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Chemical Structure| 135484-83-2
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Product Details of [ 135484-83-2 ]

CAS No. :135484-83-2 MDL No. :MFCD07783014
Formula : C8H8BrNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :MMSODGJNFCCKAZ-UHFFFAOYSA-N
M.W : 230.06 Pubchem ID :17871390
Synonyms :

Calculated chemistry of [ 135484-83-2 ]

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 2
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 49.83
TPSA : 52.32 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.32 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.05
Log Po/w (XLOGP3) : 3.36
Log Po/w (WLOGP) : 1.83
Log Po/w (MLOGP) : 2.06
Log Po/w (SILICOS-IT) : 1.65
Consensus Log Po/w : 2.19

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.62
Solubility : 0.055 mg/ml ; 0.000239 mol/l
Class : Soluble
Log S (Ali) : -4.14
Solubility : 0.0168 mg/ml ; 0.000073 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -2.97
Solubility : 0.244 mg/ml ; 0.00106 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.46

Safety of [ 135484-83-2 ]

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

Application In Synthesis of [ 135484-83-2 ]

* 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 [ 135484-83-2 ]
  • Downstream synthetic route of [ 135484-83-2 ]

[ 135484-83-2 ] Synthesis Path-Upstream   1~22

  • 1
  • [ 135484-83-2 ]
  • [ 62473-92-1 ]
YieldReaction ConditionsOperation in experiment
10%
Stage #1: With hydrogenchloride; sodium nitrite In water at 0 - 5℃; for 0.75 h;
Stage #2: With sulfur dioxide In water; acetic acid at 0 - 20℃; for 3.5 h;
Stage #3: With ammonium hydroxide In water at 10 - 20℃; for 1 h;
Preparation 49
6-Bromo-1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-one
A solution of methyl 2-amino-4-bromobenzoate (4.5 g, 20 mmol) in 20percent hydrochloric acid (30 mL) was stirred until all solids were dissolved.
The solution was cooled to 0° C. and a solution of sodium nitrite (1.4 g, 0.020 mol) in water (20 mL) was added dropwise at such a rate that the internal reaction temperature did not exceed 5° C.
The mixture was stirred at 0° C. for 45 minutes.
Sulfur dioxide was bubbled into a mixture of acetic acid (50 mL) and water (5 mL) at 0° C. until the solution was saturated.
Copper (I) chloride (2.0 g, 0.020 mol) was then added to the saturated sulfur dioxide solution.
The mixture was cooled to 0° C.
To this mixture was added the diazonium salt solution dropwise with vigorous stirring over a period of 30 minutes.
The reaction mixture was stirred at 0° C. for 1 hour and then the mixture was allowed to warm to room temperature.
The mixture was stirred at room temperature for 2 h before it was poured into ice water (250 mL) and extracted with EtOAc (3*50 mL).
The organics were washed with sat.
NaHCO3 solution and dried over anhydrous Na2SO4.
The solvent was removed in vacuo to afford an oily residue which was dissolved in tetrahydrofuran (40 mL) and cooled to 0° C.
To this mixture was added a cold (0° C.) solution of ammonium hydroxide (28percent, 40 mL) portion-wise at such a rate that the internal reaction temperature was maintained below 10° C.
The mixture was allowed to warm to room temperature and was then stirred at room temperature for 1 h.
The solvent was removed in vacuo and the residue was dissolved in saturated aqueous sodium bicarbonate (40 mL) and washed with diethyl ether (50 mL).
The aqueous layer was acidified with concentrated hydrochloric acid to pH 1.
The resulting precipitate was collected by filtration and was dried under vacuum to produce of 6-Bromo-1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-one (500 mg, 10percent yield).
1H NMR (400 MHz, DMSO) δ 8.44 (d, J=1.5, 1H), 8.04 (dd, J=8.1, 1.5, 1H), 7.81 (d, J=8.0, 1H).
10%
Stage #1: With hydrogenchloride; sodium nitrite In water at 0 - 5℃; for 0.75 h;
Stage #2: With sulfur dioxide; copper(l) chloride In water; acetic acid at 0 - 20℃; for 3.5 h;
solution of methyl 2-amino-4-bromobenzoate (4.5 g, 20 mmol) in 20percent hydrochloric acid (30 mL) was stirred until all solids were dissolved.
