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Product Details of [ 40925-68-6 ]

CAS No. :40925-68-6 MDL No. :MFCD00235171
Formula : C6H6BrNO Boiling Point : -
Linear Structure Formula :- InChI Key :JHRIPENGTGSNPJ-UHFFFAOYSA-N
M.W : 188.02 Pubchem ID :351840
Synonyms :

Calculated chemistry of [ 40925-68-6 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 2.0
Molar Refractivity : 40.57
TPSA : 46.25 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 : Yes
Log Kp (skin permeation) : -6.12 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.31
Log Po/w (XLOGP3) : 1.87
Log Po/w (WLOGP) : 1.74
Log Po/w (MLOGP) : 1.58
Log Po/w (SILICOS-IT) : 1.34
Consensus Log Po/w : 1.57

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.68
Solubility : 0.395 mg/ml ; 0.0021 mol/l
Class : Soluble
Log S (Ali) : -2.46
Solubility : 0.648 mg/ml ; 0.00344 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.32
Solubility : 0.906 mg/ml ; 0.00482 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.31

Safety of [ 40925-68-6 ]

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 [ 40925-68-6 ]

* 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 [ 40925-68-6 ]
  • Downstream synthetic route of [ 40925-68-6 ]

[ 40925-68-6 ] Synthesis Path-Upstream   1~33

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Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 13, p. 6310 - 6314
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  • [ 5676-56-2 ]
Reference: [1] Patent: WO2003/99776, 2003, A1, . Location in patent: Page 56
[2] International Journal of Mass Spectrometry, 2013, vol. 345-347, p. 120 - 131
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Reference: [1] Bulletin de la Societe Chimique de France, 1923, vol. <4> 33, p. 1828
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  • [ 56-81-5 ]
  • [ 1198-14-7 ]
Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1891, vol. <2> 44, p. 439,442
[2] Journal of Fluorescence, 2018, vol. 28, # 5, p. 1121 - 1126
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  • [ 530-62-1 ]
  • [ 14733-73-4 ]
YieldReaction ConditionsOperation in experiment
100% at 20 - 25℃; for 1.5 h; Heating / reflux Reference Example 2
5-Bromo-1,3-benzoxazol-2(3H)-one
To a solution of 2-amino-4-bromophenol (3.50 g, 18.6 mmol) in tetrahydrofuran (100 mL) is added 1,1'-carbonyldiimidazole (3.62 g, 22.3 mmol) at 20-25°C, and the mixture is refluxed for 1.5 hour.
After the reaction, the reaction solution is cooled to 20-25°C, and thereto is added a 2N aqueous hydrochloric acid solution, and the mixture is extracted with ethyl acetate.
The resulting organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, and dried over anhydrous sodium sulfate.
The resultant is filtered, and the solvent is evaporated under reduced pressure to give 5-bromo-1,3-benzoxazol-2(3H)-one (3.89 g, quantitative).
IR (cm-1): 960, 1149, 1474, 1622, 1751
95% for 2 h; Reflux To a solution of 2-amino-4-phenylphenol (6.10 g, 32.9 mmol) in THF (150 mL) was added 1,1'-carbonyldiimidaziole (6.41 g, 39.5 mml) at room temperature.
The mixture was stirred at reflux for 2 h and cooled to room temperature.
The reaction was then quenched by adding 2 M HCl solution, and the mixture was extracted with EtOAc.
The organic layer was washed with brine and dried over anhydrous sodium sulfate.
After filtration, the solvent was removed in vacuo to give 11 (6.89 g, 99percent) as a white solid
95% at 20℃; for 2 h; Inert atmosphere 1,1′-Carbonyldiimidazole (46.5 g, 287 mmol) was added to a solutionof bromophenol 2 (49.0 g, 261 mmol) in THF (300 mL) at r.t.,and the mixture was stirred at r.t. for 2 h. The reaction was then quenched with 2 M aq HCl (700 mL), and the mixture was extracted with EtOAc (2 × 500 mL). The organic layers were combined, washed with brine (500 mL), dried (NaSO4), filtered, and concentrated in vacuo to give a brown solid; yield: 53.2 g (95percent).
