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Chemical Structure| 2402-77-9
Chemical Structure| 2402-77-9
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Product Details of [ 2402-77-9 ]

CAS No. :2402-77-9 MDL No. :MFCD00006229
Formula : C5H3Cl2N Boiling Point : -
Linear Structure Formula :- InChI Key :MAKFMOSBBNKPMS-UHFFFAOYSA-N
M.W :147.99 Pubchem ID :16988
Synonyms :

Calculated chemistry of [ 2402-77-9 ]

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 : 0.0
Molar Refractivity : 34.26
TPSA : 12.89 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) : 1.77
Log Po/w (XLOGP3) : 2.11
Log Po/w (WLOGP) : 2.39
Log Po/w (MLOGP) : 1.68
Log Po/w (SILICOS-IT) : 2.73
Consensus Log Po/w : 2.14

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.64
Solubility : 0.338 mg/ml ; 0.00228 mol/l
Class : Soluble
Log S (Ali) : -2.01
Solubility : 1.44 mg/ml ; 0.00974 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.24
Solubility : 0.0859 mg/ml ; 0.000581 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.43

Safety of [ 2402-77-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 2402-77-9 ]

* 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 [ 2402-77-9 ]
  • Downstream synthetic route of [ 2402-77-9 ]

[ 2402-77-9 ] Synthesis Path-Upstream   1~37

  • 1
  • [ 2402-77-9 ]
  • [ 39620-04-7 ]
YieldReaction ConditionsOperation in experiment
45% at 190℃; for 48 h; bomb 2,3-Dichloropyridine (5.0 g, 34 mmol) and ammonium hydroxide (125 ml) were placed in a steel bomb and heated at 190 0C for 48 hours. After cooling to room temperature the reaction was diluted with EtOAc (150 ml), washed with water (3 x 50 ml), dried (MgSO4), filtered and concentrated at a reduced pressure. Recrystallisation (EtOAc) gave the title compound (2.0 g, 45percent) as pale yellow solid.LCMS data: Calculated MH+ (129/131); Found 100percent (MH+) m/z 129/131, Rt = solvent front. NMR data: 1H NMR (250 MHz, CDCl3) δ ppm 8.0 (1 H, dd, J=2, 0.6 Hz), 7.49 (1 H, d, J=4.9, 0.6 Hz), 6.6 (1 H, dd, J=A.9, 2 Hz).
Reference: [1] Organic Letters, 2003, vol. 5, # 8, p. 1369 - 1372
[2] Patent: WO2009/135842, 2009, A1, . Location in patent: Page/Page column 82-83
[3] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
  • 2
  • [ 2402-77-9 ]
  • [ 64-10-8 ]
  • [ 39620-04-7 ]
Reference: [1] Synthesis, 2005, # 6, p. 915 - 924
  • 3
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  • [ 39620-04-7 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
  • 4
  • [ 1851-22-5 ]
  • [ 16110-09-1 ]
  • [ 2402-77-9 ]
  • [ 55934-00-4 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1988, vol. 36, p. 2244 - 2247
  • 5
  • [ 2402-77-9 ]
  • [ 107-11-9 ]
  • [ 5654-93-3 ]
YieldReaction ConditionsOperation in experiment
37% With sodium t-butanolate In toluene at 140℃; for 24 h; sealed tube EXAMPLE 14; N'-(3,4-Dimethoxybenzylidene)-3-(3-methyl-lH-pyrrolo[2,3-b]pyridin-l- yl)propanehydrazide; [0516] (a) 3-Methyl-lH-pyrrolo[2,3-b]pyridine: This intermediate was prepared using a similar method to that described by Jensen et. al., Angew. Chem. Int. Ed. 2008, 47, 888-890. To a reaction tube was added toluene (5 mL), 2,3-dichloropyridine (300 mg, 2.03 mmol), Pd2dba3 (2 mg, 0.0025 mmol), dppf (6 mg, 0.01 mmol), NaOtBu (487 mg, 5.07 mmol), and allylamine (0.15 mL, 2.03 mmol). The reaction tube was sealed and heated at 140 0C for 20 hours followed by stirring at room temperature for 24 hours. The reaction mixture was washed with water, brine and dried (Na2SO4) and absorbed onto silica gel. Purification on silica gel using DCM-hexane (0 to 60percent), followed by EtOAc-hexane (80percent) provided a orange solid (100 mg, 37percent).
67 mg With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate In toluene at 140℃; for 44.3 h; Inert atmosphere; Sealed tube A mixture of 2,3-dichloropyridine (500mg), allylamine (0.254mL), NaOtBu (1.19g), Pd2dba3 (37.9mg), dppf (91.8mg) in toluene (15mL) was prepared under argon and divided into three vials. The vials were sealed and evacuated and backfilled with argon three times. The resulting green-brown suspensions were heated up to 140°C for 19.3h. Pd2dba3 (0.0125eq) and dppf (0.05eq) were added and the reaction mixture was further stirred at 140°C for 25h. After cooling down, the combined reaction mixtures were diluted with EAand washed with water and brine. The aq. layers were extracted with EA. The combined org. layers were dried over MgS04, filtrated off and evaporated to dryness. CC of the crude (Biotage, SNAP 25g cartridge, solvent A: Hept; solvent B: EA; gradient in percentB: 50 for 6CV, 50 to 70 over 3CV, 70 for 5CV, 70 to 100 over 3CV, 100 for 3CV) afforded 67mg of brown solid. LC-MS (B): tR = 0.44min; [M+H]+: 133.22.
