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[ CAS No. 122665-97-8 ] {[proInfo.proName]}

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Chemical Structure| 122665-97-8
Chemical Structure| 122665-97-8
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Product Details of [ 122665-97-8 ]

CAS No. :122665-97-8 MDL No. :MFCD03788493
Formula : C7H10F2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :HYIUDFLDFSIXTR-UHFFFAOYSA-N
M.W : 164.15 Pubchem ID :2779136
Synonyms :

Calculated chemistry of [ 122665-97-8 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.86
Num. rotatable bonds : 1
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 35.56
TPSA : 37.3 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.14 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.29
Log Po/w (XLOGP3) : 1.63
Log Po/w (WLOGP) : 2.74
Log Po/w (MLOGP) : 1.57
Log Po/w (SILICOS-IT) : 1.73
Consensus Log Po/w : 1.79

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -1.82
Solubility : 2.49 mg/ml ; 0.0152 mol/l
Class : Very soluble
Log S (Ali) : -2.03
Solubility : 1.55 mg/ml ; 0.00942 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.23
Solubility : 9.71 mg/ml ; 0.0592 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.61

Safety of [ 122665-97-8 ]

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 [ 122665-97-8 ]

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

  • Upstream synthesis route of [ 122665-97-8 ]
  • Downstream synthetic route of [ 122665-97-8 ]

[ 122665-97-8 ] Synthesis Path-Upstream   1~7

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Reference: [1] Patent: WO2011/104334, 2011, A1,
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YieldReaction ConditionsOperation in experiment
27% With 4-(tert-butyl)-2,6-dimethylphenyl sulfur trifluoride; pyridine hydrogenfluoride In dichloromethane at 0 - 20℃; for 5 h; Inert atmosphere Ethyl 4-oxycyclohexanecarboxylate (1.13g, 6.67mmol) was dissolved in anhydrous dichloromethane (10mL) in a high density polyethylene (HDPE) container. To it, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (2.5g, 9.99mol) was added and stirred under N2 at 0°C. HF-pyridine (0.64mL, 2.64mmol) was added to the vessel and the reaction was allowed to reach ambient temperature. After 5h, the reaction mixture was quenched with saturated aqueous NaHCO3. The organic layer was allowed to stir at ambient temperature in 2N NaOH for 1h. The aqueous layer was washed with dichloromethane and then acidified to pH 1 and extracted with dichloromethane. A total of 0.435g title compound was obtained at 27percent yield. 1H NMR (400MHz, CDCl3) δ 2.498–2.278 (m, 1H), 1.984–1.881 (m, 4H), 1.872–1.753 (m, 4H).
Reference: [1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5969 - 5987
[2] Tetrahedron Letters, 2005, vol. 46, # 30, p. 5005 - 5007
[3] Tetrahedron Letters, 2005, vol. 46, # 30, p. 5005 - 5007
[4] Patent: WO2013/13188, 2013, A1,
[5] Patent: US2014/275080, 2014, A1,
[6] Patent: US9416132, 2016, B2,
[7] Patent: CN105061188, 2017, B, . Location in patent: Paragraph 0029; 0030; 0031; 0032; 0033; 0034-0037
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YieldReaction ConditionsOperation in experiment
97% With water; lithium hydroxide In tetrahydrofuran at 20℃; A solution of ethyl 4,4-difluorocyclohexanecarboxylate (0.385 g, 2.003 mmol) in THF (12 mL) was treated with H2O (6 mL) followed by lithium hydroxide monohydrate (0.420 g, 10.02 mmol) and the mixture stirred vigorously at RT overnight.
The mixture was treated with EtOAc, acidified with 1M HCl until pH 4, the layers separated and the aqueous layer extracted with additional EtOAc (1*).
The combined organics were washed with brine, dried over MgSO4 and concentrated to dryness to afford 4,4-difluorocyclohexanecarboxylic acid (318 mg, 97percent) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.28 (s, 1H), 2.40 (m, 1H), 2.02-1.75 (m, 6H), 1.59 (m, 2H).
94% With sodium hydroxide In ethanol at 0 - 20℃; for 18 h; To a solution of compound ethyl 4,4-difluorocyclohexanecarboxylate (4.2 g, 21.8 mmol) in 40 mL EtOH was treated with 2N NaOH (1.34 g, 32.8 mmol) at 0° C., and the mixture was allowed to warm to r.t. and stirred for 18 h. The mixture was diluted with water and the pH was adjusted to 3-4 with 6N HCl. The mixture was extracted with toluene, dried and concentrated to give the title compound 4,4-difluorocyclohexanecarboxylic acid (3.4 g, 94percent) as a white solid. (0474) 1H-NMR (CDCl3/400 MHz): δ 2.28-2.27 (m, 1H), 2.22-2.20 (m, 1H), 2.08-2.02 (m, 3H), 1.99-1.94 (m, 3H), 1.19 (s, 1H).
92%
Stage #1: With sodium hydroxide In ethanol at 0 - 20℃; for 18 h;
Stage #2: With hydrogenchloride In ethanol; water
Step 5
4,4-Difluoro-cyclohexanecarboxylic acid:
A solution of 4,4-difluoro-cyclohexanecarboxylic acid ethyl ester (970 mg, 5.0 mmol) in ethanol (5 mL) was treated with 2N sodium hydroxide (3.8 mL, 7.6 mmol) at 0° C., and the mixture was allowed to warm to ambient temperature and stirred for an additional 18 hours.
The mixture was diluted with water (15 mL), and the pH was adjusted to 3-4 with 6 N hydrochloric acid.
The mixture was extracted with toluene, dried and concentrated to give the title compound as a white solid. Yield: 758 mg (92percent).
1H-NMR (CDCl3.) δ: 1.60-2.23 (m, 8H), 2.45 (m, 1H).
74.5%
Stage #1: at 25℃; for 2.5 h;
Stage #2: With hydrogenchloride In water
A suspension of 15.7 g ethyl 4,4-difluorocyclohexanoate (6.3 mmol), 2.1 g Candida antarctica lipase B from Novozyme (NOVO SP 435) and 375 g of buffer (Na2HPO4/NaH2PO4 pH=7.5, concentration: 50 mM) were placed in a flask. The mixture was stirred at 25°C for 2:30 h. The lipase was filtered off and the solution was acidified until pH=2 by addition of 35g of HCl 6M. A solid was formed and directly filterted. The aqueous phase was 3 times extracted with CH2Cl2. The solvent was removed using a rotavapor and 3.5 g of additional solid were obtained. The combined solids were dried. Yield: 74.5percent. The purity determined by NMR was 100percent.
55% at 40℃; for 6 h; A suspension of ethyl 4,4-difluorocyclohexanoate (41.7 g; 0.22mol) and concentrated aqueous HCl solution (107.5 g; 1.9 mol; 8.8 eq.) was placed into a round bottom flask equipped with a cooler (2°C). The mixture was heated under stirring to 40 °C for 6 h. Afterwards the solution was extracted 5 times with ethyl ether and the combined fractions were washed once with saturated aqueous NaCl solution. The solvent was removed and a solid was obtained which was recrystallised two times from hot chloroform. 19.2 g were isolated with a purity determined by NMR of 99.5percent and no olefinic compound was detectable via NMR. The yield was 55percent.

