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[ CAS No. 84449-80-9 ] {[proInfo.proName]}

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Chemical Structure| 84449-80-9
Chemical Structure| 84449-80-9
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Product Details of [ 84449-80-9 ]

CAS No. :84449-80-9 MDL No. :MFCD06657755
Formula : C14H20ClNO3 Boiling Point : -
Linear Structure Formula :- InChI Key :CMVTYSMYHSVDIU-UHFFFAOYSA-N
M.W : 285.77 Pubchem ID :5743835
Synonyms :

Calculated chemistry of [ 84449-80-9 ]

Physicochemical Properties

Num. heavy atoms : 19
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.5
Num. rotatable bonds : 5
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 80.4
TPSA : 49.77 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.46 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 0.82
Log Po/w (WLOGP) : 2.67
Log Po/w (MLOGP) : 2.06
Log Po/w (SILICOS-IT) : 2.15
Consensus Log Po/w : 1.54

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.03
Solubility : 2.65 mg/ml ; 0.00929 mol/l
Class : Soluble
Log S (Ali) : -1.45
Solubility : 10.2 mg/ml ; 0.0357 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.05
Solubility : 0.254 mg/ml ; 0.000889 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 1.8

Safety of [ 84449-80-9 ]

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 [ 84449-80-9 ]

* 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 [ 84449-80-9 ]
  • Downstream synthetic route of [ 84449-80-9 ]

