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Product Details of [ 110-13-4 ]

CAS No. :110-13-4 MDL No. :MFCD00008792
Formula : C6H10O2 Boiling Point : -
Linear Structure Formula :- InChI Key :OJVAMHKKJGICOG-UHFFFAOYSA-N
M.W :114.14 Pubchem ID :8035
Synonyms :

Calculated chemistry of [ 110-13-4 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.67
Num. rotatable bonds : 3
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 31.36
TPSA : 34.14 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) : -7.19 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.34
Log Po/w (XLOGP3) : -0.27
Log Po/w (WLOGP) : 0.94
Log Po/w (MLOGP) : 0.35
Log Po/w (SILICOS-IT) : 1.08
Consensus Log Po/w : 0.69

Druglikeness

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

Water Solubility

Log S (ESOL) : -0.18
Solubility : 75.5 mg/ml ; 0.661 mol/l
Class : Very soluble
Log S (Ali) : 0.01
Solubility : 117.0 mg/ml ; 1.03 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -1.3
Solubility : 5.67 mg/ml ; 0.0497 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.05

Safety of [ 110-13-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P201-P202-P210-P260-P264-P270-P280-P301+P312+P330-P302+P352-P305+P351+P338-P308+P313-P332+P313-P337+P313-P370+P378-P403+P235-P405-P501 UN#:N/A
Hazard Statements:H227-H302-H315-H319-H361-H373 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 110-13-4 ]

* 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 [ 110-13-4 ]
  • Downstream synthetic route of [ 110-13-4 ]

[ 110-13-4 ] Synthesis Path-Upstream   1~20

  • 1
  • [ 110-13-4 ]
  • [ 1632-74-2 ]
YieldReaction ConditionsOperation in experiment
56%
Stage #1: With hydrazine hydrate In ethanol for 3 h; Reflux
Stage #2: With palladium 10% on activated carbon In ethanol; benzeneReflux
Step A:
A mixture of hexane-2,5-dione (6 mL, 51 mmol) and hydrazine monohydrate (2.5 mL, 51 mmol) in ethanol (50 mL) was brought to reflux for 3 h, then the solvent was removed under reduced pressure.
The residue was combined with 10percent Pd/C (1.1 g) in anhydrous benzene (200 mL).
The reaction mixture was heated at reflux overnight, then cooled to room temperature and filtered through a pad of Celite.
The filtrate was concentrated and purified by silica gel column chromatography (6percent MeOH in CH2Cl2) to provide 3,6-dimethylpyridazine (3.1 g, 56percent) as a light brown oil. 1H NMR (500 MHz, CDCl3): δ 7.23 (2H, s), 2.69 (6H, s).
Reference: [1] Patent: US9617268, 2017, B2, . Location in patent: Page/Page column 395; 396
[2] Journal of the American Chemical Society, 1956, vol. 78, p. 1961,1964
[3] Journal of the American Chemical Society, 1938, vol. 60, p. 2456
[4] Journal of the Chemical Society - Dalton Transactions, 1996, # 10, p. 2117 - 2122
[5] Gazzetta Chimica Italiana, 1950, vol. 80, p. 783,786
  • 2
  • [ 110-13-4 ]
  • [ 1632-74-2 ]
  • [ 39998-39-5 ]
Reference: [1] Journal of the American Chemical Society, 1956, vol. 78, p. 1961,1964
  • 3
  • [ 110-13-4 ]
  • [ 24068-54-0 ]
YieldReaction ConditionsOperation in experiment
69% With hydrogenchloride; sulfuric acid; sodium nitrite In hydrogenchloride; ethanol; water at 50℃; for 6 h; Step 1-Synthesis of 1-(5-methylisoxazol-3-yl)ethanone (1-a)
Ethyl nitrite gas was generated in situ by addition of a solution of sodium nitrite (100 g, 1.44 mol) in 50 mL of ethanol and 400 mL of water dropwise into a solution of 50 mL of concentrated sulfuric acid in 50 mL of ethanol and 400 mL of water in a stand-alone reaction vessel.
