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Product Details of [ 3132-99-8 ]

CAS No. :3132-99-8 MDL No. :MFCD00003345
Formula : C7H5BrO Boiling Point : -
Linear Structure Formula :- InChI Key :SUISZCALMBHJQX-UHFFFAOYSA-N
M.W : 185.02 Pubchem ID :76583
Synonyms :

Calculated chemistry of [ 3132-99-8 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 39.53
TPSA : 17.07 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) : -5.77 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.68
Log Po/w (XLOGP3) : 2.34
Log Po/w (WLOGP) : 2.26
Log Po/w (MLOGP) : 2.21
Log Po/w (SILICOS-IT) : 2.68
Consensus Log Po/w : 2.23

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.89
Solubility : 0.239 mg/ml ; 0.00129 mol/l
Class : Soluble
Log S (Ali) : -2.34
Solubility : 0.85 mg/ml ; 0.00459 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.2
Solubility : 0.117 mg/ml ; 0.000634 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.12

Safety of [ 3132-99-8 ]

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 [ 3132-99-8 ]

* 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 [ 3132-99-8 ]
  • Downstream synthetic route of [ 3132-99-8 ]

[ 3132-99-8 ] Synthesis Path-Upstream   1~86

  • 1
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Reference: [1] Patent: US2018/215731, 2018, A1, . Location in patent: Paragraph 1054; 1055; 1056; 10567
  • 2
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  • [ 645-36-3 ]
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Reference: [1] Patent: US2002/6923, 2002, A1,
  • 3
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  • [ 221050-96-0 ]
Reference: [1] Journal of the American Chemical Society, 1939, vol. 61, p. 183
  • 4
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  • [ 27810-64-6 ]
Reference: [1] Journal of the American Chemical Society, 1939, vol. 61, p. 183
  • 5
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  • [ 21575-91-7 ]
Reference: [1] Tetrahedron, 2005, vol. 61, # 4, p. 875 - 878
  • 6
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  • [ 21575-91-7 ]
Reference: [1] Chemistry - An Asian Journal, 2011, vol. 6, # 8, p. 2073 - 2079
  • 7
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YieldReaction ConditionsOperation in experiment
22%
Stage #1: at 120℃; Dean-Stark
Stage #2: at 160℃; for 0.5 h;
General procedure: Aminoacetaldehyde dimethylacetal (3.0 eq.) was added to a solution of bromobenzaldehyde13b or 13c (1.0 eq.) in toluene (30 mL). Each reaction mixture was refluxed (Dean–Stark apparatus)at 120 °C. After consumption of the starting material, each reaction mixture was concentrated todryness, then dissolved in conc. H2SO4 (2 mL) and added to a cold solution of P2O5 in conc. H2SO4(0.5 mL). Each reaction mixture was heated at 160 °C for 30 min, allowed to cool to RT, neutralizedwith NaOH (10 M), extracted with EtOAc, and concentrated to dryness. Each residue was subjected toFCC to afford 6-bromoisoquinoline (14b, 30 mg, 0.14 mmol, 14percent) and 7-bromoisoquinoline (14c, 99 mg,0.47 mmol, 22percent) [20,21]. Ethylchloroformate (1.0 eq.) was added to a solution of isoquinoline 14b or14c (1.0 eq.) in DCM at 0 °C and stirred at the same temperature for 30 min, followed by additionof 2-trimethylsilylthiazole (1.0 eq.). Each reaction mixture was stirred at RT for 3 h, concentratedto dryness, and each residue was subjected to FCC. Each product was dissolved in benzene (5 mL),o-chloranil (1.0 eq.) was added, and each reaction mixture was refluxed for 5 h. Each reaction mixturewas diluted with 5percent NaOH (10 mL), extracted with DCM, and concentrated to dryness. Each reactionmixture residue was subjected to FCC to afford the products 9b and 9c.
Reference: [1] Molecules, 2017, vol. 22, # 8,
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Reference: [1] Patent: US2018/215731, 2018, A1, . Location in patent: Paragraph 1054; 1055; 1056; 10567
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 22, p. 6378 - 6382
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 22, p. 6378 - 6382
  • 11
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  • [ 107-21-1 ]
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YieldReaction ConditionsOperation in experiment
100% With toluene-4-sulfonic acid In toluene for 5.5 h; Heating / reflux EXAMPLE 28-Ethyl (S)-3-83APOS;-[(BENZOYLMETHYLAMINO)- methyl] BIPHENYL-4-YL}-2-(2-BENZOYLPHENYLAMINO)- propionate a. 2- (3-BROMOPHENYL) [1, 3] dioxolane 870 g (4.56 mol) of 3-bromobenzaldehyde, 2.6 1 (45.6 mol) of 1, 2-ethanediol, and 87 g (0.46 mol) of p-toluenesulphonic acid are dissolved in 4 1 of toluene. After refluxing for 5 h 30,1 1 of an aqueous 1N sodium hydroxide solution is added at ambient temperature. The mixture obtained is filtered through celite, and the organic phase is recovered and washed with 2 1 of water. The solvents are evaporated off and 1 060 g of acetal are obtained with a quantitative yield. b. 3-Boronic acid-benzaldehyde In a manner similar to the preparation of tert-butyl (3-boronic acid-phenyl) methylcarbamate (Example LD), using 819 g (3.57 mol) of 2- (3-BROMO- phenyl) [1, 3] dioxolane, 355 g of crude product is used without purification in the following step. c. Ethyl (S)-2-TERT-BUTOXYCARBONYLAMINO-3- (3APOS;-FORMYL- biphenyl-4-yl) propionate In a manner similar to the preparation of ethyl (S)-2-TERT-BUTOXYCARBONYLAMINO-3- [3APOS;- (TERT- butoxycarbonylmethylamino) BIPHENYL-4-YL] PROPIONATE (Example LE), using 173 g (391 mmol) of ethyl (S)- 2-TERT-BUTOXYCARBONYLAMINO-3- (4-TRIFLUOROMETHANE- sulphonyloxyphenyl) propionate and 82 g (547 mmol) of 3-boronic acid-benzaldehyde, 95.7 g of coupled product are isolated with a 61percent yield. d. Ethyl (S)-2-TERT-BUTOXYCARBONYLAMINO-3- (3APOS;-METHYL- aminomethylbiphenyl-4-yl) propionate 21.2 g (314 mmol) of methylamine hydrochloride are introduced into a solution containing 25 g (63.0 mmol) of ethyl (S)-2-tert- BUTOXYCARBONYLAMINO-3- (3APOS;-FORMYLBIPHENYL-4-YL)- propionate in 200 ml of methanol. After stirring for 30 min at ambient temperature, 6.0 g (95.4 mmol) of sodium cyanoborohydride are added portionwise. The reaction medium is stirred for 16 h and the solvents are evaporated off. The residue is dissolved in ethyl acetate, and the organic phase is washed with water and then dried over magnesium sulphate and concentrated. The crude product is purified by chromatography on a column of. silica and eluted with a heptane/ethyl acetate and then a methanol/ethyl acetate mixture. 10 g of the expected amine are isolated with a 38percent yield. e. Ethyl (S)-3- {3APOS;- [ (BENZOYLMETHYLAMINO) METHYL]- BIPHENYL-4-YL}-2-TERT-BUTOXYCARBONYLAMINOPROPIONATE 4.2 ml (36.3 mmol) of benzoyl chloride are added to a solution containing 10 g (24.3 mmol) of ethyl (S)-2-TERT-BUTOXYCARBONYLAMINO-3- (3APOS;-METHYL- aminomethylbiphenyl-4-yl) propionate and 10.1 ml (72.6 mmol) of triethylamine in 100 ml of tetrahydrofuran. The medium is stirred for 3 h and then hydrolysed, extracted with ethyl acetate, dried over magnesium sulphate, and concentrated. The residue obtained is purified by chromatography on a column of silica and eluted with a 3/2 heptane/ethyl acetate mixture. 8.0 g of expected amide are obtained with a 64percent yield. f. Ethyl (S)-2-AMINO-3-F3APOS;- [ (BENZOYLMETHYLAMINO)- METHYL] BIPHENYL-4-YL} PROPIONATE 8.0 G (15.5 mmol) of ethyl (S)-3- {3APOS;- [ (BENZO. YLMETHYLAMINO) methyl] BIPHENYL-4-YL}-2-TERT- butoxycarbonylaminopropionate are dissolved in 70 ml of dichloromethane. 12 ml (157 mmol) of trifluoroacetic acid are added in small amounts. The medium is stirred for 16 h and then brought to pH 9 with sodium carbonate, extracted with dichloromethane, dried over magnesium sulphate, and concentrated. The residue obtained is purified by chromatography on a column of silica and. eluted with a 1/1 heptane/ethyl acetate mixture. 5.2 g of expected amine are obtained with an 82percent yield. G. ETHYL (S)-3-{3APOS;-[(BENZOYLMETHYLAMINO) METHYL]- biphenyl-4-yl}-2-(2-benzoylphenylamino) propionate In a manner similar to the preparation of the ETHYL (S)-2- (2-BENZOYLPHENYLAMINO)-3- (3APOS;-METHYLAMINO- biphenyl-4-yl) propionate (Example LG), using 3.8 g (9.13 mmol) of ethyl (S)-2-AMINO-3-{3APOS;-[(BENZOYLMETHYL- amino) methyl] BIPHENYL-4-YL} PROPIONATE, 1.3 g of ethyl