The solution was cooled to 0° C. and a solution of sodium nitrite (1.4 g, 0.020 mol) in water (20 mL) was added dropwise at such a rate that the internal reaction temperature did not exceed 5° C.
The mixture was stirred at 0° C. for 45 minutes.
Sulfur dioxide was bubbled into a mixture of acetic acid (50 mL) and water (5 mL) at 0° C. until the solution was saturated.
Copper (I) chloride (2.0 g, 0.020 mol) was then added to the saturated sulfur dioxide solution.
The mixture was cooled to 0° C.
To this mixture was added the diazonium salt solution dropwise with vigorous stirring over a period of 30 minutes.
The reaction mixture was stirred at 0° C. for 1 hour and then the mixture was allowed to warm to room temperature.
The mixture was stirred at room temperature for 2 h before it was poured into ice water (250 mL) and extracted with EtOAc (3*50 mL).
The organics were washed with sat.
NaHCO3 solution and dried over anhydrous Na2SO4.
The solvent was removed in vacuo to afford an oily residue which was dissolved in tetrahydrofuran (40 mL) and cooled to 0° C.
To this mixture was added a cold (0° C.) solution of ammonium hydroxide (28percent, 40 mL) portion-wise at such a rate that the internal reaction temperature was maintained below 10° C.
The mixture was allowed to warm to room temperature and was then stirred at room temperature for 1 h.
The solvent was removed in vacuo and the residue was dissolved in saturated aqueous sodium bicarbonate (40 mL) and washed with diethyl ether (50 mL).
The aqueous layer was acidified with concentrated hydrochloric acid to pH 1.
The resulting precipitate was collected by filtration and was dried under vacuum to produce of 6-Bromo-1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-one (500 mg, 10percent yield).
1H NMR (400 MHz, DMSO) δ 8.44 (d, J=1.5, 1H), 8.04 (dd, J=8.1, 1.5, 1H), 7.81 (d, J=8.0, 1H).
Reference: [1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 4, p. 949 - 961
[2] Patent: US2008/9524, 2008, A1, . Location in patent: Page/Page column 410
[3] Patent: US2015/231142, 2015, A1, . Location in patent: Paragraph 1267
  • 2
  • [ 135484-83-2 ]
  • [ 62473-92-1 ]
YieldReaction ConditionsOperation in experiment
10% With ammonium hydroxide; acetic acid; sodium nitrite In tetrahydrofuran; hydrogenchloride; water; sodium hydrogencarbonate Preparation 49
6-Bromo-1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-one
A solution of methyl 2-amino-4-bromobenzoate (4.5 g, 20 mmol) in 20percent hydrochloric acid (30 mL) was stirred until all solids were dissolved.
The solution was cooled to 0° C. and a solution of sodium nitrite (1.4 g, 0.020 mol) in water (20 mL) was added dropwise at such a rate that the internal reaction temperature did not exceed 5° C.
The mixture was stirred at 0° C. for 45 minutes.
Sulfur dioxide was bubbled into a mixture of acetic acid (50 mL) and water (5 mL) at 0° C. until the solution was saturated.
Copper (I) chloride (2.0 g, 0.020 mol) was then added to the saturated sulfur dioxide solution.
The mixture was cooled to 0° C.
To this mixture was added the diazonium salt solution dropwise with vigorous stirring over a period of 30 minutes.
The reaction mixture was stirred at 0° C. for 1 hour and then the mixture was allowed to warm to room temperature.
The mixture was stirred at room temperature for 2 h before it was poured into ice water (250 mL) and extracted with EtOAc (3*50 mL).
The organics were washed with sat.
NaHCO3 solution and dried over anhydrous Na2SO4.
The solvent was removed in vacuo to afford an oily residue which was dissolved in tetrahydrofuran (40 mL) and cooled to 0° C.
To this mixture was added a cold (0° C.) solution of ammonium hydroxide (28percent, 40 mL) portion-wise at such a rate that the internal reaction temperature was maintained below 10° C.
The mixture was allowed to warm to room temperature and was then stirred at room temperature for 1 h.