67 mg With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate In toluene at 140℃; for 44.3 h; Inert atmosphere; Sealed tube A mixture of 2,3-dichloropyridine (500 mg), allylamine (0.254 mL), NaOtBu (1.19 g), Pd2dba3 (37.9 mg), dppf (91.8 mg) in toluene (15 mL) was prepared under argon and divided into three vials. The vials were sealed and evacuated and backfilled with argon three times. The resulting green-brown suspensions were heated up to 140° C. for 19.3 h. Pd2dba3 (0.0125 eq) and dppf (0.05 eq) were added and the reaction mixture was further stirred at 140° C. for 25 h. After cooling down, the combined reaction mixtures were diluted with EA and washed with water and brine. The aq. layers were extracted with EA. The combined org. layers were dried over MgSO4, filtrated off and evaporated to dryness. CC of the crude (Biotage, SNAP 25 g cartridge, solvent A: Hept; solvent B: EA; gradient in percent B: 50 for 6CV, 50 to 70 over 3CV, 70 for 5CV, 70 to 100 over 3CV, 100 for 3CV) afforded 67 mg of brown solid. LC-MS (B): tR=0.44 min; [M+H]+: 133.22
Reference: [1] Angewandte Chemie - International Edition, 2008, vol. 47, # 5, p. 888 - 890
[2] Patent: WO2010/132615, 2010, A1, . Location in patent: Page/Page column 111
[3] Patent: WO2013/114332, 2013, A1, . Location in patent: Page/Page column 92; 93
[4] Patent: US2014/371204, 2014, A1, . Location in patent: Paragraph 0718
  • 6
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  • [ 57266-69-0 ]
Reference: [1] Patent: CN105218437, 2016, A,
  • 7
  • [ 2402-77-9 ]
  • [ 184416-83-9 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 6, p. 2688 - 2701
  • 8
  • [ 2402-77-9 ]
  • [ 64-17-5 ]
  • [ 201230-82-2 ]
  • [ 2050-22-8 ]
Reference: [1] Heterocycles, 1999, vol. 51, # 11, p. 2589 - 2602
  • 9
  • [ 557-21-1 ]
  • [ 2402-77-9 ]
  • [ 38180-46-0 ]
YieldReaction ConditionsOperation in experiment
9.08 g With tetrakis(triphenylphosphine) palladium(0) In 1-methyl-pyrrolidin-2-one at 100℃; for 2 h; Production Example 13 (1) [0728] A mixture of 29.6 g of 2,3-dichloropyridine, 46.97 g of zinc cyanide, 11.56 g of tetratris(triphenylphosphine)palladium(0) and 150 mL of NMP was stirred at 100°C for 2 hours. Water was added to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 9.08 g of 3-chloropyridine-2-carbonitrile. 3-Chloropyridine-2-carbonitrile 1H-NMR (CDCl3) δ: 8.63 (1H, dd), 7.88 (1H, dd), 7.50 (1H, ddd)
Reference: [1] Patent: EP2881386, 2015, A1, . Location in patent: Paragraph 0728
  • 10
  • [ 2402-77-9 ]
  • [ 144-55-8 ]
  • [ 38180-46-0 ]
Reference: [1] Patent: CN105218437, 2016, A, . Location in patent: Paragraph 0007
  • 11
  • [ 2402-77-9 ]
  • [ 38180-46-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 16, p. 4611 - 4616
[2] Patent: US2003/55085, 2003, A1,
  • 12
  • [ 2402-77-9 ]
  • [ 22841-92-5 ]
YieldReaction ConditionsOperation in experiment
97.6% With hydrazine hydrate In ethanol for 25 h; Reflux In a reaction flask, 70 g of 2,3-dichloropyridine and 250 ml of ethanol having a mass concentration of 95percent were added,125ml of hydrazine hydrate with a mass concentration of 50percent was added dropwise under vigorous stirring,After completion of the dropwise addition,Heated to reflux 25h,Cooled to room temperature,A large number of white crystal precipitation, filtration, drying in 3-chloro-2-hydrazinopyridine
95% at 130℃; for 10 h; Inert atmosphere 148g of 2,3-dichloropyridine and 3700g of N, N-dimethyl propanolamine in the reactor were mixed,Add 105g 80percent hydrazine hydrate,The atmosphere was replaced with nitrogen three times with nitrogen,Then warmed to 130 ° C,Insoluble reaction was refluxed for 10 hours,The reaction is over,Cooled to 25 crystallization,Then transferred to a centrifuge centrifuge,And washing the centrifuged solid with water,Centrifugal mother liquor into N, N- dimethyl propanolamine mother liquor tank for distillation,After centrifugation, the solid was sent to a double cone dryer (-0.09 MPa, 60 ° C.)In dry,The product 3-chloro-2-hydrazinopyridine.The purity of 3-chloro-2-hydrazinopyridine in step (b) was 99.7percentThe yield is 95percentLiquid chromatogram shown in Figure 2.
