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Ingraham, Charles H. IV ; Stalinska, Joanna ; Carson, Sean C. , et al. DOI: PubMed ID:

Abstract: Glioblastomas are highly aggressive brain tumors for which therapeutic options are very limited. In a quest for new anti-glioblastoma drugs, we focused on specific structural modifications to the benzoyl-phenoxy-acetamide (BPA) structure present in a common lipid-lowering drug, fenofibrate, and in our first prototype glioblastoma drug, PP1. Here, we propose extensive computational analyses to improve the selection of the most effective glioblastoma drug candidates. Initially, over 100 structural BPA variations were analyzed and their physicochemical properties, such as water solubility (- logS), calculated partition coefficient (ClogP), probability for BBB crossing (BBB_SCORE), probability for CNS penetration (CNS-MPO) and calculated cardiotoxicity (hERG), were evaluated. This integrated approach allowed us to select pyridine variants of BPA that show improved BBB penetration, water solubility, and low cardiotoxicity. Herein the top 24 compounds were synthesized and analyzed in cell culture. Six of them demonstrated glioblastoma toxicity with IC50 ranging from 0.59 to 3.24 µM. Importantly, one of the compounds, HR68, accumulated in the brain tumor tissue at 3.7 ± 0.5 µM, which exceeds its glioblastoma IC50 (1.17 µM) by over threefold.

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Product Details of [ 16867-03-1 ]

CAS No. :16867-03-1 MDL No. :MFCD00006317
Formula : C5H6N2O Boiling Point : -
Linear Structure Formula :C5H3N(NH2)(OH) InChI Key :BMTSZVZQNMNPCT-UHFFFAOYSA-N
M.W : 110.11 Pubchem ID :28114
Synonyms :

Calculated chemistry of [ 16867-03-1 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 2.0
Molar Refractivity : 30.66
TPSA : 59.14 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.87 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.7
Log Po/w (XLOGP3) : 0.15
Log Po/w (WLOGP) : 0.38
Log Po/w (MLOGP) : -0.45
Log Po/w (SILICOS-IT) : 0.25
Consensus Log Po/w : 0.21

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.17
Solubility : 7.41 mg/ml ; 0.0673 mol/l
Class : Very soluble
Log S (Ali) : -0.95
Solubility : 12.4 mg/ml ; 0.113 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.03
Solubility : 10.3 mg/ml ; 0.0938 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.31

Safety of [ 16867-03-1 ]

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 [ 16867-03-1 ]

* 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 [ 16867-03-1 ]
  • Downstream synthetic route of [ 16867-03-1 ]

[ 16867-03-1 ] Synthesis Path-Upstream   1~79

  • 1
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Reference: [1] Patent: WO2004/838, 2003, A1, . Location in patent: Page 66-67
  • 2
  • [ 15128-82-2 ]
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YieldReaction ConditionsOperation in experiment
70%
Stage #1: With hydrogenchloride; 1,1,1,3',3',3'-hexafluoro-propanol; iron In water at 20℃; for 0.5 h;
Stage #2: With sodium hydrogencarbonate In water
General procedure: The nitro compound (1 equiv), HFIP (10 equiv), Fe powder (5 equiv) were mixed in a tube. Then 2 N HCl aqueous solutions was added to the reaction mixture. After stirring at room temperature for 30 min, the reaction mixture was neutralized with sat. NaHCO3 (aq.) and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was then purified by column chromatography on silica gel to furnish the desired amine product.
Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 37, p. 3646 - 3649
[2] Journal of the Chemical Society, <1957> 4625,
[3] Pharmaceutical Bulletin, 1957, vol. 5, p. 350,352
[4] Biochemical Journal, 1950, vol. 46, p. 506
[5] Patent: US1889303, 1930, ,
[6] Green Chemistry, 2016, vol. 18, # 8, p. 2435 - 2442
[7] Applied Catalysis A: General, 2016, vol. 525, p. 85 - 93
[8] Patent: US1889303, 1930, ,
  • 3
  • [ 6332-56-5 ]
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Reference: [1] Patent: US6218539, 2001, B1,
  • 4
  • [ 614-99-3 ]
  • [ 16867-03-1 ]
Reference: [1] Patent: US4061644, 1977, A,
  • 5
  • [ 680-31-9 ]
  • [ 611-13-2 ]
  • [ 16867-03-1 ]
Reference: [1] Patent: US4061644, 1977, A,
  • 6
  • [ 680-31-9 ]
  • [ 609-38-1 ]
  • [ 16867-03-1 ]
Reference: [1] Patent: US4061644, 1977, A,
  • 7
  • [ 874-24-8 ]
  • [ 16867-03-1 ]
Reference: [1] Patent: US4022897, 1977, A,
  • 8
  • [ 24016-03-3 ]
  • [ 16867-03-1 ]
Reference: [1] European Journal of Organic Chemistry, 2003, # 9, p. 1681 - 1686
  • 9
  • [ 10006-74-3 ]
  • [ 16867-03-1 ]
Reference: [1] Chemische Berichte, 1928, vol. 61, p. 1028
  • 10
  • [ 933-90-4 ]
  • [ 16867-03-1 ]
Reference: [1] Biochemical Journal, 1950, vol. 46, p. 506
  • 11
  • [ 40263-57-8 ]
  • [ 16867-03-1 ]
