[ CAS No. 101093-56-5 ] {[proInfo.proName]}

Name: 101093-56-5|4-(Benzyloxy)-2-methylbenzaldehyde|95%
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Quality Control of [ 101093-56-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 101093-56-5 ]

Product Details of [ 101093-56-5 ]

CAS No. :	101093-56-5	MDL No. :	MFCD01317809
Formula :	C₁₅H₁₄O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	OGVPJBJWJCZBTH-UHFFFAOYSA-N
M.W :	226.27	Pubchem ID :	2759806
Synonyms :

Calculated chemistry of [ 101093-56-5 ]

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.13
Num. rotatable bonds :	4
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	67.77
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.4 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.6
Log Po/w (XLOGP3) :	3.21
Log Po/w (WLOGP) :	3.23
Log Po/w (MLOGP) :	2.86
Log Po/w (SILICOS-IT) :	4.07
Consensus Log Po/w :	3.19

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.52
Solubility :	0.0678 mg/ml ; 0.0003 mol/l
Class :	Soluble
Log S (Ali) :	-3.43
Solubility :	0.0832 mg/ml ; 0.000368 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-5.4
Solubility :	0.000895 mg/ml ; 0.00000395 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.73

Safety of [ 101093-56-5 ]

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 [ 101093-56-5 ]

* 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 [ 101093-56-5 ]
Downstream synthetic route of [ 101093-56-5 ]

[ 101093-56-5 ] Synthesis Path-Upstream 1~9

1
[ 41438-18-0 ]
[ 100-39-0 ]
[ 101093-56-5 ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate In acetonitrile at 20℃; for 3 h;	To a mixture of A-1 (2.72 g, 19.98 mmol, 1.00 equiv) in CH3CN (30 mL) with K₂CO₃(4.14 g, 29.95 mmol, 1.50 equiv) was added BnBr (3.8 g, 22.22 mmol, 1.11 equiv). The reaction was stirred for 3 h at room temperature. Water was added and the mixture was extracted with EtOAc thrice. Concentration and chromatograph on silica gel (10:1 PE/EA) gave 3.4 g (75percent) of B-1 as white solid.

Reference： [1] Patent: US2014/256657, 2014, A1, . Location in patent: Paragraph 0297

2
[ 17671-75-9 ]
[ 68-12-2 ]
[ 101093-56-5 ]

Reference： [1] Patent: EP1544208, 2005, A1, . Location in patent: Page/Page column 22

3
[ 834-17-3 ]
[ 101093-56-5 ]

Yield	Reaction Conditions	Operation in experiment
19 mmol, 17%	With trichlorophosphate In N,N-dimethyl-formamide	a] 4-Benzyloxy-2-methyl-benzaldehyde Dry N,N-dimethylformamide (34.2 ml, 444 mmol) was added dropwise with stirring and cooling under an argon atmosphere to phosphorous oxychloride (18.3 ml, 200 mmol) at such a rate that the temperature did not exceed 10° C. After 30 min stirring at 0° C., a solution of 1-benzyloxy-3-methyl-benzene (22 g, 111 mmol) in N,N-dimethylformamide (22 ml) was added dropwise within 30 min (for the preparation of 1-benzyloxy-3-methyl-benzene see: D. Bogdal, J. Pielichowski, A. Boron, Syn. Commun. 1998, 28, 3029-3039). The reaction mixture was stirred 30 min at ambient temperature and then continuously heated to 110° C. After 10 min at 110° C., the mixture was kept at 90° C. for 3.5 h, cooled to 10° C., neutralized with 25percent aqueous sodium acetate, with cooling, and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a brown oil which was purified by column chromatography (silica gel, hexane/AcOEt=19/1) to give 4.3 g (19 mmol, 17percent) of the title compound as yellow solid. MS: 226.1 (M)⁺, 91.2. NMR: (CDCl₃, 1H, 400 MHz, δ, TMS) 2.65 (s, 3H), 5.13 (s, 2H), 6.83 (d, J=1.6, 1H), 6.91 (dxd, J=8.8, J=1.6, 1H), 7.32-7.44 (m, 5H), 7.75 (d, J=8.8, 1H), 10.12 (s, 1H).

Reference： [1] Patent: US2003/55265, 2003, A1,

4
[ 167479-46-1 ]
[ 101093-56-5 ]

Reference： [1] Patent: US6169107, 2001, A,

5
[ 17671-75-9 ]
[ 101093-56-5 ]

Reference： [1] Patent: US6169107, 2001, A,

6
[ 175153-40-9 ]
[ 101093-56-5 ]

Reference： [1] Patent: US6169107, 2001, A,

7
[ 17819-91-9 ]
[ 101093-56-5 ]

Reference： [1] Patent: US6169107, 2001, A,

8
[ 52289-54-0 ]
[ 101093-56-5 ]

Reference： [1] Journal of Organic Chemistry, 1956, vol. 21, p. 415,417, 418

9
[ 41438-18-0 ]
[ 100-44-7 ]
[ 101093-56-5 ]