Reference: [1] Patent: US2014/275080, 2014, A1, . Location in patent: Paragraph 0428
[2] Patent: WO2013/13188, 2013, A1, . Location in patent: Paragraph 00313; 00314
[3] Patent: US9416132, 2016, B2, . Location in patent: Page/Page column 134; 135
[4] Organic Letters, 2018, vol. 20, # 16, p. 4959 - 4963
[5] Patent: US2008/146605, 2008, A1, . Location in patent: Page/Page column 39-40
[6] Patent: EP1985603, 2008, A1, . Location in patent: Page/Page column 7-8
[7] Tetrahedron Letters, 2005, vol. 46, # 30, p. 5005 - 5007
[8] Patent: EP1985603, 2008, A1, . Location in patent: Page/Page column 7
[9] Organic Process Research and Development, 2008, vol. 12, # 6, p. 1094 - 1103
[10] Patent: EP1985603, 2008, A1, . Location in patent: Page/Page column 7
[11] Patent: WO2007/21309, 2007, A1, . Location in patent: Page/Page column 34-35
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Reference: [1] Patent: CN105061188, 2017, B, . Location in patent: Paragraph 0029; 0030; 0031; 0032; 0033; 0034
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Reference: [1] Patent: WO2015/62486, 2015, A1, . Location in patent: Paragraph 00219
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Reference: [1] Patent: US6262075, 2001, B1,
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  • [ 265108-36-9 ]
Reference: [1] Patent: EP3418282, 2018, A1,
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