Reference: [1] Roczniki Chemii, 1936, vol. 16, p. 502,507[2] Chem. Zentralbl., 1937, vol. 108, # I, p. 3634
  • 12
  • [ 93596-90-8 ]
  • [ 16867-03-1 ]
Reference: [1] Prace Minist. Przem. chem., <1952> Nr. 1, S. 1, 14, [2] Chem.Abstr., <1954> 1337,
  • 13
  • [ 109-00-2 ]
  • [ 16867-03-1 ]
Reference: [1] Pharmaceutical Bulletin, 1957, vol. 5, p. 350,352
  • 14
  • [ 14773-50-3 ]
  • [ 16867-03-1 ]
Reference: [1] Chemische Berichte, 1928, vol. 61, p. 1028
  • 15
  • [ 74037-50-6 ]
  • [ 16867-03-1 ]
Reference: [1] Chemische Berichte, 1928, vol. 61, p. 1028
  • 16
  • [ 186581-53-3 ]
  • [ 16867-03-1 ]
  • [ 10201-71-5 ]
Reference: [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 19, p. 3934 - 3941
  • 17
  • [ 16867-03-1 ]
  • [ 109-63-7 ]
  • [ 18107-18-1 ]
  • [ 10201-71-5 ]
Reference: [1] Patent: US5972975, 1999, A,
  • 18
  • [ 16867-03-1 ]
  • [ 10201-71-5 ]
Reference: [1] Tetrahedron Letters, 1985, vol. 26, # 21, p. 2571 - 2574
  • 19
  • [ 16867-03-1 ]
  • [ 78-39-7 ]
  • [ 86467-39-2 ]
YieldReaction ConditionsOperation in experiment
65.8%
Stage #1: at 120℃; for 4 h;
Stage #2: Cooling
80 mL of ethyl orthoacetate was added to 15 g (136 mmol) of 2-amino-3-hydroxypyridine, followed by addition of p-toluenesulfonic acid in a catalytic amount, and the mixture was reacted at 120° C. for 4 hours. After the reaction solution was cooled, triethylamine was added to the solution, to neutralize p-toluenesulfonic acid. Then, the solution was subjected to distillation under reduced pressure by using an evaporator, and then purified by silica gel column chromatography.Amount of the product: 12.0 g, Yield: 65.8percent.
Reference: [1] Monatshefte fur Chemie, 2011, vol. 142, # 1, p. 87 - 91
[2] Heterocycles, 1995, vol. 41, # 3, p. 477 - 486
[3] Monatshefte fur Chemie, 2007, vol. 138, # 7, p. 663 - 667
[4] Patent: US2009/247736, 2009, A1, . Location in patent: Page/Page column 13
[5] Tetrahedron Letters, 1990, vol. 31, # 8, p. 1155 - 1156
[6] Synthetic Communications, 1992, vol. 22, # 20, p. 2891 - 2901
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  • [ 123-54-6 ]
  • [ 86467-39-2 ]
Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 13, p. 6310 - 6314
  • 21
  • [ 16867-03-1 ]
  • [ 64-19-7 ]
  • [ 86467-39-2 ]
Reference: [1] Tetrahedron Letters, 2007, vol. 48, # 13, p. 2295 - 2298
  • 22
  • [ 16867-03-1 ]
  • [ 32894-07-8 ]
  • [ 86467-39-2 ]
Reference: [1] Tetrahedron Letters, 1990, vol. 31, # 8, p. 1155 - 1156
  • 23
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  • [ 530-62-1 ]
  • [ 60832-72-6 ]
YieldReaction ConditionsOperation in experiment
81% at 70℃; for 14 h; [00102] As shown in step 4-i of Scheme 4, l,l '-carbonyldiimidazole (57.4 g, 354.2 mmol) was added to a solution of 2-amino-3-hydroxypyridine (26.0 g, 236.1 mmol, obtained from Aldrich Chemical Co.) in THF (400 mL). The resulting reaction mixture was stirred at 70 0C for 14 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was dissolved in DCM (500 mL) and washed with 2 N NaOH (3 x 100 mL). The combined aqueous layers were cooled to 0 0C and acidified to a pH of 6 with 6 N HCl. The precipitate that was formed was collected in a fritted funnel, washed with cold water (100 mL), and dried under vacuum to afford oxazolo[4,5-δ]pyridin-2(JH)-one (Compound 1011, 26.0 g, 81percent yield): ESMS (M+Η) 137; 1H NMR (DMSO-d6) δ 12.4 (br, 1Η), 8.0 (d, 1Η), 7.6 (d, 1Η), 7.1 (dd, 1Η).
81% at 70℃; for 14 h; As shown in step 4-i of Scheme 4, 1,1'-carbonyldiimidazole (57.4 g, 354.2 mmol) was added to a solution of 2-amino-3-hydroxypyridine (26.0 g, 236.1 mmol, obtained from Aldrich Chemical Co.) in THF (400 mL). The resulting reaction mixture was stirred at 70 0C for 14 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was dissolved in DCM (500 mL) and washed with 2 N NaOH (3 x 100 mL). The combined aqueous layers were cooled to 0 0C and acidified to a pH of 6 with 6 N HCl. The precipitate that was formed was collected in a fritted funnel, washed with cold water (100 mL), and dried under vacuum to afford oxazolo[4,5-δ]pyridin-2(JH)-one (Compound 1011, 26.0 g, 81percent yield): ESMS (M+Η) 137; 1H NMR (DMSO-d6) δ 12.4 (br, 1Η), 8.0 (d, 1Η), 7.6 (d, 1Η), 7.1 (dd, 1Η).
79% for 1 h; Heating / reflux Carbonyldiimidazole (600 mmol) was added in several batches to a solution of 2-aminopyridin-3- ol (400 mmol) in tetrahydrofuran (600 ml) and the reaction was heated at reflux for 1 h. The mixture was concentrated and the residue was diluted with dichloromethane (500 ml). The solution was extracted with 1.5 N sodium hydroxide (3 x 200 ml). The pH of the aqueous layer was adjusted to 5 with 2 N hydrochloric acid and the precipitaed solids were collected by filtration to provide oxazolo[4,5-b]pyridin- 2(3H)-one in 79percent yield as a grey solid.
