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Product Details of [ 16110-09-1 ]

CAS No. :16110-09-1 MDL No. :MFCD00006239
Formula : C5H3Cl2N Boiling Point : -
Linear Structure Formula :- InChI Key :GCTFDMFLLBCLPF-UHFFFAOYSA-N
M.W : 147.99 Pubchem ID :27685
Synonyms :
4-Aminophenylacetamide

Calculated chemistry of [ 16110-09-1 ]

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) : -5.5 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.8
Log Po/w (XLOGP3) : 2.4
Log Po/w (WLOGP) : 2.39
Log Po/w (MLOGP) : 1.68
Log Po/w (SILICOS-IT) : 2.73
Consensus Log Po/w : 2.2

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.82
Solubility : 0.222 mg/ml ; 0.0015 mol/l
Class : Soluble
Log S (Ali) : -2.31
Solubility : 0.721 mg/ml ; 0.00487 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 : 1.52

Safety of [ 16110-09-1 ]

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

Application In Synthesis of [ 16110-09-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 16110-09-1 ]
  • Downstream synthetic route of [ 16110-09-1 ]

[ 16110-09-1 ] Synthesis Path-Upstream   1~48

  • 1
  • [ 16110-09-1 ]
  • [ 4214-79-3 ]
Reference: [1] Patent: US1778784, 1928, ,
  • 2
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  • [ 594-27-4 ]
  • [ 72093-07-3 ]
Reference: [1] Patent: WO2005/27837, 2005, A2, . Location in patent: Page/Page column 66-67
[2] Patent: WO2003/87037, 2003, A1, . Location in patent: Page/Page column 108
[3] Patent: WO2004/48317, 2004, A1, . Location in patent: Page 45
[4] Patent: WO2005/44785, 2005, A1, . Location in patent: Page/Page column 66
[5] Patent: WO2005/27837, 2005, A2, . Location in patent: Page/Page column 66-67
  • 3
  • [ 624-28-2 ]
  • [ 16110-09-1 ]
YieldReaction ConditionsOperation in experiment
87% With trans-bis(glycinato)copper(II) monohydrate; tetramethlyammonium chloride In ethanol at 100℃; for 24 h; Schlenk technique; Inert atmosphere General procedure: A Schlenk tube was charged with catalyst 1 (10 mol percent), aryl (or heteroaryl) bromide (1.0 mmol), tetramethylammonium chloride (Me4NCl) (2.0 mmol), and EtOH (2.0 mL) under nitrogen atmosphere. The Schlenk tube was sealed with a Teflon valve, and then the reaction mixture was stirred at 100 °C for a period as mentioned in Table 2 (the reaction progress was monitored by GC analysis). After completion of the reaction, the solvent was removed under reduced pressure. The residue obtained was purified via silica gel chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to afford aryl chlorides. The yield of the products was determined by high resolution GC–MS analysis and the identity of the products was confirmed by comparing their physical and spectral data with the known compounds.
Reference: [1] Applied Catalysis A: General, 2014, vol. 472, p. 178 - 183
[2] Chemical Communications, 2012, vol. 48, # 76, p. 9468 - 9470
  • 4
  • [ 10469-09-7 ]
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YieldReaction ConditionsOperation in experiment
82.3% With platinum on carbon; hydrogen; sodium hydroxide In water at 50℃; Autoclave; Inert atmosphere (1) 53.3 g of 3,4,5,6-tetrachloropicolinic acid, 500 ml of water and 88.0 g of 30percent sodium hydroxide were mixed together, 1000ml high pressure reactor;(2) Add 2 g of 5percent Pt / C to the reaction kettle, tightly seal the reaction kettle, replace with nitrogen 3 times, and let the pressure reach 0.4Mpa, then heat to 50 while stirring, So that the reactor pressure to 0.5Mpa after reaction, HPLC detection reaction completely, cooling to room temperature, the reaction solution;(3) The reaction liquid of step (2) is poured out, and the catalyst is recovered by filtration. The filtrate is acidified to pH 1-2 with 30percent hydrochloric acid, then cooled and crystallized, centrifuged, precipitated and washed with water to obtain 3,6-dichloropyridine acid 26.5 g, content 97.9percent, yield 82.3percent.
