3 ]
Reference: [1] Patent: WO2012/24615, 2012, A1,
  • 20
  • [ 14432-12-3 ]
  • [ 20265-39-8 ]
YieldReaction ConditionsOperation in experiment
14% With sodium methylate In tetrahydrofuran; methanol at 140℃; for 16 h; Sealed tube 4-Amino-2-chloropyridine (15 g, 117 mmol, 1.0 equiv) was dissolved in 100 mL of THF. A solution of sodium methoxide in methanol (1.0 M, 234 mL, 234 mmol, 2.0 equiv) was added and the resulting solution was refiuxed in a sealed tube for 16 hours at 14O0C. The reaction mixture was poured into 50OmL of a rapidly stirring saturated sodium bicarbonate solution. 50OmL of ethyl acetate was added and the layers were separated. The organic layer was dried over sodium sulfate, decanted, and concentrated in vacuo. Chromatography on SiO2 (30percent ethyl acetate in hexanes) provided 29b as a yellow solid (2.1 g, 14percent).
Reference: [1] Patent: WO2009/154769, 2009, A1, . Location in patent: Page/Page column 53
  • 21
  • [ 14432-12-3 ]
  • [ 124-41-4 ]
  • [ 20265-39-8 ]
Reference: [1] Patent: WO2012/24615, 2012, A1, . Location in patent: Page/Page column 56
[2] Tetrahedron, 2008, vol. 64, # 12, p. 2772 - 2782
[3] Australian Journal of Chemistry, 1982, vol. 35, # 10, p. 2025 - 2034
[4] Patent: WO2005/30213, 2005, A1, . Location in patent: Page/Page column 173
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  • [ 67-56-1 ]
  • [ 20265-39-8 ]
Reference: [1] Patent: WO2004/76424, 2004, A1, . Location in patent: Page 267
  • 23
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  • [ 6313-54-8 ]
Reference: [1] Roczniki Chemii, 1955, vol. 29, p. 1019,1025[2] Chem.Abstr., 1956, p. 12045
  • 24
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  • [ 64-17-5 ]
  • [ 89943-12-4 ]
YieldReaction ConditionsOperation in experiment
64% at 140℃; for 9 h; A solution of sodium (0.28 g, 12.2 mmol) in ethanol (3 mL) was added to 2-chloro-pyridin-4-ylamine (0.2 g, 1.56 mmol) in a sealed tube and the reaction was heated to 140° C. for 9 h. The cooled mixture was adjusted to pH 8-9 with 2N HCl. The mixture was extracted with 80:20 chloroform: 2-propanol, concentrated and chromatographed to yield 0.14 g (64percent) of the title compound as a white solid.
Reference: [1] Patent: US2008/76771, 2008, A1, . Location in patent: Page/Page column 17-18
  • 25
  • [ 14432-12-3 ]
  • [ 89943-12-4 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1951, vol. 70, p. 591,598
[2] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 285,291
  • 26
  • [ 14432-12-3 ]
  • [ 700811-29-6 ]
Reference: [1] Patent: WO2004/58176, 2004, A2, . Location in patent: Page/Page column 236
[2] Patent: WO2004/58176, 2004, A2, . Location in patent: Page/Page column 236
  • 27
  • [ 14432-12-3 ]
  • [ 7632-00-0 ]
  • [ 700811-29-6 ]
Reference: [1] Patent: WO2004/46120, 2004, A2, . Location in patent: Page 320; 321
  • 28
  • [ 14432-12-3 ]
  • [ 857730-21-3 ]
  • [ 215364-85-5 ]
Reference: [1] Patent: WO2005/61500, 2005, A1, . Location in patent: Page/Page column 158
  • 29
  • [ 14432-12-3 ]
  • [ 18511-69-8 ]
Reference: [1] Beilstein Journal of Organic Chemistry, 2014, vol. 10, p. 814 - 824
  • 30
  • [ 14432-12-3 ]
  • [ 2604-39-9 ]
  • [ 2789-25-5 ]
Reference: [1] Patent: WO2006/84281, 2006, A1, . Location in patent: Page/Page column 187
[2] Organic and Biomolecular Chemistry, 2013, vol. 11, # 38, p. 6526 - 6545
[3] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
[4] Patent: CN103819398, 2016, B, . Location in patent: Paragraph 0030-0038
[5] European Journal of Medicinal Chemistry, 2018, vol. 156, p. 240 - 251
  • 31
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  • [ 2604-39-9 ]
YieldReaction ConditionsOperation in experiment
8.89% at 0 - 100℃; for 2.5 h; To a solution of 2-chloropyridin-4-amine (10 g, 78 mmol) in conc. sulfuric acid (60 mL) at 0° C. was slowly added fuming nitric acid (30 mL).
Then reaction mixture was stirred for 30 min.
The reaction mixture was slowly poured into ice; the pH was adjusted to ˜3 with using ammonia solution.
The resultant white solid was isolated via filtration.
The solid was dissolved in conc. sulfuric acid, then heated to 100° C. for 2 h.
The reaction mixture was cooled to room temperature and poured into ice.
The aqueous solution was adjusted to pH ˜3 using ammonia solution; then was extracted with ethyl acetate.
The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
The resultant residue was purified by silica gel chromatography using 30percent ethyl acetate in Pet-ether to afford 2-chloro-5-nitropyridin-4-amine (1.2 g, 6.91 mmol, 8.89percent yield) and 2-chloro-3-nitropyridin-4-amine (6 g, 34.6 mmol, 44.4percent yield) as yellow solids. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.90 (d, J=5.77 Hz, 1H) 7.34 (br. s., 2H) 6.83 (s, 1H). MS: MS m/z 172.2 (M+-1).
Reference: [1] Patent: US9643999, 2017, B2, . Location in patent: Page/Page column 80; 81
[2] Nucleosides, nucleotides and nucleic acids, 2004, vol. 23, # 1-2, p. 67 - 76
[3] Roczniki Chemii, 1956, vol. 30, p. 1139,1144[4] Chem.Abstr., 1957, p. 12089
[5] Patent: US2014/127156, 2014, A1, . Location in patent: Page/Page column
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  • [ 2604-39-9 ]
  • [ 2789-25-5 ]
Reference: [1] Patent: WO2006/84281, 2006, A1, . Location in patent: Page/Page column 187
[2] Organic and Biomolecular Chemistry, 2013, vol. 11, # 38, p. 6526 - 6545
[3] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
[4] Patent: CN103819398, 2016, B, . Location in patent: Paragraph 0030-0038
[5] European Journal of Medicinal Chemistry, 2018, vol. 156, p. 240 - 251
  • 33
  • [ 14432-12-3 ]
  • [ 2789-25-5 ]
YieldReaction ConditionsOperation in experiment
44% at 0℃; for 1 h; Potassium nitrate (7.86 g, 0.0784 mol) was added portionwise to 2-chloro-4-aminopyridine (10.00 g, 0.078 mol) in concentrated sulfuric acid (80 mL) at 0 ° C, and the reaction was continued at 0 ° C for 1 hour. After completion, the reaction solution was poured into crushed ice, concentrated aqueous ammonia was added to adjust the pH to 3, stirred for 15 minutes, filtered, and a solid was collected. Add solid to concentrated sulfuric acid (80mL), heat to 80 ° C for 5 hours, cool, pour the reaction solution into crushed ice, add concentrated ammonia to adjust the pH to 3, stir for 15 minutes, filter, collect solids, through silica gel column Chromatographic purification,Elution with ethyl acetate/petroleum gradient (10-20percent) gave product ( 6.00 g, 44percent).
