[ CAS No. 24078-12-4 ] {[proInfo.proName]}

Name: 24078-12-4|4-Bromo-2-methylbenzaldehyde|98%
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Quality Control of [ 24078-12-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 24078-12-4 ]

CAS No. :	24078-12-4	MDL No. :	MFCD07787171
Formula :	C₈H₇BrO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RCBPVESMGNZMSG-UHFFFAOYSA-N
M.W :	199.04	Pubchem ID :	13555150
Synonyms :

Calculated chemistry of [ 24078-12-4 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	1
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	44.5
TPSA :	17.07 Å²

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) :	-5.78 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.98
Log Po/w (XLOGP3) :	2.44
Log Po/w (WLOGP) :	2.57
Log Po/w (MLOGP) :	2.52
Log Po/w (SILICOS-IT) :	3.12
Consensus Log Po/w :	2.52

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.99
Solubility :	0.204 mg/ml ; 0.00102 mol/l
Class :	Soluble
Log S (Ali) :	-2.44
Solubility :	0.72 mg/ml ; 0.00362 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.59
Solubility :	0.0512 mg/ml ; 0.000257 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.19

Safety of [ 24078-12-4 ]

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 [ 24078-12-4 ]

* 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 [ 24078-12-4 ]
Downstream synthetic route of [ 24078-12-4 ]

[ 24078-12-4 ] Synthesis Path-Upstream 1~11

1
[ 591-17-3 ]
[ 100-97-0 ]
[ 824-54-4 ]
[ 24078-12-4 ]
[ 176504-70-4 ]

Reference： [1] Russian Chemical Bulletin, 1995, vol. 44, # 11, p. 2127 - 2130[2] Izvestiya Akademi Nauk, Seriya Khimicheskaya, 1995, # 11, p. 2221 - 2224

2
[ 24078-12-4 ]
[ 17100-58-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: With diisobutylaluminium hydride In tetrahydrofuran; dichloromethane at -78 - 20℃; Stage #2: With ammonium chloride In tetrahydrofuran; dichloromethane; water	Example 20 5-[4-(hydroxymethyl)-3-methylphenyl]-1-methyl-1H-pyrrole-2-carbonitrile To a solution of 4-bromo-2-methylbenzaldehyde (1.0 g, 4.65 mmol) in THF (25 mL) at -78° C. was added diisobutylaluminum hydride (DIBAL-1.0M in dichloromethane, 20 mL, 20 mmol) over 15 minutes in a dropwise fashion. The solution was stirred overnight at room temperature and slowly poured into a saturated ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate (3*30 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give (4-bromo-2-methylphenyl)-methanol (0.88 g, 95percent). MS (ES) m/z 201.
65%	at 0 - 20℃; for 12.5 h;	4-bromo-2-methylphenyl methanol. To a solution of 4-bromo-2-methylbenzaldehyde (1.99 g, 10 mmol) in ethanol (100 mL) was added sodium borohydride (0.76 g, 20 mmol) in portions at 0°C. The mixture was stirred for 30 minutes and warmed to 20°C and stirred at the same temperature for 12 hours. The mixture was concentrated in vacuo to give (4-bromo-2- methylphenyl) methanol (1.3 g, 65percent).
65%	With methanol; sodium tetrahydroborate In ethanol at 0 - 20℃; for 12.5 h;	To a solution of 4-bromo-2-methylbenzaldehyde (1.99 g, 10 mmol) in ethanol (100 mL) was added sodium borohydride (0.76 g, 20 mmol) in portions at 0° C. The mixture was stirred for 30 minutes and warmed to 20° C. and stirred at the same temperature for 12 hours. The mixture was concentrated in vacuo to give (4-bromo-2-methylphenyl)methanol (1.3 g, 65percent).

Reference： [1] Patent: US2007/66628, 2007, A1, . Location in patent: Page/Page column 17
[2] Patent: WO2013/75083, 2013, A1, . Location in patent: Paragraph 00357; 00358
[3] Patent: US9206128, 2015, B2, . Location in patent: Page/Page column 175; 176