91% at 120℃; for 3 h; a. A mixture of 2-amino-4-bromophenol (6.0 g, 31.9 mmol) and 1 ,1'- carbonyldiimidazole (6.2 g, 38.3 mmol) in p-dioxane (30 mL) was heated at 120 °C for 3 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid (3 20 mL), water (20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in hexanes/diethyl ether (1 :1 v/v, 50 mL) and washed with hexanes (20 mL) to afford 5- bromobenzo[d]oxazol-2(3H)-one in 91 percent yield (6.2 g) as a beige solid: 1H NMR (300 MHz, DMSO-d6) £ 11.85 (br s, 1 H), 7.28-7.25 (m, 3H); MS (ES+) m/z 212.0 (M + 1), 214.0 (M + 1).
63% at 80℃; for 17 h; Inert atmosphere To a solution of 14 (1.50 g. 7.98 mmol) in 1,4-dioxane (100 mL) was added Ι, Γ-carbonyldiimidazoie (1.55 g, 9.58 mmol). The reaction was heated at 80 "C for 17 h under nitrogen. The mixture was cooied to room temperature and 2N aq. HCI (40 mL) was added. The solution was diluted with ethyl acetate (200 mL) and washed with brine (2χ50 mL). The organic iayer was dried over sodium suifate, filtered and concentrated. Purification by chromatography (silica gel, 0-50percent ethyl acetate/hexanes) afforded 15 (1.08 g, 63percent) as an orange solid:XH M (5Q0 M Hz, DMSO-c/e) δ 11.81 (s, 1H), 7.27-7.25 (m, 3 H).

Reference: [1] Patent: EP1719761, 2006, A1, . Location in patent: Page/Page column 26
[2] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 18, p. 5568 - 5582
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 20, p. 8191 - 8195
[4] Synthesis (Germany), 2013, vol. 45, # 23, p. 3269 - 3275
[5] Patent: WO2013/64984, 2013, A1, . Location in patent: Page/Page column 125
[6] Patent: WO2015/2754, 2015, A2, . Location in patent: Paragraph 0198
[7] Journal of Medicinal Chemistry, 2015, vol. 58, # 23, p. 9258 - 9272
[8] RSC Advances, 2016, vol. 6, # 115, p. 114491 - 114499
[9] Patent: WO2016/198400, 2016, A1, . Location in patent: Page/Page column 61
[10] Patent: WO2018/148745, 2018, A1, . Location in patent: Page/Page column 82, 83
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Reference: [1] Journal of the American Chemical Society, 1934, vol. 56, p. 1586,1587
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  • [ 14733-73-4 ]
Reference: [1] Journal of Pharmaceutical Sciences, 1964, vol. 53, p. 538 - 544
[2] Patent: US2895877, 1956, ,
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  • [ 439607-87-1 ]
Reference: [1] Patent: EP1219622, 2002, A2, . Location in patent: Page 17
[2] Patent: US2002/86871, 2002, A1,
[3] Journal of Medicinal Chemistry, 2010, vol. 53, # 3, p. 1222 - 1237
  • 9
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Reference: [1] Medicinal Chemistry Research, 1999, vol. 9, # 7-8, p. 631 - 642
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YieldReaction ConditionsOperation in experiment
89%
Stage #1: With triethylamine In tetrahydrofuran at 0 - 2℃; for 2.33 h;
Stage #2: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 2.33 h;
[0936] TEA (4.06 g, 0.04 mmol) was added to a solution of XXXV-1 (5 g, 27 mmol) in THF (150 mL). And then 2-chloroacetyl chloride (3.33 g, 0.03 mmol) was added in portions at 0°C. After 20 minutes, the mixture was stirred at rt for 2 hrs. The reaction mixture was cooled to 0°C and NaH (60percent, 2.2 g, 54 mmol) was added in portions. The reaction mixture was stirred at 0°C for 20 minutes then at rt for 2h before being quenched with water. The solvent was removed in vacuo and the resulting mixture diluted with water. The precipitate was filtered, washed with water and dried in vacuo to give XXXV-2 (5.5 g, 89percent yield).