The solvent was removed in vacuo and the residue was dissolved in saturated aqueous sodium bicarbonate (40 mL) and washed with diethyl ether (50 mL).
The aqueous layer was acidified with concentrated hydrochloric acid to pH 1.
The resulting precipitate was collected by filtration and was dried under vacuum to produce of 6-Bromo-1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-one (500 mg, 10percent yield).
1H NMR (400 MHz, DMSO) δ 8.44 (d, J=1.5, 1H), 8.04 (dd, J=8.1, 1.5, 1H), 7.81 (d, J=8.0, 1H).
Reference: [1] Patent: US2011/98311, 2011, A1,
  • 3
  • [ 135484-83-2 ]
  • [ 75-16-1 ]
  • [ 21440-97-1 ]
YieldReaction ConditionsOperation in experiment
72.8%
Stage #1: at 0 - 20℃; for 7 h; Inert atmosphere
Stage #2: With 1,1'-carbonyldiimidazole In tetrahydrofuran for 3 h; Inert atmosphere
Add 50g compound 16 to the 1L three-neck bottleThen add 500ml THF,Replace the air in the reaction flask with nitrogen,The reaction system is cooled to 0 ° C,Slowly add 160 ml of MeMgBr (3M in THF) under nitrogen protection.After maintaining the temperature for 1 h, the reaction was stirred for 6 h after warming to room temperature.38.8 g of N,N'-carbonyldiimidazole (CDI) was added to monitor the complete reaction of the starting materials.Continue to stir for 3h,The reaction was then quenched by the addition of saturated NH4Cl solution.The solution was separated and the aqueous phase was extracted twice with dichloromethane, 100 ml each time.The organic phase is combined and washed once with saturated brine.Dry anhydrous Na2SO4 for 1 h, remove the desiccant by filtration,After the filtrate was concentrated, the target product compound 17 was obtained as a white solid 40.5 g.The yield was 72.8percent.
Reference: [1] Patent: CN108912138, 2018, A, . Location in patent: Paragraph 0153-0155
  • 4
  • [ 67-56-1 ]
  • [ 20776-50-5 ]
  • [ 135484-83-2 ]
YieldReaction ConditionsOperation in experiment
86% for 24 h; Reflux A single-mouth bottle was charged with 10 g of 2-amino-4-bromobenzoic acid, 150 ml of methanol, and 10 ml of concentrated sulfuric acid, and the mixture was heated under reflux for 24 hrs.It was cooled to room temperature and concentrated under reduced pressure to remove methanol.Add 100 ml of ethyl acetate, 100 ml of 5percent sodium carbonate solution, stir for 5 mins, and let stand for stratification.The aqueous layer was separated and the organic layer was washed with 100 ml of water.Dry over anhydrous sodium sulfate and concentrate under reduced pressureMethyl 2-amino-4-bromobenzoate 9.16 g, yield 86percent.
85%
Stage #1: at 20℃; for 24 h;
Stage #2: With sodium hydrogencarbonate In water
PREPARATION 37; 2-Amino-4-bromobenzoic acid methyl ester.2-Amino-4-bromobenzoic acid (Boojamra et al., Journal of Organic Chemistry (1997), 62(5), 1240-1256) (0.60 g, 2.78 mmol) in MeOH (20 mL) was saturated with HCI gas, allowed to cool back to rt and saturated again. The mixture was stirred 24hrs, concentrated and partitioned between EtOAc and sat. aq. NaHCO3. The organics were washed with brine, dried (MgSO4) and concentrated to yield 0.54 g (85percent) of PP37 as a waxy brown solid: NMR (CDCI3) 7.66 (d, J = 8.7 Hz, 1 H), 6.82 (d, J= 2.1 Hz, 1 H), 6.73 (dd, J= 8.7, 2.1 Hz, 1 H), 3.83 (s, 3H).