3
[ 17100-58-2 ]
[ 24078-12-4 ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.5 h; Inert atmosphere Stage #2: With triethylamine In dichloromethane at -78 - 20℃; for 12 h; Inert atmosphere	[00281] 28B. 4-bromo-2-methylbenzaldehyde: To a solution of oxalyl chloride (249 mL, 497 mmol) in CH2CI2 (150 mL) at -78 °C under argon was added a solution of DMSO (42.4 mL, 597 mmol) in CH₂C1₂ (75 mL) dropwise with a venting needle (Note: gas was generated, slow addition was necessary). After the addition, the venting needle was removed. The reaction mixture was stirred at -78 °C under argon for 30 min. Then, a solution of 28A (20.0 g, 99.0 mmol) in CH₂C1₂ (203 mL) was added. The resulting solution was stirred at -78 °C for 30 min and then TEA (166 mL, 1190 mmol) was added dropwise. The reaction mixture was warmed to rt and stirred for 12 h. The reaction mixture was diluted with water (20 mL) and CH₂C1₂ (30 mL). The layers were separated and the aqueous layer was extracted with CH₂C1₂ (3 x 50 mL). The combined organic extracts were washed with water and brine, dried (MgSC^), filtered, and concentrated. The crude product was purified by flash chromatography to provide 28B (15.4 g, 78 mmol, 78 percent yield) as a yellow oil. ^lH NMR (400 MHz, CDC1₃) δ 10.22 (s, 1H), 7.66 (d, J= 8.28 Hz, 1H), 7.51 (dd, J= 8.28, 1.76 Hz, 1H), 7.45 (s, 1H), 2.65 (s, 3H).
73%	Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.5 h; Inert atmosphere Stage #2: With triethylamine In dichloromethane at -78℃; for 3 h; Inert atmosphere	To a solution of ID (9.30 g, 46.3 mmol) in CH₂CI₂ (200 mL) under argon was added oxalyl chloride (10.1 mL, 116 mmol) at -78 °C; then DMSO (9.85 mL, 139 mmol) was added dropwise with a venting needle. After the addition was complete, the venting needle was removed and the reaction mixture was stirred at -78 °C under argon for 30 min. Then, NEt₃ (38.7 mL, 278 mmol) was added dropwise. After stirring at the same temperature for 3 h, the reaction mixture was diluted with water (20 mL) and CH₂C1₂ (50 mL) and the layers were separated. The aqueous layer was further extracted with CH₂CI₂ (3 x 100 mL) and the combined organic extracts were washed with water and brine, dried over MgS0₄, filtered, and concentrated. The crude product was purified by silica chromatography to give IE (yellow oil, 6.70 g, 33.7 mmol, 73percent yield). 1H NMR (400 MHz, CDC1₃) δ 10.22 (1 H, s), 7.66 (1 H, d, J=8.28 Hz), 7.51 (1 H, dd, J=8.28, 1.76 Hz), 7.45 (1 H, s), 2.65 (3 H, s).

Reference： [1] Patent: WO2014/78608, 2014, A1, . Location in patent: Paragraph 00281
[2] Patent: WO2015/171757, 2015, A1, . Location in patent: Page/Page column 55
[3] Journal of Medicinal Chemistry, 1984, vol. 27, # 11, p. 1516 - 1531
[4] Patent: WO2008/91681, 2008, A2, . Location in patent: Page/Page column 225
[5] Patent: US2010/16298, 2010, A1, . Location in patent: Page/Page column 191
[6] Patent: US2010/222345, 2010, A1, . Location in patent: Page/Page column 92
[7] Patent: WO2015/35113, 2015, A1, . Location in patent: Page/Page column 263; 264

4
[ 68837-59-2 ]
[ 24078-12-4 ]

Reference： [1] ACS Catalysis, 2018, vol. 8, # 12, p. 11134 - 11139
[2] Journal of Medicinal Chemistry, 1984, vol. 27, # 11, p. 1516 - 1531
[3] Patent: WO2014/78608, 2014, A1,
[4] Patent: WO2015/35113, 2015, A1,
[5] Patent: WO2015/171757, 2015, A1,

5
[ 67832-11-5 ]
[ 24078-12-4 ]

Reference： [1] Patent: WO2008/729, 2008, A1, . Location in patent: Page/Page column 86-87
[2] Patent: CN102516115, 2016, B, . Location in patent: Paragraph 0602-0604; 0606-0608

6
[ 99548-55-7 ]
[ 24078-12-4 ]

Reference： [1] Journal of the Chemical Society, 1947, p. 690
[2] Patent: WO2015/35113, 2015, A1,

7
[ 858209-29-7 ]
[ 24078-12-4 ]

Reference： [1] Journal of the Chemical Society, 1947, p. 690

8
[ 856167-33-4 ]
[ 24078-12-4 ]

Reference： [1] Journal of the Chemical Society, 1947, p. 690

9
[ 591-17-3 ]
[ 100-97-0 ]
[ 824-54-4 ]
[ 24078-12-4 ]
[ 176504-70-4 ]

Reference： [1] Russian Chemical Bulletin, 1995, vol. 44, # 11, p. 2127 - 2130[2] Izvestiya Akademi Nauk, Seriya Khimicheskaya, 1995, # 11, p. 2221 - 2224

10
[ 75-17-2 ]
[ 583-75-5 ]
[ 24078-12-4 ]

Reference： [1] Monatshefte fuer Chemie, 1962, vol. 93, p. 271 - 273

11
[ 24078-12-4 ]
[ 27609-91-2 ]

