[ CAS No. 59263-76-2 ] {[proInfo.proName]}

Name: 59263-76-2|3-(3-Ethyl-1-methylazepan-3-yl)phenol hydrochloride|98%
Brand: Ambeed
SKU: A302225
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Quality Control of [ 59263-76-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 59263-76-2 ]

SDS Specification

Alternatived Products of [ 59263-76-2 ]

Product Details of [ 59263-76-2 ]

CAS No. :	59263-76-2	MDL No. :	MFCD00941476
Formula :	C₁₅H₂₄ClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MPJUSISYVXABBH-UHFFFAOYSA-N
M.W :	269.81	Pubchem ID :	65483
Synonyms :		Chemical Name :	3-(3-Ethyl-1-methylazepan-3-yl)phenol hydrochloride

Calculated chemistry of [ 59263-76-2 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.6
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	83.43
TPSA :	23.47 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-4.96 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	4.21
Log Po/w (WLOGP) :	3.58
Log Po/w (MLOGP) :	3.05
Log Po/w (SILICOS-IT) :	3.18
Consensus Log Po/w :	2.8

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.28
Solubility :	0.0142 mg/ml ; 0.0000525 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.41
Solubility :	0.0104 mg/ml ; 0.0000387 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.0
Solubility :	0.0269 mg/ml ; 0.0000998 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.46

Safety of [ 59263-76-2 ]

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

Application In Synthesis of [ 59263-76-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 59263-76-2 ]
Downstream synthetic route of [ 59263-76-2 ]

[ 59263-76-2 ] Synthesis Path-Upstream 1~8

1
[ 71556-73-5 ]
[ 59263-76-2 ]

Reference： [1] European Journal of Medicinal Chemistry, 1980, vol. 15, # 4, p. 375 - 385

2
[ 2556-73-2 ]
[ 59263-76-2 ]

Reference： [1] European Journal of Medicinal Chemistry, 1980, vol. 15, # 4, p. 375 - 385
[2] European Journal of Medicinal Chemistry, 1980, vol. 15, # 4, p. 375 - 385
[3] European Journal of Medicinal Chemistry, 1980, vol. 15, # 4, p. 375 - 385

3
[ 766-51-8 ]
[ 59263-76-2 ]

Reference： [1] European Journal of Medicinal Chemistry, 1980, vol. 15, # 4, p. 375 - 385
[2] European Journal of Medicinal Chemistry, 1980, vol. 15, # 4, p. 375 - 385

4
[ 71556-70-2 ]
[ 59263-76-2 ]

Reference： [1] European Journal of Medicinal Chemistry, 1980, vol. 15, # 4, p. 375 - 385

5
[ 71592-44-4 ]
[ 59263-76-2 ]

Reference： [1] European Journal of Medicinal Chemistry, 1980, vol. 15, # 4, p. 375 - 385

6
[ 71592-43-3 ]
[ 59263-76-2 ]

Reference： [1] European Journal of Medicinal Chemistry, 1980, vol. 15, # 4, p. 375 - 385

7
[ 71556-72-4 ]
[ 59263-76-2 ]

Reference： [1] European Journal of Medicinal Chemistry, 1980, vol. 15, # 4, p. 375 - 385

8
[ 50-00-0 ]
[ 59263-75-1 ]
[ 59263-76-2 ]

Reference： [1] European Journal of Medicinal Chemistry, 1980, vol. 15, # 4, p. 375 - 385

[ 59263-76-2 ] Synthesis Path-Downstream 1~39

1
[ 50-00-0 ]
[ 59263-75-1 ]
[ 59263-76-2 ]

Reference： [1]European Journal of Medicinal Chemistry,1980,vol. 15,p. 375 - 385

2
[ 71556-73-5 ]
[ 59263-76-2 ]

Reference： [1]European Journal of Medicinal Chemistry,1980,vol. 15,p. 375 - 385

3
[ 105-60-2 ]
quininoic acid ethyl ester [ No CAS ]
[ 59263-76-2 ]

