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Product Details of [ 197142-34-0 ]

CAS No. :197142-34-0 MDL No. :MFCD08691405
Formula : C11H17NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :VXIIZQXOIDYWBS-PRJMDXOYSA-N
M.W : 227.26 Pubchem ID :11020613
Synonyms :

Calculated chemistry of [ 197142-34-0 ]

Physicochemical Properties

Num. heavy atoms : 16
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.82
Num. rotatable bonds : 4
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 61.06
TPSA : 66.84 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.74 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.95
Log Po/w (XLOGP3) : 1.33
Log Po/w (WLOGP) : 1.09
Log Po/w (MLOGP) : 1.03
Log Po/w (SILICOS-IT) : 0.09
Consensus Log Po/w : 1.1

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.82
Solubility : 3.42 mg/ml ; 0.015 mol/l
Class : Very soluble
Log S (Ali) : -2.33
Solubility : 1.05 mg/ml ; 0.00462 mol/l
Class : Soluble
Log S (SILICOS-IT) : -0.19
Solubility : 148.0 mg/ml ; 0.65 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.14

Safety of [ 197142-34-0 ]

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 [ 197142-34-0 ]

* 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 [ 197142-34-0 ]
  • Downstream synthetic route of [ 197142-34-0 ]

[ 197142-34-0 ] Synthesis Path-Upstream   1~16

  • 1
  • [ 197142-33-9 ]
  • [ 197142-34-0 ]
YieldReaction ConditionsOperation in experiment
65% With sodium periodate; ruthenium(III) trichloride hydrate In tetrachloromethane; water; acetonitrile A mixture of tert-butyl (3S)-3-(hydroxymethyl)-2-azabicyclo[3.1 .0]hexane-2-carboxylate (900 mg, 4.22 mmol, 1.00 equiv) in CH3CN (10 mL)/CC14 (10 mL), NaTO4 (2.72 g, 12.72 mmol, 3.00 equiv) in water (10 mL), and RuC13.H20 (44 mg, 0.20 mmol) was stirred for overnight at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in the title compound (620 mg, 65percent) as a brown solid.
Reference: [1] Angewandte Chemie (International Edition in English), 1997, vol. 36, # 17, p. 1881 - 1884
[2] Patent: WO2015/52264, 2015, A1, . Location in patent: Paragraph 01524; 01525
[3] Patent: WO2012/18325, 2012, A1, . Location in patent: Page/Page column 145
[4] Patent: WO2012/48421, 2012, A1, . Location in patent: Page/Page column 26; 29
[5] Angewandte Chemie - International Edition, 2015, vol. 54, # 45, p. 13268 - 13272[6] Angew. Chem., 2015, # 45, p. 13466 - 13470,4
  • 2
  • [ 24424-99-5 ]
  • [ 1312338-82-1 ]
  • [ 197142-34-0 ]
YieldReaction ConditionsOperation in experiment
79%
Stage #1: With sodium ethanolate In ethanol; isopropyl alcohol at 50℃; for 1 h;
Stage #2: With water In ethanol; isopropyl alcohol at 60℃; for 18 h;
A I L round bottom flask equipped with a nitrogen inlet, overhead agitator, thermocouple and heating mantle was charged with 50 g (225 mmol) (lR,3R,5R)-2- Azabicyclo[3.1.0]hexane-3-carboxamide (.CH3SO3H) and 250 mL isopropanol. The resulting slurry was then charged with 252 mL of 23 wtpercent NaOEt in EtOH (2.68 M, 675 mmol, 3.0 equiv) and stirred at 50 °C for ca. lh. The mixture was charged with 12.2 mL (675 mmol, 3 equiv) of water and heated to 60 °C. The resulting slurry was allowed to stir at 60 °C for ca. 18h. The slurry was cooled to rt and charged with 250 mL water and 98.2 g (450 mmol, 2.0 equiv) di-/-butyldicarbonate. Ethanol and isopropanol were removed via vacuum distillation and the aqueous mixture cooled to 0 °C. The mixture was neutralized with 76 ml (456 mmol) 6M aqueous HC1 while maintaining an internal temperature < 5 °C. The product was extracted with 500 mL MTBE and the rich organic layer was washed with 100 mL water. The clear solution was concentrated down to 150 mL via vacuum distillation and the resulting slurry was charged with 600 mL