Yield	Reaction Conditions	Operation in experiment
45.6%	at 180℃; for 6 h;	A mixture of compound 1 (10.0 g, 50.0 mmol), CuCN (9.0 g, 100 mmol) and NMP (60 mL) was heated at 180° C. for 6 h. The mixture was cooled to room temperature, diluted with EA, then washed with H₂O, brine, dried and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=10/1) to give the desired product (3.30 g, 22.8 mmol, 45.6percent) as a yellow solid

Reference： [1] Patent: US2016/9706, 2016, A1, . Location in patent: Paragraph 0244; 0245

[ 24078-12-4 ] Synthesis Path-Downstream 1~88

1
[ 24078-12-4 ]
[ 90914-83-3 ]

Reference： [1]Journal of the Chemical Society,1947,p. 690

2
[ 24078-12-4 ]
[ 91445-82-8 ]

Reference： [1]Journal of the Chemical Society,1947,p. 690

3
[ 17100-58-2 ]
[ 24078-12-4 ]

Yield	Reaction Conditions	Operation in experiment
78%		[00281] 28B. 4-bromo-2-methylbenzaldehyde: To a solution of oxalyl chloride (249 mL, 497 mmol) in CH2CI2 (150 mL) at -78 C under argon was added a solution of DMSO (42.4 mL, 597 mmol) in CH2C12 (75 mL) dropwise with a venting needle (Note: gas was generated, slow addition was necessary). After the addition, the venting needle was removed. The reaction mixture was stirred at -78 C under argon for 30 min. Then, a solution of 28A (20.0 g, 99.0 mmol) in CH2C12 (203 mL) was added. The resulting solution was stirred at -78 C for 30 min and then TEA (166 mL, 1190 mmol) was added dropwise. The reaction mixture was warmed to rt and stirred for 12 h. The reaction mixture was diluted with water (20 mL) and CH2C12 (30 mL). The layers were separated and the aqueous layer was extracted with CH2C12 (3 x 50 mL). The combined organic extracts were washed with water and brine, dried (MgSC^), filtered, and concentrated. The crude product was purified by flash chromatography to provide 28B (15.4 g, 78 mmol, 78 % yield) as a yellow oil. lH NMR (400 MHz, CDC13) delta 10.22 (s, 1H), 7.66 (d, J= 8.28 Hz, 1H), 7.51 (dd, J= 8.28, 1.76 Hz, 1H), 7.45 (s, 1H), 2.65 (s, 3H).
73%		To a solution of ID (9.30 g, 46.3 mmol) in CH2CI2 (200 mL) under argon was added oxalyl chloride (10.1 mL, 116 mmol) at -78 C; then DMSO (9.85 mL, 139 mmol) was added dropwise with a venting needle. After the addition was complete, the venting needle was removed and the reaction mixture was stirred at -78 C under argon for 30 min. Then, NEt3 (38.7 mL, 278 mmol) was added dropwise. After stirring at the same temperature for 3 h, the reaction mixture was diluted with water (20 mL) and CH2C12 (50 mL) and the layers were separated. The aqueous layer was further extracted with CH2CI2 (3 x 100 mL) and the combined organic extracts were washed with water and brine, dried over MgS04, filtered, and concentrated. The crude product was purified by silica chromatography to give IE (yellow oil, 6.70 g, 33.7 mmol, 73% yield). 1H NMR (400 MHz, CDC13) delta 10.22 (1 H, s), 7.66 (1 H, d, J=8.28 Hz), 7.51 (1 H, dd, J=8.28, 1.76 Hz), 7.45 (1 H, s), 2.65 (3 H, s).
	With pyridinium chlorochromate; In dichloromethane; at 20℃; for 1h;	[0453] Experimental Details: A solution of 2.4g (11.9mmol) of compound 2 in20ml of DCM was added a slurry of 5.1g(23.8mmol) of PCC in 60ml of DCM. The reaction solution was stirred for lhour at r.t. diluted with 300ml OfEt2O and filtered. The filtrate was concentrated to give compound 3.

	With pyridinium chlorochromate; In dichloromethane; at 20℃; for 1h;	Experimental Details: A solution of 2.4 g (11.9 mmol) of compound 2 in 20 ml of DCM was added a slurry of 5.1 g (23.8 mmol) of PCC in 60 ml of DCM. The reaction solution was stirred for 1 hour at r.t. diluted with 300 ml of Et2O and filtered. The filtrate was concentrated to give compound 3.
	With manganese(IV) oxide; In dichloromethane; at 20℃; for 72h;	Manganese dioxide (360 g, 4.1 mol) was added to a solution of (4-bromo-2-methylphenyl)methanol (91.5 g, 455 mmol) in dichloromethane (500 mL) and the reaction was stirred at room temperature for 72 h. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified via chromatography (5% ethyl acetate/hex), providing the product, 4-bromo-2-methylbenzaldehyde, as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 2.64 (s, 3H), 7.43 (s, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H), 10.20 (s, 1H).
	With Dess-Martin periodane; In dichloromethane; at 0 - 30℃; for 1h;	To the solution of (4-bromo-2-methylphenyl)methanol (1.8 g, 8.1 mmol) in CH2C12 (20 mL) was added Dess-Martin Periodinane (5,1 g, 12.1 mmol) at 0C. The mixture was stirred at RT for 1 h, then diluted with water, and the solid was removed by filtration. The filtrate was extracted with CH2C12. The combined organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. Purification by normal phase silica gel column provided 4-bromo-2- methylbenzaldehyde as a yellow oil.