Reference： [1]European Journal of Medicinal Chemistry,1980,vol. 15,p. 375 - 385
[2]European Journal of Medicinal Chemistry,1980,vol. 15,p. 375 - 385
[3]European Journal of Medicinal Chemistry,1980,vol. 15,p. 375 - 385

4
[ 2556-73-2 ]
[ 59263-76-2 ]

5
[ 766-51-8 ]
[ 59263-76-2 ]

Reference： [1]European Journal of Medicinal Chemistry,1980,vol. 15,p. 375 - 385
[2]European Journal of Medicinal Chemistry,1980,vol. 15,p. 375 - 385

6
[ 71556-70-2 ]
[ 59263-76-2 ]

Reference： [1]European Journal of Medicinal Chemistry,1980,vol. 15,p. 375 - 385

7
[ 71592-44-4 ]
[ 59263-76-2 ]

Reference： [1]European Journal of Medicinal Chemistry,1980,vol. 15,p. 375 - 385

8
[ 71592-43-3 ]
[ 59263-76-2 ]

Reference： [1]European Journal of Medicinal Chemistry,1980,vol. 15,p. 375 - 385

9
[ 71556-72-4 ]
[ 59263-76-2 ]

Reference： [1]European Journal of Medicinal Chemistry,1980,vol. 15,p. 375 - 385

10
[ 75-44-5 ]
[ 190330-56-4 ]
[ 59263-76-2 ]
[ 1314003-67-2 ]

Yield	Reaction Conditions	Operation in experiment
14.6%		Preparation of Benzyl 4-[3-(3-Ethyl-1-methyl-perhydro-azepin-3-yl)-phenoxycarbamoyl]-3-methoxybenzoateA solution of benzyl 3-methoxy-4-aminobenzoate (5.0 g, 19.43 mmol) in anhydrous tetrahydrofuran (150 mL) was stirred at -75 C., under nitrogen, while 2N phosgene/toluene solution (9.7 mL, 19.4 mmol) was added over 10 seconds. Triethylamine (5.9 g, 58.29 mmol) was then added and the mixture was stirred for 45 minutes keeping temperature in range -70 to -76 C. <strong>[59263-76-2]Meptazinol hydrochloride</strong> was then added in a single portion and the suspension was stirred for a further 30 minutes before removing the cooling bath and allowing warming to room temperature (10-12 C.) over 30 minutes. Saturated aqueous sodium carbonate solution (375 mL) was then added and the mixture was extracted with ethyl acetate (375 mL and 100 mL portions). The combined extract was washed with brine, dried (magnesium sulfate) and evaporated in vacuo to leave an amber oil. TLC analysis (dichloromethane/methanol, 9:1, UV) indicated some of each starting material present together with a major product at Rf 0.40 and a lesser product at Rf 0.44. On standing solid partially crystallised from the oil and treatment with dichloromethane precipitated additional solid which was removed by filtration. TLC analysis indicated this solid was the minor product and NMR suggested it is the urea by-product. The filtrate was evaporated in vacuo and the residual oil was subjected to column chromatography on silica gel, eluting with CH2Cl2/MeOH (95:5), collecting 200 mL fractions. Fractions 3-6 contained the highest Rf TLC component. Evaporation of these fractions provided an amber oil (2.08 g). 1H NMR confirmed this was recovered benzyl 3-methoxy-4-aminobenzoate. Fractions 9-13 contained the main product contaminated with the by-product. These fractions were evaporated to obtain a solid/oil mixture, 1.40 g. Fractions 14-24 contained the major product as a single spot by TLC analysis-evaporation of these fractions provided a pale yellow oil (1.47 g, 14.6%). 'H NMR was consistent with the structure of the required product and indicated good purity.