70%
Stage #1: With triethylamine In tetrahydrofuran at 0 - 20℃; for 2.16667 h;
Stage #2: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 2.33333 h;
INTERMEDIATE 6; 6-Bromo-4H'-benzorL4'|oxazin-3-one; Triethylamine (2.4 mL, 17 mmol) was added to 2-amino-4-bromophenol (2.5 g, 13 mmol) in TηF (80 mL). The reaction was cooled in ice and chloroacetyl chloride (1.12 mL, 14 mmol) added portionwise. It was stirred with cooling for 10 min then allowed to warm to r.t. and stirred for a further 2 h. The reaction mixture was cooled in ice and sodium hydride (1.05 g of a 60percent suspension in oil, 26 mmol) was added portionwise. The mixture was stirred with ice-bath cooling for 20 min then at r.t. for 2 h <n="28"/>before being quenched with water (20 mL). The THF was removed in vacuo and the resulting mixture diluted with water (100 mL). The precipitate was filtered off, washed with water (3 x 50 mL) and dried in vacuo to yield the title compound as a beige solid (2.14 g, 70percent). δH (DMSO-d6) 4.60 (2H, s), 6.92 (IH, d, J 8.5 Hz), 7.02 (IH, d, J2.3 Hz), 7.08 (IH, dd, J 8.5, 2.3 Hz), 10.81 (IH, br s).
70%
Stage #1: With triethylamine In tetrahydrofuran at 0 - 20℃;
Stage #2: With sodium hydride In tetrahydrofuran; oil at 0 - 20℃; for 2.33333 h;
NEt3 (2.4 mL, 17 mmol) was added to 2-amino-4-bromophenol (2.5 g, 13 mmol) in TηF (80 mL). The reaction mixture was cooled to 00C, chloroacetyl chloride (1.12 mL, 14 mmol) was added portionwise and then stirred at 00C for 10 minutes before being allowed to warm to r.t. and stirred for a further 2 h. The reaction mixture was cooled to 00C and NaH (1.05 g, 60percent dispersion in oil, 26 mmol) was added portionwise. The reaction mixture was stirred at O0C for 20 minutes then at r.t. for 2 h before being quenched with water (20 mL). The solvent was removed in vacuo and the resulting mixture diluted with water (100 mL). The precipitate was filtered, washed with water (3 <n="74"/>x 50 mL) and dried in vacuo to give the title compound (2.14 g, 70percent) as a beige solid. 5H (DMSO-(I6) 10.81 (IH, br. s), 7.08 (IH, dd, J 8.5 and 2.3 Hz), 7.02 (IH5 d, J2.3 Hz), 6.92 (IH, d, J 8.5 Hz), 4.60 (2H, s).
70%
Stage #1: With triethylamine In tetrahydrofuran at 0 - 20℃;
Stage #2: With sodium hydride In tetrahydrofuran; oil at 0 - 20℃; for 2.33333 h;
To a stirred solution of 2-amino-4-bromophenol (2.5 g, 13.3 mmol) in TηF (80 mL) at 00C was added NEt3 (2.4 mL, 17.3 mmol), followed by chloroacetyl chloride (1.12 mL, 14.6 mmol) portionwise. The reaction mixture was stirred at this temperature for 10 minutes, then allowed to warm to r.t. and stirred for a further 2 h. It was then cooled to 00C and NaH (1.05 g, 60percent dispersion in oil, 26 mmol) was added portionwise. The reaction mixture was stirred at 00C for 20 minutes, then at r.t. for 2 h before being quenched with water (20 mL) and concentrated in vacuo. The residue was diluted with water (100 mL). The precipitate formed was filtered, washed with water (3 x 50 mL) and dried in vacuo to give the title compound (2.14 g, 70percent) as a beige solid that was used without further purification. δH (DMSO-d6) 10.81 (IH, br. s), 7.08 (IH, dd, J8.5 and 2.3 Hz), 7.02 (IH, d, J 2.3 Hz), 6.92 (IH, d, J 8.5 Hz), 4.60 (2H, s).