Reference： [1]Patent: WO2014/78608,2014,A1 .Location in patent: Paragraph 00281
[2]Patent: WO2015/171757,2015,A1 .Location in patent: Page/Page column 55
[3]Journal of Medicinal Chemistry,1984,vol. 27,p. 1516 - 1531
[4]Patent: WO2008/91681,2008,A2 .Location in patent: Page/Page column 225
[5]Patent: US2010/16298,2010,A1 .Location in patent: Page/Page column 191
[6]Patent: US2010/222345,2010,A1 .Location in patent: Page/Page column 92
[7]Patent: WO2015/35113,2015,A1 .Location in patent: Page/Page column 263; 264

4
[ 24078-12-4 ]
[ 107-21-1 ]
[ 91587-27-8 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 1516 - 1531

5
[ 24078-12-4 ]
[ 107816-54-6 ]
[ 908014-90-4 ]

Reference： [1]Journal of the American Chemical Society,2006,vol. 128,p. 996 - 1001
[2]Bulletin of the Chemical Society of Japan,2006,vol. 79,p. 953 - 958

6
[ 67832-11-5 ]
[ 24078-12-4 ]

Yield	Reaction Conditions	Operation in experiment
		Description 91; 4-Bromo-2-methylbenzaldehyde (D91); To 4-bromo-2-methylbenzonitrile (2 g, 10.2 mmol) in toluene (60 mL) cooled to 5 C under argon was added Dibal-H (11.2 mL, 1M solution in toluene, 11.2 mmol) dropwise. The reaction was stirred at 50C for 30 minutes then MeOH (3 mL) and 2 M H2SO4 (10 mL) were added dropwise. The mixture was stirred for ~19h then concentrated in vacuo. The residue was re-dissolved in water/EtOAc. The organic layer was dried and concentrated to give the crude title compound as a brown oil <n="88"/>(1.81 g) which was used in the next step without further purification. 6H (CDCI3, 400MHz) 10.20 (1 H, s), 7.65 (1H, d), 7.50 (1 H1 dd), 7.43 (1 H, m), 2.64 (3H, s).
	With diisobutylaluminium hydride; In hexane; at -78 - 20℃; for 1.5h;	To a solution of 4-bromo-3-methylbenzonitrile (0.975 g; 5.00 mmol) in anhyd CH2Cl2(7.5 mL) at -40 C. was added DIBAL-H (7.5 mL of a 1M solution in hexanes; 7.5 mmol), dropwise over 5 min. The mixture was stirred 30 min at -40 C., removed from the cooling bath and stirred 1 h at rt. The mixture was cooled in an ice bath, and excess hydride was quenched by dropwise addition of MeOH. After stirring 20 min, Rochelle's salt (satd aq. solution) was added, the mixture was stirred at rt overnight, and the layers were separated. The aqueous layer was extracted with CH2Cl2(×2), combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless solid (Note 1). Note 1 The title compound was oxidized rapidly on standing in air to a mixture of benzaldehyde and benzoic acid. The title compound was prepared from 4-bromo-2-methylbenzonitrile according to the procedure described for Example I-IX-1 with exceptions as follows: the reaction temperature was -78 C. (instead of -40 C.); the reaction was quenched with MeOH at -78 C. (instead of ice bath temp), followed by addition of 6M HCl at -78 C. (instead of satd Rochelle's salt); after quenching the reaction mixture was stirred 30 min at room temperature (instead of overnight). Colorless oil;

Reference： [1]Patent: WO2008/729,2008,A1 .Location in patent: Page/Page column 86-87
[2]Patent: CN102516115,2016,B .Location in patent: Paragraph 0602-0604; 0606-0608

7
[ 24078-12-4 ]
[ 144807-49-8 ]

Yield	Reaction Conditions	Operation in experiment
		Description 93; 2-Methyl-4-(methylamino)benzaldehyde (D93); To 1 ,1-dimethylethyl (4-formyl-3-methylphenyl)methylcarbamate (D92) (0.614 g, 2.47 mmol) in DCM (60 ml_) at room temperature under argon was added TFA (15 mL) dropwise. The mixture was stirred for 0.5 h then concentrated. The residue was re- dissolved in DCM and water and the aqueous layer was basified with NaOH solution. The DCM layer was separated, dried (Na2SO4) and concentrated to give the crude title compound as a yellow oil (0.397 g) which was used in the next step without further purification. deltaH (CDCI3, 400MHz) 9.98 (1 H1 s), 7.63 (1H, d), 6.47 (1H, dd), 6.35 (1H, d), 4.35 (1 H, br.s), 2.91 (3H1 d), 2.60 (3H, s). MS (ES): MH+ 150.1.