94% for 4 h; Reflux To a 1 L three-necked flask was added 148.02 g (1.0 mol) of b-1 and 500 ml of 85percent hydrazine hydrate,Mechanical stirring under reflux 4h,After a period of reflow, the reaction solution becomes clear,TLC test reaction, the raw material reaction is complete, standing, the reaction solution to precipitate a large number of white crystals, the reaction solution into 800ml of water, magnetic stirring, the reaction precipitation more crystals, filter, filter cake were washed with 200ml water three times, The infrared lamp was dried to give a white needle-like crystal B-2 having a weight of 137 g and a yield of 94percent.
94.4% With hydrazine hydrate In ethanol at 20℃; for 5 h; Reflux Step A:Add 50percent hydrazine hydrate 20m L to 2,3-dichloropyridine at room temperature(7.35g, 0.05mol) in 20mL ethanol solution, heated to reflux for 5h,Cool to room temperature and collect white acicular solid product by filtration3-chloro-2-mercaptopyridine 6.75g, yield 94.4percent
93% With hydrazine hydrate In butan-1-olReflux A mixture of 2,3-dichloropyridine (0.06 mol)80percent hydrazine hydrate (0.30 mol) andN-butanol 60 ml was added to a 100 ml three-necked flask and heated to a weak refluxing reaction overnight.After completion of the reaction, the solvent was distilled off to give 8.0 g of a white solid of (III) 3-chloro-2-hydrazinopyrid in a yield of 93percent.
91% With hydrazine hydrate In ethanol for 40 h; Reflux To a stirred solution of 4c (5.00 g, 33.8 mmol) in EtOH (25 mL) was added hydrazine monohydrate (6.77 g, 135 mmol), and the mixture was heated to reflux for 20 h.
At this point, additional hydrazine monohydrate (1.69 g, 33.8 mmol) was added, and the mixture was heated to reflux for 20 h.
The mixture was cooled by ice bath and stirred for 1 h, and then filtered to give 8 (4.40 g, 91percent) as a white solid.
Mp 164-166 °C (lit.
29
mp 163-164 °C); 1H NMR (600 MHz, DMSO-d6) δ 4.22 (br s, 2H), 6.61 (dd, J=7.6, 4.9 Hz, 1H), 7.52-7.64 (m, 2H), 8.05 (dd, J=4.7, 1.3 Hz, 1H); 13C NMR (150 MHz, DMSO-d6) δ 113.2, 113.6, 136.2, 145.7, 155.7; IR (ATR) 3284, 3195, 1592, 1494, 1455, 1412, 1343, 1264, 1122, 1033, 991, 968, 957, 930, 787, 761, 750, 726, 634, 610, 543, 497, 438, 423, 416 cm-1; HRMS (ESI): [M+H+] calcd for C5H7ClN3, 144.0328; found, 144.0323.
90.13% With hydrazine In ethanol for 26 h; Reflux In 500 ml round-bottomed flask, followed by adding 50 g of 2,3-dichloropyridine in 150 ml of ethanol, 127 g of 80percent hydrazine hydrate was heated at reflux for 26 hours with stirring, TLC monitored the reaction was completed, the reaction system was lowered to room temperature , the precipitated solid was filtered, the filter cake washed with water and dried to give white needle crystals, yield 90.13percent.
90% With hydrazine hydrate In ethanol at 80℃; for 20 h; A mixture of 50 mmol of 2,3-pyridine V,100 mmol of hydrazine hydrate,50 ml of ethanol was added to a 100 ml three-necked round bottom flask,Was heated under reflux for 20 hours 80 ° C,The solvent was distilled off under reduced pressure,The resulting solid was recrystallized from ethanol to give acicular crystals3-chloro-2-hydrazinopyridine VI 6.5 g,Yield 90percent.
90% With hydrazine hydrate In ethanol at 80℃; for 20 h; 50 mmol of 2,3-pyridine are addedV, 100 mmol of hydrazine hydrate,50 ml of ethanol was added to a 100 ml three-necked round bottom flask, heated to reflux for 20 hours at 80 degrees Celsius,The solvent was distilled off under reduced pressure,The resulting solid was recrystallized from ethanol to give acicular crystals3-Chloro-2-hydrazinopyridine VI 6.5 g, yield 90percent.
85.59% With hydrazine hydrate In ethanol at 80℃; for 20 h; A mixture of 2,3-dichloropyridine (25.0 g), 80percent hydrazine hydrate (12.69 g) was stirred in refluxing EtOH (40 mL), the reaction proceeding was monitored by TLC. After complication of the reaction, the resulting mixture was cooled to room temperature to get white needle crystal (20.76 g), yield, 85.59percent, m.p. 163–164 °C.
85.6% With hydrazine hydrate In ethanolReflux To a solution of 2,3-dichloropyridine (50.0 g) in EtOH (40 mL), 25 g hydrazinehydrate (80percent) was added and refluxed for 24 h. The resulting mixture was cooled to room temperature, which was filtered and dried to get white needle crystal (41.5 g), yield: 85.6percent, m.p. 163–164°C.
