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Chemical Structure| 130312-02-6
Chemical Structure| 130312-02-6
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Product Details of [ 130312-02-6 ]

CAS No. :130312-02-6 MDL No. :MFCD03001711
Formula : C12H13NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :LMHWEUQNJRXMCD-UHFFFAOYSA-N
M.W : 219.24 Pubchem ID :561203
Synonyms :

Calculated chemistry of [ 130312-02-6 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 16
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.33
Num. rotatable bonds : 4
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 62.01
TPSA : 46.61 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) : -6.81 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.27
Log Po/w (XLOGP3) : 1.17
Log Po/w (WLOGP) : 1.07
Log Po/w (MLOGP) : 1.06
Log Po/w (SILICOS-IT) : 1.72
Consensus Log Po/w : 1.45

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.95
Solubility : 2.46 mg/ml ; 0.0112 mol/l
Class : Very soluble
Log S (Ali) : -1.74
Solubility : 3.95 mg/ml ; 0.018 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.83
Solubility : 0.322 mg/ml ; 0.00147 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.98

Safety of [ 130312-02-6 ]

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 [ 130312-02-6 ]

* 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 [ 130312-02-6 ]
  • Downstream synthetic route of [ 130312-02-6 ]

[ 130312-02-6 ] Synthesis Path-Upstream   1~16

  • 1
  • [ 130312-02-6 ]
  • [ 100858-32-0 ]
YieldReaction ConditionsOperation in experiment
86% With recombinant Rhodococcus erythropolis DSM 43297 ketoredutase; nicotinamide adenine dinucleotide In aq. phosphate buffer; isopropyl alcohol at 50℃; for 21 h; Enzymatic reaction General procedure: The reaction mixture containing 200 mM substrate, 1mM NAD+, 5percent (v/v) 2-propanol and 10mg crude enzyme READH in 1mL potassium phosphate buffer (100mM, pH 7.0) was incubated at 50 °C. For ChKRED20, 40percent (v/v) 2-propanol and a reaction temperature of 40 °C were applied instead. The reaction was monitored by TLC, and terminated by extracting with methyl tert-butyl ether (1 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated. The samples were subjected to chiral HPLC to determine the conversion and enantiomeric excess. The products were purified by silica gel column chromatography, and identified by NMR analysis, optical rotation measurements and mass spectrometry.
Reference: [1] Process Biochemistry, 2017, vol. 56, p. 90 - 97
  • 2
  • [ 130312-02-6 ]
  • [ 100858-33-1 ]
YieldReaction ConditionsOperation in experiment
84% With recombinant Chryseobacterium sp. CA 49 ketoreductase; nicotinamide adenine dinucleotide In aq. phosphate buffer; isopropyl alcohol at 40℃; for 24 h; Enzymatic reaction General procedure: The reaction mixture containing 200 mM substrate, 1mM NAD+, 5percent (v/v) 2-propanol and 10mg crude enzyme READH in 1mL potassium phosphate buffer (100mM, pH 7.0) was incubated at 50 °C. For ChKRED20, 40percent (v/v) 2-propanol and a reaction temperature of 40 °C were applied instead. The reaction was monitored by TLC, and terminated by extracting with methyl tert-butyl ether (1 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated. The samples were subjected to chiral HPLC to determine the conversion and enantiomeric excess. The products were purified by silica gel column chromatography, and identified by NMR analysis, optical rotation measurements and mass spectrometry.
Reference: [1] Process Biochemistry, 2017, vol. 56, p. 90 - 97
  • 3
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YieldReaction ConditionsOperation in experiment
96% With sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine In dichloromethane; dimethyl sulfoxide at 0℃; A solution of intermediate 6.iii (1.10 g) in DCM (8 mL) was cooled to 0° C. and DIPEA (2.5 mL) was added dropwise, followed by a solution of sulfur trioxide pyridine complex (1.79 g) in DMSO (6.5 mL).
The reaction mixture was stirred at 0° C. for 1 h and was quenched by the addition of water (6 mL).
The aq.
layer was extracted with Et2O/Hex (1:1, 3*5 mL) and the combined org.
layers were concentrated in vacuo.
The residue obtained after work up (Et2O/Hex 1:1) was purified by chromatography (Hex/EA 5:5) to give 1.05 g (96percent yield) of a yellowish oil.