62% With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 5 h; A mixture of 2-amino-4-bromophenol (10.15g, 354.29mmol), 2-chloroacetyl chloride (7.35g, 65.15mmol) and DCM (150mL) was cooled to 0 °C. DIEA (35.06g, 271.45mmol) was added dropwise, the resulting mixture was stirred at 20 °C for 5 hours. The reaction mixture was concentrated in vacuo and H2O (70mL) was added, the precipitate was filtered to afford the compound 4a as a red solid (7.61g, 62percent). MS: 228 (M+H) +.
2.5 g
Stage #1: With triethylamine In tetrahydrofuran at 0 - 20℃; for 2.16 h;
Stage #2: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 2.3 h;
Weigh 2-amino-4-bromophenol (2.5 g, 13 mmol) into a three-neck bottle.80 mL of tetrahydrofuran was added to the system, and triethylamine (2.4 mL, 17 mmol) was added thereto.The reaction system was cooled to 0 ° C, and chloroacetyl chloride (1.12 mL, 14 mmol) was added dropwise to the reaction system.After the addition was completed, the mixture was stirred at 0 ° C for 10 minutes, and further stirred at room temperature for 2 hours.The system was then lowered to 0 ° C and sodium hydride (1.05 g, 26 mmol) was added portionwise.The reaction system was lowered to 0 ° C for 20 minutes and then raised to room temperature for 2 hours.The reaction system was concentrated, and the reaction was quenched by adding 100 mL of water, and the precipitate was filtered and washed with water.Dry the filter cake. Get 2.5g red solid

Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 1, p. 333 - 346
[2] Archiv der Pharmazie, 2018, vol. 351, # 5,
[3] Patent: WO2015/153683, 2015, A1, . Location in patent: Paragraph 0936
[4] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 3, p. 1288 - 1296
[5] Patent: WO2008/44022, 2008, A1, . Location in patent: Page/Page column 26-27
[6] Patent: WO2009/71888, 2009, A1, . Location in patent: Page/Page column 72-73
[7] Patent: WO2009/71890, 2009, A1, . Location in patent: Page/Page column 103
[8] Patent: WO2017/211303, 2017, A1, . Location in patent: Page/Page column 35
[9] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 16, p. 4700 - 4704
[10] Patent: CN108250058, 2018, A, . Location in patent: Paragraph 0288; 0291-0294
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5432 - 5435
[2] Patent: WO2014/149164, 2014, A1, . Location in patent: Paragraph 00944
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Reference: [1] Organic Process Research and Development, 2012, vol. 16, # 10, p. 1626 - 1634
[2] Medicinal Chemistry Research, 2015, vol. 24, # 7, p. 3008 - 3020
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  • [ 24036-52-0 ]
Reference: [1] European Journal of Medicinal Chemistry, 2015, vol. 92, p. 575 - 582
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YieldReaction ConditionsOperation in experiment
96.5% at 20 - 35℃; for 6 h; To a stirred solution of 2-amino-4-bromophenol (3) (59.6 g, 0.317 mol) in methanol (600 mL) at roomtemperature, solid bromine cyanide (40.3 g, 0.38 mol, 1.2 eq) was added carefully in portions and the resultingmixture was stirred at 35 oc for 6 h. (Note: the bromine cyanide is very toxic, the reagent and reaction should be5 handled carefully in the fume hood). The reaction mixture was quenched by addition of saturated aqueousNa2C03 solution and the pH value was adjusted to 7-8. The mixture was then concentrated in vacuo to removethe methanol. The residue was dissolved in ethyl acetate (600 mL), washed with water (100 mL x 2) and brine(100 mL), dried over MgS04 and filtered. The filtrate was concentrated in vacuo to afford the desired product 4(65.2 g, 96.5percent yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): i5 7.62 (s, 2H), 7.37 (d, J = 1.9 Hz,10 lH), 7.30 (d, J = 8.3 Hz, lH), 7.11 (dd, J = 8.3, 2.1 Hz, lH); 13C NMR (100 MHz, DMSO-d6): i5 163.7, 147.1,145.7, 122.2, 117.7, ll5.4, 110.0.