(S)-3-{3APOS;-[(BENZOYLMETHYLAMINO) METHYL] BIPHENYL-4-YL}-2- (2-benzoylphenylamino) propionate are isolated with a 24percent yield. Melting point: 55oC
97%
Stage #1: With toluene-4-sulfonic acid In toluene for 4 h; Heating / reflux
Stage #2: With sodium hydrogencarbonate In water; toluene at 0℃;
Preparation Example 90.
2-(3-Bromo-phenyl)-[1,3]dioxolane
3-Bromobenzaldehyde (4.00g, 21.6mmol), ethane-1,2-diol (6.03mL, 108mmol) and toluene-4-sulfonic acid monohydrate (186mg,1.08mmol) were dissolved in toluene (80mL), and the solution was stirred under reflux for 4 hours.
An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0°C, which was then extracted with ethyl acetate, the organic layer was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate.
The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 20: 1), and the title compound (4.79g, 20.9mmol, 97percent) was obtained as a colorless oil.
1H-NMR Spectrum (CDCl3) δ (ppm): 4.02-4.05 (2H, m), 4.07-4.13 (2H, m), 5.79 (1 H, s), 7.23-7.27 (1 H, m), 7.40 (1 H, d, J=7.7Hz), 7.49 (1 H, dt, J=1.1, 7.1 Hz), 7.64 (1 H, s).
Reference: [1] Patent: WO2004/46091, 2004, A2, . Location in patent: Page 58
[2] European Journal of Organic Chemistry, 2013, # 26, p. 5814 - 5819
[3] Patent: EP1782811, 2007, A1, . Location in patent: Page/Page column 84
[4] Journal of Photochemistry and Photobiology A: Chemistry, 2011, vol. 222, # 1, p. 192 - 202
[5] Synthetic Communications, 2006, vol. 36, # 5, p. 659 - 663
[6] Chemistry - A European Journal, 2017, vol. 23, # 69, p. 17576 - 17583
[7] Catalysis Science and Technology, 2014, vol. 4, # 8, p. 2618 - 2625
[8] Journal of the Chemical Society, Dalton Transactions, 2002, # 12, p. 2423 - 2436
[9] Archiv der Pharmazie, 1999, vol. 332, # 1, p. 25 - 30
[10] Journal of Medicinal Chemistry, 2007, vol. 50, # 12, p. 2799 - 2806
[11] Organometallics, 2010, vol. 29, # 17, p. 3955 - 3965
[12] Patent: WO2013/142269, 2013, A1, . Location in patent: Paragraph 0577; 0578
[13] Journal of Organic Chemistry, 2015, vol. 80, # 24, p. 12614 - 12619
[14] Patent: CN103396429, 2016, B, . Location in patent: Paragraph 0047
[15] Organic Letters, 2017, vol. 19, # 7, p. 1570 - 1573
[16] Journal of the American Chemical Society, 2018, vol. 140, # 6, p. 2050 - 2053
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YieldReaction ConditionsOperation in experiment
100% With toluene-4-sulfonic acid In ethylene glycol; toluene 2-(m-Bromophenyl)-1,3-dioxolane
To a stirred solution of 3-bromobenzaldehyde (5.00 g, 27.0 mmol) in toluene (35 ml) was added ethylene glycol (4.52 ml, 81.1 mmol) and p-toluenesulphonic acid (0.5 g).
The mixture was heated to reflux for 2 hours, cooled, and washed with water and saturated sodium hydrogen carbonate solution.
The organic layer was dried over MgSO4.
The solvent was removed under reduced pressure to give the desired product as a colourless oil (6.22 g, 100percent).
δH (CDCl3) 4.09 (4H, m), 5.79 (1H, s), 7.2-7.7 (4H) ppm.
99% With sodium hydroxide In ethylene glycol; toluene EXAMPLE IX
Preparation of 2-(3-Bromophenyl)-1,3-dioxolane
A multinecked, round bottom flask fitted with a mechanical stirrer, thermometer, and a Dean-Stark trap attached to a reflux condenser, was flushed and maintained under a positive pressure of nitrogen.
The flask was charged with 300 g (1.62 mol) of 3-bromobenzaldehyde, 110.4 g (1.78 mol) of ethylene glycol, 550 ml of toluene, and 0.1 g (0.03 wt. percent based on aldehyde) of p-toluene sulfonic acid monohydrate.
The system was brought to reflux temperature to initiate azeotropic distillation.
The mixture was refluxed for about 11 hours at which point, gas chromatography indicated no starting aldehyde was present in the reaction mixture and the theoretical amount of water had been obtained.
The system was cooled to room temperature and 300 ml of 10percent aqueous sodium hydroxide solution was added to the flask.
The resulting bi-phase mixture was allowed to stir for one-half hour and was then poured into a separatory funnel.
The aqueous layer was separated and discarded, and the organic product layer was washed with another 300 ml portion of 10percent aqueous sodium hydroxide solution followed by several washings with water.
The organic layer was dried over anhydrous potassium carbonate overnight and then filtered to remove the solid alkali.
The filtrate was concentrated on a rotary evaporator and distilled under reduced pressure.
The fraction boiling at 107°-110° C./3 mm Hg was collected thus yielding 328 g (1.4 mol, 88percent yield) of the product as a clear, water-white liquid of >99percent purity as measured by gas chromatography.
Analysis: 1 HMR (CDCl3) δ 7.45 (m, 4H, Ar--H), 5.75 (s, 1H, benzylic), 4.05 (s, 4H, --O--CH2 --CH2 --O--) ppm.
Reference: [1] Patent: US6156774, 2000, A,
[2] Patent: US4766251, 1988, A,
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Reference: [1] Synthesis, 2010, # 16, p. 2771 - 2775
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  • [ 35739-70-9 ]
  • [ 5433-01-2 ]
Reference: [1] Chemische Berichte, 1987, vol. 120, p. 123 - 124
  • 15
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  • [ 615-59-8 ]
Reference: [1] Journal of Organic Chemistry, 1981, vol. 46, # 22, p. 4562 - 4564
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YieldReaction ConditionsOperation in experiment
86% With hydroxylamine hydrochloride; sodium carbonate; scandium tris(trifluoromethanesulfonate) In water at 135℃; for 0.583333 h; Microwave irradiation; Sealed vial General MW procedure: A mixture of Sc(OTf)3 (10 mol percent, 49 mg), aldehyde (1 mmol), NH2OH*HCl (1 mmol, 69 mg) and Na2CO3 (1 mmol) was placed in a safe pressure regulation 10 mL pressurized vial containing H2O (1 mL). The vial was sealed with a 'snap-on' cap and irradiated in a single-mode CEM Discover Bench Mate microwave reactor at 300 W and 135 °C for 15-35 min. After the reaction was complete (periodic TLC monitoring), the mixture was allowed to cool to room temperature and was extracted with EtOAc (3 .x. 10 mL). The combined organic phase was dried over Na2SO4, filtered and the solvent was removed under vacuum. The leftover residue was purified by column chromatography on silica gel (EtOAc/hexane 3:7 as eluent) and then characterized based on their physical and spectral data.
63%
Stage #1: at -33℃; for 1 h; Inert atmosphere
Stage #2: at -33℃; for 1 h; Inert atmosphere; Reflux
General procedure: Under an argon atmosphere, liquid NH3 (25 mL) was condensedin a two-neck round-bottom flask immersed in a dry ice coolingbath and equipped with a dry ice reflux condenser. Aldehyde(7.34 mmol) was added, and the resulting solution (or suspension)was stirred for 1 h. KMnO4 (7.34 mmol, 1.16 g) was added,the cooling bath was removed, and the reaction mixture wasstirred for another hour with gentle reflux of NH3. Na2SO3 (22.0mmol, 2.78 g) was added, the reflux condenser was removed,and the NH3 was allowed to evaporate spontaneously. The darkbrownresidue was treated with 6 M HCl (30 mL), and theresulting precipitate was filtered, washed with H2O (100 mL)and sat. aq NaHCO3 (20 mL). All products were recrystallizedfrom EtOH.
63%
Stage #1: at -33℃; for 1 h; Inert atmosphere
Stage #2: for 1 h; Inert atmosphere; Reflux
General procedure: Under an argon atmosphere, liquid NH3 (25 mL) was condensedin a two-neck round-bottom flask immersed in a dry ice coolingbath and equipped with a dry ice reflux condenser. Aldehyde (7.34 mmol) was added, and the resulting solution (or suspension)was stirred for 1 h. KMnO4 (7.34 mmol, 1.16 g) was added,the cooling bath was removed, and the reaction mixture wasstirred for another hour with gentle reflux of NH3. Na2SO3 (22.0mmol, 2.78 g) was added, the reflux condenser was removed,and the NH3 was allowed to evaporate spontaneously. The darkbrownresidue was treated with 6 M HCl (30 mL), and theresulting precipitate was filtered, washed with H2O (100 mL)and sat. aq NaHCO3 (20 mL). All products were recrystallizedfrom EtOH.
56% With hydroxylamine hydrochloride; caesium carbonate In water; dimethyl sulfoxide at 125℃; for 48 h; General procedure: Aldehyde (0.5mmol), NH2OH·HCl (0.6mmol) and Cs2CO3 (0.6mmol) were stirred at 125°C for 48h in a 3:1 mixture of DMSO–H2O (2mL) under air. The progress of the reaction was monitored by TLC using ethyl acetate and hexane as eluent. After completion, the reaction mixture was cooled to room temperature and treated with water (1mL). The resulting mixture was extracted with ethyl acetate (3×5mL). Drying (Na2SO4) and evaporation of the solvent gave a residue that was purified on silica gel column chromatography using ethyl acetate and hexane. The purified products were identified by 1H NMR spectra and the melting points comparison with the literature data.