Reference: [1] Patent: CN108498504, 2018, A, . Location in patent: Paragraph 0022; 0023; 0024; 0025
[2] Nucleosides, nucleotides and nucleic acids, 2004, vol. 23, # 1-2, p. 67 - 76
[3] Roczniki Chemii, 1956, vol. 30, p. 1139,1144[4] Chem.Abstr., 1957, p. 12089
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  • [ 75-36-5 ]
  • [ 13602-82-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 8, p. 2556 - 2559
  • 35
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  • [ 33623-16-4 ]
Reference: [1] Australian Journal of Chemistry, 1982, vol. 35, # 10, p. 2025 - 2034
  • 36
  • [ 14432-12-3 ]
  • [ 38767-72-5 ]
YieldReaction ConditionsOperation in experiment
97% With potassium hydroxide In toluene at 170℃; for 72 h; Sealed tube A mixture of 2-chloro-4-aminopyridine 3 (127 mg, 1.0 mmol) and KOH (280.6mg, 5.0 mmol) in toluene (4.0 mL) was heated at 170°C in a sealed tube for 72h. Themixture was cooled to r.t. and the toluene was removed. The residue was purified byflash chromatography on silica gel (DCM/MeOH/NH4OH: 78/20/2) to give 5 (107 mg,97percent) as a pale yellow solid
Reference: [1] Synlett, 2016, vol. 27, # 1, p. 67 - 69
[2] Tetrahedron, 1999, vol. 55, # 41, p. 11985 - 11996
  • 37
  • [ 557-21-1 ]
  • [ 14432-12-3 ]
  • [ 98139-15-2 ]
YieldReaction ConditionsOperation in experiment
20% at 145℃; for 20 h; A mixture of 2-chloro-pyridin-4-ylamine (0.642 g, 5 mmol), Zn (CN) 2 (0.323 g, 2.75 mmol) and Pd (PPh3) 4 (0.288 g, 0.025 mmol) in 5 mL of DMF was heated at 145 C for 20 hours. After the reaction mixture cooled to room temperature, it was partitioned between ethyl acetate and H2O. The aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried (MGS04), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 9: 1 HEXANES/ETHYL acetate to provide 0.29 g (20percent) of the desired product. MS (DCI) m/e 120 (M+H) + ; IH NMR (300 MHz, DMSO-D6) 8 8.08 (d, J=5.76 Hz, 1H), 6.94 (d, J=2.34 Hz, 1H), 6.68 (dd, J=5. 76,2. 37 Hz, 1H), 6.59 (s, 2H).
Reference: [1] Patent: WO2004/76424, 2004, A1, . Location in patent: Page 131
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  • [ 14432-12-3 ]
  • [ 1692-25-7 ]
  • [ 40963-62-0 ]
YieldReaction ConditionsOperation in experiment
>= 99 %Chromat. With potassium carbonate In water at 45 - 100℃; for 22 h; (ii) Suzuki reaction of aryl halides (in water) Preparation of the catalyst-stock-solution: The catalyst stock solution was prepared as described for the aqueous Sonogshira reaction using 9-Et-2-SO3HFlu-PCy2-HBF4 (13a). Cross-coupling reaction: Aryl halide (1 mmol), boronic acid (1.2 mmol) and K2CO3 (3.2 mmol) were first added to water (4 ml), then the catalyst stock solution and two drops of Labrasol.(R). (caprylocaproyl macrogol-8 glyceride blend, saturated polyglycolized glycerides consisting of mono-, di-and triglycerides of mono- and di-fatty acids of polyethylene glycol (PEG)) were added. The reaction mixture was stirred at the respective temperatures (see Table 8) for 0.5-20 h (see Table 8). After cooling to room temperature the reaction mixture was diluted with ether (15 ml), washed with water (10 ml), the organic phase was dried over MgSO4, filtered and concentrated in vacuo. The product was isolated by column chromatography (silica, cyclohexane / ethylacetate (100:2). Alternatively the yield was determined via gas chromatography with hexadecane or diethylene glycol di-n-butylether as an internal standard.
Reference: [1] Chemistry - A European Journal, 2008, vol. 14, # 14, p. 4267 - 4279
[2] Chemistry - A European Journal, 2007, vol. 13, # 9, p. 2701 - 2716
[3] Patent: EP1894938, 2008, A1, . Location in patent: Page/Page column 53; 58; 59
  • 39
  • [ 14432-12-3 ]
  • [ 23596-25-0 ]
Reference: [1] Patent: US2016/251376, 2016, A1,
  • 40
  • [ 110-91-8 ]
  • [ 14432-12-3 ]
  • [ 35980-77-9 ]
YieldReaction ConditionsOperation in experiment
95% at 200℃; for 1 h; microwave A suspension of 26a (5.Og, 38.9mmol) in moφholine (13mL) was heated under microwave condition at 2000C for Ih. After being cooled to room temperature, precipitate appeared in the mixture. Ether (45mL) was added and the suspension was stirred for lOmin before being filtered. The filter cake was washed with ether and dried to afford 26b (6.61 g, 95percent).
87% at 200℃; for 0.5 h; Irradiation a)
2-Morpholin-4-yl-pyridin-4-ylamine
A stirred mixture of 45.8 g (356 mmol) 4-amino-2-chloropyridine in 124 ml morpholine was heated at 200° C. for 30 min in a microwave oven.
The resulting yellow solution was then cooled to room temperature whereupon crystals appeared.
400 ml ether was then added and the suspension stirred for 10 minutes before being filtered.
The filter cake was washed with ether and dried to afford 92.9 g of crystalline material (87percent yield of desired product) which 1H NMR analysis revealed to comprise 60 wt percent 2-morpholin-4-yl-pyridin-4-ylamine and 40 wt percent morpholine.
1 g at 170℃; for 16 h; A neat mixture of 2-chloropyridin-4-amine (1.0 g, 7.81 mmol) in morpholine (1 ml) was heated at 170°C for 16 h. The resulting mixture was poured into water (10 ml) and extracted with EtOAc (4 x 10 ml). The collected organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure yielding 2-morpholinopyridin-4-amine (1.0 g, 5.5 mmol). This material was used directly for the next step without further purification. LCMS: Method C, 0.64 mi MS: ES+180.21.
Reference: [1] Patent: WO2008/88881, 2008, A1, . Location in patent: Page/Page column 51
[2] Angewandte Chemie - International Edition, 2018, vol. 57, # 34, p. 11035 - 11039[3] Angew. Chem., 2018, vol. 130, # 34, p. 11201 - 11205,5
[4] Patent: US2005/65151, 2005, A1, . Location in patent: Page/Page column 6; 14
[5] Patent: WO2017/93718, 2017, A1, . Location in patent: Page/Page column 64
  • 41
  • [ 14432-12-3 ]
  • [ 96530-75-5 ]
Reference: [1] Synlett, 2016, vol. 27, # 1, p. 67 - 69
  • 42
  • [ 14432-12-3 ]
  • [ 124-41-4 ]
  • [ 96530-81-3 ]
Reference: [1] Synlett, 2010, # 18, p. 2789 - 2791
  • 43
  • [ 14432-12-3 ]
  • [ 74976-31-1 ]
Reference: [1] Patent: WO2015/38417, 2015, A1,
[2] Patent: US2016/251376, 2016, A1,
  • 44
  • [ 14432-12-3 ]
  • [ 408502-23-8 ]
Reference: [1] Patent: WO2012/24615, 2012, A1,
  • 45
  • [ 14432-12-3 ]
  • [ 98-80-6 ]
  • [ 21203-86-1 ]
YieldReaction ConditionsOperation in experiment
87% With sodium carbonate In water; toluene at 100℃; for 16 h; a)
2-Phenyl-pyridin-4-ylamine
To a stirred solution of 16.0 g (124 mmol) 2-chloro-4-aminopyridine in 200 ml toluene were added 18.2 g (149 mmol) phenylboronic acid, 7.19 g (6.22 mmol) tetrakis(triphenylphosphine)palladium(0) and 130 ml (260 mmol) 2 M aq. sodium carbonate solution.
The mixture was heated at 100° C. for 16 h and then cooled to room temperature and extracted three times with ethyl acetate.
The combined organic phases were extracted three times with 200 ml 1 M aq. hydrochloric acid.
The combined acid extracts were then made alkaline by addition of 5 M aq.
sodium hydroxide solution and extracted three times with dichloromethane.
The combined organic extracts were dried over sodium sulfate, and concentrated in vacuo.
Flash chromatography (acetone) followed by trituration in hexane containing a little ether afforded 18.5 g (87percent) 2-phenyl-pyridin-4-ylamine as a white solid. ES-MS m/e (percent): 171 (M+H+, 100).
75% at 90℃; for 14 h; Sealed tube A mixture of 4-chloropyridin-2-amine (64 g, 498 mmol), phenyl boronic acid (61 g, 500 mmol), Na2CO3 (159 g, 1.5 mol), Pd(PPh3)4 (6.4 g) in H20/EtOHJtoluene (500 mL) was heated to 90 °C in sealed vessel for 14 h. The crude mixture was cooled, filtered, and concentrated under reduced pressure. Purification (FCC, 5i02,PE:EtOAc (100:1) afforded the title compound (64 g, 75percent).
71% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In N,N-dimethyl-formamide at 110℃; for 16 h; To a stirred solution of 2-chloropyridin-4-amine (64.0 g, 498 mmol) in toluene (800 mL) were added phenylboronic acid (72.9 g, 597 mmol), Pd(PPh3)4(28.8 g, 24.9 mmol), Na2C03(105.5 g, 995.6 mmol), and water (500 mL) and was heated at 100 °C for 16 hours. The reaction was cooled to room temperature, extracted three times with ethyl acetate, and the combined organic phases were concentrated to dryness. The residue was purified by normal phase flash column chromatography (S1O2) to give the title compound (60 g, 71percent yield) as a white solid.
Reference: [1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 38, p. 7598 - 7602
[2] Angewandte Chemie - International Edition, 2006, vol. 45, # 21, p. 3484 - 3488
[3] Advanced Synthesis and Catalysis, 2018, vol. 360, # 20, p. 3990 - 3998
[4] Patent: US2005/65151, 2005, A1, . Location in patent: Page/Page column 8; 19
[5] Advanced Synthesis and Catalysis, 2009, vol. 351, # 17, p. 2912 - 2920
[6] Patent: WO2018/103060, 2018, A1, . Location in patent: Page/Page column 116
[7] Patent: WO2017/100668, 2017, A1, . Location in patent: Page/Page column 567; 568
[8] Tetrahedron Letters, 2005, vol. 46, # 20, p. 3573 - 3577
[9] Advanced Synthesis and Catalysis, 2013, vol. 355, # 11-12, p. 2274 - 2284
[10] New Journal of Chemistry, 2017, vol. 41, # 24, p. 15420 - 15432
  • 46
  • [ 14432-12-3 ]
  • [ 108-90-7 ]
  • [ 21203-86-1 ]
Reference: [1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 4, p. 616 - 622
  • 47
  • [ 14432-12-3 ]
  • [ 24424-99-5 ]
  • [ 234108-73-7 ]
YieldReaction ConditionsOperation in experiment
80% With triethylamine In dichloromethane at 20℃; Example 8; 2-[4-(2-Carboxyethy1)phenyl]-4-(3-heptyl-1- methylureido)pyridini\\3m acetate; a. tert-Butyl (2-chlox:opyrlcL-4-yl)carbamate; 1.69 g (7.78 mmol, 1 eq) of tert-butyl dicarbonate dissolved in 50 ml of dichloromethane, in the presence of 95 mg of dimethylaminopyridine, are added to a solution of 1 g (7.78 mmol, 1 eq) of 4-amino-2-chloropyridine in 30 mL of dichloromethane in EPO <DP n="51"/>the presence of 1.19 mL (1.19 mmol, 1.1 eq) of triethylamine. The reaction mixture is stirred overnight at room temperature. The reaction is stopped by adding 100 ml of water and is then extracted with dichloromethane. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 to 50/50 heptane/ethyl acetate) . The oil obtained is crystallized from pentane. 1.40 g of tert- butyl (2-chloropyrid~4-yl) carbamate are obtained. Yield = 80percent.
77%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at 20℃; for 0.5 h;
StepA; ci 1) NaHMDS N T) HGF0C20 l l l 9\\NH2 NHBoc the c : 2 [0073] To A solution containing 4-amino-2-chloropyridine (3. 05 g, 23. 72 mmol) in THF (24 ML) was added sodium bis (TRIMETHYLYSILYL) amide (47. 45 mmol) and stirred at room temperature for 30 minutes. To this solution was added BOC20 (23. 72 mmol) and the gelatinous mixture was stirred overnight. The reaction was diluted with water and extracted with ETOAC. The combined organic phase was washed with water and brine and dried over NA2S04 and concentrated to yield 4. 17 G (77percent). M+H+ (230).
73% at 20℃; for 18 h; A mixture of 4-amino-2-chloropyridine (193 mg, 1.50 mmol), di-tert-butyl-di- carbonate (393 mg, 1.80 mmol) and 4-dimethylaminopyridine (1.8 mg, 0.02 mmol) in acetonitrile (5 mL) was stirred at room temperature for 18 hours. This mixture was concentrated under reduced pressure. The residue was purified by column chroma- tography on silica-gel (hexane/ethyl acetate, 20: 1) to give tert-butyl (2-chloropyridin- 4-YL) carbamate (250 mg, 73percent).
Reference: [1] Patent: WO2006/53791, 2006, A2, . Location in patent: Page/Page column 49-50
[2] Tetrahedron Letters, 2014, vol. 55, # 49, p. 6734 - 6737
[3] Patent: WO2005/33072, 2005, A2, . Location in patent: Page/Page column 26
[4] Patent: WO2004/43926, 2004, A1, . Location in patent: Page 161
[5] Patent: US2004/102450, 2004, A1, . Location in patent: Page/Page column 100
[6] Patent: US2002/45613, 2002, A1,
[7] Patent: WO2006/91395, 2006, A2, . Location in patent: Page/Page column 40
[8] Journal of Organic Chemistry, 2008, vol. 73, # 15, p. 6025 - 6028
[9] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 14, p. 4186 - 4190
[10] Patent: WO2006/65601, 2006, A2, . Location in patent: Page/Page column 42-43
[11] Patent: WO2006/65601, 2006, A2, . Location in patent: Page/Page column 55
[12] Patent: WO2006/110638, 2006, A2, . Location in patent: Page/Page column 37-38
[13] Patent: WO2006/135627, 2006, A2, . Location in patent: Page/Page column 79-80
[14] Patent: WO2006/135627, 2006, A2, . Location in patent: Page/Page column 88-89
  • 48
  • [ 14432-12-3 ]
  • [ 762-75-4 ]
  • [ 234108-73-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2003, vol. 46, # 5, p. 681 - 684
  • 49
  • [ 14432-12-3 ]
  • [ 800402-12-4 ]
YieldReaction ConditionsOperation in experiment
78.1% With N-iodo-succinimide In acetonitrile at 70℃; for 16 h; Inert atmosphere Under nitrogen atmosphere, mixture of 2-chloro-4-aminopyridine (15 g, 0.116 mol, 1 eq) was dissolved in acetonitrile (200 ml), was heated in an oil bath to 70°C, was slowly added NIS (33 g, 0.139 mol, 1.2 eq.), stirred for 16 hours. Cooled to room temperature, saturated aqueous sodium carbonate was added and the reaction member system PH value was adjusted to 9-10, ethyl acetate (500 ml) and extracted. The organic phase was separated and washed with saturated washed twice with brine (100 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo to give 2-chloro-4-amino-5-iodopyridine (23 g, yield: 78.1 percent).
45% With potassium acetate; Iodine monochloride In acetic acid for 4 h; Reflux To 2-chloro-4-amino pyridine (33 g, 1 eq), in a 2-neck 2 L round bottomed flask, acetic acid (1.5 L) was added and stirred for 10 min. To this mixture, potassium acetate (50 g, 2 eq) was added and stirred for 10 min. Iodine monochloride (50 g, 1.2 eq) was added slowly to the mixture and the contents refluxed at 120°C for 4 h while monitoring by TLC. After completion, the acetic acid was distilled off under vacuum and the residue was basified with NaHC03 and poured into water. The aqueous mixture was extracted with EtOAc (2 x 500 mL) and the organic layer was dried over anhydrous sodium sulphate, filtered and concentrated to obtain crude product. The crude was purified by column chromatography (silica gel, 60-120) using EtOAc in hexane as the eluent. The desired product eluted at 10percent EtOAc in hexane. The fractions with product were concentrated to obtain product 2-chloro-5-iodopyridin-4-amine as white solid (23 g, 45percent). 1H NMR (DMSO-d6, 400 MHz): δ 8.190 (s, 1H), 6.625 (s, 1H), 6.517 (brs, 2H).
40% at 70℃; 2-Chloro-pyridin-4-ylamine 1b* (3.2 g, 0.025 mol) and sodium acetate (4.1 g, 0.05 mol) were stirred in acetic acid (20 ml). A solution of iodine monochloride (4.1 g, 0.025 mol) in acetic acid (10 ml) was added and the reaction mixture was heated to 70 °C for approximately 3 h (NB: solution at -50 °C, brown colour faded and precipitate formed as the reaction proceeded). The reaction mixture was cooled to room temperature, then poured onto water (700 ml), and extracted with EtOAc. The organic layer was carefully washed with a solution of Na2CO3 followed by a solution of Na2S2O3, dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography using 10percent EtOAc in DCM to yield 2-chloro-5-iodo-pyridin-4-ylamine 2b* (2.60 g, 40percent). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.34 (1 H, s), 6.63 (1 H, s), 4.78 (2 H, s).