Reference： [1]Patent: US2011/190267,2011,A1 .Location in patent: Page/Page column 57

11
[ 75-44-5 ]
[ 1291379-57-1 ]
[ 59263-76-2 ]
[ 1314003-62-7 ]

Yield	Reaction Conditions	Operation in experiment
43%		Preparation of Meptazinol Para-amino Ortho-fluorobenzoic Acid Carbamate Benzyl EsterTo a stirred solution of 4-amino-2-fluorobenzoate (3.16 g, 12.89 mmol) in dichloromethane (150 mL) at -78 C. was added triethylamine (7.18 mL, 51.54 mmol), followed by the dropwise addition of phosgene (6.77 mL, 13.54 mmol, 2M solution in toluene). The resulting solution was stirred at -78 C. for 45 minutes, and then <strong>[59263-76-2]meptazinol hydrochloride</strong> (3.48 g, 12.89 mmol) was added portion wise as a solid. Stirring was maintained at -78 C. for 45 minutes, and then the reaction mixture was allowed to warm to ambient temperature, at which point it was poured into brine. The mixture was extracted with chloroform, and the combined extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by flash column chromatography, eluting with 5% MeOH/CHCl3 increased to 10% MeOH/CHCl3, afforded the title compound as a pale yellow solid (2.8 g, 43%).

Reference： [1]Patent: US2011/190267,2011,A1 .Location in patent: Page/Page column 54-55

12
[ 75-44-5 ]
[ 1314003-64-9 ]
[ 59263-76-2 ]
[ 1314003-65-0 ]

Yield	Reaction Conditions	Operation in experiment
21.7%		Preparation of Benzyl Meptazinol Para-amino Meta-ethylbenzoate CarbamateBenzyl 4-amino-3-ethylbenzoate (4.80 g, 18.80 mmol) in tetrahydrofuran (145 mL) was treated with triethylamine (5.71 g, 56.40 mmol) and stirred at -74 C. while phosgene (2M in toluene, 9.4 mL, 18.80 mmol) was added over 20 seconds. The temperature of the reaction mixture rose to -60 C. during this addition. After 45 minutes maintaining at -70 to -75 C. <strong>[59263-76-2]meptazinol hydrochloride</strong> (5.07 g, 18.80 mmol) was charged in a single portion and stirring continued at this temperature for 45 minutes. The mixture was warmed to room temperature for 1 hour and treated with saturated aqueous sodium carbonate solution (400 mL) and extracted with ethyl acetate (400 mL and 100 mL). The combined extract was washed with brine (2×100 mL), dried (magnesium sulfate) and evaporated in vacuo. The residual oil was purified by column chromatography on silica gel, eluting with dichloromethane/methanol (97:3). Benzyl meptazinol para-amino meta-ethylbenzoate carbamate of good purity was obtained as a pale yellow oil (2.10 g 21.7%).

Reference： [1]Patent: US2011/190267,2011,A1 .Location in patent: Page/Page column 55-56

13
[ 59263-76-2 ]
3-tert-butoxycarbonyl-phenyl isocyanate [ No CAS ]
[ 1314003-53-6 ]

Yield	Reaction Conditions	Operation in experiment
64%		Preparation of Meptazinol Meta-amino Benzoic Acid Carbamate Tert-butyl Ester<strong>[59263-76-2]Meptazinol hydrochloride</strong> (3.24 g, 12 mmol) was converted to the free base in the presence of chloroform (50 mL) and an aqueous solution of saturated sodium bicarbonate (50 mL). The organic phase was dried over sodium sulphate and evaporated to dryness in vacuo, leaving a yellow oil. The oil was dissolved in anhydrous tetrahydrofuran (150 mL) and the isocyanate from the previous step (2.72 g, 12.42 mmol) was added. The reaction mixture was heated at 50 C. for 16 h whilst being monitored by TLC. After leaving to cool to room temperature the tetrahydrofuran was removed in vacuo. The residual oil was purified by column chromatography (100 g of silica, elution with CHCl3/MeOH; vol:vol 99/1, 98/2, 96/4 and 94/6) to yield meptazinol meta-amino benzoic acid carbamate tert-butyl ester in moderate yield (3.5 g, 64%).