95% at 18 - 37℃; for 15 h; Large scale [00227] Preparation of compound 2:[00228] 1. 2-Amino-4-bromophenol (12574 g) and methanol (100.6 L, 79.6 kg) were charged to anappropriately sized reactor and stirredat room temperature (-18 to 20°C).[00229] 2. A solution of cyanogen bromide (8500 g) was prepared in methanol (25.1 L, 19.9 kg) in a separate 50 gallon reactor; this solution was charged to the starting material reaction mixture via an additional funnel (total reaction volume -150 L, 40 gal).[00230] 3. The reaction mixture was heated for -15 hours at 37 °C. [00231] 4. The reaction was monitored by HPLC until it was complete.[00232] 5. Upon completion, the reaction mixture was cooled to 18 - 20 °C.[00233] 6. 40percent Sodium carbonate solution (12.41 Kg of Na2C03 in 30.2 Lwater) was addedat ambienttemperature and the mixture was stirred for ~1 hour.[00234] 7. Solvent was distilled under vacuum at 30 - 40 °C to remove most of the methanol.[00235] 8. Water (50.2 L, 50.2 kg) was charged.[00236] 9. Ethyl acetate (125 L, 113kg) was addedand the resulting mixture was stirred for ~10 minutes.[00237] 10. The agitation was stopped and the layers were allowed to separate.[00238] 11. The lower aqueous phase was drained.[00239] 12. Water (50 L, 50kg) was added to the organic layer in the reactor and the resulting mixture was stirred for at least 20 minutes.[00240] 13. The agitation was stopped and the layers were allowed to separate.[00241] 14. The lower aqueous phase was drained and combined with the aqueous phase from step 11.[00242] 15. Brine (7.0 Kg of NaCl in25 kg of H20)was addedand the resulting mixture was stirred for ~10 minutes.[00243] 16. The agitation was stopped and the layers were allowed to separate.[00244] 17. The lower aqueous phase was drained and combined with the aqueous phases from step 14.[00245] 18. Magnesium sulfate (1.9 Kg) was added and the resulting mixture was stirred for at least 15 minutes.[00246] 19. The mixture was filtered into a cleaned reactor using lum in-line filter.[00247] 20. The reactor and filter lines were washed with ethyl acetate (12 L).[00248] 21. Distillation was carried out under vacuum at 30— 40 °C to minimum steerable volume (~2 volumes, ~25 L).[00249] 22. Heptane (63 L, 43 kg) was added.[00250] 23. Distillation was carried out under vacuum at 30— 40 °C to minimum stirrable volume (~2 volumes, ~25 L).[00251] 24. Steps 22 & 23were repeated one more time.[00252] 25. Heptane (32 L) was added and the resulting mixture was stirredforat least 3 hours at ambienttemperature (18 °C to 20 °C).[00253] 26. The reaction was monitored by HPLC.[00254] 27. A solidwas collected by vacuum filtration and washed with heptane (2 x 13 L, 8.9kg).[00255] 28. The solid was dried in a vacuum oven at ~47 °C to constant weight to give brown to light brown color solid (13510 g, 95percent yield; HPLC purity 97.2percent; 'HNMR (DMSO-d6, 300 MHz) ? 7.6 (s, 2H), 7.38-7.28 (m, 2H), 7.15-7.08 (1H)).