heptane while maintaining an internal temperature >45 °C. The slurry was cooled to rt over ca. 30 min and allowed to stir at rt for ca. 2h. The product was filtered, washed with 250 mL 4: 1 heptane :MTBE and dried under vacuum at 70 °C to give 40.5 g (178 mmol, 79percent yield, 99.8 AP at 205 nm) of (lR,3S,5R)-2-(tert-butoxycarbonyl)-2- azabicyclo[3.1.0]hexane-3-carboxylic acid: 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 4.02-3.80 (m, 1H), 3.45-3.15 (m, 1H), 2.40-2.19 (m, 1H), 2.19-2.0 (m, 1H), 1.70- 1.50 (m, 1H), 1.50-1.20 (m, 9H), 0.83-0.60 (m, 1H), 0.33-0.55 (m, 1H); 13C MR (100 MHz, DMSO-d6) δ 173.7, 173.2, 155.0, 154.3, 79.4, 60.5, 60.2, 37.6, 32.6, 31.8, 28.4, 28.2, 15.6, 15.2, 14.4; HRMS calcd for C11H18N04 (M + H; ESI+): 228.1236. Found: 228.1234.
Reference: [1] Patent: WO2011/59850, 2011, A1, . Location in patent: Page/Page column 179-180
  • 3
  • [ 1208008-34-7 ]
  • [ 197142-34-0 ]
YieldReaction ConditionsOperation in experiment
59% With sodium periodate In tetrachloromethane; water; acetonitrile for 1.25 h; A semi-solution of NaIC>;4 (6.46 g, 30.2 mmol) in H2O (31 mL) was added to a solution of alcohol M3e-l/-2 (2.15 g, 10.08 mmol) in CH3CN (20 mL) and CCl4 (20 mL). RuCl3 (0.044 g, 0.212 mmol) was added immediately and the heterogeneous reaction mixture was stirred vigorously for 75 min. The reaction mixture was diluted with H2O (60 mL) and extracted with CH2CI2 (50 mL, 3x). The combined organic phase was treated with 1 mL MeOH, allowed to stand for about 5 min, and then filtered through a pad of diatomaceous earth (CELITE.(R).). The CELITE.(R). was washed with CH2Cl2 (50 mL)>; and the filtrate was concentrated in vacuo to afford a light charcoal-colored solid. 1H-NMR analysis of this crude material indicated a 1.00:0.04:0.18 mole ratio of trans acid M3f-1 :cis acid M3f-2 presumed side product, tert-butyl 3-oxo-2-azabicyclo[3.1.0]hexane-2-carboxylate, The crude material was dissolved in EtOAc (~10 mL) with heating and allowed to stand at ambient temperature with seeding. About 15 min into the cooling phase, a rapid crystal formation was observed. About 1 h later, hexanes (~6 mL) was added and the mixture refrigerated overnight (it did not appear that additional material precipitated out). The mixture was filtered and washed with ice/water-cooled hexanes/EtOAc (2:1 ratio; 20 mL) and dried under high vacuum to afford the first crop of acid M3f-1 (off-white crystals, 1,222 g). The mother liquor was concentrated in vacuo, and the residue dissolved in ~-3 mL of EtOAc with heating, allowed to stand at ambient temperature for 1 h, and then 3 mL hexanes was added and stored in a refrigerator for -15 h. A second crop of acid M3f-1 was retrieved similarly (grey crystals, 0.133 g), for a combined yield of 59percent. Acid M3f-1 : Rt = 1.48 min under the following HPLC conditions: Solvent gradient from 100percent A : 0percent B to 0percent A : 100percent B (A - 0.1percent TFA in 1:9 MeOH/H2O; B = 0.1percent TFA in 9:1 MeOH/H2O) over 3 min; detection (at) 220 nm; PHENOMENEX.(R).-Luna 3.0X50 mm S 10 column. MP (dec.) for the first crop - 147.5-149.5 0C. 1H-NMR (400 MHz, DMSO-d6} δ = 2.5 ppm) 12.46 (s, IH), 3.88 (app br s, IH), 3.27 (app br s, IH; overlapped with water signal), 2.28 (br m, IH), 2.07 (app br s, IH), 1.56 (app s, IH), 1.40/1.34 (two overlapped s, 9H), 0.71 (m, IH), 0.45 (m, IH). 13C-NMR (100.6 MHz1 DMSOd6, δ - 39.21 ppm) 172.96, 172.60, 154.45, 153.68, 78.74, 59.88, 59.58, 36.91, 31.97, 31.17, 27.77, 27.52, 14.86, 14.53, 13.69. LC/MS [M+Naf = 250.22. Anal. Calcd. for CnHi7NO4: C, 58.13; H, 7.54; N, 6.16. Found (for first crop): C, 58.24; H, 7.84; N, 6.07. Optical rotation (10 mg/mL in CHCl3): [α]D = -216 and -212 for the first and second crop, respectively.