The ethyl nitrite gas generated was bubbled into another reaction flask containing a mixture of hexane-2,5-dione (80 g, 700.88 mmol) in concentrated hydrochloric acid (10 mL).
The resulting solution was stirred for 6 hr at 50° C.
After cooling to room temperature, the reaction mixture was diluted with ether (600 mL) then washed with of saturated sodium carbonate solution (2*500 mL) and brine (500 mL).
The organic layer was dried with anhydrous sodium sulphate then concentrated in vacuo.
The crude product was purified by distillation under reduced pressure (12 mm Hg) and the fraction with the boiling point of 70° C. was collected to give 61 g (69percent) of the title compound as a colorless liquid: 1H NMR (300 MHz, CDCl3) delta 6.36 (s, 1H), 2.63 (s, 3H), 2.49 (s, 3H).
Reference: [1] Patent: US2012/214762, 2012, A1, . Location in patent: Page/Page column 102
[2] Journal of Heterocyclic Chemistry, 2003, vol. 40, # 4, p. 655 - 658
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 2, p. 627 - 640
[4] Chemische Berichte, 1909, vol. 42, p. 1879
[5] Tetrahedron Letters, 1987, vol. 28, # 47, p. 5797 - 5800
[6] Journal of Physical Organic Chemistry, 2002, vol. 15, # 5, p. 247 - 257
[7] Patent: US5470862, 1995, A,
[8] Journal of Heterocyclic Chemistry, 2009, vol. 46, # 5, p. 909 - 913
[9] Patent: WO2009/158011, 2009, A1, . Location in patent: Page/Page column 167
  • 4
  • [ 110-13-4 ]
  • [ 24068-54-0 ]
  • [ 3405-77-4 ]
Reference: [1] Gazzetta Chimica Italiana, 1948, vol. 78, p. 622,628[2] Atti X. Congr. int. Chim. Rom, 1938, p. Bd. 3, S. 110, 118
  • 5
  • [ 7697-37-2 ]
  • [ 110-13-4 ]
  • [ 24068-54-0 ]
Reference: [1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1912, vol. <5>21 I, p. 665
  • 6
  • [ 7697-37-2 ]
  • [ 110-13-4 ]
  • [ 24068-54-0 ]
  • [ 6102-98-3 ]
Reference: [1] Chemische Berichte, 1909, vol. 42, p. 1879
  • 7
  • [ 110-13-4 ]
  • [ 2530-10-1 ]
Reference: [1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1913, vol. 45, p. 1937[2] Chem. Zentralbl., 1914, vol. 85, # I, p. 1663
  • 8
  • [ 110-13-4 ]
  • [ 1918-79-2 ]
Reference: [1] Chemische Berichte, 1885, vol. 18, p. 2252
  • 9
  • [ 110-13-4 ]
  • [ 3405-77-4 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2009, vol. 46, # 5, p. 909 - 913
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 14, p. 3642 - 3657
[3] Journal of Chemical Crystallography, 2009, vol. 39, # 10, p. 766 - 771
  • 10
  • [ 110-13-4 ]
  • [ 24068-54-0 ]
  • [ 3405-77-4 ]
Reference: [1] Gazzetta Chimica Italiana, 1948, vol. 78, p. 622,628[2] Atti X. Congr. int. Chim. Rom, 1938, p. Bd. 3, S. 110, 118
  • 11
  • [ 110-13-4 ]
  • [ 1904-31-0 ]
  • [ 34605-66-8 ]
YieldReaction ConditionsOperation in experiment
98% for 4 h; Reflux Accordingly, as shown in step 3-i of Scheme 3, 1-methyl-1H-pyrazol-3-amine (compound 1007, 2.8 g, 28.8 mmol) and 2,5-hexanedione (3.38 mL, 28.8 mmol) were dissolved into 50 mL of toluene. p-Toluenesulfonic acid (1.4 mmol) was added, the reaction mixture refluxed, and water generated from the reaction collected in a Dean-Stark trap.