40% With sodium acetate; Iodine monochloride In acetic acid at 70℃; for 3 h; 10.1
Synthesis of 2-chloro-5-iodo-pyridin-4-ylamine 2b*
2-Chloro-pyridin-4-ylamine 1b* (3.2 g, 0.025 mol) and sodium acetate (4.1 g, 0.05 mol) were stirred in acetic acid (20 mL).
A solution of iodine monochloride (4.1 g, 0.025 mol) in acetic acid (10 mL) was added and the reaction mixture was heated to 70 °C for approximately 3 h (NB: solution at ∼50 °C, brown colour faded and precipitate formed as the reaction proceeded).
The reaction mixture was cooled to room temperature, then poured onto water (700 mL), and extracted with EtOAc.
The organic layer was carefully washed with a solution of Na2CO3 followed by a solution of Na2S2O3, dried over MgSO4 and concentrated in vacuo.
The crude product was purified by column chromatography using 10 percent EtOAc in DCM to yield 2-chloro-5-iodo-pyridin-4-ylamine 2b* (2.60 g, 40 percent).
1H NMR (400 MHz, CDCl3) δ(ppm): 8.34 (1 H, s), 6.63 (1 H, s), 4.78 (2 H, s).
40% With potassium acetate; Iodine monochloride In acetic acid for 4 h; Heating / reflux Iodine monochloride (0.758 g, 4.67 mmol) was added to a solution of 2-chloro-4-amino pyridine (0.500 g, 3.89 mmol) and potassium acetate (0.763 g, 7.78 mmol) in acetic acid (30 ml_). The reaction mixture was heated under reflux for 4 hr. The solvent was removed in vacuo and the residue was partitioned between aqueous sodium hydrogenocarbonate (50 ml.) and ethyl acetate (50 ml_). The organic phase was dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified by flash silica chromatography, eluting with ethyl acetate and hexane (1 / 9), to give the title compound as a pink solid (0.394 g, 40percent).1H NMR (CDCI3, 500 MHz) δ 8.33 (s, 1H), 6.63 (s, 1H), 4.85 (brs, 2H). LCMS (4) R, 1.66 min; m/z (ESI+) 254 [MH+].
39% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 3 h; To a stirred solution of 2-chloropyridin-4-amine (5 g, 39 mmol) in DMF (50 mL)was added NIS (8.75 g, 39 mmol). The reaction mixture was then heated at 80 °C for 3 h.The mixture was cooled and the DMF removed in vacuo. The residue was partitionedbetween EtOAc and water and the layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated. The product was purified via column chromatography (10percent EtOAc/pet ether) to afford 2-chloro-5-iodopyridin-4-amine (4 g, 39percent yield). ‘H NIVIR (400MHz, DMSO-d6) ö 8.20 (s, 1H), 6.64 (s, 1H), 6.50 (br s, 2H); LC/MS: 254.8 (Mj. Further elution with 12percent EtOAc/pet ether afforded 2-chloro-3- iodopyridin-4-amine (4 g, 39percent yield).
38% With N-iodo-succinimide In N,N-dimethyl-formamide at 60 - 80℃; N-iodosuccinimide (15.75 g, 70 mmol) was added to a solution of 2-chloropyridin-4-amine (9.00 g, 70 mmol) in N,N'-dimethylformamide (140 mL) and the mixture was stirred at 80 °C for 6 hours.
Further N-iodosuccinimide (7.80 g, 35 mmol) was added and the mixture was stirred at 60 °C overnight.
After cooling to room temperature, the solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate.
The organic layer was washed with a saturated aqueous solution of sodium thiosulphate, water and brine, dried (MgSO4) and concentrated.
The residue was purified by flash chromatography (6:1 to 2:1 hexanes/ethyl acetate) to yield the title compound (6.80 g, 38percent) as a beige solid.
LRMS (m/z): 255 (M+1)+.
1H-NMR δ (CDCl3): 4.77 (brs, 2H), 6.63 (s, 1H), 8.34 (s, 1H).
36% With N-iodo-succinimide In acetonitrileReflux N-lodosuccinimide (24.75 g, 110.0 mmol) was added to a solution of 2-chloro-pyridin-4-ylamine (12.85 g, 100.0 mmol) in acetonitrile (400 mL) and the mixture stirred and held at reflux overnight. Upon cooling to room temperature the solvent was removed in vacuo and residue partitioned between EtOAc (250 mL), saturated sodium thiosulfate (100 mL) andwater (250 mL). The organic layer was separated, washed with water (2 >< 250 mL), separated and the solvent removed in vacuo to afford an orange oil that was subjected to column chromatography on silica. Gradient elution with 30-50percent EtOAc in petrol afforded a pale orange solid that was rinsed with 25percent EtOAc in petrol (80 mL). Solids were collected by filtration and sucked dry to afford the title compound (7.32 g) as an off-white solid. Themother liquors were concentrated to dryness in vacuo and the residues subjected to columnchromatography on silica. Elution with 30-50percent EtOAc in petrol afforded further pure material(1.90 g). Combined yield: (9.22 g, 36percent) 1H NMR (DMSO-d6) 8.20 (1H, 5), 6.64 (1H, 5), 6.50(2H, br 5). MS: [M+H] 255.
36% With N-iodo-succinimide In acetonitrileReflux Preparation 10: 2-Chloro-5-iodo-pyridin-4-ylamineN-lodosuccinimide (24.75 g, 110.0 mmol) was added to a solution of 2-chloro-pyridin-4-ylamine(12.85 g, 100.0 mmol) in acetonitrile (400 mL) and the mixture stirred and held at refluxovernight. Upon cooling to room temperature the solvent was removed in vacuo and residuepartitioned between EtOAc (250 mL), saturated sodium thiosulfate (100 mL) and water (250 mL). The organic layer was separated, washed with water (2 >< 250 mL), separated and the solvent removed in vacuo to afford an orange oil that was subjected to column chromatography on silica. Gradient elution with 30-50percent EtOAc in petrol afforded a pale orange solid that was rinsed with 25percent EtOAc in petrol (80 mL). Solids were collected by filtration and sucked dry to afford the title compound (7.32 g) as an off-white solid. The mother liquors were concentrated to dryness invacuo and the residues subjected to column chromatography on silica. Elution with 30-50percent EtOAc in petrol afforded further pure material (1.90 g). Combined yield : (9.22 g, 36percent) 1H NMR (DMSO-d6) 8.20 (1 H, 5), 6.64 (1 H, 5), 6.50 (2H, br 5). MS: [M+H] 255.
36% With N-iodo-succinimide In acetonitrileReflux Preparation 7: 2-Chloro-5-iodo-pyridin-4-ylamine N-lodosuccinimide (24.75 g, 110.0 mmol) was added to a solution of 2-chloro-pyridin-4-ylamine (12.85 g, 100.0 mmol) in acetonitrile (400 mL) and the mixture stirred and held at reflux overnight. Upon cooling to room temperature the solvent was removed in vacuo and residue partitioned between EtOAc (250 mL), saturated sodium thiosulfate (100 mL) andwater (250 mL). The organic layer was separated, washed with water (2 >< 250 mL), separated and the solvent removed in vacuo to afford an orange oil that was subjected to column chromatography on silica. Gradient elution with 30-50percent EtOAc in petrol afforded a pale orange solid that was rinsed with 25percent EtOAc in petrol (80 mL). Solids were collected by filtration and sucked dry to afford the title compound (7.32 g) as an off-white solid. Themother liquors were concentrated to dryness in vacuo and the residues subjected to columnchromatography on silica. Elution with 30-50percent EtOAc in petrol afforded further pure material(1.90 g). Combined yield : (9.22 g, 36percent) 1H NMR (DMSO-d6) 8.20 (1H, 5), 6.64 (1H, 5), 6.50(2H, br 5). MS: [M+H] 255.