Reference： [1] Journal of Organic Chemistry, 1956, vol. 21, p. 415,417, 418

[ 101093-56-5 ] Synthesis Path-Downstream 1~88

1
[ 553-53-7 ]
[ 101093-56-5 ]
[ 102479-64-1 ]

Reference： [1]Journal of Organic Chemistry,1956,vol. 21,p. 415,417, 418

2
[ 54-85-3 ]
[ 101093-56-5 ]
[ 102479-63-0 ]

Reference： [1]Journal of Organic Chemistry,1956,vol. 21,p. 415,417, 418

3
[ 41438-18-0 ]
[ 100-44-7 ]
[ 101093-56-5 ]

Reference： [1]Journal of Organic Chemistry,1956,vol. 21,p. 415,417, 418

4
[ 101093-56-5 ]
[ 898538-71-1 ]

Yield	Reaction Conditions	Operation in experiment
82%	With pyridinium hydrobromide perbromide; In methanol; at 0 - 20℃; for 12h;	To a mixture of B-1 (2.26 g, 9.99 mmol, 1.00 equiv) in methanol (50 mL) was added pyridinium hydrobromide perbromide (90% purity, 3.52 g, 10 mmol, 1.00 equiv) at 0 C. The reaction was stirred for 12 h at room temperature. Concentration and chromatograph on silica gel (10:1 PE/EA) gave 2.5 g (82%) of C-1 as white solid.
	With pyridinium tribromide; In methanol; at 0 - 20℃; for 3h;	To a methanol suspension (3.75 mL) of 4- (benzyloxy) -2- methylbenzaldehyde (0.50 g, 2.21 mmol) cooled in ice was added pyridinium hydrobromide perbromide (1.06 g, 3.32 mmol), and the mixture was stirred for 30 minutes. The reaction mixture was stirred for 2.5 hours at room temperature. To the reaction solution were added 20% solution of Na2SO3 , water and ethyl acetate . An organic layer was extracted with ethyl acetate. To the organic layer was added 1 M hydrochloric acid (20 mL), and the mixture was stirred for 5 minutes. The organic layer was separated, washed with a saturated sodium bicarbonate <n="63"/>aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain 1.03 g of a residue. To a toluene solution (7.0 mL) of the residue were added ethylene glycol (1.89 mL, 33.9 mmol) and pyridinium p-toluenesulfonate (43 mg, 0.170 mmol), and heated to reflux for 14 hours with a Dean-Stark apparatus. After the reaction solution was cooled, its organic layer was washed with a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was recrystallized from hexane/ethyl acetate (10:1) to obtain the title compound (748 mg, 63%).
	With pyridinium hydrobromide perbromide; In methanol; at 0 - 20℃; for 12h;	To a mixture of <strong>[101093-56-5]4-(benzyloxy)-2-methylbenzaldehyde</strong> (2.26 g, 9.99 mmol, 1.00 equiv) in methanol (50 ml_) was added pyridinium hydrobromide perbromide (90% purity, 3.52g, 10mmol, I.OOequiv) at 0C. The reaction mixture was stirred for 12 h at room temperature. The mixture was concentrated and the resuldint residue purified by on silica gel (10: 1 PE/EA) to yield 4-(benzyloxy)-5-bromo-2-methylbenzaldehyde as a white solid.

Reference： [1]Patent: US2014/256657,2014,A1 .Location in patent: Paragraph 0298
[2]Patent: WO2007/136116,2007,A2 .Location in patent: Page/Page column 60-61
[3]Patent: WO2019/215633,2019,A1 .Location in patent: Page/Page column 83-84

5
[ 582-33-2 ]
[ 101093-56-5 ]
[ 959632-12-3 ]

Yield	Reaction Conditions	Operation in experiment
80%		Step A; A mixture of 2-methyl-4-benzyloxy benzaldehyde (1.22 g, 5.39 mmol) and ethyl- 3-amino benzoate (912 mg, 5.52 mmol) in glacial acetic acid (40 mL) is stirred for 30 minutes. To the mixture, sodium triacetoxy borohydride (1.25 g, 5.90 mmol) is added. After 20 hours, the mixture is concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate. The layers are separated and the aqueous layer is extracted with ethyl acetate (2x). The combined ethyl acetate layers are dried (MgSO4) and concentrated. The residue is purified by flash chromatography on 120 g silica with ethyl acetate in heptane gradient to provide benzyl intermediate (1.6 g, 80%).

Reference： [1]Patent: WO2007/140174,2007,A2 .Location in patent: Page/Page column 33

6
[ 52289-54-0 ]
[ 101093-56-5 ]

Reference： [1]Journal of Organic Chemistry,1956,vol. 21,p. 415,417, 418

7
[ 817-95-8 ]
[ 101093-56-5 ]
3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-3-hydroxy-propionic acid ethyl ester [ No CAS ]
C₂₁H₂₆O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With lithium diisopropyl amide; In tetrahydrofuran; n-heptane; at -78℃; for 4.83h;	To a-78 C cold 2 M solution of lithium diisopropylamide (305 mmol) in THF/n-heptane (152.4 ml) was added a solution of ethoxy-acetic acid ethyl ester (45.2 ml, 331 mmol) in tetrahydrofuran (240 ml) within 1.5 h under an argon atmosphere. The mixture was stirred for 30 min. A solution of <strong>[101093-56-5]4-benzyloxy-2-methyl-benzaldehyde</strong> (30 g, 132.6 mmol) in tetrahydrofuran (420 ml) was added dropwise over a period of 50 min. The reaction mixture was stirred 2 h [AT-78 C,] poured onto ice water/aqueous ammonium chloride solution 1/1 and extracted two times with ethyl acetate. The combined extracts were washed three times with ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, n-heptane/AcOEt) to give 48.8 g (136.2 mmol) of the title compound as a mixture of stereoisomers as yellow oil. MS: 376.4 [(M+NH4) +,] 341.4, 186.5.

