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[ CAS No. 401564-36-1 ] {[proInfo.proName]}

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Chemical Structure| 401564-36-1
Chemical Structure| 401564-36-1
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Product Details of [ 401564-36-1 ]

CAS No. :401564-36-1 MDL No. :MFCD22665915
Formula : C13H20N2O4S Boiling Point : -
Linear Structure Formula :- InChI Key :ULXKZRPRLJGLDM-JTQLQIEISA-N
M.W : 300.37 Pubchem ID :58516805
Synonyms :

Calculated chemistry of [ 401564-36-1 ]

Physicochemical Properties

Num. heavy atoms : 20
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.77
Num. rotatable bonds : 5
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 83.7
TPSA : 92.22 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) : -7.6 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.47
Log Po/w (XLOGP3) : 0.75
Log Po/w (WLOGP) : 0.34
Log Po/w (MLOGP) : 0.27
Log Po/w (SILICOS-IT) : 0.84
Consensus Log Po/w : 0.93

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.84
Solubility : 4.29 mg/ml ; 0.0143 mol/l
Class : Very soluble
Log S (Ali) : -2.27
Solubility : 1.63 mg/ml ; 0.00542 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.1
Solubility : 23.9 mg/ml ; 0.0796 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 3.49

Safety of [ 401564-36-1 ]

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 [ 401564-36-1 ]

* 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 [ 401564-36-1 ]
  • Downstream synthetic route of [ 401564-36-1 ]

