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[ CAS No. 90971-88-3 ] {[proInfo.proName]}

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Chemical Structure| 90971-88-3
Chemical Structure| 90971-88-3
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Product Details of [ 90971-88-3 ]

CAS No. :90971-88-3 MDL No. :MFCD00144764
Formula : C9H9BrO2 Boiling Point : -
Linear Structure Formula :- InChI Key :PYRAZCQFEMNXJA-UHFFFAOYSA-N
M.W : 229.07 Pubchem ID :15110996
Synonyms :

Calculated chemistry of [ 90971-88-3 ]

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.22
Num. rotatable bonds : 2
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 50.39
TPSA : 26.3 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) : -5.69 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.51
Log Po/w (XLOGP3) : 2.83
Log Po/w (WLOGP) : 2.54
Log Po/w (MLOGP) : 2.97
Log Po/w (SILICOS-IT) : 2.84
Consensus Log Po/w : 2.74

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.28
Solubility : 0.12 mg/ml ; 0.000523 mol/l
Class : Soluble
Log S (Ali) : -3.04
Solubility : 0.209 mg/ml ; 0.000912 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.72
Solubility : 0.0436 mg/ml ; 0.000191 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.63

Safety of [ 90971-88-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 90971-88-3 ]

* 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 [ 90971-88-3 ]
  • Downstream synthetic route of [ 90971-88-3 ]