Reference: [1] Tetrahedron Letters, 2011, vol. 52, # 44, p. 5851 - 5854
[2] RSC Advances, 2016, vol. 6, # 43, p. 37093 - 37098
[3] Advanced Synthesis and Catalysis, 2010, vol. 352, # 2-3, p. 288 - 292
[4] Synlett, 2014, vol. 25, # 9,
[5] Synlett, 2015, vol. 26, # 1, p. 84 - 86
[6] Tetrahedron Letters, 2014, vol. 55, # 20, p. 3192 - 3194
[7] Organic Letters, 2016, vol. 18, # 22, p. 5788 - 5791
[8] Applied Organometallic Chemistry, 2018, vol. 32, # 6,
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  • [ 6952-59-6 ]
  • [ 22726-00-7 ]
Reference: [1] RSC Advances, 2013, vol. 3, # 17, p. 5889 - 5894
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  • [ 51873-95-1 ]
Reference: [1] Green Chemistry, 2011, vol. 13, # 2, p. 384 - 389
  • 19
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  • [ 2136-75-6 ]
  • [ 97985-66-5 ]
Reference: [1] European Journal of Organic Chemistry, 2017, vol. 2017, # 3, p. 719 - 725
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  • [ 1099-45-2 ]
  • [ 97985-66-5 ]
Reference: [1] Synthetic Communications, 2018, vol. 48, # 3, p. 336 - 343
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[2] Journal of Organic Chemistry, 2011, vol. 76, # 15, p. 6414 - 6420
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[2] Journal of Organic Chemistry, 1988, vol. 53, # 23, p. 5545 - 5547
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  • [ 21906-32-1 ]
Reference: [1] Chimica Therapeutica, 1968, vol. 3, p. 313 - 320
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  • [ 63710-33-8 ]
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  • [ 103-84-4 ]
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Reference: [1] Zhurnal Obshchei Khimii, 1958, vol. 28, p. 739,740; engl.Ausg.S.719
  • 27
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  • [ 90965-06-3 ]
  • [ 766-81-4 ]
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  • [ 21047-57-4 ]
  • [ 766-81-4 ]
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[2] Organic Letters, 2017, vol. 19, # 1, p. 54 - 57
[3] Organic and Biomolecular Chemistry, 2018, vol. 16, # 9, p. 1461 - 1464
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  • [ 65537-54-4 ]
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  • [ 34956-29-1 ]
Reference: [1] Patent: WO2014/202528, 2014, A1,
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  • [ 15852-73-0 ]
YieldReaction ConditionsOperation in experiment
99.8% With sodium tetrahydroborate In ethanol at 20 - 25℃; Example 49
(3-Bromophenyl)methanol
Sodium borohydride (7.1 g, 186.1 mmol) in several portions was added to a solution of 3-bromobenzaldehyde (114.8 g, 620.4 mmol) in EtOH (650 mL) at 25° C.
Then the mixture was stirred for 1 h at room temperature.
The reaction was quenched with water (200 mL).
After removing EtOH, the residue was dissolved in AcOEt (500 mL), and filtered.
The filtrate was washed with water (150 mL), brine (150 mL), and dried over Na2SO4.
After removing the solvent, 115.8 g of the title compound was obtained (yield: 99.8percent).
99.8% at 20 - 25℃; Example 49
(3-Bromophenyl)methanol
Sodium borohydride (7.1 g, 186.1 mmol) in several portions was added to a solution of 3-bromobenzaldehyde (114.8 g, 620.4 mmol) in EtOH (650 mL) at 25° C.
Then the mixture was stirred for 1 h at room temperature.
The reaction was quenched with water (200 mL).
After removing EtOH, the residue was dissolved in AcOEt (500 mL), and filtered.
The filtrate was washed with water (150 mL), brine (150 mL), and dried over Na2SO4.
After removing the solvent, 115.8 g of the title compound was obtained (yield: 99.8percent).
99.8%
Stage #1: With sodium tetrahydroborate In ethanol at 20 - 25℃;
Stage #2: With water In ethanol
Example 52
(3-Bromophenyl)methanol
To a solution of 3-bromobenzaldehyde (114.8 g, 620.4 mmol) in EtOH (650 mL), NaBH4 (7.1 g, 186.1 mmol) was added in several portions at 25° C.
Then the mixture was stirred for 1 h at room temperature.
The reaction was quenched with water (200 mL).
After removing EtOH, the residue was dissolved in AcOEt (500 mL), and filtered.
The filter was washed with water (150 mL), brine (150 mL), and dried over Na2SO4.
After removing the solvent, 115.8 g of the title compound was obtained (Yield: 99.8percent).
99.8% at 20 - 25℃; for 1 h; Example 49 (3-Bromophenyl)methanolSodium borohydride (7.1 g, 186.1 mmol) in several portions was added to a solution of 3- bromobenzaldehyde (114.8 g, 620.4 mmol) in EtOH (650 mL) at 25 0C. Then the mixture was stirred for 1 h at room temperature. The reaction was quenched with water (200 mL). After removing EtOH, the residue was dissolved in AcOEt (500 mL), and filtered. The filtrate was washed with water (150 mL), brine (150 mL), and dried over Na2SOφ After removing the solvent, 115.8 g of the title compound was obtained (yield: 99.8percent).
99% With sodium tetrahydroborate In methanol at 0℃; Inert atmosphere General procedure: Aldehyde (1 mmol) was dissolved in 10 ml ofmethanol(ethanol for ketones) and cooled to 0oC. NaBH4 (3 mmol) was then added inone portion and the reaction was allowed to stir until completion as indicatedby TLC (9:1 heptanes/ethyl acetate). The reaction was quenched with 0.1 N NaOH(10 ml) and extracted three times with ethyl actetate. The organic layer waswashed with brine and dried over Na2SO4. The solvent wasremoved under reduced pressure and the resulting yellow oil was subjected toflash chromatography.