[ 84449-80-9 ] Synthesis Path-Upstream   1~16

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YieldReaction ConditionsOperation in experiment
87.7% With potassium carbonate In Isopropyl acetate; water EXAMPLE 4
Preparation of 4-(2-piperidinoethoxy)benzoic acid hydrochloride
To a 250 mL 3 neck flask equipped with mechanical stirring, condenser, and heating apparatus consisting of a RTD probe hooked via a temperature controller to a heating mantle and under nitrogen atmosphere, the following were added: 7.61 g methyl 4-hydroxybenzoate, 11.05 g β-chloroethylpiperidine hydrochloride, 16.59 g powdered potassium carbonate, and 60 mL isopropyl acetate.
The mixture was heated slowly to 80° C.
After 5 hours, high performance liquid chromatography showed reaction to be 90percent complete.
After being left overnight at 80° C., reaction was complete.
The mixture was then cooled to ambient temperature, after which 60 mL deionized water was added.
The mixture was stirred until all solids dissolved.
The aqueous layer was separated and discarded.
The organic layer was extracted 3 times with 20 mL 4N hydrochloride.
The combined aliquots, containing 4-(2-piperidinoethoxy)benzoic acid, ethyl ester, were heated at reflux (92° C., 30 minutes required to reach reflux).
After 7.5 hours at reflux, the mixture was then distilled to remove approximately 10 mL water and cooled in an ice bath for 15 minutes.
The resulting crystalline 4-(2-piperidinoethoxy)benzoic acid, hydrochloride was removed by filtration and rinsed with acetone and dried. Yield=12.53 g of product (87.7percent of theoretical).
Reference: [1] Patent: US5631369, 1997, A,
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YieldReaction ConditionsOperation in experiment
95.3% With potassium carbonate In Isopropyl acetate; water a.
To a 250 mL 3 neck flask, with mechanical stirring, condenser, and RTD probe were added the following under nitrogen atmosphere: 0.05 mol methyl 4-hydroxybenzoate, 0.06 mol β-chloroethylpiperidine hydrochloride, 16.59 grams of potassium carbonate, and 60 mL of isopropyl acetate.
The mixture was heated at 75° C.-80° C. for 20 hours, at which time all the methyl 4-hydroxybenzoate was consumed.
60 mL of water was then added to dissolve the potassium carbonate.
The organic and aqueous phases were then Separated and the aqueous layer discarded.
The organic layer was washed with a second 60 mL aliquot of water; the layers were separated and the aqueous layer discarded.
The reaction product, 4-(2-piperidinoethoxy)benzoic acid, methyl ester, was then extracted into 25 mL 8N hydrochloric acid.
The aqueous phase was separated and the organic phase discarded.
The aqueous phase was refluxed in a 50 mL round bottomed flask with magnetic stirring and condenser for 48 hours.
The mixture was then cooled to 0° C.-5° C. and the crystals removed by filtration.
The crystals were rinsed with acetone and dried overnight in 50° C. vacuum oven.
13.63 g of 4-(2-piperidinoethoxy)benzoic acid hydrochloride were recovered, which is 95.3percent of the theoretical yield.
Reference: [1] Patent: US5631369, 1997, A,
  • 3
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YieldReaction ConditionsOperation in experiment
1.36 g Inert atmosphere In a round bottomed flask equipped with nitrogen inlet and magnetic stir bar, a solution of ethyl 4-(2-(piperidin-l-yl)ethoxy)benzoate (1.58 g, 5.7 mmol) in methanol (25 mL) was added. To the above solution, 8 mL of 5percent NaOH solution was added and the reaction was stirred overnight. Methanol was evaporated and 15 mL cold water was added to the residue. The precipitated solid was filtered, washed with 5 mL water and the, dried in vacuo to give 1.36 g of 1 -(2-(4-carboxyphenoxy)ethyl)piperidin-l -ium chloride (0271) lH NMR (400 MHz, Chloroform-d) δ 7.93 (d, J = 8.9 Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H), 6.30 (bs, 1H), 4.84 (bs, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.86 (bs, 1H), 2.07 - 1.53 (m, 4H), 1.36 (t, J = 7.1 Hz, 2H). HPLC-MS: Expected: 250; Found: 250.
Reference: [1] Patent: US6372945, 2002, B1, . Location in patent: Page column 16
[2] Patent: EP1577288, 2005, A1, . Location in patent: Page/Page column 83
[3] Patent: WO2018/144900, 2018, A1, . Location in patent: Page/Page column 46
  • 4
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Reference: [1] Patent: US5852193, 1998, A,
[2] Patent: EP875507, 1998, A1,
  • 5
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Reference: [1] Patent: US5852193, 1998, A,
[2] Patent: EP875507, 1998, A1,
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Reference: [1] Patent: US5631369, 1997, A,
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YieldReaction ConditionsOperation in experiment
12.61 g (83.6% theoretical) With hydrogenchloride; potassium carbonate In water EXAMPLE 5
Preparation of 4-(2-piperidinoethoxy)benzoic acid hydrochloride
