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Chemical Structure| 361440-67-7
Chemical Structure| 361440-67-7
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Product Details of [ 361440-67-7 ]

CAS No. :361440-67-7 MDL No. :MFCD13151933
Formula : C11H18N2O3 Boiling Point : -
Linear Structure Formula :- InChI Key :VLAGXRRGXCNITB-FXQIFTODSA-N
M.W : 226.27 Pubchem ID :51358357
Synonyms :

Calculated chemistry of [ 361440-67-7 ]

Physicochemical Properties

Num. heavy atoms : 16
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.82
Num. rotatable bonds : 4
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 62.19
TPSA : 72.63 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) : -7.2 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.91
Log Po/w (XLOGP3) : 0.68
Log Po/w (WLOGP) : 0.49
Log Po/w (MLOGP) : 0.62
Log Po/w (SILICOS-IT) : -0.15
Consensus Log Po/w : 0.71

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.41
Solubility : 8.86 mg/ml ; 0.0391 mol/l
Class : Very soluble
Log S (Ali) : -1.78
Solubility : 3.74 mg/ml ; 0.0165 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.4
Solubility : 89.5 mg/ml ; 0.395 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.12

Safety of [ 361440-67-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 361440-67-7 ]

* 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 [ 361440-67-7 ]
  • Downstream synthetic route of [ 361440-67-7 ]