Reference： [1]Patent: WO2004/31162,2004,A1 .Location in patent: Page 40-41

8
[ 867-13-0 ]
[ 101093-56-5 ]
[ 638214-79-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium ethanolate; In ethanol; at 0 - 20℃; for 2h;	A] (E)-3-(4-Benzyloxy-2-methyl-phenyl)-acrylic acid ethyl ester A mixture of 11.2 g (50 mmol) of <strong>[101093-56-5]4-benzyloxy-2-methyl-benzaldehyde</strong> [PCT Int. Appl. (2002), WO 2002/092084/A1] and of 12.33 g (55 mmol) of triethyl phosphonoacetate in 25 ml of absolute ethanol was added to a cooled solution (0 C.) of sodium ethylate (freshly prepared from 1.38 g (60 mmol) of sodium and 25 ml of absolute ethanol). Subsequently, the mixture was stirred at ambient temperature for 2 hours. Then, the solvent was evaporated and the residue was partioned between tert.-butyl methyl ether and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and finally evaporated. After crystallization from a mixture of dichloromethane and n-heptane, 12.9 g of (E)-3-(4-benzyloxy-2-methyl-phenyl)-acrylic acid ethyl ester was obtained as beige crystals (87% of theory). MS: 296.1 (M)+.
		Intermediate 72 Ethyl (2E)-3-{2-methyl-4-[(phenylmethyl)oxy]phenyl}-2-propenoate. To a stirred solution of triethyl phosphonoacetate (1.40 mL, 7.06 mmol) in THF (40 mL) was added portion-wise NaH (60% dispersion in mineral oil, 399 mg, 9.98 mmol) over 2-3 mins. After effervescence had ceased, <strong>[101093-56-5]2-methyl-4-benzyloxybenzaldehyde</strong> (1.50 g, 6.62 mmol) was added, washing in with THF (4 mL), and the resulting mixture heated to reflux. After 4 h at this temperature, the mixture was allowed to cool slowly to ambient temperature over night. Saturated aqueous NH4CI (45 mL) was then added carefully and the organic solvent removed under vacuum. The resulting aqueous mixture was then extracted with DCM (2 x 40 mL) and the combined organic layer washed with brine (60 mL) and then concentrated under vacuum to give a cream coloured solid. Purification by SPE (silica, 50 g cartridge) eluting with cyclohexane : EtOAc (gradient 20: 1 to 0: 1) then EtOAc: MeOH (gradient 95: 5 to 90: 10) afforded the title compound as an oil (1.22 g). LC/MS: m/z 297.2 [[M+H] +, RT] 3.80 min.

Reference： [1]Patent: US2005/96337,2005,A1 .Location in patent: Page/Page column 53
[2]Patent: WO2004/315,2003,A1 .Location in patent: Page 54-55

9
[ 17671-75-9 ]
[ 68-12-2 ]
[ 101093-56-5 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; In tetrahydrofuran; hexane; at -78 - 0℃; for 0.666667h;	To a solution of 4-bromo-3-methylphenol (10 g) inN,N-dimethylformamide (50 mL) were added potassium carbonate (8.87 g) and benzyl bromide (6.36mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-benzyloxy-1-bromo-2-methylbenzene (14.6 g). This material was dissolved in tetrahydrofuran (200 mL). To the solution was added n-butyl lithium (2.66 mol/Ln-hexane solution, 21.7 mL) at -78C under an argon atmosphere, and the mixture was stirred for 10 minutes. To the reaction mixture was added N,N-dimethylformamide (10.1 mL), and the mixture was allowed to warm to 0C and stirred for 30 minutes. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-benzyloxy-2-methylbenzaldehyde. This material was dissolved in ethanol (100 mL). To the solution was added sodium borohydride (1.99 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added methanol, and the resulting mixture was concentrated under reduced pressure. To the residue was added a saturated aqueous sodiumhydrogen carbonate solution, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent:n-hexane/ethylacetate=6/1-3/1-1/1) to give the title compound (10.5 g).1H-NMR (CDCl3) delta ppm: 1.37 (1H, t, J=5.8Hz), 2.36 (3H, s), 4.64 (2H, d, J=5.8Hz), 5.06 (2H, s), 6.79 (1H, dd, J=8.4Hz, 2.4Hz), 6.84 (1H, d, J=2.4Hz), 7.23 (1H, d, J=8.4Hz), 7.25-7.45 (5H, m)