76.7% at 20 - 80℃; for 12 h; Cooling with ice 3.00 g (13.89 mmol) of 2-amino-4-bromobenzoic acid was placed in a 250 mL pressure-Then add 10mL of concentrated sulfuric acid under ice-cooling, stir for 5min at room temperature, then seal and heat 12KTLC at 80 ° C. After the reaction is complete, cool to room temperature.The reaction mixture was poured into an ice-water mixture. Sodium bicarbonate was slowly added to the reaction mixture until no more bubbles were formed, and then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, Petroleum ether: ethyl acetate = 15: 1, 200 mesh silica gel column chromatography, 2-amino-4-bromobenzoic acid methyl ester 2.45g, yield 76.7percent
Reference: [1] Patent: CN107778229, 2018, A, . Location in patent: Paragraph 0026
[2] Patent: WO2006/48727, 2006, A1, . Location in patent: Page/Page column 77
[3] Patent: CN103554007, 2016, B, . Location in patent: Paragraph 0044; 0052; 0053
[4] British Journal of Pharmacology, 2018, vol. 175, # 12, p. 2504 - 2519
[5] Journal of the Chemical Society, 1931, p. 72,73
[6] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8332 - 8338
[7] Advanced Synthesis and Catalysis, 2018, vol. 360, # 10, p. 1919 - 1925
  • 5
  • [ 158580-57-5 ]
  • [ 135484-83-2 ]
YieldReaction ConditionsOperation in experiment
96% With hydrogen In methanol for 1 h; 4-Bromo-2-aminomethylbenzoate : [00190] 4-Bromo-2-nitromethylbenzoate (300MG ; 1. 15MMOL) was dissolved in 25ML of methanol and shaken with 5percent Pd (c) under hydrogen atmosphere (50 PSI) for 1 hour. The reaction was filtered through celite and evaporated to give the product as a white solid (255mg; 96percent). MS: MH+= 230
96% With tin(II) chloride dihdyrate In ethyl acetate at 30℃; for 2 h; Ultrasonic irradiation Example 281 : 2-(3-Chlorobenzo[b1thiophene-2-carboxarnido)-4-(5-(4-chlorophenyl)-2- oxo-oxazolidin-3-yl)benzoic acidMethod 36SnCI2 x 2H20 (5 g, 22 mmol) was added to a solution of methyl 4-bromo-2-nitrobenzoate (0.6 g, 2.3 mmol) in ethyl acetate (20 ml). The reaction mixture was submitted to ultrasonic irradiation for 2 h at 30°C until the reaction was complete as indicated by TLC analysis. The solvent was removed under reduced pressure and the crude residue was washed with 2 M KOH. The aqueous layer was extracted with further portions of ethyl acetate, and the combined organic extracts were washed with brine and water, dried (MgS04) and concentrated under reduced pressure. The crude residue waschromatographed over silica gel (ethyl acetate / hexanes) yielding methyl 4-bromo-2- aminobenzoate (96percent).A solution of this compound (0.46 g, 2 mmol), 5-(4-chlorophenyl)oxazolidin-2-one (0.4 g, 2 mmol), Xantphos (128 mg, 0.22 mmol), Pd2(dba)3 (92 mg, 0.11 mmol) and K3P04 (2.2 mmol) in dioxane was refluxed for 7 h. After cooling, the solvent was evaporated under vacuum and the residue partitioned between water and ethyl acetate. The aqueous layer was extracted with further portions of ethyl acetate and the combined organic extracts were washed with brine and water, dried (MgS04) and concentrated under reduced pressure. The crude residue was chromatographed over silica gel (ethyl acetate / hexanes) yielding methyl 2-amino-4-(5-(4-chlorophenyl)-2-oxo-oxazolidin-3-yl)benzoate (71 percent).This compound (0.35 g, 1 mmol) was dissolved in THF, and 1.1 mmol of 3-chloro- benzo[b]thiophene carbonyl chloride was added. The reaction mixture was refluxed for 14 h and concentrated under vacuum. The crude reaction mass was washed with diethyl ether two times and dissolved in THF-water (3: 1). LiOH (1.1 mmol) was added and the solution was stirred overnight at room temperature, concentrated under vacuum, and the residue was dissolved in the minimum volume of water. After adjusting the pH to 6-7, the aqueous solution was extracted with ethyl acetate. The organic layer was dried (MgS04) and concentrated under vacuum to afford the title compound (50percent), mp >200°C.1 H NMR (400 MHz, DMSO-cfe) δ ppm: 13.70 (br.s, 1 H), 12.40 (br.s, 1 H), 8.93 (s, 1 H), 8.18 (m, 1 H), 8.09 (d, 1 H), 7.98 (m, 1 H), 7.64 (m, 2H), 7.59 (m, 2H), 7.53 (m, 3H), 5.83 (m, 1 H), 4.57 (m, 1 H), 4.04 (m, 1 H); MS: m/z = 527 [MH]+
93% With tin(ll) chloride In dichloromethane; ethyl acetate at 20℃; A. Methyl 2-amino-4-bromobenzoate To a stirred solution of 4-bromo-2-nitrobenzoic acid (EXAMPLE 5) (3.81 g, 15 mmol) in DMF (30 mL) at 0° C. was added 1,8-diazabicycloundecane (DBU) (10.3 mL, 75 mmol) followed by methyl iodide (4.67 mL, 75 mmol).