[ 361440-67-7 ] Synthesis Path-Upstream   1~19

  • 1
  • [ 361440-67-7 ]
  • [ 197142-36-2 ]
Reference: [1] Patent: WO2011/82077, 2011, A1,
  • 2
  • [ 197142-36-2 ]
  • [ 361440-67-7 ]
YieldReaction ConditionsOperation in experiment
84%
Stage #1: With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -15℃; for 0.583333 h;
Stage #2: With ammonia In tetrahydrofuran; 1,4-dioxane at -30 - 20℃;
To a solution of the title compound from Step D above (1.2 g) in THF (20 ml) was added at -15°C 4- methylmorpholine (710 μl) and then isobutyl chloroformate (780 μl) over 5 minutes and stirred then for 30 minutes. The reaction mixture was cooled to -300C and EPO <DP n="117"/>treated with a solution OfNH3 in dioxane (25 ml , 0.5 M in dioxane). The reaction mixture was stirred for 30 minutes , warmed to rt and stirred overnight. The reaction mixture was acidified to pH 4.5 with 10percent aqueous citric acid and extracted with ether (3 x 50 ml). The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica (cyclohexane/EtOAc 1 : 10) to afford the title compound (1.0 g, 84 percent, MNa+ = 248).
84%
Stage #1: With C17H28N2O5; isobutyl chloroformate In tetrahydrofuran at -15℃; for 0.583333 h; Inert atmosphere
Stage #2: With ammonia In tetrahydrofuran; 1,4-dioxane at -30 - 20℃; Inert atmosphere
To a stirred solution of Step 1 compound (1.20 g, 5.28 mmol) in THF (20 mL) at -15°C under nitrogen was added 4-methylmorpholine (0.71 mL, 6.50 mmol) and then isobutyl chloroformate (0.78 mL, 6.00 mmol) over 5 min. The reaction was stirred at -15°C for 30 min, cooled to -30°C and treated with a solution of NH3 in dioxane (50 mL, 25 mmol). The reaction mixture was stirred at -30°C for 30 min, warmed to rt and stirred overnight. The reaction mixture was quenched with citric acid solution (pH 4) and extracted with ether (3 X 50 mL). The combined organic fractions were washed with brine, dried over Na2SO4 and concentrated. Purification by flash column chromatography on silica gel with EtOAc gave the Step 2 compound, 1.00 g, 84percent.
9.84 g
Stage #1: With methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -20℃; for 0.5 h; Inert atmosphere
Stage #2: With ammonia In tetrahydrofuran at -5 - 20℃; for 3 h;
250ml three bottles were added 12g compound,120 ml of tetrahydrofuran,14 g of diisopropylethylamine,cooled to -20 ° C under nitrogen, add 9.0 g of methylsulfonyl chloride, stir for 30 min and then move to -5 ° C to continue stirring, through ammonia, 2h after stopping the ventilation, to room temperature 20 stirring 1h,100 ml of tetrahydrofuran was added,and the mixture was concentrated by adding 400 ml of ethyl acetate, 50 ml of saturated aqueous ammonium chloride solution, adjusted to pH 5 with dilute hydrochloric acid, and the ethyl acetate layer was washed once with 100 ml of saturated sodium bicarbonate and concentrated to give an oil. 20 ml of ethyl acetate, 10 m i of n-heptane, and crystallized to give 9.84 g of compound 4.
Reference: [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 10, p. 2587 - 2598
[2] Patent: WO2006/116157, 2006, A2, . Location in patent: Page/Page column 114-116
[3] Patent: EP2272825, 2015, B1, . Location in patent: Paragraph 0182; 0183
[4] Patent: CN106928124, 2017, A, . Location in patent: Paragraph 0037; 0095-0100
  • 3
  • [ 709031-38-9 ]
  • [ 75-11-6 ]
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YieldReaction ConditionsOperation in experiment
68%
Stage #1: With copper(I) bromide; zinc In tert-butyl methyl ether at 20℃; for 0.5 h; Inert atmosphere
Stage #2: at 20℃; for 4.5 h; Inert atmosphere
Zinc powder (6.5 g, 0.1 mol), copper bromide (1.4 g, 0.01 mol) and methyl tert-butyl ether (100 mL) were added respectively under nitrogen atmosphere. Diiodomethane(1.66 g, 0.5 mL) was added with stirring, then the solution was heated to reflux to initiate the reaction. After initiation of the reaction, the system would continue to reflux by itself. Added diiodomethane (26.8g, 0.1 mol) dropwise, then stirring at 20 °C for 30 min. To the vessel the compound 4 (21.2 g, dissolved in 50 mL methyl tert-butyl ether) were added in a manner so that the temperature was maintained at 20°C. After complete addition (about 1 h), the reaction were stirred for another 3.5 h. After the reactionwas completed (monitored by TLC, hexane/EtOAc = 1/1.5), added saturated aqueous NaHCO3 solution (200 mL). Filtered it after 1 h stirring. The filter cake was washed with EtOAc (100 mL×2), and the filtrate was extracted with EtOAc (200 mL×2). Combination of organic phase, dried over anhydrous sodium