Reference： [1]Patent: EP1544208,2005,A1 .Location in patent: Page/Page column 22

10
[ 101093-56-5 ]
[ 167479-46-1 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 4-bromo-3-methylphenol (10 g) inN,N-dimethylformamide (50 mL) were added potassium carbonate (8.87 g) and benzyl bromide (6.36mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-benzyloxy-1-bromo-2-methylbenzene (14.6 g). This material was dissolved in tetrahydrofuran (200 mL). To the solution was added n-butyl lithium (2.66 mol/Ln-hexane solution, 21.7 mL) at -78C under an argon atmosphere, and the mixture was stirred for 10 minutes. To the reaction mixture was added N,N-dimethylformamide (10.1 mL), and the mixture was allowed to warm to 0C and stirred for 30 minutes. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give <strong>[101093-56-5]4-benzyloxy-2-methylbenzaldehyde</strong>. This material was dissolved in ethanol (100 mL). To the solution was added sodium borohydride (1.99 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added methanol, and the resulting mixture was concentrated under reduced pressure. To the residue was added a saturated aqueous sodiumhydrogen carbonate solution, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent:n-hexane/ethylacetate=6/1-3/1-1/1) to give the title compound (10.5 g).1H-NMR (CDCl3) delta ppm: 1.37 (1H, t, J=5.8Hz), 2.36 (3H, s), 4.64 (2H, d, J=5.8Hz), 5.06 (2H, s), 6.79 (1H, dd, J=8.4Hz, 2.4Hz), 6.84 (1H, d, J=2.4Hz), 7.23 (1H, d, J=8.4Hz), 7.25-7.45 (5H, m)

Reference： [1]Patent: EP1544208,2005,A1 .Location in patent: Page/Page column 57

11
[ 101093-56-5 ]
[ 672931-13-4 ]

Yield	Reaction Conditions	Operation in experiment
		Reference Example 37; [4-(Benzyloxy)-2-methylphenyl]acetonitrile [] A suspension of potassium tert-butoxide (4.94 g) in dimethoxyethane (100 ml) was cooled to -78C, toluenesulfonylmethyl isocyanide (4.73 g) was added thereto, and then the mixture was stirred for 5 minutes. Then, a solution of 2-methyl 4-benzyloxybenzaldehyde (4.99 g) in dimethoxyethane (50 ml) was added thereto and the mixture was stirred at -78C for 1 hour and at room temperature for 1 hour. Methanol was added thereto and the mixture was heated under reflux for 1 hour. After standing to cool, the reaction solution was poured into a saturated aqueous ammonium chloride solution and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 10 : 1 to 3 : 1) to obtain an objective product (3.04 g) as crystals. Melting point 51 - 52C; 1H-NMR (CDCl3) delta 2.30 (3H, s), 3.58 (2H, s), 5.04 (2H, s), 6.77-6.79 (1H, m), 6.83 (1H, s), 7.22 (1H, d), 7.31-7.43 (5H, m).

Reference： [1]Patent: EP1535915,2005,A1 .Location in patent: Page/Page column 85

12
[ 101093-56-5 ]
C₁₂H₁₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Reference Example 36; Ethyl 3-(4-hydroxy-2-methylphenyl)propionate [] To a suspension of sodium hydride (1.33 g) in tetrahydrofuran (100 ml) was added dropwise ethyl diethylphosphonoacetate (4.16 ml) with ice-cooling and the mixture was stirred for 30 minutes. To the reaction solution was added dropwise a solution of <strong>[101093-56-5]2-methyl 4-benzyloxy benzaldehyde</strong> (5.0 g) in tetrahydrofuran (25 ml) and the mixture was stirred at 0C for 2 hours and at room temperature for 1 hour. 1 N hydrochloric acid was added thereto and the mixture was diluted with ethyl acetate. Then, the organic layer was separated and then washed with a saturated sodium bicarbonate solution, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The obtained residue was subject to silica gel column chromatography (hexane : ethyl acetate = 3 : 1) and the obtained compound was dissolved in ethanol (60 ml). After 10% palladium - carbon (2 g) was added under nitrogen gas stream, the atmosphere was substituted with a hydrogen atmosphere and the mixture was stirred at room temperature for 5 hours. Insolubles were filtered and the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 1 : 1) to obtain an objective product (4.43 g) as an oily matter.1H-NMR (CDCl3) delta 1.24 (3H, t), 2.25 (3H, s), 2.50-2.56 (2H, m), 2.85 (2H, dd), 4.13 (2H, q), 5.21 (1H, d), 6.57 (1H, dd), 6.62 (1H, d), 6.97 (1H, d).