1H NMR (DMSOd6; δ ppm): 2.48-2.61 (2H, m); 3.61-3.80 (4H, m); 5.09 (2H, s); 7.27-7.41 (5H, m).
96%
Stage #1: With pyridine-SO3 complex; N-ethyl-N,N-diisopropylamine In dichloromethane; dimethyl sulfoxide at 0℃; for 1 h;
Stage #2: With water In dichloromethane; dimethyl sulfoxide
6.iv. 3 -oxo-pyrrolidine- 1-carboxylic acid benzyl ester:A solution of intermediate .iii (1.10 g) in DCM (8 ml) was cooled to 0 0C and DIPEA (2.5 ml) was added dropwise, followed by a solution of sulfur trioxide pyridine complex (1.79 g) in DMSO (6.5 ml). The reaction mixture was stirred at 0 0C for 1 h and was quenched by the addition of water (6 ml). The aq. layer was extracted with Et2O/Hex (1 :1, 3 x 5 ml) and the combined org. layers were concentrated in vacuo. The residue obtained after work up (Et2O/Hex 1 :1) was purified by chromatography (Hex/EA 5:5) to give 1.05 g (96percent yield) of a yellowish oil. 1H NMR (DMSOd6; δ ppm): 2.48-2.61 (2H, m); 3.61-3.80 (4H, m); 5.09 (2H, s); 7.27-7.41 (5H, m).
90% With sulfur trioxide pyridine complex; dimethyl sulfoxide; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 1 h; To a stirred solution of intermediate B (15.50 g, 0.07 mol) in DCM (100 mL) was added DIPEA (35.2 mL 0.21 mol) at 0°C . A solution of pyridine sulfur trioxide (25.2g, 0.16 mol) in DMSO (70 mL) was added dropwise and the resulting mixture stirred at 0°C for 1 h. The reaction was quenched by addition of H20 and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried (Na2S04), filtered and concentrated. The crude product obtained was purified by flash chromatography (EtOAc/Pet ether=1 :2) to give compound C (13.80 g, 90percent) as yellow solid. It's structure was confirmed by LC-MS spectra. TLC:Rf=0.7(silica gel,EA:PE=1 : 1 , v/v) LC-MS :[M+23]= 242.
79% With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In acetonitrile at 70℃; for 2 h; A mixture of benzyl 3-hydroxypyrrolidinyl-1-carboxylate (14 g, 63.3 mmol) and IBX (21.3 g, 76 mmol) in acetonitrile (200 mL) was stirred at 70 °C for 2 hours. The mixture was filtered and the filtrate concentrated. The remaining residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 1:1) to give benzyl 3-oxopyrrolidinyl-1- carboxylate (11 g, 79percent) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ ppm 7.46 - 7.25 (m, 5H), 5.13 (s, 2H), 3.83 - 3.64 (m, 4H), 2.57 (s, 2H).
27% With pyridinium chlorochromate In dichloromethane at 20℃; for 72 h; Benzyl 3-hydroxypyrrolidine-1-carboxylate (0.30 g, 1.34 mmol) was dissolved in DCM (20 mL) and pyridinium chlorochromate was added (0.44 g, 2.0 mmol). The resulting slurry was stirred at room temperature for 72 h. Benzyl 3-oxopyrrolidine-1-carboxylate (0.080 g, 27percent) was isolated as a colorless oil by prep. HPLC YMC ODSA 30.x.100 mm, 20-100percent MeOH/H2O (0.1percent TFA) gradient over 10 mins at 20 mL/min flow rate at a retention time of 4.25 min. LCMS: 1.20 min [M+1] not observed (2 min gradient, MeOH/H2O 0.1percent TFA).
5.6%
Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -60 - -50℃; for 0.5 h;
Stage #2: at 20℃;
(ii) N-Benzyloxycarbonyl-3-pyrrolidinone: To a chilled (-60°C) solution of oxalyl chloride (23 mL, 98percent, 258.6 mmol) in dichloromethane (400 mL) was added dropwise a solution of anhydrous dimethyl sulfoxide (36.7 mL, 517.3 mmol) in dichloromethane (20 mL) at such a rate to keep the temperature below -40°C. The reaction mixture was then stirred at -60°C for 15 min. Then a solution of N-benzyloxycarbonyl-3-pyrrolidinol (58.22 g, step i, no more than 224.9 mmol) in dichloromethane (80 mL) was added dropwise, keeping the reaction mixture temperature below -50°C. The reaction mixture was then stirred at -60°C for 30 min before adding triethylamine (158.3 mL, 99percent, 1.125 mol). The resulting mixture was allowed to warm up to room temperature and then washed with water (600 mL), 1M HCl aqueous solution (580 mL) and water (400 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to leave 54.5 g of amber oil, which was further pumped under high vacuum with stirring at room temperature for 25 min. to give 52.08 g (5.6percent over theoretical yield) of the crude title compound suitable for the next step without any further purification.