sulfate. After removal of solvent by vacuum distillation we got a white solid. The crystallization was completed by addition of 200 mL MeOH /water (1:1 v/v) additional aging for 1 h at 20 °C. The solidwas isolated by filtration (15.4 g, 68percent), Diastereomeric ratio (dr = 40:1) was determined by HPLCanalysis. [α]D20 33.7 (c 0.71, MeOH). {lit.4d [α]D20 35.2 (c 0.71, MeOH)}. Mp 56-58 C. 1H NMR (500MHz, DMSO-d6) δ 6.30 (br s, 2H), 4.08 (s, 1H), 2.25-2.09 (m, 2H), 1.88-1.81 (m, 1H), 1.46 (s, 9H), 1.08(s, 1H), 0.41-0.29 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 172.1, 155.2, 81.7, 54.1, 38.8, 36.2, 28.4, 13.6,9.1; ESI-MS m/z: 227.2 (M+1)+; HRMS calcd for C11H18N2NaO3 (M+Na) + requires 249.1215, found249.1204.
55%
Stage #1: With diethylzinc In 1,2-dimethoxyethane; dichloromethane; toluene at -30 - -25℃; for 0.75 h;
Stage #2: at 22 - 24℃;
Stage #3: With sodium hydrogencarbonate In 1,2-dimethoxyethane; dichloromethane; water; toluene at 15℃; for 1 h;
Reactor A, was charged with Formula A compound (4 kg) dissolved in dichloromethane (18.0 L) and maintained at 20° C. A second reactor, Reactor B, was charged with dichloromethane (18.00 L) and cooled to -30° C. Reactor B was then charged with dimethoxyethane (DME) (3.36 kg), followed by a 30percent solution of diethylzinc (15.36 kg) in toluene, while maintaining the temperature between -30 and -25° C. Reactor B was then charged with diiodomethane (19.99 kg) while maintaining the reaction temperature between -30 and -25° C. After complete addition of the diiodomethane, the mixture was stirred for 45 min at -30 to -25° C. This mixture was then charged to Reactor A via a cooled pipe (-20 to -25° C.). Charging was performed slowly in portions of approximately 5percent so that the temperature of the mixture in Reactor A was maintained between 22 and 24° C. until the reaction was completed. Following completion of the reaction, the mixture in Reactor A was cooled to 5 to 10° C. The reaction mixture was then slowly charged with saturated bicarbonate solution (21.6 L) in a manner so that the reaction temperature did not exceed 15° C. Following this addition, the reaction mixture was stirred for at least 1 h while a precipitate formed. The suspension was filtered. The resulting filter cake was transferred back to the vessel, slurried again with dichloromethane (14.4 L) for 30 min, and re-filtered. Following this second filtration, the filter cake was washed with additional dichloromethane (7.2 L). The filtrates were then separated into aqueous and organic phases and the organic phase was washed with half-saturated brine (21.6 L). Solvent was then removed by vacuum at a maximum temperature of 30° C. and exchanged with heptane. A slurry of crude product in heptane was obtained. Final volume of the suspension after solvent exchange was 14.4 L. The crude product was isolated by filtration. The filter cake was washed with heptane (2.9 L) and then dried under vacuum to a constant weight. The crude yield was 2.76 kg (12.2 mol, 72percent) of (1S,3S,5S)-3-aminocarbonyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid, 1,1-dimethylethyl ester (Formula H). To purify, the crude material was slurried in an eight-fold amount of a 1:1 mixture of butyl acetate/heptane at 20 to 22° C. for 4 h. The material was filtered and the filter cake was washed with approximate 1 volume of heptane. The yield was 2.11 kg (9.33 mol, 55percent) of (1S,3S,5S)-3-aminocarbonyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid, 1,1-dimethylethyl ester (Formula H).
Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 13, p. 6233 - 6243
[2] Heterocycles, 2015, vol. 91, # 4, p. 719 - 726
[3] Patent: US2006/35954, 2006, A1, . Location in patent: Page/Page column 6-7
[4] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 4, p. 1383 - 1393
[5] Patent: EP3000893, 2016, A2, . Location in patent: Paragraph 0041; 0115
  • 4
  • [ 709031-38-9 ]
  • [ 25628-09-5 ]
  • [ 361440-67-7 ]
YieldReaction ConditionsOperation in experiment