[ 401564-36-1 ] Synthesis Path-Upstream   1~10

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YieldReaction ConditionsOperation in experiment
86% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In ethyl acetate at 2 - 7℃; for 2 h; Large scale To (2S)-1-tert-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid (Compound 8a) (60.0 kg),thiazolidine (30.3 kg) and N,N-diisopropylethylamine ( 118kg) in ethyl acetate and propylphosphonic anhydride (595kg) (cyclic trimer) was added 28wpercent at 2 -7 °C in ethyl acetate (446kg) was added and the reaction mixture was 2 -4 °C stirred for 2 hours. To this reaction mixture was added 15wpercent aqueous citric acid (600kg) for distribution, and the aqueous layer with ethyl acetate (271kg) extract. The ethyl acetate layer obtained was mixed, and sequentially washed with 10wpercent aqueous solution of diammoniumphosphate (600kg) and water (300kg). The ethyl acetate layer was concentrated to a residual volume 300L, n-heptane (739kg) at 23 -25 °C added, and the mixture wasstirred at 23 -25 °C 1 hour and stirred at 1 -5 °C. The precipitated crystals were collected by filtration, with n-heptane (164 kg) were washed and driedunder reduced pressure to yield 3-[(2S)-1-tert-butoxycarbonyl-4-oxopyrrolidin-2-ylcarbonyl]thiazolidine (compound 9a) (67.8 kg, yield 86 percent)
81.7%
Stage #1: With dicyclohexyl-carbodiimide In toluene at -10 - -5℃;
Stage #2: With dmap In toluene at -6 - 5℃; for 1.33333 h;
A solution of DCC (107.8 g) in toluene (300 mL) was added to a solution of 1-(tert-butoxycarbonyl)-4-oxo-L-proline (prepared according to the process of Example 2; 100 g) in toluene (900 mL) at -5°C to - 10°C, and the reaction mixture was stirred for 30 minutes at the same temperature. Dimethylaminopyridine (1 g) and thiazolidine (46.7 g) were slowly added to the reaction mixture at a temperature of about -6°C to -2°C over a period of about 15 to 20 minutes. The reaction mixture was allowed to warm to a temperature of 0°C to 5°C, and stirred at the same temperature for 60 minutes. When the reaction was complete, the reaction mixture was quenched with deionized water (20 mL), and stirred at 20°C to 25°C for 30 minutes. The resulting mixture was filtered through a Hyflo® bed. The filtrate was washed with aqueous sodium bicarbonate solution (50 g sodium carbonate in 500 mL deionized water). The organic layer was separated and washed with an aqueous solution of sodium chloride (50 g sodium chloride in 500 mL deionized water). Activated carbon (10 g) was added to the organic layer, and the reaction mixture was stirred at 25°C to 30°C for 30 minutes. The reaction mixture was filtered through a Hyflo® bed, and concentrated at a temperature of 50°C under reduced pressure. The residue obtained was dissolved in ethyl acetate (200 mL) at 50°C to 55°C. Hexanes (800 mL) were added at 50°C to 55°C over a period of 1 to 2 hours. The reaction mixture was further cooled to a temperature of 0°C to 5°C, and stirred at the same temperature for 3 hours. The reaction mixture was filtered to obtain a solid. The solid was washed with a pre-cooled (0°C to 5°C) mixture of ethyl acetate (80 mL) and hexanes (320 mL), and dried at a temperature of 40°C to 45°C under reduced pressure to obtain tert-Butyl (2S)-4-oxo-2-(1.3-thiazolidin-3- ylcarbonyl)pyrrolidine-1-carboxylate. Yield: 81.7percent
81.7% With dmap; dicyclohexyl-carbodiimide In toluene at -6 - 5℃; for 1.33333 h; A solution of DCC (107.8 g) in toluene (300 mL) was added to a solution of 1- (tert-butoxycarbonyl)-4-oxo-L-proline (Formula V, prepared according to Example 2; 100 g) in toluene (900 mL) at -10°C to -5°C. The reaction mixture was stirred for 30 minutesat -10°C to -5°C. 4-Dimethylaminopyridine (1 g) and thiazolidine (46.7 g) were slowly added to the reaction mixture at -6°C to -2°C over a period of 15 minutes to 20 minutes. The reaction mixture was allowed to warm to 0°C to 5°C, then stirred at the same temperature for 60 minutes. When the reaction was complete, the reaction mixture was quenched with deionized water (20 mL), then stirred at 20°C to 25°C for 30 minutes. Theresulting mixture was filtered through a Hyflo® bed. The filtrate was washed with an aqueous sodium bicarbonate solution (50 g sodium carbonate in 500 mL deionized water). The organic layer was separated, then washed with an aqueous solution of sodium chloride (50 g sodium chloride in 500 mL deionized water). Activated carbon (10 g) was added to the organic layer, then the reaction mixture was stirred at 25°C to 30°C for 30 minutes.The reaction mixture was filtered through a Hyflo® bed, then concentrated at 50°C under reduced pressure. The residue obtained was dissolved in ethyl acetate (200 mL) at 50°C to 55°C. Hexanes (800 mL) were added at 50°C to 55°C over a period of one hour to 2 hours. The reaction mixture was further cooled to 0°C to 5°C, then stirred at the same temperature for 3 hours. The reaction mixture was filtered to obtain a solid. The solidwas washed with a precooled (0°C to 5°C) mixture of ethyl acetate (80 mL) and hexanes (320 mL), then dried at 40°C to 45°C under reduced pressure to obtain tert-butyl (2S)-4- oxo-2-( 1,3 -thiazolidin-3 -ylcarbonyl)pyrrolidine- 1 -carboxylate.Yield: 81.7percent HPLC Purity: 98.97 percent