80% With hydrazine hydrate In ethanol at 70℃; for 12 h; a. In a three-necked flask, 0.3 mol of 2,3-dichloropyridine, 0.85 mol of hydrazine hydrate was added, and 350 mL of ethanol was added and the mixture was stirred at 70 ° C for 12 h.b. After the completion of the reaction to stop heating, cooling, white needle-like crystal precipitation, decompression filtration, washing the crystal, dry, that is, 3-chloro-2-hydrazinopyridine, the yield of 80percent, purity ≥ 98percent

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  • [ 71-36-3 ]
  • [ 22841-92-5 ]
Reference: [1] Patent: US6169086, 2001, A,
  • 14
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  • [ 13472-84-9 ]
Reference: [1] Tetrahedron, 1985, vol. 41, # 7, p. 1373 - 1384
  • 15
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  • [ 124-41-4 ]
  • [ 13472-84-9 ]
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  • [ 67-56-1 ]
  • [ 13472-84-9 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 8, p. 1245 - 1249
  • 17
  • [ 2402-78-0 ]
  • [ 2402-77-9 ]
  • [ 1513-65-1 ]
Reference: [1] Patent: US4071521, 1978, A,
  • 18
  • [ 2402-77-9 ]
  • [ 1480-64-4 ]
YieldReaction ConditionsOperation in experiment
71.9% With cesium fluoride In dimethyl sulfoxide at 110℃; for 20 h; General procedure: To a solution of 2,3-dichloropyridine(1.00 g, 6.76 mmol) in DMSO (33.8 ml) was added CsF (2.053 g, 13.51mmol) at room temperature. The mixture was stirred at 110 °C under air for 20h. The mixture was quenched with water at room temperature and extracted withEtOAc. The organic layer was separated, washed with water and brine, dried overNa2SO4 and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, eluted with EtOAc in hexane) togive 3-chloro-2-fluoropyridine (0.639 g, 4.86 mmol, 71.9 percent) as colorlessoil. Thecompound 3B'-8B' were prepared in amanner similar to that described for 2B'.
Reference: [1] Tetrahedron Letters, 2015, vol. 56, # 44, p. 6043 - 6046
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[3] Patent: EP1595867, 2005, A1, . Location in patent: Page/Page column 33-34
[4] Organic Letters, 2015, vol. 17, # 8, p. 1866 - 1869
[5] Patent: EP1726590, 2006, A1, . Location in patent: Page/Page column 56
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  • [ 52605-97-7 ]
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  • 20
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  • [ 124-41-4 ]
  • [ 52605-97-7 ]
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  • [ 96424-68-9 ]
Reference: [1] European Journal of Organic Chemistry, 2002, # 24, p. 4181 - 4184
[2] Patent: WO2006/10570, 2006, A1, . Location in patent: Page/Page column 44-45
  • 22
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  • [ 75-16-1 ]
  • [ 72093-03-9 ]
Reference: [1] Organic Letters, 2013, vol. 15, # 14, p. 3698 - 3701
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  • [ 77332-89-9 ]
Reference: [1] European Journal of Organic Chemistry, 2002, # 24, p. 4181 - 4184
[2] European Journal of Organic Chemistry, 2002, # 24, p. 4181 - 4184
[3] Patent: WO2008/18639, 2008, A2, . Location in patent: Page/Page column 109
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  • [ 53976-65-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 13, p. 5704 - 5718
[2] Journal of Heterocyclic Chemistry, 1980, vol. 17, p. 429 - 432
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  • [ 124-38-9 ]
  • [ 184416-84-0 ]
YieldReaction ConditionsOperation in experiment
80%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - -25℃; for 3 h;
Stage #2: at 20℃; for 18 h;
Stage #3: With hydrogenchloride; water In tetrahydrofuran; diethyl ether; hexane at 0 - 20℃;
2,3-Dichloro-isonicotinic acid[00195] To a solution of diisopropylamine (7.0 niL, 50 mmol) in anhydrous THF (100 rnL) at -25°C was added a 1.6M solution of nBuLi in hexanes (31 rnL, 50 mmol) dropwise under an inert atmosphere. The reaction mixture was then cooled to -78°C and 2,3- dichloropyridine was added. The reaction mixture was stirred at -78°C for 3 hours, then poured onto solid carbon dioxide and aged for 18 hours at room temperature. The mixture was diluted with water (100 mL) and washed with diethyl ether (3 x 40 mL) then cooled to 00C, acidified with concentrated HCl (ca. 5 mL) and extracted with diethyl ether (3 x 50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to give the title compound as a white solid (7.7 g, 80percent). 1H NMR (d6-DMSO, 400MHz) 8.49 (d, J = 5.0 Hz, IH), 7.72 (d, J = 5.0 Hz, IH).
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  • [ 74-89-5 ]
  • [ 468718-67-4 ]
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  • [ 438450-39-6 ]
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  • [ 500008-45-7 ]
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  • 29
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  • [ 500011-86-9 ]
YieldReaction ConditionsOperation in experiment
75% With potassium carbonate In ethanol for 18 h; Reflux S4. 1 eq of 5-bromo-1H-3-pyrazolecarboxylic acid (4) and 1.2 eq of 2,3-dichloropyridine were dissolved in an appropriate amount of ethanol solution,3eq potassium carbonate solid was added,Heated to reflux reaction 18h;After cooling to room temperature and washing with ethyl acetate three times, adding 1 M hydrochloric acid solution to the aqueous layer to make the pH of the reaction solution acidic, extracting with EtOAc three times, drying the organic layer over anhydrous sodium sulfate;After drying, it was concentrated by filtration to obtain the intermediate 1- (3-chloro-2-pyridyl) -3-bromo-1H-5-pyrazolecarboxylic acid (5) with a yield of 75percent.