95% at -18 - 37℃; for 15 h; Large scale Example 1: [0217] Preparation of compound 2: 1. 2-Amino-4-bromophenol (12574 g) and methanol (100.6 L, 79.6 kg) were charged to anappropriately sized reactor and stirredat room temperature (-18 to 20°C). 2. A solution of cyanogen bromide (8500 g) was prepared in methanol (25.1 L, 19.9 kg) in a separate 50 gallon reactor; this solution was charged to the starting material reaction mixture via an additional funnel (total reaction volume -150 L, 40 gal). 3. The reaction mixture was heated for -15 hours at 37 °C. 4. The reaction was monitored by HPLC until it was complete. 5. Upon completion, the reaction mixture was cooled to 18 - 20 °C. 6. 40percent Sodium carbonate solution (12.41 Kg of Na2C03 in 30.2 Lwater) was added at ambienttemperature and the mixture was stirred for ∼1 hour. 7. Solvent was distilled under vacuum at 30 - 40 °C to remove most of the methanol. 8. Water (50.2 L, 50.2 kg) was charged. 9. Ethyl acetate (125 L, 113kg) was addedand the resulting mixture was stirred for ∼10 minutes. 10. The agitation was stopped and the layers were allowed to separate. 11. The lower aqueous phase was drained. 12. Water (50 L, 50kg) was added to the organic layer in the reactor and the resulting mixture was stirred for at least 20 minutes. 13. The agitation was stopped and the layers were allowed to separate. 14. The lower aqueous phase was drained and combined with the aqueous phase from step 11. 15. Brine (7.0 Kg of NaCl in25 kg of H20)was addedand the resulting mixture was stirred for ∼10 minutes. 16. The agitation was stopped and the layers were allowed to separate. 17. The lower aqueous phase was drained and combined with the aqueous phases from step 14. 18. Magnesium sulfate (1.9 Kg) was added and the resulting mixture was stirred for at least 15 minutes. 19. The mixture was filtered into a cleaned reactor using lum in-line filter. 20. The reactor and filter lines were washed with ethyl acetate (12 L). 21. Distillation was carried out under vacuum at 30- 40 °C to minimum steerable volume (∼2 volumes, ∼25 L). 22. Heptane (63 L, 43 kg) was added. 23. Distillation was carried out under vacuum at 30- 40 °C to minimum stirrable volume (∼2 volumes, ∼25 L). 24. Steps 22 & 23were repeated one more time. 25. Heptane (32 L) was added and the resulting mixture was stirredforat least 3 hours at ambienttemperature (18 °C to 20 °C). 26. The reaction was monitored by HPLC. 27. A solidwas collected by vacuum filtration and washed with heptane (2 x 13 L, 8.9kg). 28. The solid was dried in a vacuum oven at ∼47 °C to constant weight to give brown to light brown color solid (13510 g, 95percent yield; HPLC purity 97.2percent; 'HNMR (DMSO-d6, 300 MHz) δ 7.6 (s, 2H), 7.38-7.28 (m, 2H), 7.15-7.08 (1H)).
70% at 20℃; for 8 h; Add 188g of compound 3 to 2L of methanol (Me(10),Keep the temperature at about 30°C, slowly add 120g of Bromide (BrCN), and react at room temperature for 8 hours after the addition.Then use saturated sodium carbonate solution to adjust the pH of the reaction solution to 8-9, then keep 40 °C to concentrate the methanol,It was extracted 3 times with 2 L of ethyl acetate, washed 3 times with 2 L of brine, dried over anhydrous sodium sulfate and concentrated to give 150 g of compound 4 in a yield of 70percent.

Reference: [1] Patent: WO2013/23184, 2013, A1, . Location in patent: Paragraph 00231; 00232
[2] Patent: WO2013/71272, 2013, A1, . Location in patent: Paragraph 00225-00255
[3] Patent: EP2792360, 2014, A1, . Location in patent: Paragraph 0217-0218
[4] Patent: CN105130973, 2018, B, . Location in patent: Paragraph 0053; 0064-0066
[5] Journal of Pharmaceutical Sciences, 1964, vol. 53, p. 538 - 544
[6] Patent: WO2010/51042, 2010, A1, . Location in patent: Page/Page column 136
[7] Patent: WO2014/151147, 2014, A1, . Location in patent: Paragraph 00502
[8] Patent: US2014/357651, 2014, A1, . Location in patent: Paragraph 0485
[9] Patent: US9174994, 2015, B2, . Location in patent: Page/Page column 120
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YieldReaction ConditionsOperation in experiment
29.02%
Stage #1: With hydrogenchloride In water for 6 h; Reflux
Stage #2: With lead(II) oxide In methanol for 8 h; Reflux
Preparation of 5-bromobenzoxazol-2-amine: 5.0 g (0.027 mol) of 2-amino-4-bromophenol,Thiocyanic acid according to 3.1g (0.040mol),Was added to a 100 ml round bottom flask,Then, 25 ml of 0.040 mol of hydrochloric acid was added,Reflow 6h.Let cool.Ethyl acetate 30 ml x 3 Extraction acid aqueous phase,Combine organic phase,Dried over anhydrous sodium sulfate for 12 h.The product was evaporated to dryness and dissolved in 40 ml of methanol.8.9 g (0.040 mol) of lead oxide was added,Reflux 8h,Hot filter,Get a black liquid.Recovery solvent,Column separation,Dichloromethane: methanol = 80: 1,Pale yellow solid,1.72 g,M.p. 144 to 146 ° C,Yield: 29.02percent.