Reference: [1] Patent: CN103649055, 2016, B, . Location in patent: Paragraph 0144-0147
[2] Patent: WO2015/19238, 2015, A1, . Location in patent: Page/Page column 9; 10
[3] Patent: WO2016/79699, 2016, A1, . Location in patent: Page/Page column 12
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YieldReaction ConditionsOperation in experiment
55% With sulfur trioxide pyridine complex; triethylamine In dichloromethane; dimethyl sulfoxide for 2 h; Cooling with ice A mixture of N-tert-butoxycarbonyl-l-trans-hydroxyproline (6a) (69.4 g, 0.3 mol), thiazolidine (29.4 g, 0.33 mmol), HOBT (50.5 g, 0.33 mol) and EDC (63.3 g, 0.33 mol) in DMF (300 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. To the residue was added a saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure to give 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxypyrrolidin-2-ylcarbonyl]thiazolidine (56.3 g, 62percent) as a colorless oil. To a solution of the above compound (55.4 g, 183 mmol) and triethylamine (46 mL, 330 mmol) in dichloromethane (350 mL) was added sulfur trioxide-pyridine complex (52.4 g, 329 mmol) in DMSO (150 mL) under ice cooling and the mixture was stirred for 2 h. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried and concentrated under reduced pressure. The residue purified by silica gel chromatography with n-hexane/ethyl acetate (1:1, v/v) to give the title compound (30.3 g, 55percent) as a white powder. 1H NMR (500 MHz, DMSO-d6): δ 1.36, 1.40 (9H, s), 2.36-2.45 (1H, m), 2.97-3.12 (3H, m), 3.62-3.71 (2H, m), 3.74-3.94 (2H, m), 4.33-4.80 (2H, m), 4.91-5.04 (1H, m).
Reference: [1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 16, p. 5033 - 5041
[2] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 11, p. 3662 - 3671
[3] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 9, p. 2618 - 2621
[4] Patent: EP1426366, 2004, A1, . Location in patent: Page 23
[5] Patent: US2005/209249, 2005, A1, . Location in patent: Page/Page column 25-26
[6] Patent: US2005/215603, 2005, A1, . Location in patent: Page/Page column 26
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YieldReaction ConditionsOperation in experiment
89%
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 2 h; Inert atmosphere
Stage #2: at 10 - 20℃; for 10 h;
In a dry and clean 1L four-port bottle, add 500ml of dichloromethane and stir.Further 50.0 g (218 mmol) of compound IV and 27.3 g (240 mmol) of compound III are added,Cool the system to 10-20 °C and add 32.4 g (240 mmol)1-Hydroxybenzotriazole, 46.0 g 240 mmol1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, under N2 protection,Temperature control 10 ~ 20 ° C, 59.2g (458mmol) N, N diisopropylethylamine was added dropwise, control 0.5-1h finished. After the completion of the dropwise addition, the temperature was maintained at 0 to 10°C for 2 hours, and the HPLC was followed until the compound IV was ≤ 1percent.The reaction solution was concentrated to 80-120 ml remaining, and 19.6 g (262 mmol) of compound II (40percent formaldehyde aqueous solution) was added dropwise to the system.After 10 hours of incubation at 10 to 20°C, the treatment was started, 250 ml of tap water was added, and the mixture was extracted with ethyl acetate (300 ml each time, extracted twice),,The organic phases were combined and washed once with 150 ml of 1 mol/L hydrochloric acid.Then wash it once with 100ml 20percent aqueous sodium chloride,The organic phase is concentrated to 60-100 ml and 250 ml of n-heptane are added dropwiseCrystallization, precipitation of white solids, cooling to 0-5 °C between 1h, filtration,The compound (S)-tert-butyl 4-oxo-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate (I) was obtained in a yield of 89.0percent. The HPLC purity was 99.2percent.
Reference: [1] Patent: CN105085510, 2018, B, . Location in patent: Paragraph 0033; 0035; 0036; 0037; 0039; 0041
  • 4
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Reference: [1] Patent: EP1308439, 2003, A1,
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Reference: [1] Patent: CN106349237, 2017, A, . Location in patent: Paragraph 0043; 0044; 0052
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 9, p. 2618 - 2621
[2] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 11, p. 3662 - 3671
[3] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 16, p. 5033 - 5041
[4] Patent: WO2015/19238, 2015, A1,
[5] Patent: WO2016/79699, 2016, A1,
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Reference: [1] Patent: WO2015/19238, 2015, A1,
[2] Patent: WO2016/79699, 2016, A1,
[3] Patent: CN106349237, 2017, A,
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Reference: [1] Patent: WO2015/19238, 2015, A1,
[2] Patent: WO2016/79699, 2016, A1,
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Reference: [1] Patent: CN106349237, 2017, A,
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Reference: [1] Patent: CN106349237, 2017, A,
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