Reference： [1]Patent: WO2008/729,2008,A1 .Location in patent: Page/Page column 87

9
[ 24078-12-4 ]
[ 876732-76-2 ]

Reference： [1]Bulletin of the Chemical Society of Japan,2006,vol. 79,p. 953 - 958
[2]Journal of the American Chemical Society,2006,vol. 128,p. 996 - 1001

10
[ 24078-12-4 ]
[ 908014-88-0 ]

Reference： [1]Bulletin of the Chemical Society of Japan,2006,vol. 79,p. 953 - 958

11
[ 24078-12-4 ]
[ 644985-26-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3983 - 3987

12
[ 24078-12-4 ]
5-(4-amino-2-methyl-phenyl)-4,4-dimethyl-2,4-dihydro-pyrazol-3-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3983 - 3987

13
[ 24078-12-4 ]
3-(4-benzyloxycarbonylamino-2-methyl-phenyl)-2,2-dimethyl-3-oxo-propionic acid methyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3983 - 3987

14
[ 24078-12-4 ]
[ 644985-31-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3983 - 3987

15
[ 24078-12-4 ]
5-[4-(2-benzyl-3-oxo-cyclohex-1-enylamino)-2-methyl-phenyl]-4,4-dimethyl-2,4-dihydro-pyrazol-3-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3983 - 3987

16
[ 24078-12-4 ]
3-{2-[4-(4,4-dimethyl-5-oxo-4,5-dihydro-1<i>H</i>-pyrazol-3-yl)-3-methyl-phenylamino]-6-oxo-cyclohex-1-enylmethyl}-benzonitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3983 - 3987

17
[ 68837-59-2 ]
[ 24078-12-4 ]

Reference： [1]ACS Catalysis,2018,vol. 8,p. 11134 - 11139
[2]Journal of Medicinal Chemistry,1984,vol. 27,p. 1516 - 1531
[3]Patent: WO2014/78608,2014,A1
[4]Patent: WO2015/35113,2015,A1
[5]Patent: WO2015/171757,2015,A1

18
[ 24078-12-4 ]
[ 91587-29-0 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 1516 - 1531
[2]Journal of Medicinal Chemistry,1984,vol. 27,p. 1516 - 1531

19
[ 24078-12-4 ]
[ 91587-35-8 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 1516 - 1531

20
[ 24078-12-4 ]
[ 91587-28-9 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 1516 - 1531
[2]Journal of Medicinal Chemistry,1984,vol. 27,p. 1516 - 1531

21
[ 24078-12-4 ]
[ 91587-08-5 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 1516 - 1531
[2]Journal of Medicinal Chemistry,1984,vol. 27,p. 1516 - 1531

22
[ 24078-12-4 ]
[ 91587-31-4 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 1516 - 1531
[2]Journal of Medicinal Chemistry,1984,vol. 27,p. 1516 - 1531

23
[ 24078-12-4 ]
[ 91587-30-3 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 1516 - 1531
[2]Journal of Medicinal Chemistry,1984,vol. 27,p. 1516 - 1531

24
[ 24078-12-4 ]
[ 879407-83-7 ]

Reference： [1]Journal of the Chemical Society,1947,p. 690

25
[ 24078-12-4 ]
[ 879407-22-4 ]

Reference： [1]Journal of the Chemical Society,1947,p. 690
[2]Journal of the Chemical Society,1947,p. 690

26
[ 99548-55-7 ]
[ 24078-12-4 ]

Reference： [1]Journal of the Chemical Society,1947,p. 690
[2]Patent: WO2015/35113,2015,A1

27
[ 856167-33-4 ]
[ 24078-12-4 ]

Reference： [1]Journal of the Chemical Society,1947,p. 690

28
[ 24078-12-4 ]
[ 476660-65-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; potassium nitrate; at 0℃;	Under ice-cooling, <strong>[24078-12-4]4-bromo-2-methylbenzaldehyde</strong> and potassium nitrate were added to concentrated sulfuric acid, and the mixture was stirred. The reaction solution was poured into ice water, and the thus formed precipitate was collected by filtration and then washed to obtain 4-bromo-2-methyl-5-nitrobenzaldehyde as a brown solid. N1: 2.74 (3 H, s), 10.24 (1 H, s).