To a 125 mL 3 neck flask with mechanical stirring, condenser, and a heating apparatus consisting of an RTD probe hooked via a temperature controller to a heating mantle, the following were added: 7.61 g methyl 4-hydroxybenzoate, 11.05 g β-chloroethylpiperidine hydrochloride, 16.59 g powdered potassium carbonate, and 60 mL amyl acetate.
The mixture was heated in an oil bath under nitrogen to 115° C.-120° C. for 4 hour. HPLC indicated that the reaction was complete.
The mixture was then cooled to ambient temperature and 40 mL of deionized water were added to dissolve solids.
The aqueous layer was separated and discarded and the water wash was repeated.
5 mL of the organic phase was removed as an analytical standard.
25 mL 8N hydrochloric acid was added to remaining organic phase to extract the intermediate.
The layers were separated and the acidified aqueous layers returned to the reaction flasks.
The organic phase was discarded.
The aqueous phase was heated to 95° C. until HPLC indicated complete hydrolysis of the ester (about 4 hours).
The mixtures were cooled to 0° C.-5° C. for 1 hour and filtered.
The filter cakes were rinsed with acetone (approx. 25 mL) and dried.
Yield 12.61 g (83.6percent theoretical).
Reference: [1] Patent: US5631369, 1997, A,
[2] Patent: US5631369, 1997, A,
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Reference: [1] Patent: US5852193, 1998, A,
[2] Patent: EP875507, 1998, A1,
  • 9
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Reference: [1] European Journal of Medicinal Chemistry, 2007, vol. 42, # 1, p. 71 - 80
[2] Patent: US2005/137396, 2005, A1, . Location in patent: Page/Page column 4-7
[3] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 23, p. 7250 - 7256
  • 10
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Reference: [1] European Journal of Medicinal Chemistry, 2007, vol. 42, # 1, p. 71 - 80
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 23, p. 7250 - 7256
  • 11
  • [ 99-76-3 ]
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Reference: [1] European Journal of Medicinal Chemistry, 2007, vol. 42, # 1, p. 71 - 80
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 23, p. 7250 - 7256
  • 12
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Reference: [1] Patent: WO2018/144900, 2018, A1,
  • 13
  • [ 63675-74-1 ]
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  • [ 82640-04-8 ]
Reference: [1] Patent: US5478847, 1995, A,
[2] Patent: US5567820, 1996, A,
[3] Patent: US4656187, 1987, A,
[4] Patent: US4380635, 1983, A,
[5] Patent: US4418068, 1983, A,
  • 14
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YieldReaction ConditionsOperation in experiment
70.4%
Stage #1: With pyridine; thionyl chloride In dichloromethane for 1 h; Heating / reflux
PHASE A 42 kg of methylene chloride and 7.8 kg of 4- (2-piperidinoethoxy)-benzoic acid hydrochloride (0.027 KMOL), 0.12 kg pyridine (0.0015 KMOL) are fed into a reactor and heated under reflux and then 3.96 kg of thionyl chloride (0.033 KMOL) are added. The mixture is stirred for 1 hour then about 20 litres of methylene chloride are distilled off. The mixture is cooled to 20-30 C and 6 kg of 6-ACETOXY-2- (4- ACETOXYPHENYL) benzo [b] thiophene (IV) (0.018 KMOL) are added. The mixture is stirred until is completely homogenised. PHASE B 36 kg of methylene chloride and 16.8 kg of aluminium trichloride (0.126 KMOL) are fed into a reactor. While stirring, the CHLOROMETHYLENE suspension, comprised of phase A prepared as described above, is added at 15-30 C. The mixture is stirred for 1 hour then the entire reaction mixture is poured into a reactor containing 60 kg of ice. The mixture is stirred at 15-30 C then the suspension is centrifuged, washing with 3 kg of methylene chloride and 3 kg of deionised water. The centrifuged mother liquors, containing the product, are fed into a reactor and the phases are separated. The organic phase is distilled off until obtaining an oily residue and 15 kg of methyl alcohol are added, stirred at 20-40 C and, maintaining the same temperature, 9.1 kg of 30percent sodium hydroxide (0.068 KMOL) are poured in. The mixture is stirred for 1 hour and 30 kg of deionised water and 30 kg of ethyl acetate are added. At the same temperature 7.2 kg of 37percent hydrochloric acid (0.073 KMOL) are then added. The suspension is centrifuged, washing with 6 kg of ethyl acetate and 6 kg of deionised water. At the end 6.6 kg of dried product with HPLC purity > 98percent and low aluminium content are obtained. The reaction yield calculated on the 6- ACETOXY-2- (4-ACETOXYPHENYL) benzo [b] thiophene (IV) is equal to a yield of 70.4percent.
Reference: [1] Patent: WO2005/3116, 2005, A1, . Location in patent: Page 8-9
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Reference: [1] Patent: US4380635, 1983, A,
[2] Patent: US4418068, 1983, A,
[3] Patent: US2005/137396, 2005, A1, . Location in patent: Page/Page column 7
[4] Patent: WO2011/132194, 2011, A1, . Location in patent: Page/Page column 10-11
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Reference: [1] Journal of Medicinal Chemistry, 1984, vol. 27, # 8, p. 1057 - 1066
[2] Patent: WO2011/29088, 2011, A2,
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