The reaction mixture was stirred 15 min at 0° C. then allowed to warm to room temperature and stir overnight.
The mixture was poured into water and extracted with EtOAc (2*).
The combined organic extracts were washed with water (2*), dried (MgSO4), and concentrated in vacuo.
The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-bromo-2-nitrobenzoate as a pale yellow solid (3.52 g, 90percent).
93%
Stage #1: With tin(ll) chloride In ethanol; dichloromethane at 20℃;
Stage #2: With sodium hydrogencarbonate In dichloromethane; water
To a stirred solution of 4-bromo-2-nitrobenzoic acid (3.8 g, 15 mmol) in DMF (30 mL) at 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (10.0 mL, 75.0 mmol) followed by iodomethane (4.7 mL, 75 mmol). The reaction mixture was stirred 15 min at 0° C., then was allowed to warm to room temperature and was stirred overnight. The mixture was poured into H2O and extracted with EtOAc (2.x.). The combined organic extracts were washed with H2O (2.x.), dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-bromo-2-nitrobenzoate as a pale yellow solid (3.52 g, 0.90percent). To a solution of the nitrobenzoate (3.52 g, 13.5 mmol) in 1:1 EtOAc/DCM (30 mL) at room temperature was added SnCl2.2H2O (15 g, 67 mmol). The reaction mixture was allowed to stir overnight. The solvents were evaporated in vacuo, and the residue was partitioned between satd. aq. NaHCO3 and DCM. The layers were separated, and the aqueous layer was further extracted with DCM (2.x.). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide the pure aminobenzoate as a white solid (2.89 g, 93percent). 1H NMR (400 MHz, CDCl3): 7.70 (d, J=8.6 Hz, 1H), 6.84 (d, J=1.9 Hz, 1H), 6.75 (dd, J=8.6, 1.9 Hz, 1H), 5.78 (br s, 2H), 3.86 (s, 3H).
93% With tin(ll) chloride In dichloromethane; ethyl acetate at 20℃; for 18 h; B. Methyl 2-amino-4-bromobenzoate.; To a stirred solution of 4-bromo-2-nitrobenzoic acid (3.81 g, 15 mmol) in DMF (30 mL) at 0° C. was added 1,8-diazabicycloundecane (DBU; 10.3 mL, 75 mmol) followed by Mel (4.67 mL, 75 mmol). The mixture was stirred for 15 min at 0° C., then was allowed to warm to rt and was stirred overnight. The mixture was poured into water and extracted with EtOAc (2.x.). The combined organic extracts were washed with water (2.x.), dried (MgSO4), and concentrated. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-bromo-2-nitrobenzoate as a pale yellow solid (3.52 g, 90percent). To a solution of the nitrobenzoate (3.52 g, 13.5 mmol) in 1:1 EtOAc/DCM (30 mL) at rt was added SnCl2.2H2O (15.27 g, 67 mmol). After 18 h, the mixture was concentrated, diluted with satd. aq. NaHCO3, and extracted with DCM (3.x.). The combined organic layers were dried (MgSO4) and concentrated to provide the desired aminobenzoate as a white solid (2.89 g, 93percent). 1H NMR (400 MHz, CDCl3): 7.70(d, J=8.6, 1H), 6.84 (d, J=1.9, 1H), 6.75 (dd, J=8.6, 1.9, 1H), 5.78 (br s, 2H), 3.86 (s, 3H).