73.7% With potassium carbonate In ethanol for 18 h; Reflux 1 eq of 5-bromo-1H-3-pyrazolecarboxylic acid (23) and 1.2 eq of 2,3-dichloropyridine (8) were dissolved in an appropriate amount of ethanol solution, 3 eq of potassium carbonate solid was added, and the reaction was refluxed for 18 h.After that, it was cooled to room temperature, and the mixture was washed three times with ethyl acetate.After drying and filtration, it was concentrated to give 1-(3-chloro-2-pyridyl)-3-bromo-1H-5-pyrazolecarboxylic acid (3-OH).The yield was 73.7percent.
Reference: [1] Patent: CN104844567, 2017, B, . Location in patent: Paragraph 0032; 0037; 0042; 0047
[2] Patent: CN108191822, 2018, A, . Location in patent: Paragraph 0065; 0066; 0067
  • 30
  • [ 2402-77-9 ]
  • [ 500011-86-9 ]
Reference: [1] Molecules, 2012, vol. 17, # 9, p. 10414 - 10428
[2] Chinese Journal of Chemistry, 2012, vol. 30, # 8, p. 1748 - 1758
[3] Research on Chemical Intermediates, 2013, vol. 39, # 7, p. 3071 - 3088
[4] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 8, p. 1987 - 1992
[5] Australian Journal of Chemistry, 2014, vol. 67, # 10, p. 1491 - 1503
[6] Chemical Papers, 2015, vol. 69, # 7, p. 993 - 1003
[7] Journal of Heterocyclic Chemistry, 2016, vol. 53, # 4, p. 1036 - 1045
[8] Patent: CN105669643, 2016, A,
[9] Patent: CN106187998, 2016, A,
[10] Patent: CN104031026, 2017, B,
  • 31
  • [ 2402-77-9 ]
  • [ 889865-45-6 ]
YieldReaction ConditionsOperation in experiment
85.1%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.5 h; Inert atmosphere
Stage #2: With iodine In tetrahydrofuran; hexane at -78℃; for 1 h;
Step 1:
Synthesis of 2,3-dichloro-4-iodopyridine
In an atmosphere of argon gas, at -78° C., n-butyl lithium (2.4M hexane solution, 59.12 mL, 141.9 mmol) was added dropwise to a solution of 2,3-dichloropyridine (20 g, 135.1 mmol) in anhydrous tetrahydrofuran (350 mL) to get a reaction mixture, and the reaction mixture was stirred at -78° C. for 90 minutes.
A solution of iodine (41 g, 161.5 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise, and the reaction mixture was stirred at -78° C. for 60 minutes.
The temperature was then increased to room temperature.
The reaction mixture was quenched with saturated ammonium chloride solution (100 mL), diluted with water (100 mL), and extracted with ethyl acetate (200 mL*3).
The organic phases were combined.
The combined organic phases were washed with saline solution (200 mL*2), dried with anhydrous sodium sulfate, filtrated, and concentrated.
The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=100:1) to get product as yellow solid (31.5 g, yield: 85.1percent).
1H NMR (300 MHz, DMSO-d6): 8.08 (d, J=5.4 Hz, 1H), 8.65 (d, J=5.4 Hz, 1H)
MS (ESI+): m/z 273.9 [M+H]+
72% With n-butyllithium; iodine; diisopropylamine In tetrahydrofuran; hexane; water; ethyl acetate 1)
Production of 2,3-dichloro-4-iodopyridine:
With cooling with ice, 2.66 M n-butyllithium (100 mL, 0.266 mmol) was added to a tetrahydrofuran (400 mL) solution of diisopropylamine (11.9 mL, 84.2 mmol), cooled to -70°C, and stirred for 0.5 hours.
A tetrahydrofuran (170 mL) solution of 2,3-dichloropyridine (35 g, 0.24 mmol) was dropwise added to the solution, over 25 minutes, and then stirred at -70°C for 1 hour.
A tetrahydrofuran (170 mL) solution of iodine (75 g, 0.30 mmol) was added to the reaction mixture, and warmed up to room temperature with stirring.
Water was added to the reaction mixture, and extracted twice with ethyl acetate.
The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure.
Ethyl acetate and hexane were added to the residue, the precipitated matter was taken out through filtration and dried to obtain the entitled compound (46.4 g, 72 percent) as a pale yellow solid.
71%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; diethyl ether; hexane at -78℃; for 0.5 h; Inert atmosphere
Stage #2: With iodine In tetrahydrofuran; diethyl ether; hexane at -78 - 20℃;
To a solution of n-butyllithium (5.51 mL, 13.78 mmol, 2.5M in hexane) in dry Et20 (30 mL) cooled at -78°C, under a Argon atmosphere, was added dropwise 2,2,6,6-tetramethylpiperidine (2.326 mL, 13.785 mmol). The mixture was stirred at -78°C for 10 min, and then a solution of 2,3-dichloropyridine (2 g, 13.51 mmol) in dry THF (15 mL) was added dropwise. The mixture was stirred at -78°C for 30 min. A solution of iodine (5.14 g, 20.27 mmol) in dry THF (15 mL) was added. The reaction mixture was allowed to warm to rt and stirred overnight. Sat. Sol. Na2S203 was added and the mixture was extracted with EtOAc. The combined organic layers were washed with sat. sol. NaHC03, dried, filtered and concentrated. The residue was precipitated with heptane, filtered off and dried to yield Intermediate 1-38 (2.63 g, 71percent) as a cream solid.HPLC-MS (method 4): Rt =4.5, [M+H]+ 274.