Reference： [1]Patent: EP1396490,2004,A1 .Location in patent: Page 17

29
[ 867-13-0 ]
[ 24078-12-4 ]
ethyl (2E)-3-(4-bromo-2-methylphenyl)prop-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 3h;	To a solution of <strong>[24078-12-4]4-bromo-2-methylbenzaldehyde</strong> (1 eq) and TRIETHYLPHOSPHONOACETATE (1.1 eq) in THF (0.3M) at rt was added dropwise potassium t-butoxide (1.1 eq, 1M, THF). The mixture was stirred at rt 3h, quenched with HCl 10%, diluted with ether, washed with a NAHC03 solution, brine, dried over MGS04, filtered and concentrated. Flash chromatography (Hexane : EtOAc; 90: 10 to 70: 30) afforded the title compound.

Reference： [1]Patent: WO2004/48374,2004,A1 .Location in patent: Page 63

30
[ 24078-12-4 ]
[ 17100-58-2 ]

Yield	Reaction Conditions	Operation in experiment
95%		Example 20 5-[4-(hydroxymethyl)-3-methylphenyl]-1-methyl-1H-pyrrole-2-carbonitrile To a solution of <strong>[24078-12-4]4-bromo-2-methylbenzaldehyde</strong> (1.0 g, 4.65 mmol) in THF (25 mL) at -78 C. was added diisobutylaluminum hydride (DIBAL-1.0M in dichloromethane, 20 mL, 20 mmol) over 15 minutes in a dropwise fashion. The solution was stirred overnight at room temperature and slowly poured into a saturated ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate (3*30 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give (4-bromo-2-methylphenyl)-methanol (0.88 g, 95%). MS (ES) m/z 201.
65%	With sodium tetrahydroborate; ethanol; at 0 - 20℃; for 12.5h;	4-bromo-2-methylphenyl methanol. To a solution of <strong>[24078-12-4]4-bromo-2-methylbenzaldehyde</strong> (1.99 g, 10 mmol) in ethanol (100 mL) was added sodium borohydride (0.76 g, 20 mmol) in portions at 0C. The mixture was stirred for 30 minutes and warmed to 20C and stirred at the same temperature for 12 hours. The mixture was concentrated in vacuo to give (4-bromo-2- methylphenyl) methanol (1.3 g, 65%).
65%	With methanol; sodium tetrahydroborate; In ethanol; at 0 - 20℃; for 12.5h;	To a solution of <strong>[24078-12-4]4-bromo-2-methylbenzaldehyde</strong> (1.99 g, 10 mmol) in ethanol (100 mL) was added sodium borohydride (0.76 g, 20 mmol) in portions at 0 C. The mixture was stirred for 30 minutes and warmed to 20 C. and stirred at the same temperature for 12 hours. The mixture was concentrated in vacuo to give (4-bromo-2-methylphenyl)methanol (1.3 g, 65%).

Reference： [1]Patent: US2007/66628,2007,A1 .Location in patent: Page/Page column 17
[2]Patent: WO2013/75083,2013,A1 .Location in patent: Paragraph 00357; 00358
[3]Patent: US9206128,2015,B2 .Location in patent: Page/Page column 175; 176

31
[ 24078-12-4 ]
[ 122-51-0 ]
[ 1041712-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; for 3h;Heating / reflux;	[0455] Experimental Details: A solution of 2.1 g (14 mmol) was added into a solution of ethanol which containing 1.9 g (9.55 mmol) of compound 3. The reaction solution was heated to reflux for 3hours, and then concentrated. The solid was washed with NaHCO3 and extracted with acetic ether. The organic layer was dried to give compound 4.

Reference： [1]Patent: WO2008/91681,2008,A2 .Location in patent: Page/Page column 225-226

32
C₁₇H₂₃F₃N₄O₃ [ No CAS ]
[ 24078-12-4 ]
[ 439149-99-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5455 - 5461

33
C₁₇H₂₄F₃N₅O₃ [ No CAS ]
[ 24078-12-4 ]
[ 439149-04-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5455 - 5461

34
[ 24078-12-4 ]
[ 75-64-9 ]
[ 1189171-88-7 ]

Reference： [1]Synthetic Communications,2009,vol. 39,p. 3060 - 3068

35
[ 64-17-5 ]
[ 24078-12-4 ]
[ 122-51-0 ]
[ 1041712-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	for 3h;Reflux; Heating;	Experimental Details: A solution of 2.1 g (14 mmol) was added into a solution of ethanol which containing 1.9 g (9.55 mmol) of compound 3. The reaction solution was heated to reflux for 3 hours, and then concentrated. The solid was washed with NaHCO3 and extracted with acetic ether. The organic layer was dried to give compound 4.