[ 90971-88-3 ] Synthesis Path-Upstream   1~9

  • 1
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YieldReaction ConditionsOperation in experiment
99%
Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 1 h;
Stage #2: at 20℃; for 3 h;
To a suspension of compound 4 (2.15 g, 10 mmol) in dry DCM (40 mL) and DMF (0.2 mL) at 0 °C was slowly added oxalyl chloride (1.3 mL, 15 mmol). After being stirred for 1 h at room temperature, the reaction mixture was treated with MeOH (20 mL) and then stirred for 3 h. The resulting solution was neutralized with saturated aqueous Na2CO3 (100 mL) and extracted with DCM (70 mL×2). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel, eluting with petroleum ether/ethyl acetate (30:1), to afford compound 5 (2.27 g) as colorless oil in 99percent isolated yield. 1H NMR (CDCl3, 400 MHz) δ 2.30 (s, 3H), 3.90 (s, 3H), 7.10 (dd, J=2.4, 8.4 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 20.7, 52.4, 118.2, 131.7, 131.9, 133.5, 134.1, 137.3, 166.8.
96.1% for 16 h; Reflux The 2-bromo-5-methyl benzoic acid (10.75g, 50mmol) is added to 500 ml round bottom flask, with methanol (100 ml) to dissolve fully, and then slowly adding concentrated sulfuric acid (1.5 ml, 25mmol), reaction solution gradually heated up to reflow, reaction 16 hours. Stop reaction, to be reacted after cooling to room temperature, solvent evaporating under reduced pressure, the residue is dissolved in dichloromethane (200 ml) is dissolved, and with water (200 ml) and saturated salt water (100 ml) washing, separating the organic layer, drying with anhydrous sodium sulfate. Filtering, the filtrate concentrated under reduced pressure, the resulting residue is purified by silica gel column chromatography separation ((v/v)=200/1 petroleum ether/ethyl acetate) to obtain the title compound as a yellow oily matter (11.00g, 96.1percent).
92% at 0 - 20℃; Acetyl chloride (1.66 ml, 23.3 mmol) was added to a stirred solution of 2-bromo-5- methylbenzoic acid (2.00 g, 9.30 mmol) in MeOH (50 ml) at 0°C. The reaction was then stirred at r.t. over night. More acetyl chloride (1 ml, 14.0 mmol) was added and the reaction was stirred for 24 hours. The solvent was removed in vacuo and the crude material was dissolved in Et02 (-100 ml) and washed with 0.5 M NaOH. The organic phase was dried over MgS04and removed in vacuo. Yield: 1.97 g (92percent). ¾ NMR (400 MHz, DMSO~i 6): δ 2.33 (s, 3H), 3.94 (s, 3H), 7.13 (d, 1H), 7.52 (d, 1H), 7.60 (s, 1H) The ester from above (800 mg, 3.49 mmol) in dry 1,4 dioxane (15 ml) was added to bis(pinacolato)diboron (976 mg, 3.84 mmol) and AcOK (1.27 g, 12.9 mmol). The stirred mixture was flushed with argon and l,l'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (25.6 mg, 0.035 mmol) was added. The reaction was heated in a sealed flask at 100°C for 3 hours then cooled and diluted with Et20. The organic phase was washed with water and brine, dried over MgSC>4 and removed in vacuo. The crude material was diluted with iso-hexane and purified by flash chromatography (20percent EtOAc in iso-hexane, 200 ml silica). Yield: 697 mg (72percent) as a colourless oil. 1H NMR (400 MHz, DMSO~i 6): δ 1.42 (s, 12H), 2.38 (s, 3H), 3.91 (s, 3H), 7.31- 7.35 (m, 1H), 7.38-7.43 (m, 1H), 7.76 (s, 1H). Argon was flushed through a stirred solution of intermediate D (120 mg, 0.217 mmol) and the pinacolester from above (150 mg, 0.543 mmol) in a mixture of toluene (3 ml) and MeOH (3 ml). K2C03 (150 mg, 0.543 mmol) and PEPPSI-iPr™ (19.8 mg, 0.027 mmol) were added and the reaction heated at 60°C for 2 hours in a sealed flask. The solvents were removed in vacuo and the crude material was added dioxane (2 ml), water (2 ml) and 5 M NaOH (1 ml). The reaction was stirred at 80° C for 30 min. The mixture was cooled and concentrated. Some water and 1 M NH4HCO3 (until pH~10) were added and the mixture was purified by prep-HPLC (5-40percent MeCN, in 50 mM NH3/NH4HCO3 buffer). The combined pure fractions were concentrated to dryness. The compound was dissolved in water (20 ml) and some 2 M HC1 was added. The solid was collected and washed several times with water and dried. Yield: 25 mg (18percent); yellow solid. 1H NMR (400 MHz, DMSO-i/6): δ 2.37 (s, 6 H), 3.74 (s, 4 H), 7.10 (s, 2 H), 7.29 (s, 2 H), 7.36 - 7.44 (m, 4 H), 7.47 - 7.49 (m, 2 H). HPLC: Rt =1.82 mm, 100percent (254 nm, 10-40percent MeCN in 10 mM buffer, XBndge) and Rt =1.35 mm, 97percent (400 nm, 10-90percent MeCN in 10 mM buffer, XBndge). LC-MS: m/z = 650 (M + 18).
92% at 0 - 20℃; Acetyl chloride (1.66 ml, 23.3 mmol) was added to a stirred solution of 2-bromo-5- methylbenzoic acid (2.00 g, 9.30 mmol) in MeOH (50 ml) at 0°C. The reaction was then stirred at r.t. over night. More acetyl chloride (1 ml, 14.0 mmol) was added and the reaction was stirred for 24 hours. The solvent was removed in vacuo and the crude material was dissolved in Et02 (-100 ml) and washed with 0.5 M NaOH. The organic phase was dried over MgS04 and removed in vacuo. Yield: 1.97 g (92percent). 1H NMR (400 MHz, DMSO-i¾): δ 2.33 (s, 3H), 3.94 (s, 3H), 7.13 (d, 1H), 7.52 (d, 1H), 7.60 (s, 1H)
92%
Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2 h;
Stage #2: for 6 h;
Step 1:
Preparation of methyl 2-bromo-5-methylbenzoate
To a solution of 2-bromo-5-methylbenzoic acid (215 mg, 1.0 mmol) in DCM (4 mL) and DMF (1 drop) at 0° C. was slowly added oxalyl chloride (0.13 mL, 1.5 mmol).
The reaction mixture was stirred at rt for 1 h and to it was added additional oxalyl chloride (0.13 mL, 1.5 mmol).
The reaction mixture was stirred for 1 h, added with MeOH (2 mL) and stirred for 6 h.
The mixture was treated with Na2CO3 to pH of 9 and extracted with DCM (2*10 mL).
The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure.
The residue was purified by column chromatography over silica gel eluted with PE-EA (15:1) to give methyl 2-bromo-5-methylbenzoate (210 mg; yield 92percent) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.60 (d, J=1.6 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.15 (q, J=3.2 Hz, 1H), 3.92 (s, 3H), 2.33 (s, 3H) ppm.
60% for 0.5 h; Reflux Dimethyl sulfate (2.2 mL, 21.1 mmol)was slowly dropped under stirring into a solution of 2-bromo-5-methylbenzoic acid (3.78 g,17.6 mmol) in 22mLmethanolic NaOH. Themixturewas refluxed for 30min.After cooling,waterwas added and the solutionwas 3×extracted with diethyl ether. The combined extractswere washed twice with 5percent aq NaHCO3 solution then with satd. NaCl solution and finallywith H2O. After drying over Na2SO4, the solvent was removed and the residue was purifiedby CC (Kieselgel, CH2Cl2). Yield: 2.4 g (10.5 mmol, 60percent) light-yellow liquid. IR: ν =2952, 1736 (C O), 1435, 1300, 1252, 1205, 1030. 1H NMR (in agreement with lit.11): δ= 2.33 (s, 3H, CH3), 3.92 (s, 3H, OCH3), 7.13 (dd, 1H, J = 2.0 Hz/8.0 Hz, 4-H), 7.52 (d,1H, J = 8.0 Hz, 3-H), 7.59 (d, 1 H, J = 2.0 Hz, 6-H). 13C NMR (in agreement with lit.11):δ = 20.74 (OCH3), 52.40 (ArCH3), 118.23 (Cq, ar), 131.81, 131.87, 133.42, 134.06 (CHar),137.25 (Cq,ar), 166.29 (C O). MS: m/z (percent) = 230 (37) [M]+, 228 (38) [M]+, 199(94) [M– OCH3]+, 197 (100) [M – OMe]+, 171 (23) [M – CO2CH3]+, 169 (25) [M – CO2CH3]+,91 (14) [C7H7]+, 90 (48), 89 (34), 63 (15). C9H9BrO2 (229.08): calcd. C 47.19, H 3.96, Br34.88, found C 47.01, H 3.97, Br 34.85.
5.5 g at 70℃; for 24 h; In a 250 mL single-mouth flask, 5.00 g (23.26 mmol) of Compound 1 and 6.64 g (28.99 mmol) of Compound 2 were added, 150 mL of methanol was added, and the water separator was installed and refluxed at 70° for 24 hours to stop the reaction. After spin-drying the solvent, the reaction was washed with water several times and extracted with ethyl acetate. The ethyl acetate layer was purified by rotary column chromatography to obtain 5.5 g of compound 2 as an oil