97% With 2BH4(1-)*Zn(2+)*Cl2Na2 In acetonitrile at 20℃; for 0.0333333 h; General procedure: In a round-bottomed flask (10 mL), equipped with a magneticstirrer bar, a solution of acetophenone (0.121 g, l mmol) was prepared in CH3CN(3 mL). To this solution, Zn(BH4)2/2NaCl (0.210 g,1 mmol) was added. The resulting mixture was stirred at room temperature for 60 min. The reaction was monitored by TLC(eluent; Hexane/EtOAc: 10/1). After completion of the reaction, distilled water (5 mL) was added to the reaction mixture and stirred for 5 min. The mixture was extracted with CH2Cl2 (3 ×8 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent followed column chromatography of the resulting crude material over silica gel (eluent; Hexane/EtOAc: 10/1) afforded crystals of 1-phenylethanol (0.l1 g, 93 percent yield,Table 2, entry 11).
95% for 0.00833333 h; Microwave irradiation General procedure: In a round-bottomedflask (10 mL) charged with distilled water (5 mL), LiBH4 (0.022 g, -Immo)andbenzaldehyde (0.106 g, 1 mmol) was added. After fitting the flaskto the external condenser at the inside of the oven, the mixture was irradiatedwith a microwave oven (30percentpower amplitude, 300 W) for30 sec. The progress of the reaction was monitored by TLC(eluent;CCI4/Et20: 5/2). At the end of the reduction, distilled water(5 mL) was added to the reaction mixture and it wasthen extracted with CH2Cl2(2Χ10 mL). The combined extracts were dried over anhydrous sodium sulfate. evaporation of the solvent afforded the pure liquid benzyl alcohol(0.102 g, 95percent).
94% With sodium tetrahydroborate In ethanol at 0℃; for 1 h; Cooling with ice Compound 2 was prepared according to Eur. J. Org. Chem, 2002, 19, 3326-3335. In a 250 mL roundbottom was added 3-bromobenzaldehyde 1 (10.0 g, 54.0 mmol) and EtOH (25 mL). The solution was cooled to 0 °C in an ice-water bath, sodium borohydride (1.1 1 g, 29.5 mmol) was added, and the mixture was stirred at 0 °C for 1 h. Sodium sulfate decahydrate was added, and the reaction was stirred at rt for 1 h to quench the borohydride. Diethyl ether was added, and the mixture was washed with water. The organic layer was dried with sodium sulfate and concentrated under vacuum to give 2 (9.50 g, 94percent) as a clear oil. 1H NMR (400 MHz, CDCI3): 2.34 (br. s, 1 H), 4.61 (br. s, 2 H), 7.13 - 7.33 (m, 2 H), 7.40 (d, J = 7.6 Hz, 1 H), 7.49 (s, 1 H).
94% at 0℃; for 1 h; 2.
F.
Synthesis of X069 Succinate Ester
Compound 2 was prepared according to Eur. J. Org. Chem, 2002, 19, 3326-3335.
In a 250 mL roundbottom was added 3-bromobenzaldehyde 1 (10.0 g, 54.0 mmol) and EtOH (25 mL).
The solution was cooled to 0° C. in an ice-water bath, sodium borohydride (1.11 g, 29.5 mmol) was added, and the mixture was stirred at 0° C. for 1 h.
Sodium sulfate decahydrate was added, and the reaction was stirred at rt for 1 h to quench the borohydride.
Diethyl ether was added, and the mixture was washed with water.
The organic layer was dried with sodium sulfate and concentrated under vacuum to give 2 (9.50 g, 94percent) as a clear oil. 1H NMR (400 MHz, CDCl3): 2.34 (br. s, 1H), 4.61 (br. s, 2H), 7.13-7.33 (m, 2H), 7.40 (d, J=7.6 Hz, 1H), 7.49 (s, 1H).
93% With zinc(II) tetrahydroborate In water for 0.0166667 h; Microwave irradiation; Green chemistry General procedure: Zn(BH4)2was prepared from ZnCl4 (5.452g, 0.04 mol) and NaBH4(3.177 g, 0.084 mol)according to an available procedure in the literature11.In a round-bottomed flask (10 mL) charged withdistilled water (5 mL), Zn(BH4)2(0.095 g, 1mmol)and benzaldehyde (0.106 g, 1 mmol) was added.After fitting the flask to the external condenser atthe inside of the oven, the mixture was irradiatedwitha microwave oven (30percent power amplitude, 300 W)for60 sec. The progress of the reaction wasmonitored by TLC(eluent; CH2Cl2). At the end of thereduction, distilledwater (5 mL) was added to thereaction mixture and it wasthen extracted withCH2Cl2(2×10 mL). The combined extracts were dried over anhydrous sodium sulfate. Evaporationofthe solvent afforded the pure liquid benzyl alcohol(0.102 g, 95percent).
80% With sodium dithionite; sodium hydrogencarbonate In water; isopropyl alcohol at 110℃; for 2.66667 h; Flow reactor General procedure: A 0.165 M stock solution of aldehyde or ketone (1 equiv) was prepared by dissolution in (1:1:2 IPA/H2O/NaHCO3 [1 M]). A 0.75 M stock solution of sodium dithionite (4,5 equiv) was prepared by dissolution in (1:1:2 IPA/H2O/NaHCO3 [1 M]). The injection loops (10 mL) unless otherwise stated were primed with the two stock solutions respectively. The solutions were then pumped continuously through a 2 mL mixing chip at ambient temperature followed by a 14 mL HT Teflon coil at 110 °C (aldehydes and ketones). Unless otherwise stated the flow rate was set to 0.25 mL·min−1 (64 min residence) for aldehydes and 0.20 mL·min−1 (80 min residence) for ketones. Product work-up and isolation was achieved using the approach described for the batch reductions.