Reference: [1] Patent: WO2010/117635, 2010, A1, . Location in patent: Page/Page column 100-101
  • 4
  • [ 1208008-34-7 ]
  • [ 197142-34-0 ]
  • [ 197142-36-2 ]
YieldReaction ConditionsOperation in experiment
59% With sodium periodate; water In tetrachloromethane; acetonitrile for 1.25 h; OfNaIO4 (6.46 g, 30.2 mmol) in H2O (31 mL) was added to a solution of alcohol M46e-l/-2 (2.15 g, 10.08 mmol) in CH3CN (20 mL) and CCl4 (20 mL). RuCl3 (0.044 g, 0.212 mmol) was added immediately and the heterogeneous reaction mixture was stirred vigorously for 75 min. The reaction mixture was diluted with H2O (60 mL) and extracted with CH2Cl2 (50 mL, 3x). The combined organic phase was treated with 1 mL MeOH, allowed to stand for about 5 min, and then filtered through a pad of diatomaceous earth (Celite.(R).). The Celite.(R). was washed with CH2Cl2 (50 mL), and the filtrate was concentrated in vacuo to afford a light charcoal- colored solid. 1H-NMR analysis of this crude material indicated a 1.00:0.04:0.18 mole ratio of trans acid M46f-1 :cis acid M46f-2:presumed side product, tert-bntyl 3- oxo-2-azabicyclo[3.1.0]hexane-2-carboxylate. The crude material was dissolved in EtOAc (-10 mL) with heating and allowed to stand at ambient temperature with seeding. About 15 min into the cooling phase, a rapid crystal formation was observed. About 1 h later, hexanes (~6 mL) was added and the mixture refrigerated overnight (it did not appear that additional material precipitated out). The mixture was filtered and washed with ice/water-cooled hexanes/EtOAc (2:1 ratio; 20 mL) and dried under high vacuum to afford the first crop of acid M46f-1 (off-white crystals, 1.222 g). The mother liquor was concentrated in vacuo, and the residue dissolved in ~3 mL of EtOAc with heating, allowed to stand at ambient temperature for 1 h, and then 3 mL hexanes was added and stored in a refrigerator for ~15 h. A second crop of acid M46f-1 was retrieved similarly (grey crystals, 0.133 g), for a combined yield of 59percent. Acid M46f-1: Rt = 1.48 min under the following HPLC conditions: Solvent gradient from 100percent A : 0percent B to 0percent A : 100percent B (A = 0.1percent TFA in 1 :9 MeOH/H2O; B = 0.1percent TFA in 9:1 MeOHZH2O) over 3 min; detection (at) 220 nm; Phenomenex- Luna 3.0X50 mm SlO column. MP (dec.) for the first crop = 147.5-149.5 0C. 1H- NMR (400 MHz, DMSO-d6, δ = 2.5 ppm) 12.46 (s, IH), 3.88 (app br s, IH), 3.27 (app br s, IH; overlapped with water signal), 2.28 (br m, IH), 2.07 (app br s, IH), 1.56 (app s, IH), 1.40/1.34 (two overlapped s, 9H), 0.71 (m, IH), 0.45 (m, IH). 13C- NMR (100.6 MHz, DMSO-de, δ - 39.21 ppm) 172.96, 172.60, 154.45, 153.68, 78.74, 59.88, 59.58, 36.91, 31.97, 31.17, 27.77, 27.52, 14.86, 14.53, 13.69. LC/MS [M+Naf = 250.22. Anal. Calcd. for C11H17NO4: C, 58.13; H, 7.54; N, 6.16. Found (for first crop); C, 58.24; H, 7.84; N, 6.07. Optical rotation (10 mg/raL in CHCl3): [α]r> = -216 and -212 for the first and second crop, respectively.