79% Reflux Intermediate 30: Synthesis of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine-7-sulfonyl chloride.CCIICCHH2XCOOCCIINaHCO3 N' " 1. Synthesis of oxazolo[4,5-blpyridm-2(3H)-one.Carbonyldiimidazole (600 mmol) was added in several batches to a solution of 2- aminopyridin-3-ol (400 mmol) in tetrahydrofuran (600 ml) and the reaction was heated at reflux for 1 h. The mixture was concentrated and the residue was diluted with dichloromethane (500 ml). The solution was extracted with 1.5 N sodium hydroxide (3 x 200 ml). The pH of the aqueous layer was adjusted to 5 with 2 N hydrochloric acid and the precipitaed solids were collected by filtration to provide oxazolo[4,5-b]pyridin-2(3H)-one in 79percent yield as a grey solid.
79% for 1 h; Reflux Intermediate 30: Synthesis of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine-7-sulfonyI chloride.CICH,COCI Pd/C, H- NaHCO, 1. Synthesis of oxazolo[4,5-b]pyridin-2('3//)-one.Carbonyldiimidazole (600 mmol) was added in several batches to a solution of 2- aminopyridin-3-ol (400 mmol) in tetrahydrofuran (600 ml) and the reaction was heated at reflux for 1 h. The mixture was concentrated and the residue was diluted with dichloromethane (500 ml). The solution was extracted with 1.5 N sodium hydroxide (3 x 200 ml). The pH of the aqueous layer was adjusted to 5 with 2 N hydrochloric acid and the precipitaed solids were collected by filtration to provide oxazolo[4,5-b]pyridin-2(3H)-one in 79percent yield as a grey solid.
73% Reflux Into a 3-L 3-necked round-bottom flask, was placed a solution of 2-aminopyridin-3-ol (100 g, 908.15 mmol, 1.00 equiv), 1-[(1H-imidazol-1-yl)carbonyl]-1H-imidazole (221.3 g, 1.36 mol, 1.50 equiv) in THF (1000 mL).
The resulting solution was heated to reflux overnight.
After cooling, the reaction was concentrated under vacuum.
The residue was dissolved in 1000 mL of DCM and extracted with 1M NaOH (3*800 mL).
The combined liquids were cooled with a water/ice bath and adjusted to pH 5-6 by adding 3M HCl.
The solids were collected by filtration.
The solid was dried in an oven under reduced pressure.
This resulted in 90 g (73percent) of 2H,3H-[1,3]oxazolo[4,5-b]pyridin-2-one (1-10) as a gray solid.
71% for 1.5 h; Reflux A suspension of carbonyl diimidazole (118.2 mmol, 19.1 g) and 2-amino-3-hydroxy-pyridine (90.9 mmol, 10.00 g) in THF (100 mL) was heated at reflux for 1.5 hours. (0767) The mixture was cooled and concentrated under reduced pressure. The residue was taken up in dichloromethane and extracted with 2M aqueous sodium hydroxide solution. The aqueous phase was cooled (ice/water bath) and (0768) acidified to pH5 with concentrated hydrochloric acid. (0769) The resulting precipitate was isolated by filtration, washed with water and THF then dried under suction to give the title compound as a grey powder (8.81 g, 71percent).
0.5 g for 16 h; Reflux To a stirred solution of 2-amino 3-hydroxy pyridine 1 (2 g, 16.26 mmol) in THF (20 ml ) was added CDI (2.63 g ,16.26 mmol )and the total reaction mass stirred at reflux temperature for 16 h. Reaction mass was cooled to room temperature, THF was distilled and the crude material was partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulphate and concentrated under vacuum to afford the desired compound 2 (0.5 g )

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[2] Patent: WO2010/96389, 2010, A1, . Location in patent: Page/Page column 42; 44
[3] Patent: WO2010/135014, 2010, A1, . Location in patent: Page/Page column 50-51
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[5] Patent: WO2009/23844, 2009, A2, . Location in patent: Page/Page column 120
[6] Patent: WO2010/21797, 2010, A1, . Location in patent: Page/Page column 84-85
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[9] Patent: US2014/274926, 2014, A1, . Location in patent: Paragraph 0525; 0526
[10] Patent: WO2015/115673, 2015, A1, . Location in patent: Page/Page column 76
[11] Archiv der Pharmazie, 1999, vol. 332, # 2, p. 43 - 49
[12] Patent: WO2013/42035, 2013, A1, . Location in patent: Page/Page column 30-31
[13] Patent: WO2013/114332, 2013, A1, . Location in patent: Page/Page column 116; 117; 118
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[15] Patent: WO2009/100536, 2009, A1, . Location in patent: Page/Page column 95
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  • [ 32315-10-9 ]
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YieldReaction ConditionsOperation in experiment