Reference: [1] Patent: CN105503713, 2016, A, . Location in patent: Paragraph 0054; 0055; 0056; 0057
  • 5
  • [ 2808-86-8 ]
  • [ 16110-09-1 ]
Reference: [1] Patent: US3947457, 1976, A,
  • 6
  • [ 13473-01-3 ]
  • [ 16110-09-1 ]
Reference: [1] Synthetic Communications, 1990, vol. 20, # 19, p. 2971 - 2977
  • 7
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  • [ 16110-09-1 ]
Reference: [1] Patent: US5502194, 1996, A,
  • 8
  • [ 55933-94-3 ]
  • [ 55933-95-4 ]
  • [ 16110-09-1 ]
Reference: [1] Patent: US3947457, 1976, A,
  • 9
  • [ 4214-79-3 ]
  • [ 16110-09-1 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1370 - 1380
  • 10
  • [ 75-44-5 ]
  • [ 4214-78-2 ]
  • [ 16110-09-1 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1931, vol. 486, p. 71,78
  • 11
  • [ 1851-22-5 ]
  • [ 16110-09-1 ]
  • [ 2402-77-9 ]
  • [ 55934-00-4 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1988, vol. 36, p. 2244 - 2247
  • 12
  • [ 694-85-9 ]
  • [ 16110-09-1 ]
Reference: [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 21, p. 518
  • 13
  • [ 504-29-0 ]
  • [ 16110-09-1 ]
Reference: [1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1928, vol. 60, p. 689[2] Chem. Zentralbl., 1928, vol. 99, # II, p. 1671
  • 14
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  • [ 4214-78-2 ]
  • [ 108-88-3 ]
  • [ 16110-09-1 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1931, vol. 486, p. 71,78
  • 15
  • [ 694-85-9 ]
  • [ 10026-13-8 ]
  • [ 10025-87-3 ]
  • [ 109-09-1 ]
  • [ 16110-09-1 ]
Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1916, vol. <2> 93, p. 395
  • 16
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  • [ 40473-01-6 ]
Reference: [1] European Journal of Organic Chemistry, 2002, # 24, p. 4181 - 4184
  • 17
  • [ 16110-09-1 ]
  • [ 557-21-1 ]
  • [ 89809-64-3 ]
YieldReaction ConditionsOperation in experiment
59% at 160 - 185℃; Preparation 83; 5-Chloro-2-cvanopyridine ;Add in a 22-L 3-neck round bottom equipped with overhead stirrer, reflux condenser, and thermometer, N, N/-dimethylacetamide (DMAC, 6 L), 2,5- dichloropyridine (347.0 g, 2.34 mol), zinc cyanide (138.0 g, 1.17 mol), bis (diphenylphosphino) dipalladium II CH2Cl2 complex (DPPF, 20.8 g, 0.02 mol), and zinc dust (1.6 g, 0.02 mol). Slowly warm the reaction mixture to 160 ° C. As the temperature reaches 160 ° C, an exotherm (controllable) may result and the internal temperature may rise to 180-185 ° C. Remove the heat from the dark solution and cool the mixture slowly cool to room temperature. Extract the bulk reaction mixture by taking 2 L of the dark solution, diluting with brine (2L), filtering over celite, and addition of ethyl acetate (4L). Repeat the process 3 times to extract all material, and dry the combined organics over magnesium sulfate. Cautious concentration at 25-30 ° C might give a dark liquid. (Note: Product volatility maybe observed at higher temperatures so the temperature upon concentration is kept low in all steps. ) Stir the liquid and add water (5L), resulting in a solid After 1 h, filter, and back-wash with water (2L). Dry the filter cake to give 215 g of crude product. Extract the aqueous filtrate with ethyl ether (8L). Dry the organics over magnesium sulfate and concentrate to provide 51 g of crude product. Combine with the 215 g lot and purify by chromatography over silica gel (biotage 150; eluting with 5percent ethyl acetate in hexanes increasing to 10percent ethyl acetate in hexanes) to provide a white solid of pure title compound (193 g, 59percent) ; 1H NMR (CDCl3) 8 8.68 (d, J= 2.0 Hz, 1H), 7.84 (dd, J= 2.7, 8.6 Hz, 1H), 7.66 (d, J= 8.3 Hz, 1H).