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YieldReaction ConditionsOperation in experiment
58% With diethylamino-sulfur trifluoride In ethanol; dichloromethane at 20℃; General procedure: To a flame dried flask containing a solution of aryl aldehyde (1.0 eq.) in DCM (1.0 M) at room temperature was added EtOH (5-100 μL) and DAST (1.7 eq.). The reaction was stirred over night at room temperature before it was quenched with aq. NaHCO3 (sat.) and extracted with DCM. The combined organic fractions were washed with brine, dried over MgSO4, evaporated to dryness and loaded onto a silica gel column for purification.
54% With diethylamino-sulfur trifluoride In dichloromethane at 20℃; for 4 h; Diethylaminosulfur trifluor e . g, 67.39 mmol) was added dropwise to a stirred solution of 3-bromobenzaldehyde (1 g, 5.40 mmol) in dichloromethane (10 mL). The mixture was stirred for four hours at room temperature, diluted with saturated sodium bicarbonate and extracted twice with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated to afford 1-bromo-3-(difluoromethyl)benzene (600 mg, 54percent) as a colorless liquid.
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YieldReaction ConditionsOperation in experiment
46% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; cesium acetate In tetrahydrofuran for 6 h; Reflux; Inert atmosphere Triethylborane (1.00 M in THF, 2.00 mL, 2.00 mmol) was addedto a suspension of 3-bromobenzaldehyde (84) (0.370 g,2.00 mmol), Pd(dppf)Cl2 (14.6 mg, 20.0 lmol), and CsOAc(0.384 g, 2.00 mmol) in THF (3.0 mL) under Ar., and the mixturewas heated until reflux began this being maintained for 6 h. Aftercooling to room temperature, the mixture was diluted with Et2O,washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4),filtered and concentrated in vacuo. The residue was purified by silicagel flash CC to afford 3-ethylbenzaldehyde (63) (0.123 g,0.920 mmol, 46percent) as a colorless oil; 1H-NMR (CDCl3, 400 MHz) d:1.28 (t, J = 7.2 Hz, 3H, –CH3), 2.74 (q, J = 7.2 Hz, 2H, –CH2–), 7.42–7.48, 7.69–7.72 (m, each 2H, Ar–H), 10.0 (s, 1H, –CHO); spectraldata were in agreement with those in the literature (Wang et al.,2009).
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YieldReaction ConditionsOperation in experiment
73.1% at 10℃; for 4 h; Under ice-water bath conditions,To a 1L round bottom flask 289ml three mass fraction of 98percent sulfuric acid (5.4mol),64 ml of Compound II (0.54 mol) was added dropwise slowly with stirring,Plus completed,After the temperature of the system dropped to 10 ° C, 27 ml of nitric acid (0.59 mol) in a mass ratio of 65percent was slowly added dropwise to the system,Plus complete TLC monitoring,The reaction was complete for 4 hours,The reaction was slowly poured into 2 L of ice water,Filtration,The filter cake was washed with water,Wash to the filtrate without acid,The solid was recrystallized from n-hexane and ethyl acetate to give 91 g of compound III as a white solid,Yield 73.1percent.
70% With sulfuric acid; nitric acid In water at 5 - 20℃; To concentrated nitric acid (10 mL) in concentrated sulfuric acid (120 mL) at 5°C was added 3- bromobenzaldehyde (11.7 mL, 100 mmol) dropwise. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured onto ice and the resulting precipitate removed by filtration, dissolved in dichloromethane, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 25percent ethyl acetate/isohexane, EPO <DP n="18"/>to give 5-bromo-2-nitrobenzaldehyde (16 g, 70percent). δH (500 MHz, CDCl3): 10.41 (1 H, s), 8.06 (1 H, d, J = 2.1 Hz), 8.02 (1 H, d, J = 8.6 Hz), 7.87 (1 H, dd, J = 2.1, 8.6 Hz).
68.4% at 20℃; for 6 h; Cooling with ice The concentrated sulfuric acid (70 mL) and 70percent concentrated nitric acid (5 mL) were mixed under ice-3-Bromobenzaldehyde (10 g, 54 mmol) was added.After 6 h reaction at room temperature,The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried and concentrated. The crude product was beaten (ethyl acetate / petroleum ether = 1/5, v / v) and dried to give 5-brom0-2-nitrobenzaldehyde (8.5 g) in a yield of 68.4percent.
64% With sulfuric acid; nitric acid In water at 0 - 20℃; for 5 h; 31a)
5-Bromo-2-nitro-benzaldehyde
3-Bromo-benzaldehyde (18.50 g, 99.99 mmol) was added to a stirred solution of concentrated nitric acid (70percent, 13.09 mL, 199.98 mmol) in concentrated sulfuric acid (125 mL) at 0° C.
After the addition was complete, the ice bath was removed and the reaction was allowed to stir for 5 hours at room temperature.
Then, the mixture was poured into ice and the solid was collected by filtration.
The filtrate was extracted with diethyl ether.
The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated.
The residue was combined with the solid previously obtained via the first filtration and dissolved in diethyl ether.
56% at 0℃; for 0.75 h; 10049] Therefore an alternative approach was adopted in which benzaldehyde 11 was nitrated to the known benzaldehyde 12, which in turn was subjected to reductive amination by condensing it with ammonium hydroxide, using sodium borohydride as reducing agent to produce amine 13 in high yield. Acetylation amine 13 generated acetamide 14, which was reacted with tert-butyl piperazine- 1 -carboxylate under l3uchwald-Hartwig conditions to afford intermediate 15 in good yield. Reduction of nitro group of 15 over Pd——C in a Parr apparatus produced intermediate 16 in 91percent yield high yield. Exposure of intermediate 16 under basic conditions rendered the desired diamine 17 in good yield after colunm purifications. Reaction of 17 with CDI in THF, heating the mixture at 80° C. for 6 hours, gave access to the key intermediate 10 in an overall yield of 33percent from 14. Exposure of intermediate 10 to trifluoroacetic acid in a mixture of methanol and dichloromethane finally thrnished the desired key intermediate 18 (scheme 2).
54% at 25℃; Step A: Potassium nitrate (49.2 g, 0.486 mol) was added to 240 g of cooled sulfuric acid in a three neck round bottom flask, keeping the temperature below 25 °C. This was followed by the slow addition of 3-bromobenzaldehyde (30.0 g, 0.162 mol). Once the addition was complete, the mixture was allowed to gradually warm to room temperature overnight. The mixture was then poured into 500 mLs of ice water, resulting in a light yellow precipitate. The solids were collected by filtration and dried under vacuum for several hours. Purification of the crude product was done in the following way: The collected solids were divided into two lots and each lot purified using two 340 g Biotage Snap Cartridges in series with 3: 1 Hexanes:EtOAc as the eluant. Obtained 20 g of 5-bromo-2-nitrobenzaldehyde (54percent) as a light yellow solid. NMR (400 MHz, CDC13) δ 10.42 (s, 1H), 8.07, (d, 1H), 8.03, (d, 1H), 7.89 (dd, 1H).
48% for 0.416667 h; cooling with ice Step a: To an ice cold cone, sulphuric acid (400 mL) was added fuming nitric acid (200 mL) and to this solution was added 3-bromobenzaldehyde (i) (100 g, 0.540 mol) dropwise within 15 min. The reaction mixture was stirred for 10 min at same temperature at which time TLC showed complete reaction. The reaction mixture was quenched in ice water and filtered to afford a mixture of products which was purified by flash column chromatography eluting with EtOAc/hexane (1-5 percent) to give 5-bromo-2-nitrobenzaldehyde (ii) as white solid (60 g, 48 percent).
48% Cooling with ice 5-Bromo-2-nitrobenzaldehyde (ii) To ice cold conc. sulphuric acid (400 mL) was added fuming nitric acid (200 mL) dropwise followed by 3-bromobenzaldehyde (i) (100 g, 0.540 mol) dropwise over 15 min.
The reaction mixture was stirred for 10 min and then poured carefully over ice-water.
The resulting solids were filtered and then purified by flash column chromatography on silica gel, eluting with EtOAc:n-hexane (gradient elution from 1percent to 20percent v/v) to give (ii) (60 g, 48percent).
48% at 0℃; for 0.416667 h; Fuming nitric acid (200 mL) was added to sulphuric acid (400 mL) at 0 °C and then 3- bromobenzaldehyde (100 g, 0.54 mol) was added dropwise in 15 minutes. After stirring for 10minutes at the same temperature, the reaction mixture was poured into ice water and filtered to afford the mixture of products which was purified by flash column chromatography eluting with PE / EtOAc (100 / 1 to 20 / 1) to give 5-bromo-2-nitrobenzaldehyde as white solid (60 g, 48 percent). ‘H-NMR (CDC13, 400 MHz) 10.41 (s, 1H), 8.028.06 (m, 2H), 7.88 (s, 1H). MS (M+H): 230 /232.
48% at 0℃; for 0.416667 h; Fuming nitric acid (200 mL) was added to sulphuric acid (400 mL) at 0 °C and then 3-bromobenzaldehyde (100 g, 0.54 mol) was added dropwise in 15 minutes. After stirring for 1010 minutes at the same temperature, the reaction mixture was poured into ice water and filtered toafford the mixture of products which was purified by flash column chromatography eluting withPE I EtOAc (100 I 1 to 20 I 1) to give 5-bromo-2-nitrobenzaldehyde as white solid (60 g, 48 percent).1H-NMR (CDCh, 400 MHz) 8 10.41 (s, 1H), 8.02~8.06 (m, 2H), 7.88 (s, 1H). MS (M+Ht: 230I 232.