86.2% With sodium hydroxide In chloroform; water; toluene at 74 - 88℃; Industrial scale In 2L to three-opening bottle 810g30percent of aqueous sodium hydroxide solution and 110g2-amino-3-hydroxy-pyridine, stirring to dissolve, will 340g triphosgene is dissolved in 600 ml of toluene and 300 ml chloroform solution; to the slow heating three-mouth bottle 80 °C rear, dropping the toluene and the chloroform solution of triphosgene, the reaction temperature is controlled at 74 the [...] 88 °C between, the end of the dropping reaction 8 hours; cooling to the 20 [...] 30 °C, reaction with hydrochloric acid or sodium hydroxide to adjust PH value is neutral, to continue to lower the temperature to 10 °C the following, a filter, a water washing of the filter cake, drying the white solid obtained oxazole [4,5-b] pyridine -2 (3H) ketone 91.4g, the yield is 86.2percent, after separating the filtrate, dry recovery of toluene and chloroform
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
[2] Patent: CN105924454, 2016, A, . Location in patent: Paragraph 0013
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  • [ 530-62-1 ]
  • [ 60832-72-6 ]
  • [ 1408253-36-0 ]
Reference: [1] Patent: US2014/113824, 2014, A1, . Location in patent: Paragraph 0293-0295; 0300-0303
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  • [ 201230-82-2 ]
  • [ 60832-72-6 ]
Reference: [1] ChemSusChem, 2015, vol. 8, # 13, p. 2204 - 2211
[2] Phosphorus and Sulfur and the Related Elements, 1988, vol. 38, p. 137 - 148
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YieldReaction ConditionsOperation in experiment
0.5 g for 16 h; Reflux Step-1 [0134] To a stirred solution of 2-amino 3-hydroxy pyridine 1 (2 g, 16.26 mmol) in THF (20 ml) was added CDI (2.63 g, 16.26 mmol) and the total reaction mass stirred at reflux temperature for 16 h. Reaction mass was cooled to room temperature, THF was distilled and the crude material was partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulphate and concentrated under vacuum to afford the desired compound 2 (0.5 g)
Reference: [1] Patent: US2014/249170, 2014, A1, . Location in patent: Paragraph 0133; 0134
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  • [ 74124-79-1 ]
  • [ 60832-72-6 ]
Reference: [1] Synthetic Communications, 1982, vol. 12, # 3, p. 213 - 218
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  • [ 57-13-6 ]
  • [ 60832-72-6 ]
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  • [ 32276-00-9 ]
  • [ 60832-72-6 ]
  • [ 86-93-1 ]
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Reference: [1] Phytochemistry, 2005, vol. 66, # 15, p. 1797 - 1803
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[2] Patent: WO2016/97918, 2016, A1,
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  • [ 60832-72-6 ]
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  • [ 541-41-3 ]
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  • [ 109103-43-7 ]
Reference: [1] Journal of the Chemical Society, <1957> 4625,
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  • [ 75-36-5 ]
  • [ 31354-48-0 ]
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[2] Tetrahedron Letters, 2004, vol. 45, # 7, p. 1465 - 1468
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  • [ 108-24-7 ]
  • [ 31354-48-0 ]
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  • [ 100-44-7 ]
  • [ 24016-03-3 ]
YieldReaction ConditionsOperation in experiment
77.3% With tetrabutylammomium bromide; sodium hydroxide In water at 40 - 75℃; for 6 h; Large scale temperature below 40 ° C, to the 300L stainless steel reactor 48L of purified water was added slowly stirring 48kg sodium hydroxide, stirring until dissolved.To sodium hydroxide solution followed by adding 16kg 2-amino-3-hydroxypyridine, 1.6kg tetrabutylammonium bromide, 17.92L benzyl chloride, plus warming to 70 ~ 75 ° C reaction 6 hours, stirring was stopped,Let stand, liquid separation; aqueous phase extraction with toluene (20Lx3);Purified water washing (30Lx2), the organic phase was collected, concentrated to a large amount of solid precipitation, temperature 0 ~ 5 ° C, crystallization was stirred for 2 hours, centrifuged,The filter cake was rinsed with 3.2 L of pre-cooled toluene and dried under vacuum at 50~55 ° C. for 3 hours to afford Intermediate II as a bright yellow solid, 22.5 kg of 2-amino-3-benzyloxypyridine, with a molar yield of 77.3percent , Purity 99.53percent.
60% With tetrabutylammomium bromide; sodium hydroxide In dichloromethane at 20℃; for 19 h; 2-Amino-3-hydroxypyridine (11 g, 100 mmol), chlorobenzyl (12.66 mL, 110 mmol) and tetrabutylammonium bromide (3 g, 10 mmol) were dissolved in 50 mL of 40percent sodium hydroxide solution and 50 mL of dichloromethane The mixture was stirred at room temperature for 19 h. After the reaction is completed, liquid is dispensed, The aqueous phase is diluted with water and extracted three times with dichloromethane. Combine the organic phase, Drying with anhydrous sodium sulfate, Filter and concentrate, Column chromatography of the residue gave the title compound as a brown solid (12 g, 60percent yield).