Reference: [1] Tetrahedron, 2014, vol. 70, # 14, p. 2383 - 2388
[2] Patent: CN105461699, 2016, A, . Location in patent: Paragraph 0739; 0740; 0741; 0742; 0743
[3] Patent: WO2013/9259, 2013, A1, . Location in patent: Page/Page column 90; 91
[4] Patent: WO2013/36196, 2013, A1, . Location in patent: Page/Page column 95
[5] Patent: US2013/131016, 2013, A1, . Location in patent: Paragraph 0199
[6] Chemistry - A European Journal, 2015, vol. 21, # 19, p. 7030 - 7034
[7] Phosphorus, Sulfur and Silicon and the Related Elements, 2015, vol. 190, # 12, p. 2142 - 2153
[8] Patent: US2006/287386, 2006, A1, . Location in patent: Page/Page column 18
[9] Patent: EP2915804, 2015, A1, . Location in patent: Paragraph 1250-1252
[10] Patent: CN107915733, 2018, A, . Location in patent: Paragraph 0024; 0025; 0026
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Reference: [1] Patent: US2003/153570, 2003, A1,
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Reference: [1] Patent: US6200981, 2001, B1,
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  • 5
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420
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Reference: [1] Neurochemical Research, 2017, vol. 42, # 6, p. 1823 - 1832
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  • [ 1088994-22-2 ]
Reference: [1] Patent: CN105461699, 2016, A,
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