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[ CAS No. 1459-96-7 ] {[proInfo.proName]}

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Chemical Structure| 1459-96-7
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Product Details of [ 1459-96-7 ]

CAS No. :1459-96-7 MDL No. :MFCD01312167
Formula : C12H18O4 Boiling Point : -
Linear Structure Formula :- InChI Key :HDOVTVDGSLEUSK-UHFFFAOYSA-N
M.W : 226.27 Pubchem ID :2802857
Synonyms :

Calculated chemistry of [ 1459-96-7 ]

Physicochemical Properties

Num. heavy atoms : 16
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.83
Num. rotatable bonds : 4
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 57.62
TPSA : 52.6 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) : -6.77 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.66
Log Po/w (XLOGP3) : 1.28
Log Po/w (WLOGP) : 1.67
Log Po/w (MLOGP) : 1.73
Log Po/w (SILICOS-IT) : 2.23
Consensus Log Po/w : 1.91

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.79
Solubility : 3.71 mg/ml ; 0.0164 mol/l
Class : Very soluble
Log S (Ali) : -1.98
Solubility : 2.35 mg/ml ; 0.0104 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.24
Solubility : 1.31 mg/ml ; 0.00581 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.35

Safety of [ 1459-96-7 ]

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 [ 1459-96-7 ]

* 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 [ 1459-96-7 ]
  • Downstream synthetic route of [ 1459-96-7 ]