Reference: [1] Patent: WO2005/66126, 2005, A1, . Location in patent: Page/Page column 74-75
  • 18
  • [ 16110-09-1 ]
  • [ 89809-64-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 16, p. 5215 - 5223
[2] Patent: US2003/55085, 2003, A1,
  • 19
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  • [ 67-56-1 ]
  • [ 13473-01-3 ]
YieldReaction ConditionsOperation in experiment
65% With sodium hydride In mineral oil a.
5-Chloro-2-methoxypyridine
Sodium hydride (60percent in mineral oil, 5.50 g, 115 mmol, 2 eq) was added portionwise to dry methanol (distilled from Mg, 25 mL) under a nitrogen atmosphere.
To this solution was added 2,5-dichloropyridine (10.0 g, 68 mmol).
After refluxing the resulting solution for 18 h, the reaction was cooled and treated with excess solid potassium bicarbonate.
The reaction was filtered and concentrated to 50percent of its original volume upon which the solution solidified.
The solids were washed with hexane and combined washes were concentrated to an oil.
The title compound was purified by reduced pressure distillation (102° C., 2400 pascal) to yield 6.30 g (65percent) of a colorless oil. MS (CI, CH4) m/z 144 (M+,100), 146 (44), 172 (M+28,19), 124 (9).
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 8, p. 1245 - 1249
[2] Patent: US5512575, 1996, A,
  • 20
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  • [ 13473-01-3 ]
Reference: [1] Patent: US4588733, 1986, A,
  • 21
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  • [ 124-41-4 ]
  • [ 13473-01-3 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 1583 - 1592
  • 22
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  • [ 151-21-3 ]
  • [ 109-89-7 ]
  • [ 1066-54-2 ]
  • [ 86873-60-1 ]
Reference: [1] Patent: US5380861, 1995, A,
  • 23
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  • [ 405230-82-2 ]
Reference: [1] Nucleosides, Nucleotides and Nucleic Acids, 2001, vol. 20, # 12, p. 1975 - 2000
  • 24
  • [ 16110-09-1 ]
  • [ 67-56-1 ]
  • [ 201230-82-2 ]
  • [ 132308-19-1 ]
Reference: [1] Tetrahedron, 2005, vol. 61, # 26, p. 6330 - 6336
  • 25
  • [ 16110-09-1 ]
  • [ 132308-19-1 ]
Reference: [1] Patent: US5380861, 1995, A,
  • 26
  • [ 16110-09-1 ]
  • [ 67-56-1 ]
  • [ 201230-82-2 ]
  • [ 132308-19-1 ]
  • [ 881-86-7 ]
Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 19, p. 3719 - 3722
  • 27
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  • [ 67-56-1 ]
  • [ 201230-82-2 ]
  • [ 881-86-7 ]
Reference: [1] Organic Letters, 2004, vol. 6, # 13, p. 2097 - 2100
  • 28
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  • [ 67-56-1 ]
  • [ 201230-82-2 ]
  • [ 132308-19-1 ]
  • [ 881-86-7 ]
Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 19, p. 3719 - 3722
  • 29
  • [ 16110-09-1 ]
  • [ 64-17-5 ]
  • [ 201230-82-2 ]
  • [ 5552-44-3 ]
  • [ 128072-93-5 ]
Reference: [1] Heterocycles, 1999, vol. 51, # 11, p. 2589 - 2602
  • 30
  • [ 16110-09-1 ]
  • [ 27032-63-9 ]
YieldReaction ConditionsOperation in experiment