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[32] Patent: CN103467300, 2016, B,
[33] Patent: CN106943602, 2017, A, . Location in patent: Paragraph 0050; 0052; 0053
[34] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 1, p. 146
[35] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 1, p. 146
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  • [ 3132-99-8 ]
  • [ 882772-99-8 ]
  • [ 20357-20-4 ]
Reference: [1] Synthesis, 2008, # 14 SPEC. ISS., p. 2199 - 2210
  • 49
  • [ 3132-99-8 ]
  • [ 506-59-2 ]
  • [ 4885-18-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 3, p. 1320 - 1336
  • 50
  • [ 3132-99-8 ]
  • [ 58971-11-2 ]
Reference: [1] Patent: WO2011/47156, 2011, A1,
  • 51
  • [ 3132-99-8 ]
  • [ 29124-57-0 ]
Reference: [1] Patent: CN105669566, 2016, A,
  • 52
  • [ 3132-99-8 ]
  • [ 87199-16-4 ]
Reference: [1] ChemCatChem, 2018, vol. 10, # 19, p. 4253 - 4257
  • 53
  • [ 3132-99-8 ]
  • [ 74-89-5 ]
  • [ 67344-77-8 ]
YieldReaction ConditionsOperation in experiment
81% With sodium tetrahydroborate In methanol; water at 0 - 20℃; for 3.5 h; Step B: To a solution of 3-bromobenzaldehyde (47.5 mL, 0.4 mol) in methanol (460 mL) at room temperature was added a solution of methylamine in water (35 mL, 0.4 mol, 40 wt. percent solution). The resultant solution was cooled to 0° C. and sodium borohydride (22 g, 0.6 mol) was added to it in portions. The reaction solution was stirred at 0° C. for 3 hours and 30 minutes, and then warmed to room temperature. The resultant reaction mixture was concentrated in vacuo and partitioned between dichloromethane and water. The aqueous layer was separated and washed with dichloromethane (3.x.). The combined organic extract was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired benzylamine (76 g, 81percent) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J=1.5 Hz, 1H), 7.40-7.37 (m, 1H), 7.24-7.16 (m, 2H), 3.73 (s, 2H), 2.45 (s, 3H).; Example 81 Preparation of (+)-N-methyl-2-(2-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)ethanesulfonamide, L-tartrate salt and (-)-N-methyl-2-(2-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)ethanesulfonamide, L-tartrate salt Step A: To a solution of 3-bromobenzaldehyde (47.5 mL, 0.4 mol) in methanol (460 mL) at room temperature was added a solution of methylamine in water (35 mL, 0.4 mol, 40 wt percent solution). The resultant solution was cooled to 0° C. and sodium borohydride (22 g, 0.60 mol) was added to it in portions. The reaction solution was stirred at 0° C. for 3 hours and 30 minutes, and then warmed to room temperature. The resultant reaction mixture was concentrated in vacuo and partitioned between dichloromethane and water. The aqueous layer was separated and washed with dichloromethane (3.x.). The combined organic extracts were washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the benzylamine (76 g, 81percent) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J=1.5 Hz, 1H), 7.40-7.37 (m, 1H), 7.24-7.16 (m, 2H), 3.73 (s, 2H), 2.45 (s, 3H).
Reference: [1] Patent: US2007/21408, 2007, A1, . Location in patent: Page/Page column 94; 103
[2] Journal of Medicinal Chemistry, 1981, vol. 24, # 2, p. 140 - 145
[3] Patent: WO2009/149258, 2009, A2, . Location in patent: Page/Page column 21; 48
[4] Patent: US2014/275101, 2014, A1, . Location in patent: Paragraph 0072; 0145; 0146
[5] Patent: WO2015/127559, 2015, A1, . Location in patent: Page/Page column 55; 56
[6] Patent: WO2008/141082, 2008, A1, . Location in patent: Page/Page column 67-68; 77; 80; 83-84; 90
  • 54
  • [ 3132-99-8 ]
  • [ 593-51-1 ]
  • [ 67344-77-8 ]
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[2] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 16, p. 2527 - 2531
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 972 - 986
  • 55
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Reference: [1] Journal of Medicinal Chemistry, 1984, vol. 27, # 9, p. 1111 - 1118
  • 56
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[2] Tetrahedron Letters, 2000, vol. 41, # 40, p. 7623 - 7627
[3] Journal of Organic Chemistry, 1981, vol. 46, # 11, p. 2280 - 2286
[4] Chemistry - A European Journal, 2011, vol. 17, # 27, p. 7632 - 7644
[5] Organic Letters, 2014, vol. 16, # 9, p. 2318 - 2321
[6] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 24, p. 7543 - 7564
  • 57
  • [ 3132-99-8 ]
  • [ 544-97-8 ]
  • [ 52780-14-0 ]
  • [ 134615-22-8 ]
Reference: [1] Journal of Organic Chemistry, 2008, vol. 73, # 1, p. 168 - 176
[2] European Journal of Organic Chemistry, 2012, # 9, p. 1703 - 1706
  • 58
  • [ 3132-99-8 ]
  • [ 75-16-1 ]
  • [ 52780-14-0 ]
  • [ 134615-22-8 ]
Reference: [1] European Journal of Organic Chemistry, 2013, # 4, p. 748 - 750
  • 59
  • [ 3132-99-8 ]
  • [ 141-82-2 ]
  • [ 117391-50-1 ]
YieldReaction ConditionsOperation in experiment
70% With ammonium acetate In ethanol for 16 h; Heating / reflux A mixture of 200 grams (1.08 mol) of 3-bromobenzaldehyde, 112 grams (1.08 mol) of malonic acid, and 166.5 g (2.16 mol) of ammonium acetate was suspended in 1.125 liters of absolute ethanol. The mixture was mechanically stirred and brought to reflux temperature, whereupon the solution clarified. The mixture was kept at reflux for 16 h, and a precipitate formed. The mixture was chilled to 0° C., and the solid product was collected by filtration and washed with cold ethanol to yield 184 grams (70percent) of 3-amino-3-(3-bromophenyl)propanoic acid as a white solid which was carried forward without further purification or analytical characterization.
94.74 g With ammonium acetate In ethanolReflux A solution of 3-bromobenzaldehyde (50 mL, 0.43 mol), malonic acid (49.09 g, 0.47 mol) and ammonium acetate (49.73 g, 0.65 mol) in absolute ethanol (300 mL) was refluxed overnight then cooled to room temperature.
The suspension was filtered, washing with hexanes. The solid was dried under vacuum to give 3-amino-3-(3-bromophenyl)propanoic acid (2-1, 94.74 g) as a white solid.
Reference: [1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 9, p. 1570 - 1576
[2] Patent: US2008/194535, 2008, A1, . Location in patent: Page/Page column 25
[3] Journal of Organic Chemistry, 2009, vol. 74, # 23, p. 9152 - 9157
[4] Bulletin de la Societe Chimique de France, 1987, # 6, p. 1079 - 1083
[5] Chemistry - A European Journal, 2014, vol. 20, # 37, p. 11768 - 11775
[6] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 6, p. 1356 - 1365
[7] Patent: US2018/312523, 2018, A1, . Location in patent: Paragraph 1607; 1608
  • 60
  • [ 3132-99-8 ]
  • [ 141-82-2 ]
  • [ 14473-91-7 ]
  • [ 117391-50-1 ]
Reference: [1] Russian Journal of General Chemistry, 2005, vol. 75, # 7, p. 1113 - 1124
  • 61
  • [ 773837-37-9 ]
  • [ 3132-99-8 ]
  • [ 79422-73-4 ]
Reference: [1] Tetrahedron, 2011, vol. 67, # 23, p. 4185 - 4191
  • 62
  • [ 3132-99-8 ]
  • [ 93777-26-5 ]
Reference: [1] Journal of the American Chemical Society, 2018, vol. 140, # 8, p. 2789 - 2792