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  • [ 100-39-0 ]
  • [ 24016-03-3 ]
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  • 40
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[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 828 - 835
[3] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
[4] Patent: WO2016/97918, 2016, A1,
[5] Patent: US4022897, 1977, A,
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  • [ 115-80-0 ]
  • [ 52333-88-7 ]
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[2] Monatshefte fur Chemie, 2007, vol. 138, # 7, p. 663 - 667
[3] Tetrahedron Letters, 1990, vol. 31, # 8, p. 1155 - 1156
[4] Synthetic Communications, 1992, vol. 22, # 20, p. 2891 - 2901
  • 43
  • [ 16867-03-1 ]
  • [ 52333-88-7 ]
Reference: [1] Patent: US4038396, 1977, A,
  • 44
  • [ 16867-03-1 ]
  • [ 69214-22-8 ]
Reference: [1] Journal of Chemical Research, Miniprint, 1986, # 11, p. 3368 - 3390
[2] Tetrahedron Letters, 1985, vol. 26, # 21, p. 2571 - 2574
  • 45
  • [ 107-20-0 ]
  • [ 16867-03-1 ]
  • [ 69214-22-8 ]
Reference: [1] Journal of Chemical Research, Miniprint, 1986, # 2, p. 670 - 688
  • 46
  • [ 16867-03-1 ]
  • [ 20348-23-6 ]
Reference: [1] Acta Chemica Scandinavica (1947-1973), 1969, vol. 23, p. 2322 - 2324
  • 47
  • [ 16867-03-1 ]
  • [ 600-00-0 ]
  • [ 20348-21-4 ]
YieldReaction ConditionsOperation in experiment
97% With potassium carbonate In acetone at 70℃; for 16 h; Step-(i): Synthesis of 2,2-dimethyl-2H-pyridor3,2-biri,41oxazin-3(4H)-one (18.1) To a stirred solution of 2-aminopyridin-3-ol (5 g, 45.45 mmol) in acetone (50 mL) was added K2CO3 (25.09 g, 181.81 mmol) followed by ethyl 2-bromo-2-methylpropanoate (13.29 g, 68.18 mmol) at 20-35°C and the reaction mixture was allowed to stir at 70°C for 16 h. Then the reaction mixture was cooled to 20-35°C and diluted with ice water. The obtained solid was filtered and washed with water to get the desired compound as a white solid (5 g, 97percent); H NMR (400MHz, DMSO-<) δ 11.17 (s, 1H), 7.91 (d, /=4.4 Hz, 1H), 7.34 (d, /=7.8 Hz, 1H), 6.98 (dd, /=4.9 Hz, 7.9 Hz, 1H), 1.41 (s, 6H); LC-MS: 179.3 (M+l)+.
Reference: [1] Patent: WO2015/71780, 2015, A1, . Location in patent: Page/Page column 22
[2] Tetrahedron Letters, 2010, vol. 51, # 14, p. 1852 - 1855
[3] Acta Chemica Scandinavica (1947-1973), 1969, vol. 23, p. 2322 - 2324
  • 48
  • [ 16867-03-1 ]
  • [ 20348-21-4 ]
Reference: [1] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 3, p. 262 - 267
  • 49
  • [ 16867-03-1 ]
  • [ 79-04-9 ]
  • [ 20348-09-8 ]
YieldReaction ConditionsOperation in experiment
4.3 g With sodium hydrogencarbonate In water; butanone at 20 - 75℃; for 1.5 h; Cooling with ice 2-Amino-3-ol (45 mmol) and sodium hydrogen carbonate (51 mmol) in water (30 ml) and 2-butanone (30 ml) mixed solution. Under ice-cooling, chloroacetyl chloride (51 mmol) of 2-butanone (10 ml) was slowly added, maintaining the temperature during the addition does not exceed 10 ° C. It was stirred at room temperature for 30 minutes, stirring for 1 hour at 75 ° C, and concentrated recrystallization (methanol / water = 1: 1) to give 4.3 g of the title compound.
Reference: [1] Bioorganic and Medicinal Chemistry, 1998, vol. 6, # 2, p. 133 - 142
[2] Helvetica Chimica Acta, 1976, vol. 59, p. 1593 - 1612
[3] Patent: CN103130792, 2016, B, . Location in patent: Paragraph 0605-0607
  • 50
  • [ 16867-03-1 ]
  • [ 5292-43-3 ]
  • [ 20348-09-8 ]
YieldReaction ConditionsOperation in experiment
2.3 g With sodium hydroxide In dichloromethane; water at 20℃; for 24 h; A mixture of 3-hydroxy-2-aminopyridine 2 (3 g, 27 mmol), tert-butylbromoacetate3 (4 mL, 27 mmol), Adogen-464 (168 mg) and NaOH solution (40percent in water, 15 mL) was dissolved in DCM (25 mL).The reaction mixture was stirred at room temperature for 24 h. Themixture was then washed with water (3 × 50 mL) and the organic layerscombined. The organic portion was dried, (MgSO4) and concentratedin vacuo. The resulting crude yellow oil was purified by columnchromatography (silica gel, 3percent MeOH in DCM) to afford amine 4:Yellow oil; yield 2.3 g, 38percent; Rf (5percent MeOH in DCM) 0.50; IR (νmax,cm–1) film: 3483 (w), 1748 (s), 1616 (s), 1476 (s), 1154 (s); 1H NMR(300 MHz, CDCl3) δ 7.67 (1H, d, J = 5 Hz, H py), 6.80 (1H, d, J = 8 Hz,H py), 6.55 (1H, dd, J = 8, 5 Hz, H py), 4.85 (2H, br. s, NH2), 4.49 (2H,s, CH2), 1.45 (9H, s, 3 × CH3); 13C NMR (75 MHz, CDCl3) δ 167.7 (s),150.7 (s), 140.9 (s), 140.1 (d), 117.7 (d), 113.3 (d), 82.9 (s), 66.3 (t), 28.2(q); LRMS (ES) m/z (percent): 266 [M + H + CH3CN]+ (30).3–5