[ 1459-96-7 ] Synthesis Path-Upstream   1~21

  • 1
  • [ 106004-06-2 ]
  • [ 1459-96-7 ]
YieldReaction ConditionsOperation in experiment
50% With N,N,N,N,N,N-hexamethylphosphoric triamide; n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - -20℃; for 3.75 h; To a cooled (-300C) solution Of 1Pr2NH (18.7 niL) in THF (18O mL) was dropwise added a 2.5M solution of BuLi in hexane (53.6 niL). The mixture was stirred between -2O0C and -30°C for 20 min and then cooled to -78°C. This solution was canulated over a period of 30 min into a cooled (-780C) mixture of the title compound from Step A above (32 g) and HMPA (90 mL) in THF (440 mL) not allowing the temperature of the mixture to exceed - 7O0C. Stirring at -78°C was continued for 25 min and then the mixture was allowed to warm to room temperature over a period of 11A h. The mixture was kept at room temperature for 1 Ii and then quenched with saturated aqueous NH4Cl. The volatiles were removed by evaporation and the mixture was diluted with cyclohexane and H2O. The aqueous phase was separated and extracted with cyclohexane (3 x). The combined organic phases were washed with H2O and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated. The remaining residue was recrystallized from cyclohexane to give the title compound (13.8 g, 50percent). [MH]+ = 227.
50%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -30 - -20℃; for 0.333333 h;
Stage #2: at -78 - 20℃; for 2.91667 h;
Step B. To a cooled (-300C) solution Of 1Pr2NH (18.7 mL) in THF (180 mL) was dropwise added a 2.5M solution of BuLi in hexane (53.6 mL). The mixture was stirred between -2O0C and -3O0C for 20 min and then cooled to -78°C. This solution was canulated over a period of 30 min into a cooled (-780C) mixture of the title compound from Step A above (32 g) and HMPA (9O mL) in THF (440 mL) not allowing the temperature of the mixture to exceed -700C. Stirring at -780C was continued for 25 min and then the mixture was allowed to warm to room temperature over a period of VA h. The mixture was kept at room temperature for 1 h and then quenched with saturated aqueous NH4Cl. The volatiles were removed by evaporation and the mixture was diluted with cyclohexane and H2O. The aqueous phase was separated and extracted with cyclohexane (3 x). The combined organic phases were washed with H2O and saturated aqueous NaCl, dried (MgSO4), filtered and concentrated. The remaining residue was recrystallized from cyclohexane to give the title compound (13.8 g, 50percent). [MH]+ = 227.
Reference: [1] Australian Journal of Chemistry, 1985, vol. 38, # 11, p. 1705 - 1718
[2] Patent: WO2006/128184, 2006, A2, . Location in patent: Page/Page column 164-165
[3] Patent: WO2008/63671, 2008, A2, . Location in patent: Page/Page column 177
[4] Synthetic Communications, 2007, vol. 37, # 8, p. 1267 - 1272
[5] Patent: US6649600, 2003, B1, . Location in patent: Page/Page column 51-52
[6] Patent: US6649600, 2003, B1, . Location in patent: Page/Page column 62
[7] Patent: WO2006/12441, 2006, A1, . Location in patent: Page/Page column 32-33
[8] Patent: US2010/267738, 2010, A1, . Location in patent: Page/Page column 31-32
[9] Patent: WO2012/145569, 2012, A1, . Location in patent: Page/Page column 134; 135
[10] Patent: WO2013/3383, 2013, A1, . Location in patent: Page/Page column 64
  • 2
  • [ 94-60-0 ]
  • [ 107-04-0 ]
  • [ 1459-96-7 ]
Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 4, p. 781 - 784
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 24, p. 5731 - 5737
[3] Patent: US6649600, 2003, B1, . Location in patent: Page/Page column 62
[4] Organic Letters, 2015, vol. 17, # 2, p. 226 - 229
[5] Journal of the American Chemical Society, 2017, vol. 139, # 36, p. 12488 - 12494
  • 3
  • [ 340023-18-9 ]
  • [ 1459-96-7 ]
Reference: [1] Patent: US6649600, 2003, B1, . Location in patent: Page/Page column 60
  • 4
  • [ 174685-35-9 ]
  • [ 1459-96-7 ]
YieldReaction ConditionsOperation in experiment
3.8 g With Raney nickel In ethanol for 48 h; Inert atmosphere; Reflux [1286] A solution of dimethyl m,4H lispTO[l ,3-dithiol^ late (9.00 g) in ethanol (50 mL) was added to a suspension of Raney nickel (65.0 g) in ethanol (125 mL), and the resultant was heated to reflux for 24 hours in an argon atmosphere. After the reaction mixture was filtered using celite, Raney nickel (65.0 mL) was added to the filtrate, and the resultant was heated to reflux for 24 hours. After the reaction mixture was filtered using celite, the filtrate was concentrated under reduced pressure, thereby obtaining the title compound (3.80 g). lH NMR (400 MHz, DMSO-de)6 1.79 (12H, s), 3.63 (6H, s).
Reference: [1] Synthesis, 1996, # 1, p. 71 - 76
[2] Chemical Communications, 2008, # 46, p. 6123 - 6125
[3] Patent: WO2014/142363, 2014, A1, . Location in patent: Paragraph 1286
  • 5
  • [ 57293-62-6 ]
  • [ 1459-96-7 ]
Reference: [1] Synthesis, 1996, # 1, p. 71 - 76
[2] Patent: WO2014/142363, 2014, A1,
[3] Patent: CN101709034, 2017, B,
  • 6
  • [ 6289-46-9 ]
  • [ 1459-96-7 ]
Reference: [1] Synthesis, 1996, # 1, p. 71 - 76
[2] Patent: WO2014/142363, 2014, A1,
[3] Patent: CN101709034, 2017, B,
  • 7
  • [ 67-56-1 ]
  • [ 711-02-4 ]
  • [ 1459-96-7 ]
Reference: [1] Patent: CN101709034, 2017, B, . Location in patent: Paragraph 0007; 0024; 0026; 0027; 0034; 0035
  • 8
  • [ 1659-67-2 ]
  • [ 1459-96-7 ]
Reference: [1] Journal of Organic Chemistry, 1970, vol. 35, p. 917 - 923
  • 9
  • [ 1659-95-6 ]
  • [ 1459-96-7 ]
Reference: [1] Journal of Organic Chemistry, 1970, vol. 35, p. 917 - 923
  • 10
  • [ 100-21-0 ]
  • [ 1459-96-7 ]
Reference: [1] Journal of Organic Chemistry, 1970, vol. 35, p. 917 - 923
  • 11
  • [ 1659-96-7 ]
  • [ 1459-96-7 ]
Reference: [1] Journal of Organic Chemistry, 1970, vol. 35, p. 917 - 923
  • 12
  • [ 94-60-0 ]
  • [ 1459-96-7 ]
Reference: [1] Patent: WO2013/3383, 2013, A1,
[2] Patent: WO2012/145569, 2012, A1,
  • 13