  • 63
  • [ 3132-99-8 ]
  • [ 187746-76-5 ]
Reference: [1] Synthesis, 1997, # 1, p. 79 - 86
  • 64
  • [ 3132-99-8 ]
  • [ 190273-89-3 ]
Reference: [1] Patent: CN105669566, 2016, A,
  • 65
  • [ 6165-69-1 ]
  • [ 3132-99-8 ]
  • [ 129746-42-5 ]
YieldReaction ConditionsOperation in experiment
86% With sodium carbonate In 1,2-dimethoxyethane 3-(3-Thienyl)benzaldehyde (2a)
3.11 g of 3-thiopheneboronic acid (0.024 mol) are added to a solution of 3-bromobenzaldehyde (3 g, 0.016 mol) in 1,2-dimethoxyethane (80 ml), followed by addition of aqueous 2N sodium carbonate solution (5.15 g, 0.048 mol) and a catalytic amount of tetrakis(triphenylphosphine)palladium (0.56 g, 4.9 10-4 mol).
The reaction mixture is heated at 80° C. for 16 hours and is then cooled to room temperature and poured into water.
The resulting mixture is extracted with ethyl acetate and the organic phase is washed with saturated aqueous sodium chloride solution.
The organic phase is dried over magnesium sulfate and filtered, and the solvent is evaporated off under reduced pressure.
The title product is isolated by chromatography on a column of silica (eluent: 90/10 cyclohexane/ethyl acetate).
2.61 g of a pale yellow solid are recovered.
Yield: 86percent
m.p.: 59° C.
1H NMR (CDCl3) δ: 7.46 (s, 2H); 7.53-7.59 (m, 2H); 7.79 (d, J=7.68 Hz, 1H); 7.86 (d, J=8.88 Hz, 1H).
Reference: [1] Patent: US6417222, 2002, B1,
[2] ChemMedChem, 2016, p. 2194 - 2204
  • 66
  • [ 3132-99-8 ]
  • [ 82311-69-1 ]
Reference: [1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 9, p. 1570 - 1576
  • 67
  • [ 3132-99-8 ]
  • [ 1692-15-5 ]
  • [ 208190-04-9 ]
YieldReaction ConditionsOperation in experiment
30 g With palladium diacetate; sodium carbonate; triphenylphosphine In water; isopropyl alcohol at 80℃; for 48 h; Inert atmosphere Step 1Into a 2 L 3-necked round-bottom flask, purged and maintained with an inertatmosphere of nitrogen, was placed a solution of pyridin-4-ylboronic acid (30 g, 244 mmol, 1 equiv) in 2-propanol/water (800/40 mL), Na2C03 (77.3 g, 729 mmol, 3 equiv), Pd(OAc)2 (5.46 g, 24.3 mmol, 0.1 equiv), PPh3 (12.75 g, 48.7 mmol, 0.2 equiv) and 3- bromobenzaldehyde (45 g, 243 mmol, 1 equiv). The mixture was stirred for 48 h at 80°C in an oil bath. Then the solids were filtered out and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 1 : 1 ethyl acetate/petroleum ether) to give 30 g of 3-(pyridin-4-yl)benzaldehyde as orange oil.
30 g With palladium diacetate; sodium carbonate; triphenylphosphine In water; isopropyl alcohol at 80℃; for 48 h; Inert atmosphere Into a 2 L 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of pyridin-4-ylboronic acid (30 g, 244 mmol, 1 equiv) in 2-propanol/water(800/40 mL), Na2CO3 (77.3 g, 729 mmol, 3 equiv), Pd(OAc)2 (5.46 g, 24.3 mmol,0.1 equiv), PPh3 (12.75 g, 48.7 mmol, 0.2 equiv) and 3-bromobenzaldehyde (45 g, 243 mmol, 1 equiv). The mixture was stirred for 48 h at 80°C in an oil bath. Then the solids were filtered out and the filtrate was concentrated under vacuum. The residue was purified by columnchromatography on silica gel (eluting with 1:1 ethyl acetate/petroleum ether) to give 30 g of 3-(pyridin-4-yl)benzaldehyde as orange oil.
Reference: [1] Angewandte Chemie - International Edition, 2006, vol. 45, # 17, p. 2761 - 2766
[2] Patent: WO2013/16807, 2013, A1, . Location in patent: Page/Page column 23-24
[3] Patent: WO2015/127559, 2015, A1, . Location in patent: Page/Page column 31
  • 68
  • [ 3132-99-8 ]
  • [ 73183-34-3 ]
  • [ 380151-86-0 ]
YieldReaction ConditionsOperation in experiment
99.102%
Stage #1: With potassium acetate In 1,4-dioxane for 0.25 h; Sealed tube; Inert atmosphere
Stage #2: With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In 1,4-dioxane at 90℃;
A 500 mL sealed tube was charged with 3-bromobenzaldehyde (9.25 g, 50.0 mmol), potassium acetate (9.8 g, 1.3 mmol), bis(pinacolato)diboran (15.3 g, 60.3 mmol) in1,4-dioxane (50 mL) and was degasified with nitrogen for 15 mm. Then, Pd(dppf)C12 (0.82 g, 31 .7 mmol) was added to the resultant and heated at 90 00 over night. The reaction mixture was filtered through celite and the filtrate was partitioned between water and ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated. The product was purified by column chromatography toyield the title product (11.5 g, 99.102percent) as a colorless liquid. LCMS: (M+H)=233.2;1H NMR: (DMSO-d6, 300MHz) 6 10.06 (5, 1H), 8.21(s, 1H), 8.01-8.04 (d, 1H), 7.96-7.99 (d, 1 H), 7.61-7.66 (t, 1 H), 1 .33 (5, 1 2H).
99.102%
Stage #1: With potassium acetate In 1,4-dioxane for 0.25 h; Sealed tube; Inert atmosphere
Stage #2: With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In 1,4-dioxane at 90℃;
A 500 mL sealed tube was charged with 3-bromobenzaldehyde (9.25 g, 50.0 mmol), potassium acetate (9.8 g, 1.3 mmol), bis(pinacolato)diboran (15.3 g, 60.3 mmol) in 1,4-dioxane (50 mL) and was degasified with nitrogen for 15 mm. Then, Pd(dppf)C12(0.82 g, 31 .7 mmol) was added to it and the reaction mixture thus obtained was heated at 90 00 over night. The reaction mixture was filtered through celite and the filtrate was partitioned between water and ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated. The product was purified by column chromatography to yield the title product (11.5 g, 99.102percent) as a colorless
88.9% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80℃; Inert atmosphere A mixture of 3-bromo benzaldehyde (5, 1.68 g, 9.08 mmol), bis(pinacolato)diboron (3.4 g, 13.4 mmol), catalyst Pd(dppf)Cl2 (199 mg,0.27 mmol), and potassium acetate (2.67 g, 27.24 mmol) in degassed 1,4-dioxane (50 ml) was stirred at 80 °C for 6 h under N2 atmosphere. Progress of the reaction was monitored using TLC. The reaction mixture was quenched by adding cold water to it and the separated the product was extracted by dichloromethane (25 mL x 3). The organic phase was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by silica gel (60–120mesh) chromatography (petroleum ether, 60–80 °C/dichloromethane, 1:3) to give compound 6 (1.86 g, 88.9percent) as pale white solid; mp 51 °C;1H NMR (300 MHz, CDCl3, δ ppm): 1.36 (s, 12 H), 7.51–8.31 (m, 4 H),10.1 (s, 1 H).
78% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 120℃; for 0.166667 h; Microwave irradiation General procedure: To 1,4-dioxane (2 mL) in a microwave reaction vessel were added the corresponding aldehyde (0.20 g, 9.9 mmol), bis(pinacolato)diboron (0.28 g, 1.1 mmol), potassium acetate (0.29 g, 3.0 mmol), and (1,1-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.022 g, 0.030 mmol). The reaction mixture was heated in the microwave reactor at power 100 W and 120 °C for 10 min. After solvent was removed in vacuo, the residue was treated with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and removed in vacuo. The residue was purified by flash column chromatography over silica gel (hexane : ethyl acetate, 12 : 1) The product was obtained in 76percent yield;