Reference： [1]Patent: US2011/190267,2011,A1 .Location in patent: Page/Page column 51

14
[ 75294-50-7 ]
[ 59263-76-2 ]
[ 1314003-46-7 ]

Yield	Reaction Conditions	Operation in experiment
61%		Stage 2-Preparation of Protected Ester (2)Meptazinol HCl (966 mg, 3.61 mmol) was converted to the free base in the presence of chloroform (50 ml) and an aqueous solution of NaHCO3 saturated (50 ml). The organic phase was dried over sodium sulphate and evaporated to dryness, leaving a yellow oil. The yellow oil was dissolved in 50 ml of dry THF and isocyanate 7 (876 mg, 4 mmol) was added. The RM was heated at 50 C. for 16 h during which time it was monitored by TLC. The RM was cooled down to room temperature and the THF was removed under vacuum. The residual oil was then purified by column chromatography (100 g of SiO2, elution with CHCl3/MeOH; v:v 99/1, 98/2, 96/4 and 94/6). The ester 2 was isolated in moderate yield (998 mg, 61%).

Reference： [1]Patent: US2011/190267,2011,A1 .Location in patent: Page/Page column 45-46

15
[ 59263-76-2 ]
[ 54340-58-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium hydrogencarbonate; In dichloromethane; water; at 15 - 35℃;	Stage 1-Salt Release of Meptazinol FreebaseMeptazinol.HCl (20.0 g, 1 eq) was suspended in DCM (25 vol) and water (3 vol) at 15 to 25 C. Sodium hydrogen carbonate (6.5 g, 1.05 eq.) was charged and the mixture was warmed to 30 to 35 C. and stirring continued until gas evolution had ceased (40 min) and then maintained at 30 to 35 C. for a further 40 minutes. The phases were separated, the organic phase dried over Na2SC4, maintaining 30 to 35 C., filtered, vessel/cake wash with DCM (2 vol) and the filtrates were concentrated to dryness, which generated meptazinol freebase as a white solid 17.0 g, 98.3% th yield.
94.8%	With sodium hydrogencarbonate; In dichloromethane; water; at 20℃; for 1h;	In a 250 mL round bottom flask, meptazol hydrochloride (5.4 g, 20 mmol,), NaHCO3 (1.84 g,22mmol, 1.1eq), H2O (100ml), dichloromethane (60ml), stirred at room temperature for 1h, the aqueous layer was separated, and the aqueous layer was dichloromethane.The alkane was extracted three times (60 ml×3), and the organic layer was combined and dried over anhydrous sodium sulfate.Come outThe solvent gave 4.4 g of a gray solid, yield 94.8%.
92%	With ammonia; In water; at 5 - 23℃;pH 4.5 - 9;	Example 6Preparation of Meptazinol Freebase Meptazinol.HCl salt (5.0 g, 1 eq, 1 wt) was charged to a flask equipped with a magnetical stirrer bar. Water (8vol) was added and a clear solution was quickly obtained. The temperature was adjusted to 18-23 C. (pH solution=4.5). Aqueous ammonia was slowly charged and after 3 drops, the pH raised to 8.3 and a sticky solid appeared which blocked the stirrer. The magnetical stirrer was replaced by a mechanical stirrer. With a good agitation, addition of aqueous ammonia was resumed until pH 9 was reached (a total charge of 1.45 mL of aqueous ammonia used). The white slurry was stirred at 18-23 C. for 30 min and the pH rechecked. The white slurry was cooled to 5-10 C., stirred for 1 hr then filtered. The cake was washed with purified water (2×5vol) and dry on the filter under a flow N2.Performing the salt release of <strong>[59263-76-2]meptazinol hydrochloride</strong> under aqueous conditions using aq. ammonia as base gave a 92% th yield of meptazinol.

Reference： [1]Patent: US2011/190267,2011,A1 .Location in patent: Page/Page column 46-47
[2]Patent: CN109651250,2019,A .Location in patent: Paragraph 0048; 0049
[3]Patent: US2012/165520,2012,A1 .Location in patent: Page/Page column 17

16
[ 59263-76-2 ]
[ 1314003-13-8 ]