When no more water was generated (about 4 hours), the reaction mixture was cooled and the volatiles removed under reduced pressure.
The residue was passed through a plug of silica gel using dichloromethane as eluent to yield an oil, which solidified upon standing.
The solid was broken up, suspended in hexane, vigorously stirred for one hour, and collected by filtration to provide 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-pyrazole (compound 1008, 5.0 g, 98percent yield) as a white powder: ESMS (M+1)=175; 1H-NMR (CDCl3) δ 7.38 (d, J=4 Hz, 1H), 6.14 (d, J=4 Hz, 1H), 5.84 (s, 2H), 3.95 (s, 3H), 2.09 (s, 6H).
98.1% With acetic acid In toluene at 155℃; Step 1)
3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-pyrazole
To a solution of 1-methyl-1H-pyrazol-3-amine (3.90 g, 40.16 mmol) and hexane-2,5-dione (4.58 g, 40.13 mmol) in toluene (80 mL) was added acetic acid (0.73 g, 12.16 mmol).
The reaction mixture was heated to 155° C. and stirred overnight, then cooled down to rt and concentrated in vacuo.
The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/10) to give the title compound as a yellow solid (6.90 g, yield 98.1percent).
LC-MS (ESI, pos. ion) m/z: 176.3 [M+H]+;
1H NMR (400 MHz, CDCl3): δ (ppm) 7.41 (d, J=2.1 Hz, 1H), 6.17 (d, J=2.2 Hz, 1H), 5.87 (s, 2H), 3.94 (s, 3H), 2.13 (s, 6H).
94% With toluene-4-sulfonic acid In benzene at 115℃; for 4 h; A solution of 1-methyl-1H-pyrazol-3-ylamine (0.92 g, 9.5 mmol) in benzene (4.8 mL) was treated with hexane-2,5-dione (1.34 mL, 11.4 mmol) and para-toluenesulfonic acid (182 mg, 0.95 mmol) and was heated to 115° C. under Dean-Stark conditions for 4 h. After this time, the reaction was cooled to 25° C., concentrated in vacuo and dried under high vacuum overnight. The resulting residue was dissolved in methylene chloride (100 mL) and was washed with water (1.x.150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO, 80 g, 1:4 ethyl acetate/hexanes) afforded 3-(2,5-dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole (1.57 g, 94percent) as a green oil; ES+-HRMS m/e calcd for C10H13N3 [M+H+] 176.1182, found 176.1182.
69% at 20 - 100℃; for 6 h; Inert atmosphere A solution of 1 -methyl-1 -/-pyrazol-3-amine (2 g, 20.6 mmol,) in AcOH (50 mL) was treated with 2,5-hexane dione (4.9 g, 43.29 mmol) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was heated to 100 °C for 1 h then stirred at ambient temperature for 5 h. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene. The crude product was purified by column chromatography on silica gel using 10percent EtOAc- hexanes eluent to give 3-(2,5-dimethyl-1 H-pyrrol-1 -yl)-1 -methyl-1 H-pyrazole as a liquid (2.5 g, 69percent). 1 H NMR (300 MHz, CDCI3): δ = 7.39 (d, J = 2.1 Hz, 1 H), 6.15 (d, J = 2.4 Hz, 1 H), 5.84 (s, 2H), 3.92 (s, 3H), 2.10 (s, 6H).
63% With acetic acid In toluene for 3 h; Reflux To a solution of 1-methyl-3-aminopyrazole (50 g, 0.52 mol) in toluene (2 L), hexane-2,5-dione (58.5 g) and acetic acid (12.5 mL) were added. The solution was then refluxed for 3 hours. After the reaction mixture was cooled, water (0.6 L) was added thereto. The mixture was neutralized with sodium carbonate, and then separated. The organic layer was then concentrated. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether 1:10) to yield 62 as a brown solid (57 g, y. 63percent). 1H-NMR (500 Mz) (CDCl3): 2.10 (s, 6H), 3.92 (s, 3H), 5.84 (s, 1H), 6.14 (d, J = 3.5 Hz, 1H), 7.38 (d, J = 3.5 Hz, 1H).