Reference: [1] Journal of Chemical Research, 2016, vol. 40, # 12, p. 753 - 757
  • 51
  • [ 16867-03-1 ]
  • [ 79-11-8 ]
  • [ 20348-09-8 ]
Reference: [1] Patent: WO2004/14384, 2004, A2, . Location in patent: Page/Page column 256; 262
  • 52
  • [ 16867-03-1 ]
  • [ 105-36-2 ]
  • [ 20348-09-8 ]
Reference: [1] Tetrahedron Letters, 2010, vol. 51, # 14, p. 1852 - 1855
  • 53
  • [ 16867-03-1 ]
  • [ 20348-09-8 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1984, vol. 21, # 4, p. 1081 - 1086
[2] Patent: US2016/145268, 2016, A1,
  • 54
  • [ 16867-03-1 ]
  • [ 96-34-4 ]
  • [ 20348-09-8 ]
Reference: [1] Acta Chemica Scandinavica (1947-1973), 1969, vol. 23, p. 2322 - 2324
  • 55
  • [ 16867-03-1 ]
  • [ 35570-68-4 ]
Reference: [1] Helvetica Chimica Acta, 1976, vol. 59, p. 1593 - 1612
  • 56
  • [ 16867-03-1 ]
  • [ 21594-52-5 ]
Reference: [1] Phytochemistry, 2005, vol. 66, # 15, p. 1797 - 1803
[2] Journal of Medicinal Chemistry, 1993, vol. 36, # 4, p. 497 - 503
[3] Helvetica Chimica Acta, 1976, vol. 59, p. 1593 - 1612
[4] Patent: WO2013/42035, 2013, A1,
[5] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
[6] Patent: US2014/249170, 2014, A1,
[7] Patent: WO2016/97918, 2016, A1,
[8] Patent: WO2009/100536, 2009, A1,
  • 57
  • [ 16867-03-1 ]
  • [ 35575-96-3 ]
Reference: [1] Helvetica Chimica Acta, 1976, vol. 59, p. 1593 - 1612
  • 58
  • [ 16867-03-1 ]
  • [ 122-51-0 ]
  • [ 273-97-2 ]
YieldReaction ConditionsOperation in experiment
68% at 160℃; Inert atmosphere To a solution of 2-amino-3-hydroxypyridine (90.1 mmol) in triethylorthoformate (720.7 mmol) was added p-toluenesulphonic acid (4.50 mmol) and the mixture was stirred under nitrogen at 160 °C overnight. The triethylorthoformate was removed in vacuo and the crude material was purified by column chromatography, eluting with cyclohexane/ethyl acetate 5percent-40percent to give the title compound as a beige solid (68percent). LRMS [M + H] 121.1 m/z; 1H NMR (DMSO, 400 MHz) δ 9.04 (s, 1H), 8.58 (dd, J = 4.8, 1.4 Hz,1H), 8.26 (dd, J = 8.2, 1.4 Hz, 1H), 7.50 (dd, J = 8.2, 4.8 Hz, 1H), 6.41 (s, 2H); 13C NMR (DMSO, 101 MHz) δ 157.7, 154.5, 147.1, 142.0, 121.5, 120.1.
Reference: [1] Monatshefte fur Chemie, 2011, vol. 142, # 1, p. 87 - 91
[2] Journal of Organic Chemistry, 2011, vol. 76, # 13, p. 5444 - 5449
[3] European Journal of Medicinal Chemistry, 2013, vol. 66, p. 450 - 465
[4] Tetrahedron Letters, 1990, vol. 31, # 8, p. 1155 - 1156
[5] Synthetic Communications, 1992, vol. 22, # 20, p. 2891 - 2901
[6] Monatshefte fur Chemie, 2007, vol. 138, # 7, p. 663 - 667
[7] Patent: WO2005/74904, 2005, A2, . Location in patent: Page/Page column 56; 59-60
[8] Patent: US2004/19218, 2004, A1, . Location in patent: Page 18
[9] Patent: WO2003/97617, 2003, A1, . Location in patent: Page/Page column 50
[10] Patent: WO2004/108661, 2004, A1, . Location in patent: Page/Page column 44; 50; 53;
[11] Patent: WO2005/28454, 2005, A1, . Location in patent: Page/Page column 46; 52; 55
[12] Patent: WO2005/63742, 2005, A2, . Location in patent: Page/Page column 21; 24
[13] Patent: WO2004/838, 2003, A1, . Location in patent: Page 72
[14] Patent: WO2004/838, 2003, A1, . Location in patent: Page 75
[15] Patent: WO2005/74904, 2005, A2, . Location in patent: Page/Page column 56; 59-60
  • 59
  • [ 16867-03-1 ]
  • [ 149-73-5 ]
  • [ 273-97-2 ]
Reference: [1] Monatshefte fur Chemie, 2011, vol. 142, # 1, p. 87 - 91
  • 60
  • [ 16867-03-1 ]
  • [ 150-13-0 ]
  • [ 95331-56-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 13, p. 1647 - 1650
[2] Journal of Enzyme Inhibition and Medicinal Chemistry, 2017, vol. 32, # 1, p. 513 - 521
[3] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 8, p. 2350 - 2353
  • 61
  • [ 16867-03-1 ]
  • [ 140-89-6 ]
  • [ 53052-06-5 ]
YieldReaction ConditionsOperation in experiment
86.95% at 110℃; Step 1: Preparation of oxazolo[4,5-b]pyridine-2-thiol A solution of 2-aminopyridin-3-ol (5.0g, 45.45 mmol) and potassium ethyl xanthate (8.0g, 49.99 mmol) in pyridine (50mL) was heated at 110°C overnight. The reaction mixture was cooled to 0°C, added ice water and acidified with Cone. HCl. The solid was filtered and dried under vacuum to afford the title compound (6.0g, 86.95percent). 1HNMR (DMSO-d6, 300MHz): δ 8.24-8.22 (d, 1H), 7.90-7.87 (d, 1H), 7.30-7.26 (m, 1H). LCMS: m/z: 153.0 (M+l) +.