36% With N-iodo-succinimide In acetonitrile at 82℃; NIS (24.75 g, 110.0 mmol) was added to a solution of 2-chloropyridin-4-ylamine (12.85 g, 100.0 mmol) in MeCN (400 mL),and the mixture was stirred and held at reflux overnight. Uponcooling to r.t. the solvent was removed in vacuo and the residuepartitioned between EtOAc (250 mL), sat. Na2S2O3 (100 mL), andH2O (250 mL). The organic layer was separated, washed withH2O (2 × 250 mL), separated, and the solvent removed in vacuoto afford an orange oil that was subjected to column chromatographyon silica gel. Elution with 30–50percent EtOAc in PE afforded apale orange solid that was rinsed with 25percent EtOAc in PE (80 mL).The solids were collected by filtration and sucked dry to afford2-chloro-5-iodopyridin-4-ylamine (7.32 g) as an off-white solid.The mother liquors were concentrated to dryness in vacuo andthe residues subjected to column chromatography on silica.Elution with 30–50percent EtOAc in PE afforded further pure material(1.90 g). Combined yield 9.22 g, 36percent. 1H NMR (400 MHz, DMSOd6):δ = 8.20 (s, 1 H), 6.64 (s, 1 H), 6.50 (br s, 2 H). MS: m/z = 255,257 [M + H]+.
28.2% at 70℃; for 20 h; To a solution of 17.3 (5.0 g, 54.6 mmol,) in acetic acid (10 ml) was added sodium acetate (8.938 g, 109.0 mmol, 2.0 eq) and iodine monochloride (4.069 g, 65.5 mmol, 1.2 eq). Reaction mixture was heated at 70° C. for 20 hours. After completion of the reaction, mixture was concentrated under reduced pressure and residue was diluted with water and basified with sodium bicarbonate solution. Compound was extracted in EtOAc and washed with brine. Organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford crude material which was purified by chromatography using 12percent to afford pure 17.4 (2.8 g, 28.2percent), m/z=255.1 [M+H]+.

Reference: [1] Patent: CN105622638, 2016, A, . Location in patent: Paragraph 0194
[2] Patent: WO2015/38417, 2015, A1, . Location in patent: Page/Page column 73; 74
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 10229 - 10240
[4] Journal of Medicinal Chemistry, 2016, vol. 59, # 11, p. 5221 - 5237
[5] Patent: WO2014/207260, 2014, A1, . Location in patent: Page/Page column 77
[6] Patent: EP2818472, 2014, A1, . Location in patent: Paragraph 0089
[7] Patent: WO2009/44162, 2009, A1, . Location in patent: Page/Page column 237
[8] Patent: WO2016/210037, 2016, A1, . Location in patent: Page/Page column 36; 37
[9] Patent: EP2108641, 2009, A1, . Location in patent: Page/Page column 49
[10] Patent: WO2014/60768, 2014, A1, . Location in patent: Page/Page column 93
[11] Patent: WO2014/60767, 2014, A1, . Location in patent: Page/Page column 105; 106
[12] Patent: WO2014/60770, 2014, A1, . Location in patent: Page/Page column 124
[13] Synlett, 2015, vol. 26, # 18, p. 2570 - 2574
[14] Patent: US2016/251376, 2016, A1, . Location in patent: Paragraph 0477; 0480; 0481
[15] Patent: WO2006/59164, 2006, A2, . Location in patent: Page/Page column 23-24
[16] Patent: WO2006/67532, 2006, A1, . Location in patent: Page/Page column 18
[17] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 23, p. 7107 - 7112
[18] Patent: WO2010/130796, 2010, A1, . Location in patent: Page/Page column 103-104
[19] Patent: WO2004/104001, 2004, A2, . Location in patent: Page 74-75
  • 50
  • [ 14432-12-3 ]
  • [ 800402-12-4 ]
  • [ 909036-46-0 ]
YieldReaction ConditionsOperation in experiment
41% With sodium acetate; Iodine monochloride In acetic acid at 70℃; for 3.5 h; 4-Amino-2-chloro-5-iodopyridine (11); [00197] 4-Amino-2-chloropyridine (3.20 g 25 mmole) was stirred in acetic acid (20 mL) with sodium acetate (4.1 g 50 mmol) To the mixture was added a solution of iodine monochloride (4.1 g 25 mmol) in acetic acid (10 mL) and the reaction was heated at 70 °C for 3.5 h. Most of the acetic acid was evaporated and the reaction diluted with water (200 mL). The products were extracted with ethyl acetate (80, 70, 70 mL). The combined extracts were washed with 10percent sodium carbonate solution (100 mL), with 5percent sodium thiosulfate solution and with brine; then dried and evaporated. The crude product was purified by flash column chromatography on silica; eluting with 5percent ethyl acetate in dichloromethane, with 10percent ethyl acetate in dichloromethane and with 20percent ethyl acetate in dichloromethane to give first a small amount of di-iodinated product (618mg, 6.5percent); then the desired product 4-amino-5-iodo-2-chloropyridine (11 ) (2.64 g, 41 percent) and then the isomeric 4-amino-2-chloro-3-iodopyridine (12) (2.61 g, 41 percent). 4-Amino-5-iodo-2- chloropyridine (11 ) : 1 H-NMR (500 MHz, DMSO-d6): 6.48 (br s, 2H), 6.63 (s, 1 H), 8.19 (s, 1 H). 4-Amino-2-chloro-3-iodopyridine (12): 1 H-NMR (500MHz, DMSO-d6): 6.50 (br s, 2H), 6.54 (d, J= 5.36 Hz, 1 H); 7.74 (d, J= 5.68 Hz, 1 H).
41% at 70℃; for 3.5 h; 4-Amino-2-chloro-5-iodopyridine (11)
4-Amino-2-chloropyridine (3.20 g 25 mmole) was stirred in acetic acid (20 mL) with sodium acetate (4.1 g 50 mmol) To the mixture was added a solution of iodine monochloride (4.1 g 25 mmol) in acetic acid (10 mL) and the reaction was heated at 70° C. for 3.5 h.
Most of the acetic acid was evaporated and the reaction diluted with water (200 mL).
The products were extracted with ethyl acetate (80, 70, 70 mL).
The combined extracts were washed with 10percent sodium carbonate solution (100 mL), with 5percent sodium thiosulfate solution and with brine; then dried and evaporated. The crude product was purified by flash column chromatography on silica; eluting with 5percent ethyl acetate in dichloromethane, with 10percent ethyl acetate in dichloromethane and with 20percent ethyl acetate in dichloromethane to give first a small amount of di-iodinated product (618 mg, 6.5percent); then the desired product 4-amino-5-iodo-2-chloropyridine (11) (2.64 g, 41percent) and then the isomeric 4-amino-2-chloro-3-iodopyridine (12) (2.61 g, 41percent). 4-Amino-5-iodo-2-chloropyridine (11): 1H-NMR (500 MHz, DMSO-d6): 6.48 (br s, 2H), 6.63 (s, 1H), 8.19 (s, 1H). 4-Amino-2-chloro-3-iodopyridine (12): 1H-NMR (500 MHz, DMSO-d6): 6.50 (br s, 2H), 6.54 (d, J=5.36 Hz, 1H); 7.74 (d, J=5.68 Hz, 1H).
39% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 3 h; Intermediate 252A: 2-chloro-5-iodopyridin-4-amine To a stirred solution of 2-chloropyridin-4-amine (5 g, 39 mmol) in DMF (50 mL) was added NIS (8.75 g, 39 mmol). The reaction mixture was then heated at 80 °C for 3 h. The mixture was cooled and the DMF removed in vacuo. The residue was partitioned between EtOAc and water and the layers were separated. The organic layer was dried over Na2S04, filtered, and concentrated. The product was purified via column chromatography (10percent EtO Ac/pet ether) to afford 2-chloro-5-iodopyridin-4-amine (4 g, 39percent yield). LCMS: 254.8 (M+). Further elution with 12percent EtO Ac/pet ether afforded 2- chloro-3-iodopyridin-4-amine (4 g, 39percent yield).
11.6 g at 80℃; for 3 h; 2-Chloro-4-aminopyridine (25 g, 194 mmol)And potassium acetate (19. 05 g, 194 mmol) were dissolved in 250 mL acetic acid and heated to 80 ° C. A solution of (31.56 g, 194 mmol) in acetic acid (40 mL) was added dropwise and the reaction mixture was stirred at 80 C for 3 h. The reaction mixture was cooled to room temperature and neutralized with saturated aqueous NaHC03 solution. A dark, off-white solid precipitated, which was dissolved in dichloromethane and washed with saturated aqueous NaHSO3, dried over Na2S04, concentrated and purified by column chromatography using hexane and ethyl acetate as eluents. 1. 6 g of the title compound were isolated,Along with 13. 4 g of the non-targeted isomer.