41% for 6 h; Reflux A solution of 2,5-dichioropyridine (13a) (7.4 g, 50.0 mmol) and hydrazine hydrate(101 mL, 3250 mmol) in Pyridine (100 mL) was heated at reflux for 6 h and concentratedin vacuum to dryness. The residue obtained was dissolved in DCM (500 mL), washed with I N aqueous NaOH (500 mL), water (3 x 500 mL). The organic layer was dried over MgSO4 filtered and concentrated in vacuum to dryness to furnish 5-chloro-2- hydrazinylpyridine (13b) (2.95 g, 20.55 mniol, 41percent yield) as light yellow solid. ‘H NMR(300 MHz, DMSO-d6)ö 7.97 (d,.J= 2.5 Hz, IH), 7.67 (s, IH), 7.50 (dd,J= 9.0, 2.6 Hz,IH), 6.73 (dd,.J= 9.0. 0.6 Hz, IH), 4.17 (s, 2H); MS (ES+) 144.2 (M+I).
Reference: [1] Journal of the American Chemical Society, 2011, vol. 133, # 17, p. 6780 - 6790
[2] Patent: US2003/187014, 2003, A1,
[3] Patent: WO2015/134998, 2015, A1, . Location in patent: Page/Page column 147
[4] Patent: US5750550, 1998, A,
[5] Patent: US4997835, 1991, A,
[6] Patent: US4622401, 1986, A,
[7] Patent: US4260767, 1981, A,
[8] Patent: EP1333031, 2003, A1,
[9] Patent: WO2012/54749, 2012, A1, . Location in patent: Page/Page column 64-65
  • 31
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  • [ 124-38-9 ]
  • [ 1702-17-6 ]
Reference: [1] European Journal of Organic Chemistry, 2001, # 7, p. 1371 - 1376
  • 32
  • [ 16110-09-1 ]
  • [ 102830-75-1 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 1583 - 1592
[2] Patent: US5512575, 1996, A,
  • 33
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  • [ 75-36-5 ]
  • [ 128072-93-5 ]
Reference: [1] Patent: US2003/186969, 2003, A1,
  • 34
  • [ 16110-09-1 ]
  • [ 64-17-5 ]
  • [ 201230-82-2 ]
  • [ 128072-93-5 ]
Reference: [1] Heterocycles, 1999, vol. 51, # 11, p. 2589 - 2602
[2] Tetrahedron Letters, 1999, vol. 40, # 19, p. 3719 - 3722
  • 35
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  • [ 64-17-5 ]
  • [ 201230-82-2 ]
  • [ 5552-44-3 ]
  • [ 128072-93-5 ]
Reference: [1] Heterocycles, 1999, vol. 51, # 11, p. 2589 - 2602
  • 36
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  • [ 124-38-9 ]
  • [ 88912-26-9 ]
YieldReaction ConditionsOperation in experiment
87%
Stage #1: With n-butyllithium; N,N,N',N'',N'''-pentamethyldiethylenetriamine In tetrahydrofuran; hexane at -75℃; for 2 h;
2,5-Dichloro-4-pyridinecarboxylic acid was prepared according to known procedures (see Eur. J. Org. Chem. 2001, 1371-1376), as follows: At -75 °C, 2,5-dichloropyridine (3.7 g, 25 mmol) was added to a solution of butyllithium (1.6M in hexane) (25 mmol) and N,N,N',N",N"- pentamethyldiethylenetriamine (5.3 mL, 4.3 g, 25 mmol) in tetrahydrofuran (50 mL). After 2 h at - 75 °C, the mixture was poured onto an excess of freshly crushed dry ice. Water (50 mL) was10 added, the aqueous phase decanted and washed with diethyl ether (3 x 20 mL) and neutralized with 5N HCl to pH 1. The precipitate was filtered and washed with water to give 2.7g of white solid as a pure product. The filtrate was extracted with ethyl acetate and the combined organic layers were evaporated to dryness. The residue was recrystallized from ethanol to give another batch of pure product. (The filtrate was evaporated to small volume and the precipitate was filtered and washed15 with water to give another batch of product); m.p. 227-229 °C (from ethanol); 4.2 g (87percent).