Reference： [1]Patent: EP1535915,2005,A1 .Location in patent: Page/Page column 84-85

13
[ 834-17-3 ]
[ 101093-56-5 ]

Yield	Reaction Conditions	Operation in experiment
4.3 g (19 mmol, 17%)	With trichlorophosphate; In N,N-dimethyl-formamide;	a] 4-Benzyloxy-2-methyl-benzaldehyde Dry N,N-dimethylformamide (34.2 ml, 444 mmol) was added dropwise with stirring and cooling under an argon atmosphere to phosphorous oxychloride (18.3 ml, 200 mmol) at such a rate that the temperature did not exceed 10 C. After 30 min stirring at 0 C., a solution of 1-benzyloxy-3-methyl-benzene (22 g, 111 mmol) in N,N-dimethylformamide (22 ml) was added dropwise within 30 min (for the preparation of 1-benzyloxy-3-methyl-benzene see: D. Bogdal, J. Pielichowski, A. Boron, Syn. Commun. 1998, 28, 3029-3039). The reaction mixture was stirred 30 min at ambient temperature and then continuously heated to 110 C. After 10 min at 110 C., the mixture was kept at 90 C. for 3.5 h, cooled to 10 C., neutralized with 25% aqueous sodium acetate, with cooling, and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a brown oil which was purified by column chromatography (silica gel, hexane/AcOEt=19/1) to give 4.3 g (19 mmol, 17%) of the title compound as yellow solid. MS: 226.1 (M)+, 91.2. NMR: (CDCl3, 1H, 400 MHz, delta, TMS) 2.65 (s, 3H), 5.13 (s, 2H), 6.83 (d, J=1.6, 1H), 6.91 (dxd, J=8.8, J=1.6, 1H), 7.32-7.44 (m, 5H), 7.75 (d, J=8.8, 1H), 10.12 (s, 1H).

Reference： [1]Patent: US2003/55265,2003,A1

14
[ 167479-46-1 ]
[ 101093-56-5 ]

Yield	Reaction Conditions	Operation in experiment
	With manganese dioxide; In methanol; chloroform;	d) Preparation of 4-benzyloxy-2-methylbenzaldehyde A mixture of 0.70 g (3.07 mmol) of 4-benzyloxy-2-methylbenzyl alcohol, 2.67 g (30.7 mmol) of manganese dioxide, 0.5 ml of methanol and 20 ml of chloroform was stirred at room temperature for 11 hours. Then insoluble matters were filtered off and the filter-rate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 0.60 g of 4-benzyloxy-2-methylbenzaldehyde.

Reference： [1]Patent: US6169107,2001,A

15
ethyl azide acetate [ No CAS ]
[ 101093-56-5 ]
ethyl 3-(4-benzyloxy-2-methylphenyl)-2-azidopropenoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium ethanolate; In ethanol;	e) Preparation of ethyl 3-(4-benzyloxy-2-methylphenyl)-2-azidopropenoate The reaction was carried out in a manner similar to Reference Example 13 a) except for using 2.80 g (12.4 mmol) of <strong>[101093-56-5]4-benzyloxy-2-methylbenzaldehyde</strong>, 6.39 g (49.5 mmol) of ethyl azide acetate, 3.37 g (49.5 mmol) of sodium ethoxide and 50 ml of ethanol. Ethyl 3-(4-benzyloxy-2-methylphenyl)-2-azidopropenoate was thus obtained in the yield of 3.24 g.

Reference： [1]Patent: US6169107,2001,A

16
[ 101093-56-5 ]
[ 17819-91-9 ]

Yield	Reaction Conditions	Operation in experiment
		4-Benzyloxy-2-methylbenzoic acid; A solution of <strong>[101093-56-5]4-benzyloxy-2-methylbenzaldehyde</strong> (20 g) in 1 ,4-dioxane (300 mL) was mixed with sodium dihydrogen phosphate (42.4 g) and sulfamic acid (13.7 g) and, while cooling, a <n="92"/>solution of sodium chlorite (1 1.2 g) in water (200 mL) was added in such a way that the temperature did not rise above 10C. After 20 minutes, sodium sulfite (14.5 g) was added, and the mixture was stirred at 10C for a further 15 minutes. The reaction mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated.The product with the molecular weight of 242.28 (C15H14O3) was obtained in this way; MS (ESI): 243 (M+H+).

Reference： [1]Patent: WO2007/93366,2007,A1 .Location in patent: Page/Page column 90-91

17
[ 101093-56-5 ]
[ 105-54-4 ]
[ 668480-56-6 ]

Yield	Reaction Conditions	Operation in experiment
45%		To a solution of butyric acid ethyl ester (2.9 ml, 22.1 mmol) in tetrahydrofuran (125 ml) was added a 2 M solution of lithium diisopropylamide in tetrahydrofuran (11.6 ML, 23.2 mmol) dropwise over 15 minutes at-78 C under an argon atmosphere. After stirring for 10 minutes a solution of <strong>[101093-56-5]4-benzyloxy-2-methyl-benzaldehyde</strong> (5 g, 22.1 mmol) in tetrahydrofuran (125 ML) was added dropwise over 30 minutes and stirring was continued for 20 h AT-78 C. Saturated aqueous ammonium chloride (60 ML) was added dropwise and the mixture was warmed to ambient temperature. Ice water/brine 1/1 was added and the mixture was extracted two times with ethyl acetate. The combined organic layers were washed with ice water/brine 1/1 and dried over sodium sulfate. The filtrate was concentrated to dryness and the residue purified by column chromatography (silica gel, heptane/AcOEt) to give 3.4 g (9.9 mmol, 45 %) of the title compound as a mixture of two diastereomeric racemates as light yellow oil. MS: 365.3 (M+Na) +, 360.3 (M+NH4) +, 325.4.