93% With n-butyllithium; C40H54NiP2 In tetrahydrofuran; hexane at 0 - 20℃; for 16 h; Inert atmosphere In a dry three-necked flask, argon is protected. Adding ^ e40Tf (2. 2g), chiral nickel catalyst [(Ph3P)(TBu) 3P) Ni (CH2 (Ph) (Me) CH2)] (0.704 g) in anhydrous tetrahydrofuran (20 mL), cooled to 0 ° C,(S) -1-Ν-tert-butoxycarbonyl-2,3-dihydro-2-l-formamide (2. lg). And then under argon protection conditions,Slowly dropwise addition of n-butyllithium n-hexane solution (1.6111001 / 1,6.61 ^), after dripping, naturally rose to room temperature to continue to stirMix for 16 hours. A solution of undecane (1. OmL), n-pentane water (10 mL) was added from 200 mL of n-pentaneAnd 200mL of water mixed after standing stratification, take the middle layer of 10mL), stirring for 1 hour, standing stratified, organicThe phases were dried over magnesium sulfate overnight. Filtered and concentrated to give a colorless oil. The oil was on a silica gel column and the oil was madeThe mixture was homogenized in silica gel and eluted with n-hexane / ethyl acetate (20: 1) elution. The elution was complete and collectedAt the end of the product point, the eluent was concentrated under reduced pressure at 45 ° C to give a white solid, S (1S, 3S, 5S) -3- (aminocarbonylYl) -2-azabicyclo [3 · L 0] hexane-2-carboxylate (2 · lg, yield 93percent). 66> 99percent, (^> 99percent.
Reference: [1] Patent: CN106554301, 2017, A, . Location in patent: Paragraph 0040; 0041; 0042; 0043; 0044; 0045; 0046-0049
  • 5
  • [ 709031-38-9 ]
  • [ 74-95-3 ]
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YieldReaction ConditionsOperation in experiment
0.5 g With copper(I) bromide; zinc In tetrahydrofuran at 25 - 40℃; for 28 h; Inert atmosphere 500ml three-necked flask followed by adding 10g of compound 7, 12.3g of zinc powder,6.77 g of CuBr and 200 ml of tetrahydrofuran,25 ° C under stirring,N2 protection,Added dropwise CH2Br282g, warmed to 30 ° C, trifluoroacetic acid (1.5ml) was slowly added dropwise, the reaction liquid color changed from gray-green to purple-black, the reaction was initiated at 40 ° C under reaction 28h,The mixture was concentrated under reduced pressure, added with 500 mL of ethyl acetate, 200 mL of water and 200 mL of saturated aqueous sodium bicarbonate solution. The mixture was stirred, suction filtered and separated into phases. The ethyl acetate phase was concentrated and extracted with n-heptane /Ester = 20: 1 was passed through the column to give 0.5 g of compound 4 (yield 4.7percent).
Reference: [1] Patent: CN106928124, 2017, A, . Location in patent: Paragraph 0140-0142
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  • [ 178172-26-4 ]
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Reference: [1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 4, p. 1383 - 1393
[2] Journal of Organic Chemistry, 2014, vol. 79, # 13, p. 6233 - 6243
[3] Journal of Organic Chemistry, 2014, vol. 79, # 13, p. 6233 - 6243
[4] Patent: EP2272825, 2015, B1,
[5] Patent: EP3000893, 2016, A2,
[6] Patent: CN106928124, 2017, A,
  • 7
  • [ 24424-99-5 ]
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Reference: [1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 4, p. 1383 - 1393
[2] Patent: EP2272825, 2015, B1,
[3] Patent: EP3000893, 2016, A2,
  • 8
  • [ 144978-35-8 ]
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Reference: [1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 4, p. 1383 - 1393
[2] Patent: EP2272825, 2015, B1,
[3] Patent: EP3000893, 2016, A2,
  • 9
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Reference: [1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 4, p. 1383 - 1393
[2] Patent: EP2272825, 2015, B1,
[3] Patent: EP3000893, 2016, A2,
  • 10
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Reference: [1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 4, p. 1383 - 1393
[2] Patent: CN106928124, 2017, A,
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Reference: [1] Heterocycles, 2015, vol. 91, # 4, p. 719 - 726
[2] Patent: CN106554301, 2017, A,
  • 12
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Reference: [1] Heterocycles, 2015, vol. 91, # 4, p. 719 - 726
[2] Patent: EP3000893, 2016, A2,
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Reference: [1] Heterocycles, 2015, vol. 91, # 4, p. 719 - 726
[2] Patent: CN106554301, 2017, A,
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Reference: [1] Patent: EP2272825, 2015, B1,
[2] Patent: CN106928124, 2017, A,
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Reference: [1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 4, p. 1383 - 1393
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Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 13, p. 6233 - 6243
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Reference: [1] Heterocycles, 2015, vol. 91, # 4, p. 719 - 726
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Reference: [1] Patent: CN106928124, 2017, A,
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Reference: [1] Patent: CN106928124, 2017, A,
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