Reference: [1] Patent: WO2010/17401, 2010, A1, . Location in patent: Page/Page column 71
  • 5
  • [ 1208008-34-7 ]
  • [ 197142-34-0 ]
YieldReaction ConditionsOperation in experiment
59% With ruthenium trichloride; sodium periodate In tetrachloromethane; water; acetonitrile for 1.25 h; A semi-solution of NaI04 (6.46 g, 30.2 mmol) in water (31 mL) was added to a solution of (3S)-tert-butyl 3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (mixture of cis/trans isomers) (2.15 g, 10.08 mmol) in CH3CN (20 mL) and CCl4 (20 mL). RuCl3 (0.044 g, 0.212 mmol) was added immediately and the heterogeneous reaction mixture was stirred vigorously for 75 min. The reaction mixture was diluted with water (60 mL) and extracted with CH2CI2 (50 mL, 3x). The combined organic phases was treated with 1 mL MeOH, allowed to stand for about 5 min and then filtered through a pad of diatomaceous earth (CELITE.(R).). The pad was washed with CH2CI2 (50 mL) and the filtrate was concentrated in vacuo to afford a light charcoal-colored solid. The crude material was dissolved in EtOAc (~10 mL) with heating and allowed to stand at ambient temperature with seeding. About 15 min into the cooling phase, a rapid crystal formation was observed. About 1 h later, hexanes (~6 mL) was added and the mixture refrigerated overnight (it did not appear that additional material precipitated out). The mixture was filtered and washed with ice/water-cooled hexanes/EtOAc (2: 1 ratio; 20 mL) and dried under high vacuum to afford the first crop of (lR,3S,5R)-2-(tert- butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (off-white crystals, 1.222 g). The mother liquor was concentrated in vacuo and the residue dissolved in ~3 mL of EtOAc with heating, allowed to stand at ambient temperature for 1 h and then 3 mL hexanes was added and stored in a refrigerator for ~15 h. A second crop of (1R,3S,5R)- 2-(/er/-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid was retrieved similarly (grey crystals, 0.133 g), for a combined yield of 59percent. LC/MS [M+Na]+ = 250.22. Rt = 1.48 min under the following HPLC conditions: Solvent gradient from 100percent A : 0percent B to 0percent A : 100percent B (A = 0.1percent TFA in 1 :9 methanol/water; B = 0.1percent TFA in 9: 1 methanol/water) over 3 min; detection at 220 nm; PHENOMENEX.(R). Luna 3.0X50 mm S10 column. MP (dec.) for the first crop = 147.5-149.5 °C. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.46 (s, 1H), 3.88 (app br s, 1H), 3.27 (app br s, 1H; overlapped with water signal), 2.28 (br m, 1H), 2.07 (app br s, 1H), 1.56 (app s, 1H), 1.40/1.34 (two overlapped s, 9H), 0.71 (m, 1H), 0.45 (m, 1H). 13C-NMR (100.6 MHz, DMSO-d6) 172.96, 172.60, 154.45, 153.68, 78.74, 59.88, 59.58, 36.91, 31.97, 31.17, 27.77, 27.52, 14.86, 14.53, 13.69. Anal. Calcd. for C11H17NO4: C, 58.13;H, 7.54; N, 6.16. Found (for first crop): C, 58.24;H, 7.84; N, 6.07. Optical rotation (10 mg/mL in CHC13): [a] D = - 216 and -212 for the first and second crop, respectively.