[00294] 1H NMR (400MHz, DMSO-d6): a 14.43 (brs, 1H, exchangeable with D2O), 8.64 (s, 1 H), 7.87 (s, 1 H).[00295]2-(2,5-DicHoro-pyridke-4-carb.infin.yl)-3<(S)-1-hydroxymethyl-2-methyl-propylamino)- acrylic acid ethyl ester was synthesized using the same procedure described in example IA, (91 percent20 yield).[00296] 1H NMR (DMSO-d6, 400MHz): δ 10.94 (dd, J=9.6 and 13.8Hz, 1H, NH, exchangeable with D2O), 8.48 (s, 1H), 8.28 (d, J=14.3Hz,1H, it becomes singlet after D2O exchange), 7.51 (s, 1H), 5.07 (t, J=5.1Hz,1H, OH, exchangeable with D2O), 3.92 (q, J=7.0Hz, 2H), 3.62 (m, 2H), 3.40 (m, 1H), 1.95 (m, 1H), 0.94 (d, J=6.6Hz, 3H), 0.91 (d, J=6.6Hz, 3H), 0.89 (t, J=7.0Hz, 3H). MS:25 375, 377 (M+l).
47%
Stage #1: With n-butyllithium; N,N,N',N'',N'''-pentamethyldiethylenetriamine In tetrahydrofuran at -78℃; for 2 h;
Stage #2: at -78℃;
2, 5-Dichloropyridine was added to a THF solution of n-BuLi and PMDTA and stirred for 2 hours at -780C before quenching with dry ice. The product was isolated by acid-base work-up in 47percent yield.
Reference: [1] European Journal of Organic Chemistry, 2001, # 7, p. 1371 - 1376
[2] Patent: WO2009/89263, 2009, A2, . Location in patent: Page/Page column 95
[3] Patent: WO2008/141385, 2008, A1, . Location in patent: Page/Page column 83
[4] Patent: WO2008/46135, 2008, A1, . Location in patent: Page/Page column 53
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  • [ 444120-91-6 ]
Reference: [1] Tetrahedron, 2002, vol. 58, # 14, p. 2885 - 2890
  • 38
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  • [ 76-09-5 ]
  • [ 444120-94-9 ]
Reference: [1] Tetrahedron, 2002, vol. 58, # 14, p. 2885 - 2890
  • 39
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  • [ 244221-57-6 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 16, p. 5215 - 5223
[2] European Journal of Organic Chemistry, 2002, # 24, p. 4181 - 4184
  • 40
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  • [ 75-36-5 ]
  • [ 244221-57-6 ]
YieldReaction ConditionsOperation in experiment
85% With sodium iodide In acetonitrile a)
5-Chloro-2-iodo-pyridine

To a refluxing solution of 2,5-dichloro-pyridine (12.2 g, 82.2 mmol), sodium iodide (37.0 g, 247 mmol) and acetonitrile (170 mL) under argon was added acetyl chloride (9.0 mL, 127 mmol) and the solution was refluxed for 5 h.
To the solution was added more sodium iodide (24.9 g, 166 mmol) and the solution was refluxed for 16 h.
More sodium iodide (12.5 g, 83.6 mmol) was added and the solution was refluxed for 4.5 h.
The solution was cooled to room temperature, and was partitioned between 10percent sodium thiosulfate/10percent aqueous sodium carbonate (300 mL) and ether (400 mL).
The ether layer was washed with brine (100 mL) and dried over anhydrous sodium sulfate.