Reference: [1] Patent: WO2012/123745, 2012, A1, . Location in patent: Page/Page column 67-68
[2] Patent: US2013/345181, 2013, A1, . Location in patent: Page/Page column 0625; 0631
[3] Patent: WO2016/210034, 2016, A1, . Location in patent: Page/Page column 171-172
[4] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4567 - 4570
[5] Patent: CN102449107, 2016, B, . Location in patent: Paragraph 0318; 0319; 0320
  • 51
  • [ 14432-12-3 ]
  • [ 800402-12-4 ]
  • [ 909036-46-0 ]
  • [ 1171919-00-8 ]
YieldReaction ConditionsOperation in experiment
49.7% With potassium acetate; Iodine monochloride In acetic acid at 70℃; for 4 h; Inert atmosphere A mixture of 2-chloro-4-amino pyridine 1 (20g, 0.15mol), potassium acetate (22.9g, 0.23mol) and ICl (27.7g, 0.17mol) in glacial acetic acid (200mL) was heated to 70°C for 4h. The solvent was concentrated under reduced pressure. The residue was neutralized with 10percent NaHCO3 solution (250mL) and extracted with two 300-mL portions of EtOAc. The combined organic extracts were washed with brine (200mL) and dried over anhydrous Na2SO4. The solvent was removed in vacuum. The crude product showed a mixture of iodopyridines 2, 3 and 4 in the ratio 45:45:10. The required compound 2 (elution 2) was isolated via normal phase preparative HPLC (mobile phase: 60:40, 0.1percent TFA in hexane-IPA; column: SunFire Silica 19*150mm, 5μm; Flow rate: 18.0mL/min) in 49.7percent yield (19.7g) as an off white solid.
49.7% at 70℃; for 4 h; Inert atmosphere A mixture of 2-chloro-4-amino pyridine 1 (20g, 0.15mol), potassium acetate (22.9g, 0.23mol) and ICl (27.7g, 0.17mol) in glacial acetic acid (200mL) was heated to 70°C for 4h. After completion of the reaction, the solvent was concentrated under reduced pressure. The residue was neutralized with 10percent NaHCO3 solution (250mL) and extracted with two 300-mL portions of EtOAc. The combined organic extracts were washed with brine (200mL) and dried over anhydrous Na2SO4. The solvent was removed in vacuum. The crude product showed a mixture of iodopyridines 2, 3 and 4 in the ratio 45:45:10. The required compound 2 (elution 3) was isolated via normal phase preparative HPLC (mobile phase: 60:40, 0.1percent TFA in hexane-IPA; column: SunFire Silica 19×150mm, 5μm; Flow rate: 18.0mL/min) in 49.7percent yield (19.7g) as an off white solid; mp 102.9–104.1°C; 1H NMR (400MHz, DMSO-D6): δ 7.73 (d, J=4.0Hz, 1H), 6.52 (d, J=4.0Hz, 1H), 6.50 (s, 2H); MS (m/z): 255.0 [M+H]+. Anal. calcd. for C5H4ClIN2: C, 23.60; H, 1.58; N, 11.01; found: C, 23.59; H, 1.578; N, 10.99
Reference: [1] European Journal of Medicinal Chemistry, 2014, vol. 77, p. 288 - 297
[2] Journal of Molecular Structure, 2014, vol. 1081, p. 85 - 95
[3] Journal of Organic Chemistry, 2012, vol. 77, # 11, p. 5006 - 5016
[4] European Journal of Medicinal Chemistry, 2017, vol. 131, p. 275 - 288
  • 52
  • [ 14432-12-3 ]
  • [ 800402-12-4 ]
  • [ 1171919-00-8 ]
Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 23, p. 9382 - 9394
  • 53
  • [ 14432-12-3 ]
  • [ 909036-46-0 ]
YieldReaction ConditionsOperation in experiment
45% at 70℃; for 16 h; Inert atmosphere A 50 mL single necked round bottom flask equipped with a magnetic stirrer bar,reflux condenser and nitrogen line was charged with 2-chloropyridin-4-amine 12 (2.50 g, 19.4 mmol, 1.0 equiv), sodiumacetate trihydrate (3.97 g, 29.2 mmol, 1.5 equiv), iodine monochloride(3.47 g, 21.4 mmol, 1.1 equiv) and glacial acetic acid(13.0 mL) and heated at 70 °C with magnetically facilitated stirring under nitrogen for 16 h, at which point tlc and GC/MS (EI) analysisshowed that the starting material had been consumed. The reactionmixture was cooled and transferred to a separating funnel where itwas carefully quenched with portion wise addition of solidpowdered sodium hydrogencarbonate (32.3 g), water (75 mL) and ethyl acetate (75 mL). The resultant effervescence was allowed to subside and the mixture was not shaken. The layers were thenseparated and the aqueous layer was extracted with ethyl acetate(6 x 25 mL), with shaking. The organic layers were combined anddried over magnesium sulfate and the solvent was removed viarotary evaporation. The residue was purified by portionwise flashcolumn chromatography over silica using n-hexane/ethyl acetate(94:6 to 60:40) mixtures as eluent to give 2-chloro-3-iodopyridin-4-amine 13 as a light brown solid (2.21 g, 45percent), a sample of whichhad 1H NMR spectral data and low resolution GC/MS (EI) massspectral data identical to those in the literature [12].
42% With N-iodo-succinimide In N,N-dimethyl-formamide at 20 - 55℃; 2-Chloro-4-aminopyridine (1.8 g, 14 mmol) was dissolved in 28 ml dimethylformamide. N-lodosuccinimide (3.15 g, 14 mmol) was added and the mixture was stirred at room temperature overnight.
Additional N-iodosuccinimide (3.15 g, 14 mmol) was added and the mixture wasa stirred at 55ºC overnight.
The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water.
The aqueous was extracted with ethyl acetate and the combined organics were dried over sodium sulphate, filtered and evaporated.
Purification by flash chromatography (ethyl acetate-hexane gradient, 15:85 rising to 25:75) gave 1.5 g (5.9 mmol, 42percent) of the title compound as a purple solid.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.34 (1 H, s), 6.63 (1 H, s), 4.75 (2 H, br. s.).
42% With N-iodo-succinimide In N,N-dimethyl-formamide at 20 - 55℃; PREPARATION 41 2-Chloro-3-iodopyridin-4-amine 2-Chloro-4-aminopyridine (1 .8 g, 14 mmol) was dissolved in 28 ml dimethylformamide. N-lodosuccinimide (3.15 g, 14 mmol) was added and the mixture was stirred at room temperature overnight. Additional N-iodosuccinimide (3.15 g, 14 mmol) was added and the mixture wasa stirred at 55 °C overnight. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The aqueous was extracted with ethyl acetate and the combined organics were dried over sodium sulphate, filtered and evaporated under reduced pressure. Purification by flash chromatography (ethyl acetate-hexane gradient, 15:85 rising to 25:75) gave 1 .5 g (5.9 mmol, 42percent) of the title compound as a purple solid. 1 H N MR (300 MHz, CHLOROFORM-d) δ ppm 8.34 (1 H, s), 6.63 (1 H, s), 4.75 (2 H, br. s.).
42% With N-iodo-succinimide In N,N-dimethyl-formamide at 20 - 55℃; 2-Chloro-4-aminopyridine (1.8 g, 14 mmol) was dissolved in 28 ml   dimethylformamide. N-Iodosuccinimide (3.15 g, 14 mmol) was added and the mixture was stirred at room temperature overnight. Additional   N-iodosuccinimide (3.15 g, 14 mmol) was added and the mixture wasa stirred at 55 ºC overnight. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The aqueous was extracted with ethyl acetate and the combined organics were dried over sodium sulphate, filtered and evaporated under reduced pressure. Purification by flash chromatography (ethyl acetate-hexane gradient, 15:85 rising to 25:75) gave 1.5 g (5.9 mmol, 42percent) of the   title compound as a purple solid. [0369] 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.34 (1 H, s), 6.63 (1 H, s), 4.75 (2 H, br. s.).