Reference: [1] Patent: WO2011/59850, 2011, A1, . Location in patent: Page/Page column 178-179
  • 6
  • [ 1208008-34-7 ]
  • [ 1310363-30-4 ]
  • [ 197142-34-0 ]
  • [ 197142-36-2 ]
YieldReaction ConditionsOperation in experiment
59% With ruthenium trichloride; sodium periodate In tetrachloromethane; water; acetonitrile for 1.25 h; General procedure:  A semi-solution of NaIO4(6.46 g, 30.2 mmol) in H2O (31 mL) was added to a solution of alcohol10a/b (2.15 g, 10.08 mmol) in CH3CN(20 mL) and CCl4 (20 mL). RuCl3(0.044 g, 0.212 mmol) was added immediately and the heterogeneous reactionmixture was stirred vigorously for 75 min. The reaction mixture was diluted with H2O(60 mL) and extracted with CH2Cl2 (50 mL, 3x). The combined organic phase was treated with 1mL MeOH, allowed to stand for about 5 min, and then filtered through a pad ofCelite. The Celite was washed with CH2Cl2(50 mL), and the filtrate was concentrated invacuo to afford a light charcoal-colored solid. 1H-NMR analysis of this crudematerial indicated a 1.00:0.04:0.18 mole ratio of trans acid 3a : cis acid 3b : side product tert-butyl3-oxo-2-azabicyclo[3.1.0]hexane-2-carboxylate (12). The crude material wasdissolved in EtOAc (~10 mL) with heating and allowed to stand at ambient temperaturewith seeding. About 15 min into thecooling phase, a rapid crystal formation was observed. About 1 h later, hexanes (~6 mL) was added andthe mixture refrigerated overnight (it did not appear that additional materialprecipitated out). The mixture wasfiltered and washed with ice/water-cooled hexanes/EtOAc (2:1 ratio; 20 mL) anddried under high vacuum to afford the first crop of acid 3a (off-white crystals, 1.222 g). The mother liquor was concentrated in vacuo, and the residue dissolved in~3 mL of EtOAc with heating, allowed to stand at ambient temperature for 1 h,and then 3 mL hexanes was added and stored in a refrigerator for ~15 h. A second crop of acid 3a was retrieved similarly (grey crystals, 0.133 g), for a combinedyield of 59percent. Acid 3a: Rt = 1.48 min under the following HPLC conditions:Solvent gradient from 100percent A : 0percent B to 0percent A : 100percent B (A = 0.1percent TFA in 1:9MeOH/H2O; B = 0.1percent TFA in 9:1 MeOH/H2O) over 3 min;detection 220 nm; Phenomenex-Luna 3.0X50 mm S10 column. MP (dec.) for the first crop = 147.5-149.5°C. 1H-NMR (400 MHz, DMSO-D6,d =2.5 ppm) 12.46 (s, 1H), 3.88 (app br s, 1H), 3.27 (app br s, 1H; overlappedwith water signal), 2.28 (br m, 1H), 2.07 (app br s, 1H), 1.56 (app s, 1H),1.40/1.34 (two overlapped s, 9H), 0.71 (m, 1H), 0.45 (m, 1H). 13C-NMR (100.6 MHz, DMSO-D6,d =39.21 ppm) 172.96, 172.60, 154.45, 153.68, 78.74, 59.88, 59.58, 36.91, 31.97,31.17, 27.77, 27.52, 14.86, 14.53, 13.69.LC/MS [M+Na]+ = 250.22.Anal. Calcd. for C11H17NO4: C, 58.13;H, 7.54; N, 6.16. Found (for first crop):C, 58.24; H, 7.84; N, 6.07. Opticalrotation (10 mg/mL in CHCl3): [a]D = -216 and-212 for the first and second crop, respectively. Characterization of pyrolidinone 12:A different setup of the above oxidation conducted on stereoisomeric mixture 11a/b (213 mg) was processed up to thework-up step similarly. Then, a silica gel mesh of the crude material wasprepared and submitted to flash chromatography (30-50percent EtOAc/hexanes) to affordpyrolidinone 12 (21 mg), containingminor unidentified impurities. 1H-NMR(400 MHz, CDCl3, d = 7.29 ppm) 3.59 (m, 1H), 2.91 (dd, J = 18.8, 7.5 Hz,1H), 2.55 (d, J = 18.8 Hz, 1H), 1.57 (s, 9H), 1.54-1.46 (m, 1H), 1.03 (m, 1H),0.47 (m, 1H). 13C-NMR (100.6MHz, CDCl3, δ = 76.65 ppm)173.2, 150.0, 82.7, 36.1, 34.6, 27.7, 14.6, 5.1. LC/MS [M+Na]+ = 220.12.