54%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; Inert atmosphere
Stage #2: With iodine In tetrahydrofuran at -78 - -30℃;
n-Butyllithium (15.0 mL, 2.5M, 37.5 mmol) was added dropwise to a solution of diisopropylamine (3.76 g, 37.2 mmol) and THF (50 mL) at -78 0C under N2. After 30 min, a solution of 2,3-dichloropyridine (5.0 g, 34 mmol) and THF (50 mL) was added dropwise. After an additional hour at -78 0C, iodine (8.6 g, 34 mmol) was added. The resulting solution was stirred at -30 0C for 5 min, quenched with sat'd sodium thiosulfate (200 mL), and extracted with EtOAc (200 mL x 3). The combined extracts were washed with sat'd sodium bicarbonate (200 ml), washed with brine (200 mL x 2), <n="81"/>dried, filtered, concentrated, and then purified by silica gel chromatography (1 :10- EtOAc/PE) to give 2,3-dichloro-4-iodopyridine as a white solid.; n-BuLi (15 mL, 2.5M) was added to a solution of diisopropylamine (3.76 g, 37.23 mmol) in THF (50 mL) cooled to -780C and the resulting mixture was stirred for 30 min at -780C. This was followed by the addition of a solution of 2,3-dichloropyridine (5 g, 34.01 mmol) in THF (50 mL) and the mixture was stirred at -780C for 1 h. To the <n="87"/>mixture was added I2 (8.58 g, 33.78 mmol) and the mixture was warmed to -3O0C and stirred for 5 min.. Aqueous NaS2O3 (200 mL) was then added and the aqueous layer was extracted with EtOAc (2 x 100 mL). The organics were combined, washed with bicarb (200 mL) and brine (2 x 200 mL), dried, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/PE) to afford 5.1 g (54percent) of 2,3-dichloro-4-iodopyridine as a white solid.
44%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; diethyl ether; hexane at -78℃; for 0.5 h;
Stage #2: With iodine In tetrahydrofuran; diethyl ether; hexane at -78 - 20℃;
Reaction performed under nitrogen atmosphere. To a solution of n-butyllithium (27.6 ml, 69 mmol, 2.5 M in hexanes) in dry Et2O (150 ml) cooled at -78 0C, was added 2,2,6,6-tetramethylpiperidine (11.64 ml, 69 mmol) dropwise. The resulting reaction mixture was stirred at -78 0C for 10 min. and then a solution of 2,3-dichloropyridine (10 g, 67.57 mmol) in dry THF (75 ml) was added dropwise. The mixture was stirred at -78 0C for 30 minutes and then a solution of iodine (25.38 g, 100 mmol) in dry THF (75 ml) was added. The mixture was allowed to warm to room temperature overnight, quenched with Na2S2O3 (aqueous sat. solution) and extracted twice with EtOAc. The combined organic extracts were washed with NaHCO3 (aqueous sat. solution), dried (Na2SO4) and evaporated in vacuo. The crude residue was precipitated with heptane, filtered off and dried to yield compound D16 (8.21 g, 44percent) as a pale cream solid. LCMS: MW (theor): 273; [MH+]: did not ionise; RT (min): 2.73 (Method 21).
44%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; diethyl ether; hexane at -78℃; Inert atmosphere
Stage #2: With iodine In tetrahydrofuran; diethyl ether; hexane at -78 - 20℃;
Description 1 2,3-dichloro-4-iodo-pyridine (Dl)To a solution of n-butyllithium (27.6 ml, 69 mmol, 2.5 M in hexanes) in dry Et2O (150 ml) cooled at -78 0C, under nitrogen atmosphere, was added 2,2,6,6- tetramethylpiperidine (11.64 ml, 69 mmol) dropwise. The resulting reaction mixture was stirred at -78 0C for 10 min, and then a solution of 2,3-dichloropyridine (1O g, 67.57 mmol) in dry THF (75 ml) was added dropwise. The mixture was stirred at -78 0C for 30 min and then a solution of iodine (25.38 g, 100 mmol) in dry THF (75 ml) was added. The mixture was allowed to warm to room temperature overnight, quenched with Na2S2O3 (aqueous sat. solution) and extracted twice with EtOAc. The combined organic extracts were washed with NaHCO3 (aqueous sat. solution), dried (Na2SO4) and concentrated in vacuo. The crude residue was precipitated with heptane, filtered off and concentrated to yield intermediate compound Dl (8.21 g, 44percent) as a pale cream solid.