55% With toluene-4-sulfonic acid In toluene at 115℃; for 6 h; Dean-Stark To a stirred suspension of 1-methyl-1H-pyrazol-3-amine 76a (0.5 g, 5.1 mmol) in toluene (20 mL) in an round bottom flask fitted with Dean-Stark apparatus was charged with hexane-2,5-dione (0.70 g, 6.1 mmol) followed by p-toluene sulfonic acid (0.097 g, 0.51 mmol) and the reaction mixture was heated at 115°C for about 6 h. The reaction mixture was cooled to room temperature. Reaction mass was concentrated fully under reduced pressure, residue obtained was dissolved in DCM, given water wash followed by brine wash, dried over Na2504 and concentrated under redcued pressure to obtain 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-pyrazole 76b (0.55 g, 55percent yield) as green oil. 1HNMR (400 MHz, CDC13): 6 7.39 (d, 111), 6.15 (s, 1H), 5.85 (s, 2H), 3.92 (s, 3H), 2.10 (s, 6H), MS: 176.11 (M+H).
52% With toluene-4-sulfonic acid In toluene for 20 h; Reflux To a solution of 1-Methyl-1H-pyrazol-3-ylamine (2 g, 20.59 mmol), hexane-2,5-dione (2.82 g, 24.71 mmol) in toluene (35 ml) was added PTSA.H2O (392 mg, 2.059 mmol).
The mixture was refluxed for 20 h, after which the toluene was removed and water was added water.
The aqueous layer was then extracted with EtOAc, separated, and the organic phase was washed with brine, dried over Na2SO4, concentrated, and the crude material purified by column chromatography to give 3-(2,5-Dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole (1.9 g, 52percent).

Reference: [1] Patent: US2011/81316, 2011, A1, . Location in patent: Page/Page column 15; 16
[2] Patent: US2016/229837, 2016, A1, . Location in patent: Paragraph 0589; 0590; 0591
[3] Patent: US2009/264434, 2009, A1, . Location in patent: Page/Page column 27; 43
[4] Patent: WO2016/131098, 2016, A1, . Location in patent: Page/Page column 141
[5] Patent: EP2426135, 2012, A1, . Location in patent: Page/Page column 116
[6] Patent: WO2015/25197, 2015, A1, . Location in patent: Paragraph 000151
[7] Patent: US2011/71150, 2011, A1, . Location in patent: Page/Page column 32
  • 12
  • [ 67-56-1 ]
  • [ 2809-69-0 ]
  • [ 7664-93-9 ]
  • [ 3002-24-2 ]
  • [ 4437-51-8 ]
  • [ 110-13-4 ]
Reference: [1] Doklady Akademii Nauk Armyanskoi SSR, 1953, vol. 16, p. 103,105[2] Chem.Abstr., 1955, p. 8259
[3] Chemische Berichte, 1955, vol. 88, p. 1017,1026
  • 13
  • [ 110-13-4 ]
  • [ 6223-78-5 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1988, vol. 107, p. 529 - 535
  • 14
  • [ 542-92-7 ]
  • [ 110-13-4 ]
  • [ 6974-97-6 ]
YieldReaction ConditionsOperation in experiment
87% With sodium In methanol for 24 h; Inert atmosphere Preparation of 4,7-dimethylindeneUnder argon, the sodium wire was pressed into a three-necked flask(426 mmol, 9.8 g),Slowly add about 100mLDry methanol, until the sodium wire disappeared, adding the new system of cyclopentadiene (260mmol, 21.2mL) andCyclopentene2,5-hexanedione(170 mmol, 26.5 mL) and stirred for 24 h for bubbling.Add 50 mL of water to quench the reaction. After the methanol solvent was removed by steaming,With dilute hydrochloric acid to adjust the pH to neutral after the liquid,The aqueous phase was extracted with 200 mL of petroleum ether three times. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered,Rotate the solvent to remove the dark brown liquid,This was subjected to distillation under reduced pressure, and a fraction of 76 to 80 ° C was collected at 4 mmHg,To give 21.5 g of a yellow oily liquid,
56 % With sodium In methanol; diethyl ether; water EXAMPLE 1
4,7-Dimethylindene (1)
34.4 g (1.50 mol) of sodium were dissolved in 300 ml of absolute methanol.