84%
Stage #1: at 20℃; for 24 h;
Stage #2: With sodium hydroxide In water
Step 2. Preparation of Methyl 2-amino-4-bromobenzoate Add tin (II) chloride (65.9 g, 292 mmol) to a suspension of methyl 4-bromo-2- nitrobenzoate (15.2 g, 58.4 mmol) in concentrated hydrochloric acid (120 mL) at room temperature and stir for 24 h. Slowly pour the mixture into water (700 mL) and adjust the pH to 9 with solid potassium hydroxide. Filter the white suspension through Celite, then stir the filter cake with ethyl acetate and filter that suspension. Separate the filtrate and extract the aqueous layer with ethyl acetate (200 mL). Combine the organic layers, dry over sodium sulfate, filter and remove the solvent under reduced pressure to afford the title compound as an off-white solid (11.3 g, 84 percent)

Reference: [1] Patent: WO2005/32493, 2005, A2, . Location in patent: Page/Page column 51
[2] Patent: WO2012/59442, 2012, A2, . Location in patent: Page/Page column 111
[3] Journal of Medicinal Chemistry, 2006, vol. 49, # 21, p. 6371 - 6390
[4] Patent: US2004/224983, 2004, A1, . Location in patent: Page 15
[5] Patent: US2005/38032, 2005, A1, . Location in patent: Page/Page column 11
[6] Patent: US2006/69286, 2006, A1, . Location in patent: Page/Page column 29; 61
[7] Patent: WO2005/37796, 2005, A1, . Location in patent: Page/Page column 51
[8] Patent: WO2006/62093, 2006, A1, . Location in patent: Page/Page column 56-57
[9] Patent: EP1860098, 2007, A1, . Location in patent: Page/Page column 41
  • 6
  • [ 7439-89-6 ]
  • [ 158580-57-5 ]
  • [ 135484-83-2 ]
Reference: [1] Patent: EP1820795, 2007, A1,
  • 7
  • [ 82-73-5 ]
  • [ 135484-83-2 ]
Reference: [1] Patent: US2004/92569, 2004, A1,
  • 8
  • [ 67-56-1 ]
  • [ 6941-75-9 ]
  • [ 135484-83-2 ]
  • [ 1356116-29-4 ]
  • [ 1356116-26-1 ]
Reference: [1] Organic Letters, 2012, vol. 14, # 3, p. 946 - 949
  • 9
  • [ 591-19-5 ]
  • [ 135484-83-2 ]
Reference: [1] Patent: CN103554007, 2016, B,
  • 10
  • [ 99277-71-1 ]
  • [ 135484-83-2 ]
Reference: [1] Patent: EP1860098, 2007, A1,
  • 11
  • [ 6326-79-0 ]
  • [ 135484-83-2 ]
Reference: [1] Patent: CN103554007, 2016, B,
  • 12
  • [ 135484-83-2 ]
  • [ 20776-50-5 ]
YieldReaction ConditionsOperation in experiment
98%
Stage #1: With water; sodium hydroxide In tetrahydrofuran; ethanol at 50℃; for 3 h;
Stage #2: With hydrogenchloride In water
Compound 36 (10 g, 43.5 mmol) and NaOH (5.2 g, 130.4 mmol) were dissolved in H20 (40 mL), CH3CH2OH (40 mL) and THF (120 mL). The reaction mixture was stirred for 3 hours at 50°C. The organic solvent was then removed under vacuum. The residue was extracted with ethyl acetate (3 x 50 mL). The water layer was acidified with con. HCl until pH=2 and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were concentrated under vacuum to afford product 37 (9.3 g, 98percent yield).