44%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexanes; diethyl ether at -78℃; for 0.666667 h; Inert atmosphere
Stage #2: With iodine In hexanes; diethyl ether; THjF (tetrahydrofuran) at -78 - 20℃;
To a solution of H-butyllithium (27.6 ml, 69 mmol, 2.5 M in hexanes) in dry Et2O (150 ml) cooled at -78 0C, under a nitrogen atmosphere, was added 2,2,6,6- tetramethylpiperidine (11.64 ml, 69 mmol) dropwise and the resulting reaction mixture was stirred at -78 0C for 10 min. A solution of 2,3-dichloropyridine (10 g, 67.57 mmol) in dry THF (75 ml) was then added dropwise. The mixture was stirred at -78 0C for 30 min. and then a solution of iodine (25.38 g, 100 mmol) in dry THF (75 ml) was added. The mixture was allowed to warm to r.t. overnight, quenched with Na2S2O3 (aqueous sat. solution) and extracted twice with EtOAc. The combined organic extracts were washed with NaHCO3 (aqueous sat. solution), dried (Na2SO4) and concentrated in vacuo. The crude residue was precipitated with heptane, filtered off and concentrated to yield intermediate compound D6 (8.21 g, 44percent) as a pale cream solid.
44%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexanes; diethyl ether at -78℃; for 0.666667 h; Inert atmosphere
Stage #2: With iodine In tetrahydrofuran; hexanes; diethyl ether at -78 - 20℃;
To a solution of "-butyllithium (27.6 ml, 69 mmol, 2.5 M in hexanes) in dry Et2O (150 ml) cooled at -78 0C, under a nitrogen atmosphere, was added 2,2,6,6- tetramethylpiperidine (11.64 ml, 69 mmol), dropwise. The resulting reaction mixture was stirred at -78 0C for 10 min., and then a solution of 2,3-dichloropyridine (10 g, 67.57 mmol) in dry THF (75 ml) was added dropwise. The mixture was stirred at -78 0C for 30 min. and then a solution of iodine (25.38 g, 100 mmol) in dry THF (75 ml) was added. The mixture was allowed to warm to r.t. overnight, quenched with Na2S2O3 (aqueous sat. solution) and extracted twice with EtOAc. The combined organic extracts were washed with NaHCO3 (aqueous sat. solution), dried (Na2SO4) and concentrated in vacuo. The crude residue was precipitated with heptane, filtered off and dried to yield intermediate compound DlO (8.21 g, 44percent) as a pale cream solid.
44%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; diethyl ether; hexane at -78℃; for 0.5 h; Inert atmosphere
Stage #2: With iodine In tetrahydrofuran; diethyl ether; hexane at -78 - 20℃; Inert atmosphere
Intermediate 12,3-Dichloro-4-iodo-pyridine (1-1)To a solution of n-BuLi (27.6 mL, 69 mmol, 2.5 M in hexanes) in dry Et20 (150 mL) cooled at -78 °C, under a nitrogen atmosphere, was added 2,2,6,6-tetramethylpiperidine (11.64 mL, 69 mmol) dropwise. The resulting r.m. was stirred at -78 °C for 10 min, and then a solution of 2,3-dichloropyridine (10 g, 67.57 mmol) in dry THF (75 mL) was added dropwise. The mixture was stirred at -78 °C for 30 min and then a solution of iodine (25.38 g, 100 mmol) in dry THF (75 mL) was added. The mixture was allowed to warm to r.t. overnight, quenched with Na2S203 (aq sat. sol.) and extracted twice with EtOAc. The combined organic extracts were washed with NaHC03 (aq. sat. sol), dried (Na2S04) and concentrated in vacuo. The crude residue was precipitated with heptane, filtered off and dried to yield intermediate 1-1 (8.21 g, 44percent) as a pale cream solid.
44%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; diethyl ether; hexane at -78℃; for 0.5 h; Inert atmosphere
Stage #2: With iodine In tetrahydrofuran; diethyl ether; hexane at -78 - 20℃;
Intermediate 1 (1-1)o-4-iodo-pyridine (I- 1)To a solution of "-butyllithium (27.6 ml, 69 mmol, 2.5 M in hexanes) in dry Et20 (150 ml) cooled at -78 °C, under a nitrogen atmosphere, was added 2,2,6,6-tetramethyl- piperidine (11.64 ml, 69 mmol), dropwise. The resulting reaction mixture was stirred at -78 °C for 10 min., and then a solution of 2,3-dichloropyridine (10 g, 67.57 mmol) in dry THF (75 ml) was added dropwise. The mixture was stirred at -78 °C for 30 min. and then a solution of iodine (25.38 g, 100 mmol) in dry THF (75 ml) was added. The mixture was allowed to warm to r.t. overnight, quenched with Na2S203 (aqueous sat. solution) and extracted twice with EtOAc. The combined organic extracts were washed with NaHC03 (aqueous sat. solution), dried (Na2S04) and concentrated in vacuo. The crude residue was precipitated with heptane, filtered off and dried to yield intermediate compound 1-1 (8.21 g, 44percent) as a pale cream solid.