Reference： [1]Patent: WO2004/20420,2004,A1 .Location in patent: Page 147

18
[ 101093-56-5 ]
[ 140130-20-7 ]
[ 668477-24-5 ]

Yield	Reaction Conditions	Operation in experiment
96%		[(S)-4-BENZYL-3-ETHOXYACETYL-OXAZOLIDIN-2-ONE] (12.45 [G,] 47 mmol) (for the preparation of (S) -4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D. Haigh, H. C. Birrell, B. C. C. Cantello, D. S. Eggleston, R. C. Haltiwanger, R. M. Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron : Asymmetry 1999, [10,] 1353-1367) was dissolved in dry dichloromethane (270 ml) under an argon atmosphere and the solution was cooled [TO-78 C.] Triethylamine (7.98 ml, 57 mmol) was added, followed by the slow addition, over approximately 20 min, of di-n-butylboron triflate (1 M solution in dichloromethane, 50 ml, 50 mmol) such that the reaction temperature was kept [BELOW-70 C.] The mixture was stirred at-78 [C] for 50 min, the cooling bath was replaced with an ice bath and the mixture stirred at [0 C] for additional 50 min before being recooled [TO-78 C.] A solution of 4-benzyloxy-2-methyl- benzaldehyde (10.7 g, 47 mmol) in dry dichloromethane (130 ml) was added over ca. 45 min, such that the reaction temperature was maintained below-70 C. The resulting mixture was stirred at-78 C for 45 min, warmed [FROM-78 C] to [0 C] and stirred at 0 [C] for a further 1.5 h. The reaction mixture was poured onto ice water/brine and extracted two times with dichloromethane. The combined extracts were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 22.3 g (45.6 mmol, 96 %) of the title compound as colorless oil. According [TO'H-NMR] spectroscopy, one of the four isomers is strongly predominating. The configuration was tentatively assigned as 2S, 3R according to D. Haigh et [AL.,] Tetrahedron : Asymmetry 1999, [10,] 1353-1367. MS: 512.3 [(M+NA)] [+,] 472.3, 447.2, 387.2, 327.2, 295.3, 267.3, 232.1, 175.1.
96%		(S) -4-Benzyl-3-ethoxyacetyl-oxazolidin-2-one (12.45 g, 47 mmol) (for the preparation of (S) -4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D. Haigh, H. C. Birrell, B. C. C. Cantello, D. S. Eggleston, R. C. Haltiwanger, R. M. Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron : Asymmetry 1999, 10, 1353-1367) was dissolved in dry dichloromethane (270 ml) under an argon atmosphere and the solution was cooled TO-78 C. Triethylamine (7.98 ml, 57 mmol) was added, followed by the slow addition, over approximately 20 min, of di-n-butylboron triflate (1 M solution in dichloromethane, 25 ml, 50 mmol) such that the reaction temperature was kept BELOW-70 C. The mixture was stirred at-78 C for 50 min, the cooling bath was replaced with an ice bath and the mixture stirred at 0 C for additional 50 min before being recooled TO-78 C. A solution of 4-benzyloxy-2-methyl- benzaldehyde (10.7 g, 47 mmol) in dry dichloromethane (130 ml) was added over ca. 45 min, such that the reaction temperature was maintained BELOW-70 C. The resulting mixture was stirred at-78 C for 45 min, warmed FROM-78 C to 0 C and stirred at 0 C for a further 1.5 h. The reaction mixture was poured onto ice water/brine and extracted two times with dichloromethane. The combined extracts were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, CYCLOHEXANE/ACOET) to give 22.3 g (45.6 mmol, 96 %) of the title compound as colorless oil. According to LH-NMR spectroscopy, one of the four isomers is strongly predominating. The configuration was tentatively assigned as 2S, 3R according to D. Haigh et AL., Tetrahedron : Asymmetry 1999, 10, 1353-1367. MS: 512.3 (M+Na) +, 472.3, 447.2, 387.2, 327.2, 295.3, 267.3, 232.1, 175.1.

Reference： [1]Patent: WO2004/31162,2004,A1 .Location in patent: Page 37
[2]Patent: WO2004/20420,2004,A1 .Location in patent: Page 69

19
[ 101093-56-5 ]
[ 16847-90-8 ]
[ 668477-03-0 ]