Reference: [1] Patent: WO2012/13643, 2012, A1, . Location in patent: Page/Page column 48
  • 13
  • [ 135484-83-2 ]
  • [ 98-80-6 ]
  • [ 4445-43-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 13, p. 1595 - 1600
  • 14
  • [ 135484-83-2 ]
  • [ 112253-70-0 ]
Reference: [1] Patent: WO2012/13643, 2012, A1,
[2] European Journal of Medicinal Chemistry, 2018, vol. 152, p. 235 - 252
  • 15
  • [ 135484-83-2 ]
  • [ 946122-05-0 ]
YieldReaction ConditionsOperation in experiment
74% With lithium aluminium tetrahydride In tetrahydrofuran at -10 - 20℃; Step 1: a solution of methyl 2-amino-4-bromobenzoate (500 mg, 2.17 mmol) in dry THF (10 mL) was cooled at -10°C. Then, a solution of lithium aluminium hydride (1 M in THF) (6.5 mL, 6.52 mmol) was added dropwise to the solution. The mixture was allowed to reach rt and the solution was stirred at rt overnight.The reaction was cooled down with a ice water bath and quenched with a mixture of MeOH and sat. solution of sodium potassium tartrate. The solution was stirred at rt for additional 6h. The reaction mixture was diluted with EtOAc/H20 and the two phases were separated. The organic layer was dried over Mg504, filtered and the solution was concentrated to dryness to afford (2-amino-4-bromophenyl)methanol Ex.44a (326 mg, 74percent) as sticky brown solid.
Reference: [1] Patent: WO2018/138359, 2018, A1, . Location in patent: Page/Page column 41; 61
[2] Journal of Organic Chemistry, 2014, vol. 79, # 3, p. 1235 - 1246
  • 16
  • [ 135484-83-2 ]
  • [ 1261470-87-4 ]
Reference: [1] Organic Letters, 2018, vol. 20, # 17, p. 5190 - 5193
  • 17
  • [ 135484-83-2 ]
  • [ 1223434-15-8 ]
YieldReaction ConditionsOperation in experiment
980 mg
Stage #1: With hydrogenchloride; sodium nitrite In water for 1 h; Cooling with ice
Stage #2: With potassium cyanide In water; ethyl acetate for 1 h; Cooling with ice
To an ice-cooled mixture of Compound I (1.5 g) and 2N hydrochloric acid was added a mixture of sodium nitrite (540 mg) and water (6.5 mL), and the mixture was stirred for 1 hour. The reaction mixture was neutralized by the addition of sodium carbonate. Then, to an ice-cooled mixture of copper cyanide (759 mg), potassium cyanide (637 mg), ethyl acetate (8 mL) and water (4 mL) was added the reaction mixture of Compound I which was prepared above, and the mixture was stirred for 1 hour. The reaction mixture was filtered through Celite, and to the filtrate was added water, and the mixture was extracted with ethyl acetate.
The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 10/0 to 8/2) to give Compound II (980 mg).
Reference: [1] Patent: EP2612848, 2013, A1, . Location in patent: Paragraph 0437; 0438; 0439
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  • [ 1223434-15-8 ]
Reference: [1] Patent: EP2565182, 2013, A1,
[2] Patent: US2018/215731, 2018, A1,
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  • [ 135484-83-2 ]
  • [ 917-61-3 ]
  • [ 114703-12-7 ]
YieldReaction ConditionsOperation in experiment
72% at 20℃; for 22 h; Synthesis of 2,4-dichloro-7-morpholin-4-ylquinazoline 87.0 g (1.33 mol) of   sodium cyanate were added to 269.0 g (1.17 mol) of   methyl 2-amino-4-bromobenzoate in 1.2 l of   acetic acid with stirring at room temperature, and the mixture was subsequently stirred for a further 22 h. The reaction mixture was diluted with 1.5 l of   water, and the residue was filtered off with suction. 0.42 l of   sodium hydroxide solution (32percent) was added to the solid, the mixture was diluted with 3.5 l of water and heated on a steam bath for 4 h. After cooling, the solid residue was filtered off with suction. Conventional work-up gave 205.2 g of   7-bromo-1H-benzo[d]-1,3-oxazine-2,4-dione; HPLC/MS (M+H)+=243 as solid.
Reference: [1] Patent: US2013/12489, 2013, A1, . Location in patent: Paragraph 0173
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  • [ 114703-12-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 21, p. 4904 - 4907
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  • [ 135484-83-2 ]
  • [ 959237-68-4 ]
Reference: [1] Patent: US2013/12489, 2013, A1,
[2] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 21, p. 4904 - 4907
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  • [ 135484-83-2 ]
  • [ 1245643-21-3 ]
Reference: [1] Patent: KR2016/37198, 2016, A,
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