Reference: [1] Patent: WO2014/202580, 2014, A1, . Location in patent: Page/Page column 80; 81
[2] Patent: WO2014/202528, 2014, A1, . Location in patent: Page/Page column 67
[3] Advanced Synthesis and Catalysis, 2016, vol. 358, # 6, p. 977 - 983
[4] Journal of Photochemistry and Photobiology A: Chemistry, 2018, vol. 364, p. 6 - 15
[5] Journal of the American Chemical Society, 2016, vol. 138, # 1, p. 84 - 87
[6] Chemical and Pharmaceutical Bulletin, 2014, vol. 62, # 9, p. 906 - 914
[7] Applied Organometallic Chemistry, 2011, vol. 25, # 7, p. 537 - 541
[8] Journal of the American Chemical Society, 2018, vol. 140, # 27, p. 8429 - 8433
  • 69
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  • [ 364794-80-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 20, p. 2989 - 2992
  • 70
  • [ 3132-99-8 ]
  • [ 128796-39-4 ]
  • [ 343604-24-0 ]
Reference: [1] Patent: WO2005/118542, 2005, A1, . Location in patent: Page/Page column 45-46
[2] ChemMedChem, 2016, p. 2194 - 2204
[3] Archiv der Pharmazie, 2005, vol. 338, # 1, p. 9 - 17
[4] Pharmazie, 2003, vol. 58, # 12, p. 854 - 856
[5] Organic Letters, 2011, vol. 13, # 5, p. 952 - 955
[6] Angewandte Chemie - International Edition, 2018, vol. 57, # 17, p. 4622 - 4626[7] Angew. Chem., 2018, vol. 130, # 17, p. 4712 - 4716,5
  • 71
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  • [ 189628-37-3 ]
Reference: [1] Journal of the American Chemical Society, 2017, vol. 139, # 2, p. 888 - 896
  • 72
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  • [ 139155-55-8 ]
Reference: [1] Patent: WO2011/34828, 2011, A1,
  • 73
  • [ 3132-99-8 ]
  • [ 96-32-2 ]
  • [ 151583-29-8 ]
  • [ 79432-87-4 ]
Reference: [1] European Journal of Organic Chemistry, 2015, vol. 2015, # 20, p. 4532 - 4543
  • 74
  • [ 3132-99-8 ]
  • [ 151583-29-8 ]
Reference: [1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 9, p. 2612 - 2621
  • 75
  • [ 3132-99-8 ]
  • [ 17933-03-8 ]
  • [ 216443-78-6 ]
Reference: [1] Patent: US6150413, 2000, A,
  • 76
  • [ 3132-99-8 ]
  • [ 899350-32-4 ]
Reference: [1] Patent: WO2014/99503, 2014, A1,
  • 77
  • [ 3132-99-8 ]
  • [ 1001756-23-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 188 - 193
  • 78
  • [ 3132-99-8 ]
  • [ 882772-99-8 ]
YieldReaction ConditionsOperation in experiment
48% at 0 - 20℃; for 1.33333 h; A solution of nitric acid (0.6mL), and concentrated sulfuric acid (8.1mL), was stirred at 0°C, then 6a (3.0g, 0.11mmol) was added over a period of 20min. The mixture was stirred at rt for 1h and then poured into ice. The white solid formed was filtered and washed with water. The crude product was purified by flash chromatography (1:4, EtOAc/n-hexane) to obtain title compound as white solid (yield 48percent). 1H NMR (300MHz, CDCl3) δ 7.60 (t, J=7.5Hz, 1H), 7.92 (d, J=2.4Hz, 1H), 7.94 (d, J=2.4Hz, 1H), 9.87 (s, 1H).
Reference: [1] European Journal of Medicinal Chemistry, 2013, vol. 70, p. 233 - 247
[2] Organic and Biomolecular Chemistry, 2018, vol. 16, # 28, p. 5113 - 5118
  • 79
  • [ 3132-99-8 ]
  • [ 882772-99-8 ]
  • [ 20357-20-4 ]
Reference: [1] Synthesis, 2008, # 14 SPEC. ISS., p. 2199 - 2210
  • 80
  • [ 3132-99-8 ]
  • [ 4637-24-5 ]
  • [ 342617-08-7 ]
Reference: [1] Patent: WO2008/51493, 2008, A2, . Location in patent: Page/Page column 165
  • 81
  • [ 3132-99-8 ]
  • [ 1241894-37-0 ]
Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 17, p. 7822 - 7830
[2] Tetrahedron Letters, 2016, vol. 57, # 8, p. 959 - 963
[3] Patent: CN106943602, 2017, A,
  • 82
  • [ 3132-99-8 ]
  • [ 1670-14-0 ]
  • [ 864377-31-1 ]
YieldReaction ConditionsOperation in experiment
83% With nickel diacetate; sodium carbonate In toluene at 110℃; for 30 h; 100mlThree mouthfulsIn the bottleM-bromobenzaldehyde(10.8mmol, 2g),Benzoquinone hydrochloride(21.6mmol, 3.8g), Na2CO3 (21.6 mmol, 2.2 g), Ni(OAc) 2 (1.08 mmol, 0.27 g),The molar ratio is charged at 1:2:2:0.1.The solvent was chosen to be 50 g of toluene.The reaction was controlled to stir at 110 ° C for 30 h.filter,Washed,Recrystallization from absolute ethanol,The obtained cake was vacuum dried to obtain a product of 3.6 g.The yield was 83percent.
68% With copper(II) acetate monohydrate; sodium carbonate In toluene at 100℃; for 24 h; General procedure: A mixture ofaldehyde 1 (6.8 mmol), amidine hydrochloride 2 (2 g,11.4 mmol), Na2CO3 (1.21 g, 11.4 mmol, 1.0 equiv) andCu(OAc)2 (10 molpercent) was stirred in toluene (20 mL) under100 °C in air for 24 h. After completion of the reaction, themixture was cooled to room temperature. The water wasadded to the reaction system and atmospheric distillation untiltoluene was evaporated. The resulting solution was filteredand residue with hot water washed 3 times. The crude productwas purified by column chromatography on silica gel usingpetroleum ether/EtOAc (100:1) as an eluent to give the correspondingproducts 7a-7x.
Reference: [1] Patent: CN108264490, 2018, A, . Location in patent: Paragraph 0068; 0069; 0070; 0071
[2] Journal of Fluorescence, 2018, vol. 28, # 2, p. 707 - 723
  • 83
  • [ 3132-99-8 ]
  • [ 864377-31-1 ]
YieldReaction ConditionsOperation in experiment
52% With sodium carbonate; copper dichloride In toluene at 130℃; 2.1Weigh 3.7 g of m-bromobenzaldehyde 7.7 g, Benzamidine hydrochloride0.405 g CuCl26.36g of sodium carbonate is dissolved in 60mL of toluene, the temperature is set to 130 ° C, the reaction is turned on;2.2After the reaction was completed, after cooling to room temperature, the cake was plated with silica gel and diatomaceous earth, and the reaction mixture was filtered.Concentrate the reaction to give a brown solid, then at room temperatureBeating with petroleum ether to an off-white solid 4.1g, yield 52percent,HPLC = 99percent;
Reference: [1] Patent: CN106800555, 2018, B, . Location in patent: Paragraph 0075; 0131; 0132
  • 84
  • [ 3132-99-8 ]
  • [ 864377-31-1 ]
Reference: [1] Patent: EP2415769, 2012, A1,
[2] Patent: KR2017/79348, 2017, A,
[3] Patent: US9966541, 2018, B2,
[4] Patent: JP2018/90561, 2018, A,
  • 85
  • [ 3132-99-8 ]
  • [ 1670-14-0 ]
  • [ 98-86-2 ]
  • [ 864377-28-6 ]
YieldReaction ConditionsOperation in experiment
26%
Stage #1: With sodium methylate In methanol; ethanol at 20℃; for 9 h; Inert atmosphere; Reflux
Stage #2: With sodium hydroxide In methanol; ethanol at 70℃; for 5 h;
3-bromobenzaldehyde (18.5 g, 100 mmol), acetophenone (12.0 g, 100 mmol), 1N-sadium methoxide/methanol solution (10 ml) and ethanol (200 ml) were stirred for five hours at the room temperature under an Ar gas atmosphere. Subsequently, the reactant mixture was heated and stirred for another four hours at a reflux temperature. Next, benzamidine hydrochloride (9.4 g, 60 mmol) and sodium hydroxide (8.0 g, 200 mmol) were added thereto and stirred for five hours at 70 degrees C. After the reaction, the reactant mixture was filtered to separate an extract. The extract was refined by silica-gel column chromatography (a developing solvent: dichloromethane) to provide an intermediate body X6 as a white solid. A yield of the intermediate body X6 was 10.1 g and a yield rate thereof was 26percent.
Reference: [1] Patent: US2016/343955, 2016, A1,
[2] Patent: EP2489664, 2012, A1, . Location in patent: Page/Page column 46-47
  • 86
  • [ 3132-99-8 ]
  • [ 1423-27-4 ]
  • [ 675596-31-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 7, p. 2975 - 2990
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Chemical Structure| 1122-91-4

[ 1122-91-4 ]

4-Bromobenzaldehyde

Similarity: 0.97

Chemical Structure| 5769-33-5

[ 5769-33-5 ]

4-Bromo-2,6-dimethylbenzaldehyde

Similarity: 0.94

Chemical Structure| 74553-29-0

[ 74553-29-0 ]

2,5-Dibromobenzaldehyde

Similarity: 0.94

Chemical Structure| 36276-24-1

[ 36276-24-1 ]

3-Bromo-4-methylbenzaldehyde

Similarity: 0.94

Aldehydes

Chemical Structure| 56990-02-4

[ 56990-02-4 ]

3,5-Dibromobenzaldehyde

Similarity: 0.97

Chemical Structure| 1122-91-4

[ 1122-91-4 ]

4-Bromobenzaldehyde

Similarity: 0.97

Chemical Structure| 5769-33-5

[ 5769-33-5 ]

4-Bromo-2,6-dimethylbenzaldehyde

Similarity: 0.94

Chemical Structure| 74553-29-0

[ 74553-29-0 ]

2,5-Dibromobenzaldehyde

Similarity: 0.94

Chemical Structure| 36276-24-1

[ 36276-24-1 ]

3-Bromo-4-methylbenzaldehyde

Similarity: 0.94