Yield	Reaction Conditions	Operation in experiment
77%		A suspension of (1, 2-diethoxy-2-oxoethyl) triphenyl phosphonium chloride [Tetrahedron 50 (25), 7543-56 (1994) ] (35.5 g, 82.9 mmol) and DBU (13.6 ml, 91.2 mmol) in THF (60 ml) was stirred for 10 min at ambient temperature. 4-Benzyloxy-2-methyl- benzaldehyde (12.5 g, 55.2 mmol) was added and the reaction mixture was heated under reflux for 16 h. The solvent was concentrated at reduced pressure, the residue was taken up in AcOEt and washed with saturated aqueous NH4C1 solution and brine. The organic layer was dried over sodium sulfate, the solvent removed under reduced pressure and the residue purified by column chromatography (silica gel, hexane/AcOEt) to give 14.5 g (42.6 mmol, 77 %) of the title compound as yellow liquid. MS: 340.2 (M) +, 249.2, 147.1, [91.] 1.
77%		A suspension of (1, 2-diethoxy-2-oxoethyl) triphenyl phosphonium chloride [Tetrahedron 50 (25), 7543-56 (1994) ] (35.5 g, 82.9 mmol) and DBU (13.6 ml, 91.2 mmol) in THF (60 ml) was stirred for 10 min at ambient temperature. 4-BENZYLOXY-2-METHYL- benzaldehyde (12.5 g, 55.2 mmol) was added and the reaction mixture was heated under reflux for 16 h. The solvent was concentrated at reduced pressure, the residue was taken up in AcOEt and washed with saturated aqueous NH4C1 solution and brine. The organic layer was dried over sodium sulfate, the solvent removed under reduced pressure and the residue purified by column chromatography (silica gel, hexane/AcOEt) to give 14.5 g (42.6 mmol, 77 %) of the title compound as yellow liquid. MS: 340.2 (M) +, 249.2, 147.1, 91.1.
77%		A suspension of (1, 2-diethoxy-2-oxoethyl) triphenyl phosphonium chloride [Tetrahedron 50 (25), 7543-56 (1994) ] (35.5 g, 82. 9 mmol) and DBU (13.6 ML, 91.2 mmol) in THF (60 ML) was stirred for 10 min at ambient temperature. 4-BENZYLOXY-2-METHYL- benzaldehyde (12.5 g, 55.2 mmol) was added and the reaction mixture was heated under reflux for 16 h. The solvent was concentrated at reduced pressure, the residue was taken up in AcOEt and washed with saturated aqueous NH4CL solution and brine. The organic layer was dried over sodium sulfate, the solvent removed under reduced pressure and the residue purified by column chromatography (silica gel, hexane/AcOEt) to give 14.5 g (42.6 mmol, 77 %) of the title compound as yellow liquid. MS: 340.2 (M) +, 249.2, 147.1, 91.1.

Reference： [1]Patent: WO2004/31162,2004,A1 .Location in patent: Page 80
[2]Patent: WO2004/41275,2004,A1 .Location in patent: Page/Page column 64
[3]Patent: WO2004/20420,2004,A1 .Location in patent: Page 61-62

20
[ 1048041-42-4 ]
[ 101093-56-5 ]
[ 1048335-58-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2492 - 2496

21
[ 101093-56-5 ]
[ 36476-78-5 ]
[ 1240307-34-9 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In dichloromethane;Sealed tube;	General Procedure C: Synthesis of compounds in Table C; Compounds in Table C were produced as part of a one dimensional array with the only variant being the aldehyde monomer which is given in Table C. The aldehydes were purchased pre-weighed from the Sigma Aldrich Custom Packaged Reagent service.; A 20 mL vial was charged with a solution of an aldehyde monomer in DCM (0.6 mmol pre-weighed, 1.20 eq, 2.0 mL DCM), MP-cyanoborohydride resin (Biotage, 3.0 eq), azetidine-3- carboxylic acid in 1.O mL of DCM (1.0 eq, 41.67 mg), and a solution of HOAc in DCM (3.0 eq, 59.34 mmol total, 76.24 muL, 500 muL of DCM). This was capped and shaken for about 4-5 h, monitoring the reaction until there was complete product formation. After product formation the material was filtered and the solvent was removed in vacuo (Speed Vac) from the crude mixture. The material was then dissolved in 1.4 mL of DMSO:MeOH solution (1 :1 v/v) and purified by preparative HPLC on a Phenomenex Luna C8(2) 5 um IOOA AXIA column (30 mm x 75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-6.0 min linear gradient 10-100% A, 6.0-7.0 min 100% A, 7.0- 8.0 min linear gradient 100-10% A). Samples were injected in 1.5 mL DMSO:MeOH (1 :1). An Agilent 1100 Series Purification system was used, consisting of the following modules: Agilent 1100 Series LC/MSD SL mass spectrometer with API-electrospray source; two Agilent 1100 Series preparative pumps; Agilent 1100 Series isocratic pump; Agilent 1100 Series diode array detector with preparative (0.3 mm) flow cell; Agilent active-splitter, IFC-PAL fraction collector / autosampler. The make-up pump for the mass spectrometer used 3 : 1 MeOH:water with 0.1 % formic acid at a flow rate of 1 mL/min. Fraction collection was automatically triggered when the EIC for the target mass exceeded the threshold specified in the method. The system was controlled using Agilent Chemstation (Rev B.10.03), Agilent A2Prep, and Leap FractPal software, with custom Chemstation macros for data export. Products were characterized by MS and LC/MS (Table 2, Method a).