Reference: [1] Tetrahedron Letters, 2013, vol. 54, # 49, p. 6722 - 6724
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Reference: [1] Angewandte Chemie (International Edition in English), 1997, vol. 36, # 17, p. 1881 - 1884
[2] Angewandte Chemie (International Edition in English), 1997, vol. 36, # 17, p. 1881 - 1884
[3] Patent: WO2011/59850, 2011, A1,
[4] Patent: WO2012/18325, 2012, A1,
[5] Patent: WO2015/52264, 2015, A1,
[6] Angewandte Chemie - International Edition, 2015, vol. 54, # 45, p. 13268 - 13272[7] Angew. Chem., 2015, # 45, p. 13466 - 13470,4
[8] Patent: WO2012/48421, 2012, A1,
[9] Patent: WO2010/117635, 2010, A1,
  • 8
  • [ 197142-32-8 ]
  • [ 197142-34-0 ]
Reference: [1] Angewandte Chemie (International Edition in English), 1997, vol. 36, # 17, p. 1881 - 1884
[2] Patent: WO2012/18325, 2012, A1,
[3] Patent: WO2015/52264, 2015, A1,
[4] Angewandte Chemie - International Edition, 2015, vol. 54, # 45, p. 13268 - 13272[5] Angew. Chem., 2015, # 45, p. 13466 - 13470,4
[6] Patent: WO2012/48421, 2012, A1,
  • 9
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  • [ 197142-34-0 ]
Reference: [1] Patent: WO2011/59850, 2011, A1,
[2] Patent: WO2012/18325, 2012, A1,
[3] Patent: WO2015/52264, 2015, A1,
[4] Patent: WO2012/48421, 2012, A1,
[5] Patent: WO2010/117635, 2010, A1,
  • 10
  • [ 17342-08-4 ]
  • [ 197142-34-0 ]
Reference: [1] Patent: WO2011/59850, 2011, A1,
[2] Patent: WO2012/18325, 2012, A1,
[3] Patent: WO2015/52264, 2015, A1,
[4] Angewandte Chemie - International Edition, 2015, vol. 54, # 45, p. 13268 - 13272[5] Angew. Chem., 2015, # 45, p. 13466 - 13470,4
[6] Patent: WO2012/48421, 2012, A1,
[7] Patent: WO2010/117635, 2010, A1,
  • 11
  • [ 24424-99-5 ]
  • [ 197142-34-0 ]
Reference: [1] Angewandte Chemie - International Edition, 2015, vol. 54, # 45, p. 13268 - 13272[2] Angew. Chem., 2015, # 45, p. 13466 - 13470,4
[3] Patent: WO2012/48421, 2012, A1,
[4] Patent: WO2010/117635, 2010, A1,
  • 12
  • [ 1208008-33-6 ]
  • [ 197142-34-0 ]
Reference: [1] Patent: WO2011/59850, 2011, A1,
[2] Patent: WO2010/117635, 2010, A1,
  • 13
  • [ 98-79-3 ]
  • [ 197142-34-0 ]
Reference: [1] Patent: WO2012/48421, 2012, A1,
  • 14
  • [ 7149-65-7 ]
  • [ 197142-34-0 ]
Reference: [1] Patent: WO2012/48421, 2012, A1,
  • 15
  • [ 1208008-34-7 ]
  • [ 197142-34-0 ]
  • [ 197142-36-2 ]
YieldReaction ConditionsOperation in experiment