Reference: [1] Patent: US2009/247578, 2009, A1, . Location in patent: Page/Page column 14
[2] Patent: WO2008/56335, 2008, A1, . Location in patent: Page/Page column 34
[3] Patent: WO2014/32, 2014, A1, . Location in patent: Page/Page column 51; 52
[4] Chemical Communications, 2007, # 21, p. 2136 - 2138
[5] Patent: WO2017/216726, 2017, A1, . Location in patent: Page/Page column 581
[6] Patent: US2007/161685, 2007, A1, . Location in patent: Page/Page column 126
[7] Journal of Medicinal Chemistry, 2007, vol. 50, # 12, p. 2818 - 2841
[8] Patent: EP1087934, 2004, B1, . Location in patent: Page 26
[9] Journal of Medicinal Chemistry, 1992, vol. 35, # 8, p. 1393 - 1398
[10] Patent: US2002/58809, 2002, A1,
[11] Patent: EP1553074, 2005, A1, . Location in patent: Page/Page column 51
  • 4
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 5, p. 1265 - 1268
[2] Patent: WO2005/44195, 2005, A2, . Location in patent: Page/Page column 38
[3] Patent: WO2004/43940, 2004, A1, . Location in patent: Page 48
[4] Patent: WO2005/116029, 2005, A1, . Location in patent: Page/Page column 51
[5] Patent: WO2005/108382, 2005, A1, . Location in patent: Page/Page column 38-39
[6] Patent: WO2005/44195, 2005, A2, . Location in patent: Page/Page column 38
  • 5
  • [ 100858-32-0 ]
  • [ 130312-02-6 ]
YieldReaction ConditionsOperation in experiment
88% With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide In dichloromethane for 2 h; Molecular sieve; Inert atmosphere Step 2: preparation of benzyl 3-oxopyrrolidine-1-carboxylate. To a solution ofbenzyl (3S)-3-hydroxypyrrolidine-1-carboxylate (7.5 g, 33.9 mmol) in dichloromethane(1.2 L) was added 4-methylmorpholine N-oxide (5.96 g, 50.0 mmol), tetrapropylammonium perruthenate (0.60 g, 1 .7 mmol), and 4 A molecular sieves (7.0 g). The reaction mixture was allowed to stir under nitrogen for 2 h, after which it was filtered through a silica gel plug and eluted with diethyl ether. The filtrate canconcentrated to afford the title compound as clear oil (6.5 g, 88percent).
Reference: [1] Patent: WO2014/68527, 2014, A1, . Location in patent: Page/Page column 82
  • 6
  • [ 79-37-8 ]
  • [ 95656-88-5 ]
  • [ 130312-02-6 ]
YieldReaction ConditionsOperation in experiment
86% With dimethyl sulfoxide; triethylamine In dichloromethane; water Example A
1-Benzyloxycarbonyl-3-pyrrolidone
A dichloromethane (40 ml) solution of 16.58 ml (233.6 mmol) of dimethyl sulfoxide was added dropwise to a dichloromethane (200 ml) solution of 10.19 ml (116.8 mmol) of oxalyl chloride at -78° C., and the mixture was stirred for 10 minutes at the same temperature.
To the reaction solution was added dropwise a solution of 23.50 g of literary known 1-benzyloxycarbonyl-3-hydroxypyrrolidine in 200 ml of dichloromethane at -78° C., followed by 60 minutes of stirring at the same temperature.
This solution was mixed with 74.02 ml (531.1 mmol) of triethylamine at -78° C., and stirred for 60 minutes at the same temperature and then at room temperature for 60 minutes.
After completion of the reaction, 500 ml of water was added dropwise to the reaction solution, and the organic layer was separated.
The aqueous layer was washed with dichloromethane (100 ml*2), and combined organic layer was washed with saturated brine (300 ml*1).
After drying the organic layer over sodium sulfate, the solvent was evaporated.
The resulting residue was subjected to a silica gel column chromatography to yield 20.1 g (86percent) of the title compound as an oily product from the elude of n-hexane:ethyl acetate=1:1.
1H-NMR (400 MHz, CDCl3) δ: 2.58-2.62 (2H, m), 3.82-3.87 (4H, m), 5.18 (2H, s), 7.30-7.37 (5H, m).
Reference: [1] Patent: US6469023, 2002, B1,
  • 7
  • [ 114615-82-6 ]
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  • [ 130312-02-6 ]
Reference: [1] Patent: US6331545, 2001, B1,
  • 8
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  • [ 130312-02-6 ]
Reference: [1] Patent: WO2014/32, 2014, A1,
[2] Patent: WO2014/68527, 2014, A1,
[3] Patent: WO2017/216726, 2017, A1,
[4] Patent: WO2004/43940, 2004, A1,
[5] Patent: WO2005/116029, 2005, A1,
[6] Patent: WO2005/108382, 2005, A1,
[7] Patent: WO2005/44195, 2005, A2,
  • 9
  • [ 82267-35-4 ]
  • [ 130312-02-6 ]
Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 16, p. 2277 - 2280
  • 10
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Reference: [1] Journal of Medicinal Chemistry, 1992, vol. 35, # 8, p. 1393 - 1398
  • 11
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  • [ 130312-02-6 ]
Reference: [1] Patent: WO2008/56335, 2008, A1,
  • 12
  • [ 25070-76-2 ]
  • [ 130312-02-6 ]
Reference: [1] Patent: WO2008/56335, 2008, A1,
  • 13
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Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 16, p. 2277 - 2280
  • 14
  • [ 51814-19-8 ]
  • [ 130312-02-6 ]
Reference: [1] Archiv der Pharmazie, 2008, vol. 341, # 12, p. 780 - 786
  • 15
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Reference: [1] Patent: WO2008/56335, 2008, A1,
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  • [ 95656-88-5 ]
Reference: [1] Process Biochemistry, 2017, vol. 56, p. 90 - 97
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