Reference： [1]Patent: WO2010/93704,2010,A1 .Location in patent: Page/Page column 75-76
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 9154 - 9170

22
[ 101093-56-5 ]
[ 1779-49-3 ]
[ 1286280-56-5 ]

Yield	Reaction Conditions	Operation in experiment
97%		To a suspension methyltriphenyl-phosphonium bromide (18.95 g, 53.05 mmol) in 150 mL THF at 0C was added 31.8 mL (50.84 mmol) of 1.6 M nBuLi. The resulting mixture was stirred at 0C for 1 hr, followed by a slow addition of the aldehyde (10.0 g, 44.21 mmol) dissolved in 40 mL THF. The ice bath was removed, and stirred for 2 hr at rt. It was then diluted with ether and quench with water. The organic layer was washed with brine and dried over MgS04. It was purified in the ISCO using 1-5 EtOAc/hex to obtain 9.67 g (97%) of the styrene. NMR (400 MHz, CHLOROFORM-if) delta ppm 7.33 - 7.48 (m, 6 H), 6.90 (dd, J=17.4, 10.9 Hz, 1 H), 6.80 - 6.85 (m, 2 H), 5.56 (dd, J=17.4, 1.5 Hz, 1 H), 5.21 (dd, J=10.9, 1.5 Hz, 1 H), 5.09 (s, 2 H), 2.36 (s, 3 H).

Reference： [1]Patent: WO2011/44195,2011,A1 .Location in patent: Page/Page column 38

23
[ 101093-56-5 ]
[ 1286280-35-0 ]

Reference： [1]Patent: WO2011/44195,2011,A1

24
[ 101093-56-5 ]
[ 1286280-80-5 ]

Reference： [1]Patent: WO2011/44195,2011,A1

25
[ 101093-56-5 ]
[ 1286280-44-1 ]

Reference： [1]Patent: WO2011/44195,2011,A1

26
[ 101093-56-5 ]
[ 1286280-57-6 ]

Reference： [1]Patent: WO2011/44195,2011,A1

27
[ 101093-56-5 ]
[ 1286280-58-7 ]

Reference： [1]Patent: WO2011/44195,2011,A1

28
[ 101093-56-5 ]
[ 1286280-59-8 ]

Reference： [1]Patent: WO2011/44195,2011,A1

29
[ 101093-56-5 ]
[ 1286280-60-1 ]

Reference： [1]Patent: WO2011/44195,2011,A1

30
[ 2537-48-6 ]
[ 101093-56-5 ]
[ 1314759-58-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3885 - 3889

31
[ 101093-56-5 ]
[ 1314759-65-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3885 - 3889

32
[ 101093-56-5 ]
[ 1314759-66-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3885 - 3889

33
[ 101093-56-5 ]
[ 1314759-74-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3885 - 3889

34
[ 101093-56-5 ]
C₂₃H₂₇NO₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3885 - 3889

35
[ 101093-56-5 ]
[ 1314839-82-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3885 - 3889

36
[ 101093-56-5 ]
[ 1314759-85-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3885 - 3889

37
[ 41438-18-0 ]
[ 100-39-0 ]
[ 101093-56-5 ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate; In acetonitrile; at 20℃; for 3h;	To a mixture of A-1 (2.72 g, 19.98 mmol, 1.00 equiv) in CH3CN (30 mL) with K2CO3 (4.14 g, 29.95 mmol, 1.50 equiv) was added BnBr (3.8 g, 22.22 mmol, 1.11 equiv). The reaction was stirred for 3 h at room temperature. Water was added and the mixture was extracted with EtOAc thrice. Concentration and chromatograph on silica gel (10:1 PE/EA) gave 3.4 g (75%) of B-1 as white solid.
	With potassium carbonate; In acetonitrile; at 20℃; for 3h;	To a mixture of <strong>[41438-18-0]4-hydroxy-2-methylbenzaldehyde</strong> (2.72 g, 19.98 mmol, 1.00 equiv) in ChbCN (30 ml_) with K2CO3 (4.14 g, 29.95 mmol, 1.50 equiv) was added BnBr (3.8 g, 22.22 mmol, 1.11 equiv). The reaction mixture was stirred for 3 h at room temperature. Water was added and the mixture was extracted with EtOAc thrice. The mixture was then concentrated and the residue pruified by chromatography on silica gel (10:1 PE/EA) to yield 4-(benzyloxy)-2-methylbenzaldehyde as white solid.

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 9792 - 9805
[2]Patent: US2014/256657,2014,A1 .Location in patent: Paragraph 0297
[3]Patent: WO2019/215633,2019,A1 .Location in patent: Page/Page column 83

38
[ 101093-56-5 ]
benzo[b]thiophen-2-yl(4-(benzyloxy)-5-bromo-2-methylphenyl)methanol [ No CAS ]

Reference： [1]Patent: US2014/256657,2014,A1
[2]Patent: WO2019/215633,2019,A1

39
[ 101093-56-5 ]
2-[[4-(benzyloxy)-5-bromo-2-methylphenyl]methyl]-1-benzothiophene [ No CAS ]

Reference： [1]Patent: US2014/256657,2014,A1
[2]Patent: WO2019/215633,2019,A1

40
[ 101093-56-5 ]
C₅₀H₄₈O₆S [ No CAS ]