Reference: [1] Patent: US2017/29404, 2017, A1, . Location in patent: Paragraph 0122-0125
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 6, p. 2688 - 2701
[3] Patent: WO2006/59778, 2006, A1, . Location in patent: Page/Page column 57-58
[4] Patent: EP1820797, 2007, A1,
[5] Patent: WO2013/5057, 2013, A1, . Location in patent: Page/Page column 118
[6] Molecules, 2012, vol. 17, # 9, p. 10683 - 10707,25
[7] Molecules, 2012, vol. 17, # 9, p. 10683 - 10707
[8] Patent: WO2009/117421, 2009, A2, . Location in patent: Page/Page column 85-86
[9] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297
[10] Patent: WO2009/62676, 2009, A2, . Location in patent: Page/Page column 53
[11] Patent: WO2010/130422, 2010, A1, . Location in patent: Page/Page column 51-52
[12] Patent: WO2010/130423, 2010, A1, . Location in patent: Page/Page column 51
[13] Patent: WO2010/130424, 2010, A1, . Location in patent: Page/Page column 99
[14] Patent: WO2012/62752, 2012, A1, . Location in patent: Page/Page column 24
[15] Patent: WO2012/62750, 2012, A1, . Location in patent: Page/Page column 36-37
[16] Patent: WO2010/60589, 2010, A1, . Location in patent: Page/Page column 32
[17] Patent: US2007/4772, 2007, A1, . Location in patent: Page/Page column 26-27
  • 32
  • [ 768-66-1 ]
  • [ 2402-77-9 ]
  • [ 889865-45-6 ]
YieldReaction ConditionsOperation in experiment
42%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.166667 h; Inert atmosphere
Stage #2: at -78℃; for 0.5 h; Inert atmosphere
Stage #3: With iodine In tetrahydrofuran; diethyl ether; hexane at -78 - 20℃; for 1 h; Inert atmosphere
Toa - 78°Csolution of tetramethylpiperidine (11.6 mL, 69.0 mmol) in anhydrous Et2O(150 mL) was added dropwise a 2.5 M solution of n-BuLi in hexane (27.6 mL, 69.0 mmol). The reaction mixture was stirred at −78°C during 10 minutes and then asolution of 2-3-dichloropyridine (10.0 g, 67.6 mmol) in THF (75 mL) was addeddropwise. Temperature was maintained at 78°C during 30 minutes and finally a solutionof I2 (25.4 g, 100.0 mmol) in THF (75 mL) was added and thetemperature allowed to raise at room temperature during 1h. The reaction mixurewas quenched with a saturated solution of Na2S2O3(100 mL), extracted with EtOAc (3 x 100 mL). The combined organic phases werewashed with a saturated solution of NaHCO3 (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residuewas purified by chromatography on silica gel with cyclohexane as eluent toafford 2-3-dichloro-4-iodopyridine as a beige solid (15.5 g, 42percentyield).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 1, p. 114 - 120
  • 33
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  • [ 951677-39-7 ]
Reference: [1] European Journal of Organic Chemistry, 2008, # 8, p. 1458 - 1463
  • 34
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  • [ 885167-73-7 ]
Reference: [1] Patent: WO2014/201127, 2014, A2,
  • 35
  • [ 2402-77-9 ]
  • [ 68-12-2 ]
  • [ 884495-41-4 ]
YieldReaction ConditionsOperation in experiment
34.9%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.333333 h;
Stage #2: at -78℃; for 0.25 h;
Stage #3: With water In tetrahydrofuran; hexane at 20℃;
To a solution of 2,3-dichloropyridine (10 g, 67.57 mmol) [C.A.S. 2402-77-9] in dryTHF (200 ml) cooled at -78°C under a nitrogen atmosphere, n-butyllithium (37.165 ml, 74 mmol, 2 M in hexanes) was dropwise added. The resulting reaction mixture was stirred at -78 0C for 20 min. Then dry DMF (6.28 ml, 81.087 mmol) was added dropwise. After 15 min stirring at - 78°C, the mixture was allowed to warm to room temperature, quenched with water and extracted with DCM. The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The crude residue was purified by short open column chromatography (DCM as eluent). The desired product fractions were collected and evaporated in vacuo to give a residue that was further purified by column chromatography (silica gel; DCM/heptane up to 50percent as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate compound D41 (4.15 g, 34.9percent) as a white solid.GCMS = RT (min): 7.9.
34.9%
Stage #1: With n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 0.333333 h; Inert atmosphere
Stage #2: at -78℃; for 0.25 h;
To a solution of 2,3-dichloropyridine [C.A.S. 2402-77-9] (10 g, 67.57 mmol) in dry THF (200 ml) cooled at -78 0C under a nitrogen atmosphere, was added dropwise n- butyllithium (37.165 ml, 74 mmol, 2 M in hexanes). The resulting reaction mixture was stirred at -78 0C for 20 min. Then dry DMF (6.28 ml, 81.087 mmol) was added dropwise. After 15 min. stirring at -78 0C, the mixture was allowed to warm to r.t., quenched with water and extracted with DCM. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by short open column chromatography (DCM as eluent). The desired product fractions were collected and concentrated in vacuo to give a residue that was further purified by column chromatography (silica gel; DCM/heptane up to 50percent as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D36 (4.15 g, 34.9percent) as a white solid.
Reference: [1] Patent: WO2009/62676, 2009, A2, . Location in patent: Page/Page column 65
[2] Patent: WO2010/130424, 2010, A1, . Location in patent: Page/Page column 109-110
[3] Patent: US2010/298334, 2010, A1, . Location in patent: Page/Page column 57
  • 36
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  • [ 1416551-60-4 ]
Reference: [1] Molecules, 2012, vol. 17, # 9, p. 10683 - 10707,25
[2] Molecules, 2012, vol. 17, # 9, p. 10683 - 10707
  • 37
  • [ 2402-77-9 ]
  • [ 23719-80-4 ]
  • [ 1355066-87-3 ]
  • [ 865664-04-6 ]
Reference: [1] Organic Letters, 2013, vol. 15, # 14, p. 3698 - 3701
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