86.95% at 110℃; A solution of 2-aminopyridin-3-ol (5.0 g, 45.45 mmol) and potassium ethyl xanthate (8.0 g, 49.99 mmol) in pyridine (50 mL) was heated at 1100 C. overnight. The reaction mixture was cooled to 00 C., added ice water and acidified with Conc. HC1. The solid was filtered and dried under vacuum to afford the title compound (6.0 g, 86.95percent). 10206] ‘HNMR (DMSO-d5, 300 MHz): ö 8.24-8.22 (d, 1H), 7.90-7.87 (d, 1H), 7.30-7.26 (m, 1H). LCMS: mlz:153.0 (M+1).
Reference: [1] Patent: WO2015/104688, 2015, A1, . Location in patent: Page/Page column 36
[2] Patent: US2016/340366, 2016, A1, . Location in patent: Paragraph 0205; 0206
[3] Monatshefte fur Chemie, 2011, vol. 142, # 9, p. 895 - 899
[4] Journal of Organic Chemistry, 1995, vol. 60, # 17, p. 5721 - 5725
[5] European Journal of Medicinal Chemistry, 2005, vol. 40, # 1, p. 15 - 23
[6] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 1, p. 114 - 125
[7] Patent: EP1308439, 2003, A1,
  • 62
  • [ 75-15-0 ]
  • [ 16867-03-1 ]
  • [ 53052-06-5 ]
YieldReaction ConditionsOperation in experiment
67% With potassium hydroxide In ethanol for 10 h; Reflux In a 100 ml round bottom flask was placed 2- amino-3-hydroxy pyridine (2.20g, 20 mmol) and 40 ml of absoluteethanol was added and the mixture was stirred for 15minutes. In the meanwhile, 2.0g (29 mmol) KOH pelletswere powdered and transferred into the flask followed by theaddition of 15 ml of carbon disulfide. The resulting mixturewas refluxed over an oil bath for 8 hours when a yellowprecipitate appeared. The contents of the flask were cooledto room temperature. The solvent was rotary evaporated andthe residue was transferred in to a beaker and 75 ml of waterwas added followed by neutralization with acetic acid. Theprecipitated product was filtered under vacuum and washedwith 3x50 ml of water and dried under vacuum over night toyield 2.1g of light yellow solid product (yield, 65percent).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 5, p. 2075 - 2078
[2] Advanced Synthesis and Catalysis, 2017, vol. 359, # 11, p. 1837 - 1843
[3] Letters in Organic Chemistry, 2010, vol. 7, # 7, p. 519 - 527
[4] Archiv der Pharmazie, 2017, vol. 350, # 8,
  • 63
  • [ 16867-03-1 ]
  • [ 53052-06-5 ]
Reference: [1] Patent: US4351832, 1982, A,
  • 64
  • [ 16867-03-1 ]
  • [ 137-26-8 ]
  • [ 53052-06-5 ]
Reference: [1] Green Chemistry, 2017, vol. 19, # 23, p. 5591 - 5598
  • 65
  • [ 16867-03-1 ]
  • [ 78-95-5 ]
  • [ 79707-11-2 ]
Reference: [1] Journal of Medicinal Chemistry, 1985, vol. 28, # 7, p. 876 - 892
[2] Patent: US4450164, 1984, A,
  • 66
  • [ 16867-03-1 ]
  • [ 174669-74-0 ]
YieldReaction ConditionsOperation in experiment
65%
Stage #1: at 0℃; for 1 h;
100 ml of pyridine hydrofluoride (Py. (HF)x, from Fluka, 70percent of the sample consisting of hydrogen fluoride, 30percent of the sample consisting of pyridine), cooled at 0° C., are admixed cautiously and in succession with 3.7 g of 2-amino-3-hydroxypyridine (molecular mass: 110.12; 33.6 mmol) and 3 g of NaNO2 (molecular mass: 69.00; 43.5 mmol).
The mixture is stirred at 0° C. for 1 hour and then slowly rendered basic with 10N aqueous NaOH solution, transferred to a decanter and extracted with EtOAc.
The organic phases are combined, washed with water and brine, dried with Na2SO4 and concentrated to dryness.
The residue is purified by passing it through a silica gel column (eluent: heptane/EtOAc: 50/50) to give 2.5 g (65percent) of 2-fluoro-3-hydroxypyridine in the form of a solid, which is used without further purification.
Rf(EtOAc/heptane: 80/20): 0.65. m.p.: 131° C. 1H NMR (DMSO-d6, 298 K): δ: 10.41 (s, 1H); 7.64 (td, J: 1.7 and 4.7 Hz, 1H); 7.42 (dd, J: 1.7, 1.7 and 10.8 Hz, 1H); 7.17 (ddd, J: 1.3, 4.7 and 7.8 Hz, 1H).
13C NMR (DMSO-d6 298 K): δ: 152.8 (d, J1F-C: 233 Hz, C; 140.2 (d, J2F-C: 27 Hz, C); 135.6 (d, J3F-C) 13 Hz, CH) 126.2 (d, J3F-C: 5 Hz, CH); 122.6 (CH).MS(DCI/NH4+): C5H4FNO: 131[M+NH4+]; 114[M+H+]. Anal. (C5H4FNO) C, H, N.
55% With hydrogen bromide; sodium nitrite In water at 0℃; for 1 h; A solution of 2-amino-3-hydroxypyridine (2 g, 17.8 mmol) in aqueous 48percent HBr (75 mL) was cooled to 0° C. was carefully treated with NaNO2 (10.0 g, 0.14 mol) in portions. The mixture was stirred at 0° C. for 1 h, then neutralized to pH about 7 with 2N NaOH, and extracted with EtOAc (100 mL.x.3). The combined organic extract was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give a brown solid. The crude material was purified by flash chromatography on a silica gel column eluted with 50percent EtOAc/hexanes to give 1.10 g (55percent) of 2-fluoro-3-pyridinol as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.80-7.70 (m, 1H), 7.60-7.50 (m, 1H), 7.15-7.05 (m, 1H); LRMS (ESI), m/z 114 (M+H).