Reference： [1]Patent: US2010/16298,2010,A1 .Location in patent: Page/Page column 191

36
[ 75-77-4 ]
[ 1240304-54-4 ]
[ 24078-12-4 ]
[ 32469-28-6 ]
[ 1359948-56-3 ]

Yield	Reaction Conditions	Operation in experiment
		(11) Reference Example 1-11: Intermediate (A)[0088] To a solution of compound (A9) (210 g, 0.621 mol) in THF (3.1 L), 2.76 M n- butyllithium in hexane (236 mL, 0.652 mol) was added dropwise over 20 minutes at -86C to -74C under an argon atmosphere, and stirred at the same temperature for 35 minutes. Then, a solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-l,5-lactone (305 g, 0.652 mol) in THF (890 mL) was added dropwise over 38 minutes and stirred at the same temperature for 50 minutes. Further, trimethylchlorosilane (82.8 mL, 0.652 mmol) was added dropwise over 4 minutes and stirred at the same temperature for 3 hours. Then, 2.76 M n-butyllithium in hexane (326 mL, 0.901 mol) was added dropwise over 23 minutes and stirred at the same temperature for 40 minutes. Finally, a solution of 4-bromo-2- methylbenzaldehyde (136 g, 0.683 mmol) in THF (890 mL) was added dropwise over 43 minutes and stirred at the same temperature for 35 minutes. The reaction mixture was diluted with water (3.1 L) and warmed to room temperature. After addition of toluene (3.1 L), the organic layer was separated and the solvent was distilled off under reduced pressure.[0089] The resulting residue (633 g) was dissolved in methanol (3.1 L), and methanesulfonic acid (4.03 mL, 0.0621 mol) was added thereto, followed by heating under reflux for 1 hour. The reaction mixture was cooled to room temperature, neutralized with triethylamine (17.3 mL, 0.124 mol) and then concentrated. The concentrated product (413 g) was dissolved in toluene (1.1 L) and washed three times with water (1.65 L). The organic layer was diluted with toluene (0.55 L) and extracted with 1 M aqueous sodium hydroxide (0.55 L). The aqueous layer was washed with toluene (1.65 L) and acidified by addition of 2 M aqueous hydrochloric acid (0.43 L). The resulting aqueous layer was extracted with toluene (1.1 L). The organic layer was washed with 10% aqueous sodium chloride (1.1 L), followed by distilling off the solvent under reduced pressure. [0090] The resulting residue (273 g) was dissolved in THF (1.01 L). To this solution, diisopropylethylamine (776 mL, 4.53 mol), acetic anhydride (381 mL, 4.03 mol) and 4-dimethylaminopyridine (615 mg, 5.04 mmol) were added and stirred at room temperature for 21 hours. The reaction mixture was cooled on ice, and water (1.0 L) and toluene (1.0 L) were added thereto. The organic layer was separated and washed with saturated aqueous sodium bicarbonate (1.0 L), followed by distilling off the solvent under reduced pressure. [0091] The resulting residue (390 g) was dissolved in acetonitrile (3.85 L). To this solution, water (9.07 mL, 0.504 mol) and t-BuMe2SiH (334 mL, 2.02 mol) were added and cooled on ice, followed by dropwise addition of TMSOTf (392 mL, 2.17 mol) over 30 minutes. After stirring at the same temperature for 1 hour, acetic anhydride (95.2 mL, 1.01 mol) was added dropwise over 10 minutes and stirred at the same temperature for an additional 15 minutes. To the reaction mixture, toluene (3.85 mL) and 3% aqueous sodium bicarbonate (1.92 L) were added. The organic layer was separated and washed with 3% aqueous sodium bicarbonate (1.92 L) and 10% aqueous sodium chloride (1.92 L), and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure and the resulting residue was crystallized from 2-propanol (1.42 L). The resulting precipitate was filtered to give intermediate (A) (201 g, 47%; 4 steps) as a colorless powder.

Reference： [1]Patent: WO2010/95768,2010,A1 .Location in patent: Page/Page column 28-29