59% With sodium periodate; water In tetrachloromethane; acetonitrile for 1.25 h; OfNaIO4 (6.46 g, 30.2 mmol) in H2O (31 mL) was added to a solution of alcohol M46e-l/-2 (2.15 g, 10.08 mmol) in CH3CN (20 mL) and CCl4 (20 mL). RuCl3 (0.044 g, 0.212 mmol) was added immediately and the heterogeneous reaction mixture was stirred vigorously for 75 min. The reaction mixture was diluted with H2O (60 mL) and extracted with CH2Cl2 (50 mL, 3x). The combined organic phase was treated with 1 mL MeOH, allowed to stand for about 5 min, and then filtered through a pad of diatomaceous earth (Celite.(R).). The Celite.(R). was washed with CH2Cl2 (50 mL), and the filtrate was concentrated in vacuo to afford a light charcoal- colored solid. 1H-NMR analysis of this crude material indicated a 1.00:0.04:0.18 mole ratio of trans acid M46f-1 :cis acid M46f-2:presumed side product, tert-bntyl 3- oxo-2-azabicyclo[3.1.0]hexane-2-carboxylate. The crude material was dissolved in EtOAc (-10 mL) with heating and allowed to stand at ambient temperature with seeding. About 15 min into the cooling phase, a rapid crystal formation was observed. About 1 h later, hexanes (~6 mL) was added and the mixture refrigerated overnight (it did not appear that additional material precipitated out). The mixture was filtered and washed with ice/water-cooled hexanes/EtOAc (2:1 ratio; 20 mL) and dried under high vacuum to afford the first crop of acid M46f-1 (off-white crystals, 1.222 g). The mother liquor was concentrated in vacuo, and the residue dissolved in ~3 mL of EtOAc with heating, allowed to stand at ambient temperature for 1 h, and then 3 mL hexanes was added and stored in a refrigerator for ~15 h. A second crop of acid M46f-1 was retrieved similarly (grey crystals, 0.133 g), for a combined yield of 59percent. Acid M46f-1: Rt = 1.48 min under the following HPLC conditions: Solvent gradient from 100percent A : 0percent B to 0percent A : 100percent B (A = 0.1percent TFA in 1 :9 MeOH/H2O; B = 0.1percent TFA in 9:1 MeOHZH2O) over 3 min; detection (at) 220 nm; Phenomenex- Luna 3.0X50 mm SlO column. MP (dec.) for the first crop = 147.5-149.5 0C. 1H- NMR (400 MHz, DMSO-d6, δ = 2.5 ppm) 12.46 (s, IH), 3.88 (app br s, IH), 3.27 (app br s, IH; overlapped with water signal), 2.28 (br m, IH), 2.07 (app br s, IH), 1.56 (app s, IH), 1.40/1.34 (two overlapped s, 9H), 0.71 (m, IH), 0.45 (m, IH). 13C- NMR (100.6 MHz, DMSO-de, δ - 39.21 ppm) 172.96, 172.60, 154.45, 153.68, 78.74, 59.88, 59.58, 36.91, 31.97, 31.17, 27.77, 27.52, 14.86, 14.53, 13.69. LC/MS [M+Naf = 250.22. Anal. Calcd. for C11H17NO4: C, 58.13; H, 7.54; N, 6.16. Found (for first crop); C, 58.24; H, 7.84; N, 6.07. Optical rotation (10 mg/raL in CHCl3): [α]r> = -216 and -212 for the first and second crop, respectively.