The solution was decanted, and dried in vacuo to yield 16.8 g (85percent) of the title compound as a brown solid. 1H NMR (CDCl3): 8.36 (d, J=2.75 Hz, 1H), 7.66 (d, J=8.79 Hz, 1H), 7.32 (dd, J=8.38, 2.61 Hz, 1H).
There is 5 mol percent of starting material 2,5-dichloro-pyridine in the product as determined by NMR.
Reference: [1] Patent: US2003/45546, 2003, A1,
  • 41
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  • [ 185315-51-9 ]
Reference: [1] Patent: EP2669285, 2013, A1,
[2] Tetrahedron Letters, 2014, vol. 55, # 43, p. 5963 - 5966
  • 42
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  • [ 796851-03-1 ]
YieldReaction ConditionsOperation in experiment
53%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; 2-Methylpentane at -78℃; for 1.5 h; Inert atmosphere
Stage #2: With iodine In tetrahydrofuran; 2-Methylpentane at -78℃; Inert atmosphere
a) A solution of 2,5-dichloropyridine (10 g, 67.57 mmol) in THF (17 mL) was added dropwise to a stirred solution of n-BuLi in isohexane (33.8 mL, 67.57 mmol) and diisopropylamine (9.63 mL, 67.57 mmol) in THF (68.0 mL) cooled to -780C, over a period of 1 hour under a nitrogen atmosphere. The resulting mixture was stirred at -780C for 30 minutes and then a solution of I2 (17.49 g, 68.92 mmol) in THF (17.0 mL) was added dropwise. The resulting solution was stirred at -78 0C for 1 hour and then quenched with water (75 mL) and allowed to warm to room temperature. The mixture was extracted with Et2O (3x 100 mL) and the combined organic layers were dried over MgSO4, and then evaporated. The residue was triturated with CH2Cl2 to give a solid which was dried under vacuum to afford 2,5-dichloro-4-iodopyridine (9.72 g, 53percent yield). The filtrate was evaporated and the residue purified by chromatography on silica, eluting with a gradient of 50-100percent CH2Cl2 in isohexane. Fractions containing product were combined and evaporated and the residue triturated with MeOH to leave a second crop of 2,5-dichloro-4- iodopyridine (5.74 g, 31percent yield); 1H NMR spectrum: (300 MHz, DMSO) δ 7.85 (IH, s), 8.34 (IH, s).
Reference: [1] Tetrahedron Letters, 2004, vol. 45, # 42, p. 7873 - 7877
[2] Patent: WO2009/153589, 2009, A1, . Location in patent: Page/Page column 117
[3] Patent: WO2009/66786, 2009, A1, . Location in patent: Page/Page column 120
[4] Patent: US2017/29404, 2017, A1, . Location in patent: Paragraph 0267-0269
[5] ACS Chemical Neuroscience, 2017, vol. 8, # 9, p. 1980 - 1994
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  • [ 1353056-41-3 ]
  • [ 1353056-42-4 ]
  • [ 796851-03-1 ]
Reference: [1] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297
  • 44
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  • [ 869886-67-9 ]
Reference: [1] Patent: WO2005/113541, 2005, A1,
[2] Patent: WO2005/113541, 2005, A1,
  • 45
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  • [ 68-12-2 ]
  • [ 102645-33-0 ]
YieldReaction ConditionsOperation in experiment
56%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h;
Stage #2: at -78 - 20℃; for 3 h;
2,5-dichloropyridine-4-carbaldehvde A solution of 2,5-dichloropyridine (27.0 g, 180 mmol) in THF (65 mL) was added via cannula to a cooled solution of LDA (100 mL of a 1 .8 M solution, 180 mmol) in THF (80 mL) at -78 °C. The mixture was stirred at -78 °C for 30 mins, then a solution of DMF (21.1 mL, 271 mmol) in THF (25 mL) was added slowly via syringe. The reaction was stirred at -78 °C for 3 hours and was then warmed to R.T. gradually. The solution was poured into a mixture of ice (800 mL) and cone. HCI (150 mL) and stirred for 20 mins before being basified with NaOH (3.0 M) to pH 9-10, and extracted with Et20 (2 x 500 mL). The combined organic layers were dried over MgS04 and concentrated to give the crude product as pale yellow solid. This solid was suspended in n-hexane with trace EtOAc and boiled for 5 mins. The liquors were decanted and stripped to yield a yellow solid which was purified by Biotage flash chromatography (65i, loaded in DCM / EtOAc, eluted with heptane - 20 percent EtOAc / heptane over 8 CV, then holding for 5 CV) to afford the title compound (17.9 g, 56 percent) as a pale yellow solid, 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1 H) 8.76 (s, 1 H) 10.22 (s, 1 H).