41% at 70℃; 2-Chloro-pyridin-4-ylamine 1a* (3.2 g, 25 mmol) and sodium acetate (4.1 g, 50 mmol) were stirred in acetic acid (20 mL). A solution of iodine monochloride (4.1 g, 25 mmol) in acetic acid (10 mL) was added and the reaction mixture was heated to 70 °C for approximately three h (NB: reaction mixture became a solution at -50 °C, the brown colour faded and a precipitate formed as the reaction proceeded). The reaction mixture was cooled to room temperature, then poured onto water (700 mL), and extracted with AcOEt (2 χ 750 mL). The organic phase was carefully washed with a saturated aqueous solution of sodium carbonate (500 mL) followed by a 10percent solution of sodium thiosulfate (500 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography using 10percent AcOEt in DCM to yield 2-chloro-3-iodo-pyridin-4-ylamine 2a* (2.6 g, 41 percent). NMR (400 MHz, CDCl3) δ (ppm): 7.88 (1 H, d, J = 5.5 Hz), 6.46 (1 H, d, J = 5.5 Hz), 4.96 (2 H, s).
41% With sodium acetate; Iodine monochloride In acetic acid at 70℃; for 3 h; 10.3
Synthesis of 2-chloro-3-iodo-pyridin-4-ylamine 2a*
2-Chloro-pyridin-4-ylamine 1a* (3.2 g, 25 mmol) and sodium acetate (4.1 g, 50 mmol) were stirred in acetic acid (20 mL).
A solution of iodine monochloride (4.1 g, 25 mmol) in acetic acid (10 mL) was added and the reaction mixture was heated to 70 °C for approximately three h (NB: reaction mixture became a solution at ∼50 °C, the brown colour faded and a precipitate formed as the reaction proceeded).
The reaction mixture was cooled to room temperature, then poured onto water (700 mL), and extracted with AcOEt (2 x 750 mL).
The organic phase was carefully washed with a saturated aqueous solution of sodium carbonate (500 mL) followed by a 10percent solution of sodium thiosulfate (500 mL), dried over MgSO4 and concentrated in vacuo.
The crude product was purified by column chromatography using 10percent AcOEt in DCM to yield 2-chloro-3-iodo-pyridin-4-ylamine 2a* (2.6 g, 41 percent).
1H NMR (400 MHz, CDCl3) δ (ppm): 7.88 (1 H, d, J = 5.5 Hz), 6.46 (1 H, d, J = 5.5 Hz), 4.96 (2 H, s).

Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 128, p. 202 - 212
[2] Patent: EP2526945, 2012, A1, . Location in patent: Page/Page column 63
[3] Patent: WO2013/10880, 2013, A1, . Location in patent: Page/Page column 94
[4] Patent: EP2548876, 2013, A1, . Location in patent: Paragraph 0368; 0369
[5] Patent: WO2014/207260, 2014, A1, . Location in patent: Page/Page column 78
[6] Patent: EP2818472, 2014, A1, . Location in patent: Paragraph 0091
[7] Patent: WO2006/114180, 2006, A1, . Location in patent: Page/Page column 81-82
  • 54
  • [ 14432-12-3 ]
  • [ 800402-12-4 ]
  • [ 909036-46-0 ]
YieldReaction ConditionsOperation in experiment
41% With sodium acetate; Iodine monochloride In acetic acid at 70℃; for 3.5 h; 4-Amino-2-chloro-5-iodopyridine (11); [00197] 4-Amino-2-chloropyridine (3.20 g 25 mmole) was stirred in acetic acid (20 mL) with sodium acetate (4.1 g 50 mmol) To the mixture was added a solution of iodine monochloride (4.1 g 25 mmol) in acetic acid (10 mL) and the reaction was heated at 70 °C for 3.5 h. Most of the acetic acid was evaporated and the reaction diluted with water (200 mL). The products were extracted with ethyl acetate (80, 70, 70 mL). The combined extracts were washed with 10percent sodium carbonate solution (100 mL), with 5percent sodium thiosulfate solution and with brine; then dried and evaporated. The crude product was purified by flash column chromatography on silica; eluting with 5percent ethyl acetate in dichloromethane, with 10percent ethyl acetate in dichloromethane and with 20percent ethyl acetate in dichloromethane to give first a small amount of di-iodinated product (618mg, 6.5percent); then the desired product 4-amino-5-iodo-2-chloropyridine (11 ) (2.64 g, 41 percent) and then the isomeric 4-amino-2-chloro-3-iodopyridine (12) (2.61 g, 41 percent). 4-Amino-5-iodo-2- chloropyridine (11 ) : 1 H-NMR (500 MHz, DMSO-d6): 6.48 (br s, 2H), 6.63 (s, 1 H), 8.19 (s, 1 H). 4-Amino-2-chloro-3-iodopyridine (12): 1 H-NMR (500MHz, DMSO-d6): 6.50 (br s, 2H), 6.54 (d, J= 5.36 Hz, 1 H); 7.74 (d, J= 5.68 Hz, 1 H).
41% at 70℃; for 3.5 h; 4-Amino-2-chloro-5-iodopyridine (11)
4-Amino-2-chloropyridine (3.20 g 25 mmole) was stirred in acetic acid (20 mL) with sodium acetate (4.1 g 50 mmol) To the mixture was added a solution of iodine monochloride (4.1 g 25 mmol) in acetic acid (10 mL) and the reaction was heated at 70° C. for 3.5 h.
Most of the acetic acid was evaporated and the reaction diluted with water (200 mL).
The products were extracted with ethyl acetate (80, 70, 70 mL).
The combined extracts were washed with 10percent sodium carbonate solution (100 mL), with 5percent sodium thiosulfate solution and with brine; then dried and evaporated. The crude product was purified by flash column chromatography on silica; eluting with 5percent ethyl acetate in dichloromethane, with 10percent ethyl acetate in dichloromethane and with 20percent ethyl acetate in dichloromethane to give first a small amount of di-iodinated product (618 mg, 6.5percent); then the desired product 4-amino-5-iodo-2-chloropyridine (11) (2.64 g, 41percent) and then the isomeric 4-amino-2-chloro-3-iodopyridine (12) (2.61 g, 41percent). 4-Amino-5-iodo-2-chloropyridine (11): 1H-NMR (500 MHz, DMSO-d6): 6.48 (br s, 2H), 6.63 (s, 1H), 8.19 (s, 1H). 4-Amino-2-chloro-3-iodopyridine (12): 1H-NMR (500 MHz, DMSO-d6): 6.50 (br s, 2H), 6.54 (d, J=5.36 Hz, 1H); 7.74 (d, J=5.68 Hz, 1H).
39% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 3 h; Intermediate 252A: 2-chloro-5-iodopyridin-4-amine To a stirred solution of 2-chloropyridin-4-amine (5 g, 39 mmol) in DMF (50 mL) was added NIS (8.75 g, 39 mmol). The reaction mixture was then heated at 80 °C for 3 h. The mixture was cooled and the DMF removed in vacuo. The residue was partitioned between EtOAc and water and the layers were separated. The organic layer was dried over Na2S04, filtered, and concentrated. The product was purified via column chromatography (10percent EtO Ac/pet ether) to afford 2-chloro-5-iodopyridin-4-amine (4 g, 39percent yield). LCMS: 254.8 (M+). Further elution with 12percent EtO Ac/pet ether afforded 2- chloro-3-iodopyridin-4-amine (4 g, 39percent yield).
11.6 g at 80℃; for 3 h; 2-Chloro-4-aminopyridine (25 g, 194 mmol)And potassium acetate (19. 05 g, 194 mmol) were dissolved in 250 mL acetic acid and heated to 80 ° C. A solution of (31.56 g, 194 mmol) in acetic acid (40 mL) was added dropwise and the reaction mixture was stirred at 80 C for 3 h. The reaction mixture was cooled to room temperature and neutralized with saturated aqueous NaHC03 solution. A dark, off-white solid precipitated, which was dissolved in dichloromethane and washed with saturated aqueous NaHSO3, dried over Na2S04, concentrated and purified by column chromatography using hexane and ethyl acetate as eluents. 1. 6 g of the title compound were isolated,Along with 13. 4 g of the non-targeted isomer.