Reference: [1] Patent: CN103772376, 2017, B, . Location in patent: Paragraph 0136; 0137
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Reference: [1] Patent: WO2014/151147, 2014, A1,
[2] Patent: US2014/357651, 2014, A1,
[3] Patent: US9174994, 2015, B2,
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  • [ 207115-22-8 ]
YieldReaction ConditionsOperation in experiment
1.1 g
Stage #1: With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5 h;
Stage #2: With potassium iodide In water at 0 - 20℃;
To a solution of 2-amino-4-bromophenol (2 g, 8.9 mmol, 1.0 equiv) in HC1 (5 M, 12.5 mE, 7.0 equiv) was added drop-wise a solution of sodium nitrite (0.62 g, 8.9 mmol, 1.0 equiv) in water (5 mE) at 00 C. The mixture was stirred at this temperature for 30 mm afier which a cooled solution of KI (1.5 g, 8.9 mmol, 1.0 equiv) inH2O (14 mE) was slowly added at 00 C. The mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (200 mE) and the separated aqueous phase was extracted with ethyl acetate (100 mEx3). The combined organic fraction was washed with Na2S2O3 (10percent, 40 mE), water (100 mEx2) and brine (40 mE), dried over Na2SO4 and concentrated to dryness.11219] The residue was purified by flash silica gel chromatography (ethyl acetate/hexanes) to afford 1.1 g 4-bromo-2- iodo-pheno as a yellow solid.
Reference: [1] Patent: US2015/368278, 2015, A1, . Location in patent: Paragraph 1218; 1219
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  • [ 16750-67-7 ]
  • [ 823-54-1 ]
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  • [ 107986-47-0 ]
  • [ 28165-50-6 ]
Reference: [1] Journal of Organic Chemistry, 1987, vol. 52, # 10, p. 2002 - 2010
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Reference: [1] Journal of Organic Chemistry, 1988, vol. 53, # 20, p. 4762 - 4769
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  • [ 28165-50-6 ]
Reference: [1] Journal of Organic Chemistry, 1987, vol. 52, # 10, p. 2002 - 2010
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Reference: [1] Journal of Organic Chemistry, 1988, vol. 53, # 20, p. 4762 - 4769
  • 22
  • [ 40925-68-6 ]
  • [ 106-93-4 ]
  • [ 105655-01-4 ]
YieldReaction ConditionsOperation in experiment
19% With potassium carbonate In N,N-dimethyl-formamide at 125℃; for 15 h; Inert atmosphere To a solution of 2-amino-4-bromophenol (4e) (200.0 mg, 1.06 mmol) and K2C03 (735.3 mg, 5.32 mmol) in anhydrous DMF (3 mL) was added 1,2-dibromoethane (0.14 mL, 1.60 mmol) under argon. The resulting mixture was stirred at 125 °C for 15 h. After being quenched with H20 (5 mL), the aqueous layer was extracted with EtOAc (2 x 15 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 10:90 to 20:80) to afford 3e (44.0 mg, 19percent) as a brown oil; ‘H NMR (CDC13, 400 MHz) 6.74—6.69 (2 H, m), 6.64 (1 H, d, J = 8.7 Hz), 4.22—4.20 (2 H, m), 3.89 (2 H, br),3.04—3.38 (2 H, m); ‘3C NMR (CDC13, 100 MHz) 142.9, 135.0, 121.0, 118.0, 117.6, 113.1,64.9, 40.5.