Reference: [1] Patent: WO2011/27249, 2011, A2, . Location in patent: Page/Page column 58
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 23, p. 6578 - 6581
[3] Patent: WO2006/50506, 2006, A1, . Location in patent: Page/Page column 132
[4] Patent: WO2005/73232, 2005, A1, . Location in patent: Page/Page column 34
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YieldReaction ConditionsOperation in experiment
99% With 1,1'-bis-(diphenylphosphino)ferrocene; triethylamine In methanol at 100℃; for 11 h; A 10 L bottle was charged with dichloropyridine, palladium acetate, dppf (1,1'-Bis(diphenylphosphino)ferrocene), and TEA in methanol 6 L. The bottle was stirred then contents transferred to an 5 gallon stainless steel stirred reaction vessel (Kla=1.42 (at) 40percent fill and 1000 rpm) via vacuum. The bottle was rinsed with another 2 L methanol, and the rinse was added to reaction vessel by the same method. The vessel was tested for leaks using nitrogen, then purged with nitrogen three times and carbon monoxide three times with the final carbon monoxide charge to be 50 psig of Carbon monoxide. The pressurized vessel was heated to a temperature of 100° C. The agitation rate was 1000 rpm. The reaction was allowed to progress for eleven hours, then allowed to cool to room temperature and sampled. Reaction was judged to be complete when 3percent LCAP or less of starting material remained. Batch was transferred to a 50 L r.b. flask equipped with a thermocouple and stir paddle. Flask was connected to a batch concentrator and concentration begun at approximately 25-30 in Hg of applied vacuum. Intermittent heating of batch was applied to maintain temp at approximately 30-35° C. Concentration was discontinued when copious precipitate was noted. Saturated brine 20 L was added via addition funnel over one hour. Batch was aged with gentle stirring overnight. In morning, a methanol/ice bath was applied to cool batch to -5° C. for 1.5 hours. Solids were collected by filtration and rinsed with 5 L brine twice, then dried under nitrogen tent overnight to give 3.47 Kg of product intimately mixed with sodium chloride: 57 wt percent, 1.98 Kg of product in the isolated solids, 99percent yield, ML losses 0.41percent. The product can be stored at this point if desired. NMR 1H δ: 3.87 (s, 3H), 7.69 (dd, J=8.4, 2.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 8.54 (d, J=2.4 Hz, 1H). NMR 13C δ: 52.8, 125.8, 135.7, 136.6, 145.7, 148.6, 164.6. Solids and tetrahydrofuran were charged to a 50 L r.b. flask equipped with stir paddle. The batch was stirred for one hour, at which point the water content (Kf) of the batch was less than 1000 ug/0.5 mL. The batch was concentrated with incremental tetrahydrofuran addition to azeotropically dry to Kf of 780 ug/0.5 mL. HPLC assay was 122 mg/g of THF solution, 1.97 Kg product in 16.06 Kg of solution.
Reference: [1] Patent: US2004/102472, 2004, A1, . Location in patent: Page 49; 50
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Reference: [1] Patent: WO2008/141385, 2008, A1,
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Reference: [1] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297
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