A mixture of 53.8 ml (43.6 g, 0.66 mol) of cyclopentadiene and 67.3 g (0.59 mol) of 2,5-hexanedione was slowly added dropwise at 0° C.
When the addition had ended, the mixture was stirred at 0° C. for a further hour and then at room temperature for a further two hours. 200 ml of water and 300 ml of diethyl ether were added to the reaction mixture.
The organic phase was separated off in a separating funnel and the aqueous phase was washed twice with 50 ml of diethyl ether each time.
The combined organic phases were washed twice with 50 ml of water each time and then dried over sodium sulfate.
The solvent was removed in vacuo and the oily residue was subjected to fractional distillation (48°-52° C., 0.1 torr).
Yield 48.8 g (56 percent).
For the NMR data, see Table 1.
Reference: [1] Patent: CN106565404, 2017, A, . Location in patent: Paragraph 0076; 0077; 0078
[2] Tetrahedron, 1995, vol. 51, # 15, p. 4347 - 4358
[3] Tetrahedron Letters, 1994, vol. 35, # 36, p. 6627 - 6630
[4] Patent: US5194619, 1993, A,
  • 15
  • [ 7732-18-5 ]
  • [ 542-92-7 ]
  • [ 110-13-4 ]
  • [ 6974-97-6 ]
Reference: [1] Patent: US5194619, 1993, A,
  • 16
  • [ 542-92-7 ]
  • [ 110-13-4 ]
  • [ 6974-97-6 ]
Reference: [1] Tetrahedron Letters, 1994, vol. 35, # 36, p. 6627 - 6630
  • 17
  • [ 1072-97-5 ]
  • [ 110-13-4 ]
  • [ 228710-82-5 ]
YieldReaction ConditionsOperation in experiment
92% With toluene-4-sulfonic acid In toluene for 14 h; Heating / reflux 5-Bromopyridin-2-yl-amine (13. 8g, 0. 08MOL), acetonylacetone (14. 1 ml, 0. 12mol) and p-toluenesulphonic acid (100MG) were dissolved in toluene (180ML) and REFLUXED under Dean Stark conditions for 14 hours. After cooling, the brown solution was poured into water (200MOI) and extracted with toluene (2 x 200ml). The organic extracts were combined and washed with brine (50MI) then dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give crude product. This was purified by column chromatography on silica eluting with ethyl acetate: pentane (1: 3) to give the title compound as a brown oil (18. 4g, 0. 073MOL, 92percent). 1H NMR (CDC13, 400MHZ) 8 : 2.18 (s, 6H), 5.90 (s, 2H), 7.11 (d, 1 H), 7.92 (d, 1 H), 8.62 (s, 1 H). LRMS: M/Z 253 (M-H+, Br isotope).
92% for 14 h; Heating / reflux; Dean Stark conditions 5-Bromopyridin-2-yl-amine (13.8g, O.Oβmol), acetonylacetone (14.1 ml, 0.12mol) and p-toluenesulphonic acid (100mg) were dissolved in toluene (180ml) and refluxed under Dean Stark conditions for 14 hours. After cooling, the brown solution was poured into water (200ml) and extracted with toluene (2 x 200ml). The organic extracts were combined and washed with brine (50ml) then dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give crude product. This was purified by column chromatography on silica eluting with ethyl acetate: pentane (1 :3) to give the title compound as a brown oil (18.4g, 0.073mol, 92percent). 1H NMR (CDCI3, 400MHz) δ: 2.18 (s, 6H), 5.90 (s, 2H), 7.11 (d, 1 H), 7.92 (d, 1 H), 8.62 (s, 1 H). LRMS: m/z 253 (M-H+, Br isotope).