Reference: [1] Heterocyclic Communications, 2012, vol. 18, # 3, p. 143 - 146
[2] Patent: WO2018/183633, 2018, A1, . Location in patent: Paragraph 0006; 0008; 0017;0106; 0107
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Reference: [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 10, p. 1465 - 1474
[2] Patent: WO2011/130628, 2011, A1,
[3] Patent: US2013/102595, 2013, A1,
[4] Patent: JP2015/187145, 2015, A,
[5] Patent: WO2014/149164, 2014, A1,
  • 24
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  • [ 122-51-0 ]
  • [ 132244-31-6 ]
YieldReaction ConditionsOperation in experiment
89.5% for 8 h; Inert atmosphere; Reflux Under the protection of nitrogen,2-amino-4-bromophenol (2g, 10.64mmol)Add 30 ml of triethyl orthoformate,Reflux for 8 h.TLC was monitored and the reaction was cooled to room temperature.The crude product was obtained by distilling off triethyl orthoformate under reduced pressure.Further column chromatography gave a white product of 1.89 g.The yield was 89.5percent.
79% for 1.5 h; Reflux A solution of 2-amino-4-bromophenol (6.0 g, 32 mmol) in triethylorthoformate (120 mL, 720 mmol) was refluxed for 1.5 h. The mixture was then cooled and the organic solvent was removed under reduced pressure to give the crude product 5.5 g that was purified by column chromatography using Ethyl acetate:Hexanes to furnish the desired titled compound (5.0 g, 79percent) as pale brown solid.
70% at 150℃; for 8 h; Inert atmosphere General procedure: A solution of substituted 2-aminophenol (20 mmol) in triethyl orthoformate (30 mL) was heated to 150°C for 8 h under argon. The mixture was cooled to room temperature and the triethyl orthoformate was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford substituted benzoxazole.
Reference: [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6337 - 6352
[2] Patent: CN108503634, 2018, A, . Location in patent: Paragraph 0316; 0317; 0318; 0319
[3] Organic Letters, 2011, vol. 13, # 3, p. 522 - 525
[4] Patent: WO2015/162538, 2015, A1, . Location in patent: Page/Page column 47
[5] Tetrahedron Letters, 2015, vol. 56, # 3, p. 511 - 513
[6] Chemical Communications, 2015, vol. 51, # 81, p. 15059 - 15062
[7] Patent: WO2003/99776, 2003, A1, . Location in patent: Page 60
[8] Journal of Organic Chemistry, 2016, vol. 81, # 23, p. 11743 - 11750
[9] Tetrahedron Letters, 2019, vol. 60, # 1, p. 68 - 71
  • 25
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YieldReaction ConditionsOperation in experiment
95% for 2 h; Reflux A solution of 2-amino-4-bromophenol (LVIII) (10 g, 53.5 mmol, 1 eq) in trimethyl orthoformate (200 mL) was stirred at reflux for 2 h. After cooling, the solution was concentrated under reduced pressure to remove trimethyl orthoformate to give 5-bromobenzo[d]oxazole (LIX) (10.06 g, 50.8 mmol, 95.0percent). Used in the next reaction without additional purification.
Reference: [1] Patent: US2014/243349, 2014, A1, . Location in patent: Paragraph 1741; 1742
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  • [ 638192-65-1 ]
Reference: [1] Patent: US2014/243349, 2014, A1,
  • 27
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  • [ 719310-31-3 ]
Reference: [1] Patent: WO2011/130628, 2011, A1,
[2] Patent: JP2015/187145, 2015, A,
[3] Patent: US2013/102595, 2013, A1,
  • 28
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  • [ 936902-12-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6337 - 6352
[2] Patent: CN108503634, 2018, A,
  • 29
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Reference: [1] Patent: WO2015/153683, 2015, A1,
[2] Patent: WO2017/211303, 2017, A1,
  • 30
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Reference: [1] Patent: WO2013/71272, 2013, A1,
[2] Patent: WO2013/23184, 2013, A1,
[3] Patent: WO2014/151147, 2014, A1,
[4] Patent: WO2014/151147, 2014, A1,
[5] Patent: US2014/357651, 2014, A1,
[6] Patent: US2014/357651, 2014, A1,
[7] Patent: US9174994, 2015, B2,
[8] Patent: US9174994, 2015, B2,
[9] Patent: CN105130973, 2018, B,
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Reference: [1] Patent: WO2013/23184, 2013, A1,
[2] Patent: WO2013/23184, 2013, A1,
  • 32
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Reference: [1] Patent: WO2013/71272, 2013, A1,
[2] Patent: EP2792360, 2014, A1,
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Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 13, p. 6310 - 6314
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