Reference: [1] Patent: WO2012/123745, 2012, A1, . Location in patent: Page/Page column 67-68
[2] Patent: US2013/345181, 2013, A1, . Location in patent: Page/Page column 0625; 0631
[3] Patent: WO2016/210034, 2016, A1, . Location in patent: Page/Page column 171-172
[4] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4567 - 4570
[5] Patent: CN102449107, 2016, B, . Location in patent: Paragraph 0318; 0319; 0320
  • 55
  • [ 14432-12-3 ]
  • [ 800402-12-4 ]
  • [ 909036-46-0 ]
  • [ 1171919-00-8 ]
YieldReaction ConditionsOperation in experiment
49.7% With potassium acetate; Iodine monochloride In acetic acid at 70℃; for 4 h; Inert atmosphere A mixture of 2-chloro-4-amino pyridine 1 (20g, 0.15mol), potassium acetate (22.9g, 0.23mol) and ICl (27.7g, 0.17mol) in glacial acetic acid (200mL) was heated to 70°C for 4h. The solvent was concentrated under reduced pressure. The residue was neutralized with 10percent NaHCO3 solution (250mL) and extracted with two 300-mL portions of EtOAc. The combined organic extracts were washed with brine (200mL) and dried over anhydrous Na2SO4. The solvent was removed in vacuum. The crude product showed a mixture of iodopyridines 2, 3 and 4 in the ratio 45:45:10. The required compound 2 (elution 2) was isolated via normal phase preparative HPLC (mobile phase: 60:40, 0.1percent TFA in hexane-IPA; column: SunFire Silica 19*150mm, 5μm; Flow rate: 18.0mL/min) in 49.7percent yield (19.7g) as an off white solid.
49.7% at 70℃; for 4 h; Inert atmosphere A mixture of 2-chloro-4-amino pyridine 1 (20g, 0.15mol), potassium acetate (22.9g, 0.23mol) and ICl (27.7g, 0.17mol) in glacial acetic acid (200mL) was heated to 70°C for 4h. After completion of the reaction, the solvent was concentrated under reduced pressure. The residue was neutralized with 10percent NaHCO3 solution (250mL) and extracted with two 300-mL portions of EtOAc. The combined organic extracts were washed with brine (200mL) and dried over anhydrous Na2SO4. The solvent was removed in vacuum. The crude product showed a mixture of iodopyridines 2, 3 and 4 in the ratio 45:45:10. The required compound 2 (elution 3) was isolated via normal phase preparative HPLC (mobile phase: 60:40, 0.1percent TFA in hexane-IPA; column: SunFire Silica 19×150mm, 5μm; Flow rate: 18.0mL/min) in 49.7percent yield (19.7g) as an off white solid; mp 102.9–104.1°C; 1H NMR (400MHz, DMSO-D6): δ 7.73 (d, J=4.0Hz, 1H), 6.52 (d, J=4.0Hz, 1H), 6.50 (s, 2H); MS (m/z): 255.0 [M+H]+. Anal. calcd. for C5H4ClIN2: C, 23.60; H, 1.58; N, 11.01; found: C, 23.59; H, 1.578; N, 10.99
Reference: [1] European Journal of Medicinal Chemistry, 2014, vol. 77, p. 288 - 297
[2] Journal of Molecular Structure, 2014, vol. 1081, p. 85 - 95
[3] Journal of Organic Chemistry, 2012, vol. 77, # 11, p. 5006 - 5016
[4] European Journal of Medicinal Chemistry, 2017, vol. 131, p. 275 - 288
  • 56
  • [ 14432-12-3 ]
  • [ 800401-54-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 23, p. 7107 - 7112
[2] Patent: WO2004/104001, 2004, A2,
  • 57
  • [ 14432-12-3 ]
  • [ 215364-85-5 ]
YieldReaction ConditionsOperation in experiment
62% at 0 - 20℃; for 1 h; Inert atmosphere To a stirred solution of 2-chloropyridin-4-amine 17A (2 g, 15.56 mmol) in acetic acid (20 mL) was added NBS (2.77 g, 15.56 mmol) portion-wise at 00 C under nitrogen. Then reaction mixture was allowed to stir at room temperature for 1 h. The solvent was removed under reduced pressure, followed by azeotropic distillation with ethanol. The cmde compound was purified by silica gel chromatography (40 g RediSep® column, eluting with a gradient of 10-20 percent ethyl acetate in petroleum ether) to yield Compound 15B (2 g, 9.64 mmol, 62.0 percent yield) as a white solid. LCMS: m/z = 209.0 [M+Hf’; ret. time 0.84 mm; condition B.
47% at 20℃; 10879] To a solution of 2-chioro-4-amino-pyridine (5.00 g,38.9 mmol) in acetic acid (50 mE) was added N-bromosuccinimide (7.61 g, 42.8 mmol) maintaining the temperature at rt by using an ice-bath. The mixture was stirred at rt overnight. The mixture was concentrated under vacuum with the help of toluene for azeotropic evaporation of the acid. The residuewas dried in high vacuum before it was purified by chromatography on silica gel (biotage, CyHex/EtOAc, 90:10 to 50:50) to give the product (3.80 g, 47percent) as a colourless solid
Reference: [1] Patent: WO2016/133838, 2016, A1, . Location in patent: Paragraph 0315
[2] Patent: US2016/16951, 2016, A1, . Location in patent: Paragraph 0878; 0879
[3] Patent: WO2008/8539, 2008, A2, . Location in patent: Page/Page column 133
[4] Patent: US2014/336182, 2014, A1, . Location in patent: Paragraph 0306-0307
[5] Patent: WO2008/124083, 2008, A2, . Location in patent: Page/Page column 47
  • 58
  • [ 14432-12-3 ]
  • [ 857730-21-3 ]
  • [ 215364-85-5 ]
Reference: [1] Patent: WO2005/61500, 2005, A1, . Location in patent: Page/Page column 158
  • 59
  • [ 14432-12-3 ]
  • [ 36953-37-4 ]
Reference: [1] Synlett, 2016, vol. 27, # 1, p. 67 - 69
[2] Synlett, 2016, vol. 27, # 1, p. 67 - 69
  • 60
  • [ 14432-12-3 ]
  • [ 24424-99-5 ]
  • [ 68-12-2 ]
  • [ 893423-62-6 ]
Reference: [1] Patent: WO2005/100356, 2005, A1, . Location in patent: Page/Page column 47
  • 61
  • [ 14432-12-3 ]
  • [ 893423-62-6 ]
Reference: [1] Patent: WO2006/135627, 2006, A2,
[2] Patent: WO2006/135627, 2006, A2,
  • 62
  • [ 14432-12-3 ]
  • [ 215364-86-6 ]
Reference: [1] Patent: US2014/336182, 2014, A1,
[2] Patent: WO2008/124083, 2008, A2,
  • 63
  • [ 14432-12-3 ]
  • [ 952138-19-1 ]
Reference: [1] Patent: US2014/336182, 2014, A1,
[2] Patent: WO2008/124083, 2008, A2,
  • 64
  • [ 14432-12-3 ]
  • [ 960298-00-4 ]
Reference: [1] Synlett, 2016, vol. 27, # 1, p. 67 - 69
  • 65
  • [ 14432-12-3 ]
  • [ 858839-90-4 ]
Reference: [1] Synlett, 2016, vol. 27, # 1, p. 67 - 69
  • 66
  • [ 14432-12-3 ]
  • [ 1383716-84-4 ]
  • [ 1383716-33-3 ]
YieldReaction ConditionsOperation in experiment
49%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃; for 0.5 h; Inert atmosphere
Stage #2: at 20℃; for 1 h;
l-(2-(2-chloropyridin-4-ylamino)-4,-(cyclopropylmethyl)-4,5,-bipyrimidin-2'- ylamino)-2-methylpropan-2-ol (16a): To a solution of 4-amino-2-chloropyridine (53.3 mg, 0.415 mmol) in THF (277 μ) cooled to -78°C under nitrogen, LiHMDS (415 μ, 0.415 mmol) was added dropwise. The reaction mixture was warmed up to rt, then was stirred for 30 min. To the reaction mixture cooled back to -78°C, l-(4'- (cyclopropylmethyl)-2-(methylsulfinyl)-4,5'-bipyrimidin-2'-ylamino)-2-methylpropan-2- ol (5-3) (50 mg, 0.138 mmol) was added, and the reaction mixture was warmed up to rt, then was stirred for additional lh. According to LC/MS, the reaction was complete. The crude product was purified by reverse-phase HPLC [30-100percent organic phase over 15 min] followed by Biotage silica gel chromatography [10 g SNAP column, 100percent DCM to 12percent MeOH/DCM] to obtain the desired product (29mg, 49percent).
Reference: [1] Patent: WO2012/85815, 2012, A1, . Location in patent: Page/Page column 55-56;73
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