91.2% With toluene-4-sulfonic acid In tolueneReflux; Dean-Stark 2-Amino-5-bromopyridine (2) (10 mmol, 1.73 g), 2,5-hexanedione (12 mmol, 1.13 g) and p-toluene sulfonic acid (3 mmol, 0.52 g) was dissolved in toluene (30 mL) and heated to reflux in a Dean-Stark apparatus for 8-10 h until compound 2 can not be detected by TLC. After cooling to room temperature, the reaction mixture was washed with a saturated aqueous NaHCO3 solution, water and brine. The organic phase was dried with MgSO4 and concentrated in vacuum. The resulting orange liquid was dried under high vacuum and cooled to orange solid 3 (2.28 g, yield = 91.2 percent), m.p. 67.6-68.9 °C (lit. [9] 69 °C); 1H NMR (400 Hz, CDCl3), δ (ppm): 2.130 (s, 6H, 2*CH3), 5.905 (s, 2H, CH), 7.115-7.132 (d, 1H, pyr-H), 7.922-7.944 (dd, 1H, pyr-H), 8.651-8.656 (d, 1H, pyr-H); 13C NMR (100 MHz, CDCl3), δ (ppm): 13.19, 107.40, 118.91, 123.01, 128.59, 140.51, 150.41, 150.70.
80% With toluene-4-sulfonic acid In n-heptaneHeating / reflux 2-Amino-5-bromopyridine (6.0 Kg, 34.7 mol), 2,5-hexanedione (4.35 Kg, 38.2 mol) and p- toluenesulfonic acid (12 g) were dissolved in heptane (36 L) and refluxed under Dean Stark conditions overnight. The equipment was set for distillation and heptane (18 L) was removed by distillation. The mixture was cooled to 2O0C for 60 minutes. Seed crystals were added and the mixture granulated at 200C for 2 hours and then at 5°C overnight. The product was collected by filtration, washed with heptane (2*6 L) and dried at 45°C under vacuum overnight. Yield = 80percent (7.0 Kg) δH (CDCI3 300MHz) 2.20 (6H, s), 5.95 (2H, s), 7.15 (1H, d), 7.95 (1 H, d), 8.70 (1 H, s) ppm. MS m/z 253 (MH+, Br isotope).
80% With toluene-4-sulfonic acid In n-heptaneHeating / reflux 5-Bromo-2-(2,5-dimethylpyrrol-1-yl)pyridine
2-Amino-5-bromopyridine (6.0 Kg, 34.7 mol), 2,5-hexanedione (4.35 Kg, 38.2 mol) and p-toluenesulfonic acid (12 g) were dissolved in heptane (36 L) and refluxed under Dean Stark conditions overnight.
The equipment was set for distillation and heptane (18 L) was removed by distillation.
The mixture was cooled to 20° C. for 60 minutes.
Seed crystals were added and the mixture granulated at 20° C. for 2 hours and then at 5° C. overnight.
The product was collected by filtration, washed with heptane (2*6 L) and dried at 45° C. under vacuum overnight. Yield=80percent (7.0 Kg) δH (CDCl3 300 MHz) 2.20 (6H, s), 5.95 (2H, s), 7.15 (1H, d), 7.95 (1H, d), 8.70 (1 H, s) ppm. MS m/z 253 (MH+, Br isotope).
80% With acetic acid In cyclohexaneHeating / reflux Example 138
5-Bromo-2-(2,5-dimethyl-pyrrol-1-yl)-pyridine
Hexane-2,5-dione (97 mL, 831 mmol) was added to a solution of 2-amino-5-bromo-pyridine (125 g, 722 mmol) in cyclohexane (625 mL) and acetic acid (20 mL).