Reference: [1] Patent: WO2010/17401, 2010, A1, . Location in patent: Page/Page column 71
  • 16
  • [ 1208008-34-7 ]
  • [ 1310363-30-4 ]
  • [ 197142-34-0 ]
  • [ 197142-36-2 ]
YieldReaction ConditionsOperation in experiment
59% With ruthenium trichloride; sodium periodate In tetrachloromethane; water; acetonitrile for 1.25 h; General procedure:  A semi-solution of NaIO4(6.46 g, 30.2 mmol) in H2O (31 mL) was added to a solution of alcohol10a/b (2.15 g, 10.08 mmol) in CH3CN(20 mL) and CCl4 (20 mL). RuCl3(0.044 g, 0.212 mmol) was added immediately and the heterogeneous reactionmixture was stirred vigorously for 75 min. The reaction mixture was diluted with H2O(60 mL) and extracted with CH2Cl2 (50 mL, 3x). The combined organic phase was treated with 1mL MeOH, allowed to stand for about 5 min, and then filtered through a pad ofCelite. The Celite was washed with CH2Cl2(50 mL), and the filtrate was concentrated invacuo to afford a light charcoal-colored solid. 1H-NMR analysis of this crudematerial indicated a 1.00:0.04:0.18 mole ratio of trans acid 3a : cis acid 3b : side product tert-butyl3-oxo-2-azabicyclo[3.1.0]hexane-2-carboxylate (12). The crude material wasdissolved in EtOAc (~10 mL) with heating and allowed to stand at ambient temperaturewith seeding. About 15 min into thecooling phase, a rapid crystal formation was observed. About 1 h later, hexanes (~6 mL) was added andthe mixture refrigerated overnight (it did not appear that additional materialprecipitated out). The mixture wasfiltered and washed with ice/water-cooled hexanes/EtOAc (2:1 ratio; 20 mL) anddried under high vacuum to afford the first crop of acid 3a (off-white crystals, 1.222 g). The mother liquor was concentrated in vacuo, and the residue dissolved in~3 mL of EtOAc with heating, allowed to stand at ambient temperature for 1 h,and then 3 mL hexanes was added and stored in a refrigerator for ~15 h. A second crop of acid 3a was retrieved similarly (grey crystals, 0.133 g), for a combinedyield of 59percent. Acid 3a: Rt = 1.48 min under the following HPLC conditions:Solvent gradient from 100percent A : 0percent B to 0percent A : 100percent B (A = 0.1percent TFA in 1:9MeOH/H2O; B = 0.1percent TFA in 9:1 MeOH/H2O) over 3 min;detection 220 nm; Phenomenex-Luna 3.0X50 mm S10 column. MP (dec.) for the first crop = 147.5-149.5°C. 1H-NMR (400 MHz, DMSO-D6,d =2.5 ppm) 12.46 (s, 1H), 3.88 (app br s, 1H), 3.27 (app br s, 1H; overlappedwith water signal), 2.28 (br m, 1H), 2.07 (app br s, 1H), 1.56 (app s, 1H),1.40/1.34 (two overlapped s, 9H), 0.71 (m, 1H), 0.45 (m, 1H). 13C-NMR (100.6 MHz, DMSO-D6,d =39.21 ppm) 172.96, 172.60, 154.45, 153.68, 78.74, 59.88, 59.58, 36.91, 31.97,31.17, 27.77, 27.52, 14.86, 14.53, 13.69.LC/MS [M+Na]+ = 250.22.Anal. Calcd. for C11H17NO4: C, 58.13;H, 7.54; N, 6.16. Found (for first crop):C, 58.24; H, 7.84; N, 6.07. Opticalrotation (10 mg/mL in CHCl3): [a]D = -216 and-212 for the first and second crop, respectively. Characterization of pyrolidinone 12:A different setup of the above oxidation conducted on stereoisomeric mixture 11a/b (213 mg) was processed up to thework-up step similarly. Then, a silica gel mesh of the crude material wasprepared and submitted to flash chromatography (30-50percent EtOAc/hexanes) to affordpyrolidinone 12 (21 mg), containingminor unidentified impurities. 1H-NMR(400 MHz, CDCl3, d = 7.29 ppm) 3.59 (m, 1H), 2.91 (dd, J = 18.8, 7.5 Hz,1H), 2.55 (d, J = 18.8 Hz, 1H), 1.57 (s, 9H), 1.54-1.46 (m, 1H), 1.03 (m, 1H),0.47 (m, 1H). 13C-NMR (100.6MHz, CDCl3, δ = 76.65 ppm)173.2, 150.0, 82.7, 36.1, 34.6, 27.7, 14.6, 5.1. LC/MS [M+Na]+ = 220.12.
Reference: [1] Tetrahedron Letters, 2013, vol. 54, # 49, p. 6722 - 6724
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