Reference: [1] Patent: US2005/249662, 2005, A1, . Location in patent: Page/Page column 8-9
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 1998, vol. 41, # 5, p. 451 - 463
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 2008, vol. 51, # 9, p. 336 - 342
[4] Patent: US2010/29650, 2010, A1, . Location in patent: Page/Page column 64
[5] Organic and Biomolecular Chemistry, 2015, vol. 13, # 12, p. 3667 - 3676
[6] Patent: US6133253, 2000, A,
[7] Patent: WO2009/140163, 2009, A1, . Location in patent: Page/Page column 45
  • 67
  • [ 16867-03-1 ]
  • [ 169205-95-2 ]
Reference: [1] European Journal of Medicinal Chemistry, 2005, vol. 40, # 1, p. 15 - 23
[2] Journal of Organic Chemistry, 1995, vol. 60, # 17, p. 5721 - 5725
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 5, p. 2075 - 2078
[4] Patent: WO2015/104688, 2015, A1,
[5] Patent: US2016/340366, 2016, A1,
[6] Advanced Synthesis and Catalysis, 2017, vol. 359, # 11, p. 1837 - 1843
  • 68
  • [ 16867-03-1 ]
  • [ 122450-96-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 1998, vol. 6, # 2, p. 133 - 142
[2] Patent: CN103130792, 2016, B,
  • 69
  • [ 16867-03-1 ]
  • [ 391906-83-5 ]
Reference: [1] Patent: WO2008/118718, 2008, A2,
  • 70
  • [ 16867-03-1 ]
  • [ 754230-78-9 ]
Reference: [1] Journal of the American Chemical Society, 2015, vol. 137, # 27, p. 8851 - 8857
  • 71
  • [ 16867-03-1 ]
  • [ 100-44-7 ]
  • [ 754230-78-9 ]
Reference: [1] Archiv der Pharmazie, 2011, vol. 344, # 3, p. 158 - 164
  • 72
  • [ 16867-03-1 ]
  • [ 130049-82-0 ]
Reference: [1] Patent: WO2011/73997, 2011, A2,
[2] Patent: WO2012/42368, 2012, A1,
[3] Organic Preparations and Procedures International, 2016, vol. 48, # 3, p. 296 - 302
[4] Patent: CN107311998, 2017, A,
  • 73
  • [ 16867-03-1 ]
  • [ 877399-47-8 ]
Reference: [1] Patent: CN108341802, 2018, A,
  • 74
  • [ 16867-03-1 ]
  • [ 908248-27-1 ]
Reference: [1] Patent: US2014/274926, 2014, A1,
[2] Patent: WO2015/115673, 2015, A1,
  • 75
  • [ 16867-03-1 ]
  • [ 894852-01-8 ]
Reference: [1] Patent: WO2015/71780, 2015, A1,
  • 76
  • [ 16867-03-1 ]
  • [ 114414-17-4 ]
YieldReaction ConditionsOperation in experiment
48.5 g at 5 - 125℃; for 12 h; Bromine (11.2 mL, 0.21 mole) was added dropwise to a mechanically stirred suspension of 2-aminopyridin-3-ol (20 g, 0.18 mole) in acetic acid (300 mL) at 5 - 10 °C and brought to room temperature. The reaction mixture was heated at 120 - 125 °C, maintained for 12 hours and concentrated to get a crude mass that was triturated with diethyl ether (50 mL x 3) and dried under vacuum to obtain 2-amino-4-bromopyridin-3-ol hydrobromide as dark brown compound that was used as such without any purification. Yield: 48.5 g; Mass (m/z): 189.3, 191.1 (M+H)+.
Reference: [1] Patent: WO2018/42362, 2018, A1, . Location in patent: Page/Page column 125
  • 77
  • [ 16867-03-1 ]
  • [ 10035-10-6 ]
  • [ 7789-45-9 ]
  • [ 114414-17-4 ]
Reference: [1] Acta Crystallographica, Section C: Crystal Structure Communications, [2] Acta Crystallographica, Section C: Crystal Structure Communications, 1988, vol. 44, p. 450 - 453
  • 78
  • [ 16867-03-1 ]
  • [ 24424-99-5 ]
  • [ 902835-93-2 ]
YieldReaction ConditionsOperation in experiment
95% With guanidine hydrochloride In ethanol at 35 - 40℃; for 2.5 h; General procedure: Amine (1 mmol) was added to a magnetically stirred solution of guanidine hydrochloride (15 molpercent) and di-tert-butyl dicarbonate (1.2 mmol) in EtOH (1 mL), at 35-40°C and stirred for appropriate time (Table 1). After completion of the reaction (followed by TLC or GC), EtOH was evaporated under vacuum and the residue either was washed with water to remove the catalyst or was dissolved in CH2Cl2 (or EtOAc) and filtered off to separate out the catalyst. Evaporation of the organic solvent (if used in work up) gives almost a pure product. In the cases of using an excess (Boc)2O the product was washed with petroleum ether or hexane to recover the residual (Boc)2O. If necessary, the product was further purified either by crystallization (hexane and dichloromethane, or diethyl ether and petroleum ether) or silica gel column chromatography using EtOAc-hexane (1: 6) as eluent.
Reference: [1] Tetrahedron Letters, 2011, vol. 52, # 12, p. 1260 - 1264
[2] Monatshefte fur Chemie, 2011, vol. 142, # 10, p. 1035 - 1043
  • 79
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  • [ 1207175-73-2 ]
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
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