37
[ 1240304-46-4 ]
[ 24078-12-4 ]
C₃₈H₆₉BrO₇Si₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(7) Reference Example 1-7: Compound (A7) [Chem. 16][0077] To a solution of compound (A6) (13.4 g, 15.9 mmol) in THF (140 mL), 2.6 M n-butyllithium in hexane (7.7 mL, 20.0 mmol) was added dropwise over 10 minutes at -78C under a nitrogen atmosphere and stirred at the same temperature for 5 minutes. Then, a solution of <strong>[24078-12-4]4-bromo-2-methylbenzaldehyde</strong> (3.2 g, 15.9 mmol) in THF (24 mL) was added dropwise over 15 minutes and stirred at the same temperature for 45 minutes. To the reaction mixture, saturated aqueous ammonium chloride (100 mL) and water (100 mL) were added. This mixture was warmed to room temperature and then extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure.[0078] The resulting residue was dissolved in a solution containing methanesulfonic acid (0.9 g) in methanol (200 mL), and stirred at room temperature for 0.5 hours. After neutralization with triethylamine, the reaction mixture was concentrated. The resulting residue was purified by silica gel column chromatography (chloroformrmethanol = 10:1 -» 8:1) to give compound (A7) (5.75 g, 73%) as a colorless amorphous substance. [0079] 1H NMR (600 MHz, METHANOL-d4) delta ppm 1.01 and 1.04 (each d, J=6.88 Hz, 3 H) 1.18 and 1.19 (each d, J=6.88 Hz, 3 H) 2.24 and 2.26 (each s, 3 H) 2.95-3.07 (m, 1 H) 3.35-3.69 (m, 5 H) 3.78-3.87 (m, 1 H) 4.37-4.50 (m, 1 H) 5.59 (s, 1 H) 6.80 (s, 1 H) 6.98- 7.10 (m, 2 H) 7.24-7.30 (m, 1 H) 7.33 (s, 1 H).MS ESI/APCI Dual posi: 479[M-OH]+, 481[M+2-OH]+.
		General procedure: A 2.7-M n-butyllithium hexane solution (4.7mL, 12.9mmol) was added dropwise to a THF (40mL) solution of compound 25b (8.7g, 12.9mmol) at -78C in an argon atmosphere, and the mixture was stirred for 10min at the same temperature. Then, a THF (25mL) solution of 4-bromobenzaldehyde (8a) (2.6g, 14.2mmol) was added dropwise over 15min, and the mixture was stirred for 30min at the same temperature. A saturated aqueous solution of ammonium chloride was added to the reaction liquid; after the mixture was warmed to room temperature, the warmed mixture was extracted twice with ethyl acetate. The combined organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in a methanol (65mL) solution containing methanesulfonic acid (0.2g), and the solution was stirred for 14h at room temperature. The reaction liquid was neutralized with triethylamine (1.8mL), and the reaction mixture was concentrated. The resulting residue was purified using acidic silica gel column chromatography (chloroform?chloroform:methanol ratio=9:1) to obtain an intermediate compound (26f) as a colorless amorphous substance (2.9g). Compound 26f (2.9g, 5.8mmol) was dissolved in pyridine (18mL). Acetic anhydride (9mL) was added to the resulting solution, and the mixture was stirred for 5h at room temperature. Ice water was added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with 3-N hydrochloric acid and a saturated saline solution and then dried over anhydrous magnesium sulfate. The desiccant was filtered out, and the solvent was distilled off under reduced pressure to obtain a crude product (3.3g). Et3SiH (1.1mL, 7.1mmol) was added to a solution of the crude product (3.3g) in chloroform (25mL) and acetonitrile (25mL), and the mixture was cooled with ice in a nitrogen atmosphere. Under ice cooling, BF3·OEt2 (0.9mL, 7.1mmol) was added dropwise over 10min, and the mixture was stirred for 30min at the same temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction liquid, and the mixture was extracted with chloroform. Then, the organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified using acidic silica gel column chromatography (hexane:ethyl acetate ratio=9:1?6:4) to obtain the title compound as a colorless oil (2.9g, 34% in 4 steps).

Reference： [1]Patent: WO2010/95768,2010,A1 .Location in patent: Page/Page column 25
[2]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 394 - 409

38
[ 24078-12-4 ]
[ 1119-51-3 ]
[ 1253045-33-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5548 - 5551

39
[ 24078-12-4 ]
C₂₈H₄₀N₂O₂SSi [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3083 - 3088

40
[ 24078-12-4 ]
C₂₂H₂₈N₂O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3083 - 3088

41
[ 24078-12-4 ]
C₂₈H₄₂N₂O₄Si [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3083 - 3088

42
[ 24078-12-4 ]
C₂₆H₃₁N₃O₃S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3083 - 3088

43
[ 24078-12-4 ]
C₂₂H₂₆N₂O₂S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3083 - 3088

44
[ 24078-12-4 ]
C₂₂H₂₅ClN₂OS [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3083 - 3088

45
[ 24078-12-4 ]
C₂₇H₃₃N₃O₃S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3083 - 3088

46
[ 24078-12-4 ]
C₁₂H₁₄O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3083 - 3088

47
[ 24078-12-4 ]
[ 1374355-18-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3083 - 3088

48
[ 24078-12-4 ]
[ 913829-39-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3083 - 3088

49
[ 24078-12-4 ]
isopropyltriphenylphosphonium iodide [ No CAS ]
[ 913829-38-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3083 - 3088

50
[ 24078-12-4 ]
[ 151073-69-7 ]
[ 1422008-73-8 ]

Yield	Reaction Conditions	Operation in experiment
82%	With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride; In tetrahydrofuran; at 20℃;Inert atmosphere;	General procedure: To a solution of 15a (4.43 g, 23.9 mmol) in THF (100 mL) were added 4-ethoxy-4-oxobutylzinc bromide (0.5 M THF solution, 48 mL, 24 mmol) and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride ( PEPPSI-IPr catalyst) (163 mg, 0.239 mmol) under an argon atmosphere, and the mixture was stirred at room temperature overnight. After dilution with EtOAc, the resulting mixture was washed with 1 N HCl and water and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc = 97:3-9:1-4:1) to give 16a (4.60 g, 87%) as an oil with a slight yellow color.