  • [ 106004-06-2 ]
  • [ 1459-96-7 ]
  • [ 106004-05-1 ]
Reference: [1] Australian Journal of Chemistry, 1985, vol. 38, # 11, p. 1705 - 1718
  • 14
  • [ 619-81-8 ]
  • [ 1459-96-7 ]
Reference: [1] Patent: WO2012/145569, 2012, A1,
  • 15
  • [ 1459-96-7 ]
  • [ 18720-35-9 ]
YieldReaction ConditionsOperation in experiment
70% With potassium hydroxide; water In methanol at -78 - -20℃; for 3.75 h; Heating / reflux A mixture of the title compound from Step B above (20 g) and KOH (5.5 g) in MeOH/H2O (10:1, 106 mL) was heated to reflux overnight, cooled to room temperature and concentrated. The residue was diluted with EtOAc and extracted with IN aqueous NaOH (2 x 100 mL). The organic phase was dried (MgSO4), filtered and concentrated to give the starting material as a white solid. The combined aqueous phases were adjusted with 2N aqueous HCl to pH 1-2 and extracted with EtOAc (4 x 25O mL). The combined turbid organic phases were filtered through a fluted filter, washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to give the title compound as a colorless solid (13.1 g, 70percent). [MH]+ = 213.
70%
Stage #1: With potassium hydroxide; water In methanolHeating / reflux
Stage #2: With hydrogenchloride In water
Step C. A mixture of the title compound from Step B above (20 g) and KOH (5.5 g) in MeOH/H2O (10:1, 106 mL) was heated to reflux overnight, cooled to room temperature and concentrated. The residue was diluted with EtOAc and extracted with IN aqueous NaOH (2 x 10O mL). The organic phase was dried (MgSO4), filtered and concentrated to give the starting material as a white solid. The combined aqueous phases were adjusted with 2N aqueous HCl to pH 1-2 and extracted with EtOAc (4 x 250 mL). The combined turbid organic phases were filtered through a fluted filter, washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to give the title compound as a colorless solid (13.1 g, 70percent). [MH]+ = 213.
58% With water; sodium hydroxide In methanol at 20 - 75℃; for 16 h; To a mixture of dimethyl bicyclo[2.2.2]octane-l,4-dicarboxylate (2.0 g, 8.84 mmol) in 10 mL MeOH was added NaOH (0.35 g, 8.8 mmol) and 0.5 mL water. The mixture was stirred at 75 °C for 4 h and at rt for 12 h. The mixture was diluted with water and washed with Ε20. The aqueous layer was acidified to pH 2 with 1 N aq. HCl and filtered. The filtrate was extracted with CHCI3. The extract was dried and concentrated in vacuo to give 4-(methoxycarbonyl)bicyclo[2.2.2]octane-l-carboxylic acid (1.2 g, 58percent yield). To the above acid (1.2 g, 5.65 mmol) was added SOCI2 (10 mL, 5.65 mmol). The mixture was stirred for at 90 °C for 3 h. The solution was concentrated in vacuo and re- dissolved in DCM and concentrated in vacuo 3 times to remove excess SOCI2. The residue (1.0 g, 4.3 mmol) was dissolved in 10 mL THF and acetylacetone iron (III) salt (0.046 g, 0.13 mmol) was added. The orange mixture was cooled to 0 °C and (3,5- difluorophenyl)magnesium bromide (11.3 mL of a 0.5 M solution in THF, 5.64 mmol) was added dropwise. The mixture was stirred at 0 °C for 2 h. I aq. HCl was added and the mixture was extracted with EtOAc. The combined organic layers were dried (MgS04) and concentrated in vacuo. The residue was purified by flash chromatography (Si02; 10percent EtOAc: hexanes) to afford the title compound (0.9 g, 67percent yield). lK NMR (500 MHz, CDCI3) δ 7.06 - 7.12 (m, 2H), 6.93 (tt, J = 8.63, 2.24 Hz, 1H), 3.69 (s, 3H), 1.93 - 1.98 (m, 6H), 1.88 - 1.93 (m, 6H).
55%
Stage #1: With water; potassium hydroxide In methanol for 24 h; Reflux
Stage #2: With hydrogenchloride In water
A solution of dimethyl bicyclo[2.2.2]octane-l,4-dicarboxylate (58.0 g, 0.25 mol) in methanol (600 mL) was heated under reflux. To this solution was added a solution of potassium hydroxide (9.8 g, 0.175 mol) in methanol (100 mL) and water (12 mL) over 30 minutes. The reaction mixture was refluxed for 24 h. The solvent was then removed and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (2 x200 mL) to recover starting material (22.0 g), and the aqueous layer was acidified to pH 3 by addition of hydrochloric acid. A precipitate was formed and extracted with ethyl acetate (3 x 300 mL). The combined extracted were washed with brine, dried over sodium sulfate and concentrated to give the titled product (30.0 g, 0.14 mol, 55 percent yield).1H NMR(400 MHz, CDCI3) δ ppm 3.65 (s, 3H), 1.81 (s. 12H); MS (ESI) m/z 211.3 [M-H]".
120.4 g With methanol; sodium hydroxide In tetrahydrofuran at 20℃; for 15.5 h; Step 3A-3 A-4 To a solution of A.3 (149.2 g) in anhydrous tetrahydrofuran (2.2 L) was added a solution of sodium hydroxide (264 mL, 2.5 M in methanol) at room temperature, the mixture was stirred at the same temperature for 15.5 hours. The insoluble materials (material A) were collected by filtration and washed with tetrahydrofuran. The combined filtrate and washing were concentrated in vacuo. After dilution of the residue with water, the mixture was washed with hexane. To the aqueous solution was added material A obtained above, the mixture was washed with hexane and adjusted to pH 1 by addition of concentrated hydrochloric acid under cooling with ice. The mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo to give A.4 (120.4 g).
5.6 g With sodium hydroxide In methanol at 50℃; for 5 h; 10.0 g of a compound represented by the formula (I-70-1), 100 mL of methanol and 7.1 g of a 25percent sodium hydroxide aqueous solution were added to a reaction vessel, and the mixture was stirred at 50 ° C. for 5 hours. Cool and add chloroform. 10percent hydrochloric acid was added to adjust the pH of the aqueous layer to 4 to 5, and liquid separation treatment was carried out. The organic layer was washed with brine and dried over sodium sulfate. Purification by column chromatography (hexane / ethyl acetate) gave 5.6 g of a compound represented by the formula (I-70-2).

Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 24, p. 5731 - 5737
[2] Patent: WO2006/128184, 2006, A2, . Location in patent: Page/Page column 164-165
[3] Patent: WO2008/63671, 2008, A2, . Location in patent: Page/Page column 177-178
[4] Patent: WO2014/159802, 2014, A1, . Location in patent: Paragraph 00189
[5] Journal of Medicinal Chemistry, 2009, vol. 52, # 6, p. 1558 - 1568
[6] Patent: WO2012/145569, 2012, A1, . Location in patent: Page/Page column 135
[7] Organic Letters, 2015, vol. 17, # 2, p. 226 - 229
[8] Tetrahedron Letters, 1999, vol. 40, # 4, p. 781 - 784
[9] Synthesis, 1996, # 1, p. 71 - 76
[10] Journal of Organic Chemistry, 1970, vol. 35, p. 917 - 923
[11] Patent: US6649600, 2003, B1, . Location in patent: Page/Page column 52
[12] Patent: US2010/267738, 2010, A1, . Location in patent: Page/Page column 32
[13] Patent: WO2013/3383, 2013, A1, . Location in patent: Page/Page column 64
[14] Patent: WO2015/5901, 2015, A1, . Location in patent: Page/Page column 467; 468
[15] Patent: US9273058, 2016, B2, . Location in patent: Page/Page column 527; 528
[16] Patent: CN101709034, 2017, B, . Location in patent: Paragraph 0007; 0024; 0025; 0026; 0027; 0036; 0037
[17] Patent: JP2017/210409, 2017, A, . Location in patent: Paragraph 0202-0204
  • 16
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  • [ 711-02-4 ]
  • [ 18720-35-9 ]
Reference: [1] Australian Journal of Chemistry, 1986, vol. 39, p. 2061 - 2066
  • 17
  • [ 1459-96-7 ]
  • [ 1127-13-5 ]
Reference: [1] Journal of Organic Chemistry, 1970, vol. 35, p. 917 - 923
[2] Patent: WO2015/5901, 2015, A1,
[3] Patent: WO2012/145569, 2012, A1,
  • 18
  • [ 1459-96-7 ]
  • [ 78385-84-9 ]
Reference: [1] Patent: US9273058, 2016, B2,
  • 19
  • [ 1459-96-7 ]
  • [ 94994-15-7 ]
Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 4, p. 781 - 784
[2] Patent: US9273058, 2016, B2,
[3] Patent: JP2017/210409, 2017, A,
  • 20
  • [ 1459-96-7 ]
  • [ 94994-25-9 ]
Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 4, p. 781 - 784
[2] Patent: US9273058, 2016, B2,
  • 21
  • [ 1459-96-7 ]
  • [ 23062-51-3 ]
Reference: [1] Journal of Organic Chemistry, 1970, vol. 35, p. 917 - 923
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 24, p. 5731 - 5737
[3] Patent: WO2015/5901, 2015, A1,
[4] Patent: US9273058, 2016, B2,
[5] Patent: WO2012/145569, 2012, A1,
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