The solution was heated to reflux under argon atmosphere with a Dean-Stark trap.
A total of 30 mL of water was collected from the Dean-Stark trap.
The mixture was allowed to cool to room temperature, diluted with water, and extracted with diethyl ether.
The organic phase was washed with 1N hydrochloric acid (4 x), saturated aqueous sodium bicarbonate solution (2x) and saturated aqueous sodium chloride solution (2x).
The organic phase was dried (MgSO4) and concentrated in vacuo to yield a yellow solid.
The product was dissolved in hot hexanes (200 mL).
Charcoal was added and the mixture filtered.
Crystallization proceeded over three hours at 0°C.
The solid was collected by filtration to yield yellow crystals (145 g, 80percent).
Mp = 69°C; 1H NMR (CDCl3, 300MHz) δ 8.66 (d, 9 Hz, 1 H), 7.96 (dd, 9 Hz, 8 Hz, 1 H), 7.15 (d, 8 Hz, 1 H), 5.91 (s, 2 H), 2.14 (s, 6 H); MS (CI) m/z 251 (MH+); Anal. Calcd. for C11H11BrN2: C, 52.61; H, 4.42; N, 11.16; Br, 31.82. Found: C, 52.62; H, 4.56; N, 11.18; Rf = 0.4 (60:40 dichloromethane / hexanes).

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[3] Patent: WO2008/87512, 2008, A1, . Location in patent: Page/Page column 51-52
[4] Asian Journal of Chemistry, 2016, vol. 28, # 6, p. 1403 - 1404
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[10] Patent: WO2004/108675, 2004, A1, . Location in patent: Page 97
[11] Patent: WO2010/22307, 2010, A2, . Location in patent: Page/Page column 16
[12] Patent: WO2004/108676, 2004, A1, . Location in patent: Page 132
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YieldReaction ConditionsOperation in experiment
80% With acetic acid In cyclohexane; water EXAMPLE 138 STR91 5-Bromo-2-(2,5-dimethyl-pyrrol-1-yl)-pyridine
Hexane-2,5-dione (97 mL, 831 mmol) was added to a solution of 2-amino-5-bromo-pyridine (125 g, 722 mmol) in cyclohexane (625 mL) and acetic acid (20 mL).
The solution was heated to reflux under argon atmosphere with a Dean-Stark trap.
A total of 30 mL of water was collected from the Dean-Stark trap.
The mixture was allowed to cool to room temperature, diluted with water, and extracted with diethyl ether.
The organic phase was washed with 1N hydrochloric acid (4*), saturated aqueous sodium bicarbonate solution (2*) and saturated aqueous sodium chloride solution (2*).
The organic phase was dried (MgSO4) and concentrated in vacuo to yield a yellow solid.
The product was dissolved in hot hexanes (200 mL).
Charcoal was added and the mixture filtered.
Crystallization proceeded over three hours at 0° C.
The solid was collected by filtration to yield yellow crystals (145 g, 80percent). Mp=69° C.; 1 H NMR (CDCl3, 300 MHz) δ 8.66 (d, 9 Hz, 1 H), 7.96 (dd, 9 Hz, 8 Hz, 1 H), 7.15 (d, 8 Hz, 1 H), 5.91 (s, 2 H), 2.14 (s, 6 H); MS (CI) m/z 251 (MH+); Anal. Calcd. for C11 H11 BrN2: C, 52.61; H, 4.42; N, 11.16; Br, 31.82. Found: C, 52.62; H, 4.56; N, 11.18; Rf =0.4 (60:40 dichloromethane/hexanes).
Reference: [1] Patent: US6051586, 2000, A,
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Reference: [1] Patent: US6297382, 2001, B1,
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  • [ 110-13-4 ]
  • [ 1202769-66-1 ]
Reference: [1] Patent: US2012/214762, 2012, A1,
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 2, p. 627 - 640
[3] Patent: WO2009/158011, 2009, A1,
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