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Product Details of [ 226410-00-0 ]

CAS No. :226410-00-0 MDL No. :MFCD20661619
Formula : C6H6ClNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :YFKTWBUEAJFGRQ-UHFFFAOYSA-N
M.W : 159.57 Pubchem ID :5324605
Synonyms :

Calculated chemistry of [ 226410-00-0 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.17
Num. rotatable bonds : 2
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 37.08
TPSA : 42.09 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) : -6.19 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.75
Log Po/w (XLOGP3) : 1.52
Log Po/w (WLOGP) : 1.45
Log Po/w (MLOGP) : 0.64
Log Po/w (SILICOS-IT) : 1.89
Consensus Log Po/w : 1.45

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.02
Solubility : 1.51 mg/ml ; 0.00944 mol/l
Class : Soluble
Log S (Ali) : -2.01
Solubility : 1.55 mg/ml ; 0.00972 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.29
Solubility : 0.822 mg/ml ; 0.00515 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.64

Safety of [ 226410-00-0 ]

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 [ 226410-00-0 ]

* 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 [ 226410-00-0 ]
  • Downstream synthetic route of [ 226410-00-0 ]

[ 226410-00-0 ] Synthesis Path-Upstream   1~4

  • 1
  • [ 872-32-2 ]
  • [ 226410-00-0 ]
YieldReaction ConditionsOperation in experiment
15.41%
Stage #1: With N-chloro-succinimide In tetrachloromethane at 85℃;
Stage #2: With sodium methylate In methanol for 3 h; Reflux
5-Methyl-3,4-dihydro-2H-pyrrole (1.00 g, 12.0 mmol) was dissolved in carbon tetrachloride. To the solution was added NCS (12.85 g, 96 mmol) as a solid and reaction mixture heated to 85 0C and stirred overnight. The mixture was cooled to 0 0C and the precipitate filtered off and the solvent evaporated. The residue was dissolved in methanol and sodium methoxide (3.90 g, 72.2 mmol) was added. The resulting suspension was heated to reflux and stirred for 3 h. The methanol was evaporated and the residue suspended in Et20. The solid was filtered off and the ether evaporated. The residue was dissolved in DCM and 2M HCI was added. The biphasic solution was stirred until no SM remained. The phases were separated and the organic layer was dried over MgSO4 and evaporated to an orange oil. The crude oil was adsorbed onto silica and run on 40 g of silica with EtOAc and Hexanes to afford the title compound as an orange solid (0.2958 g, 1.854 mmol, 15.41 percent yield). 1H NMR (400 MHz, CDCI3): δ ppm 9.54 (br. s., 1 H), 6.80 (s., 1 H), 6.17 (s., 1 H), 3.83 (s, 3 H). MS: m/z 160.0 (M+1 ).
Reference: [1] Patent: WO2008/154271, 2008, A1, . Location in patent: Page/Page column 143
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 22, p. 7967 - 7978
[3] Patent: EP2612848, 2013, A1,
[4] Patent: US2013/267521, 2013, A1,
[5] Patent: WO2014/15675, 2014, A1,
[6] Patent: WO2014/15523, 2014, A1,
[7] Patent: WO2014/15830, 2014, A1,
[8] Patent: US2014/256719, 2014, A1, . Location in patent: Page/Page column
[9] Patent: WO2014/154723, 2014, A1,
[10] Patent: US2015/111887, 2015, A1,
[11] Patent: KR2017/74381, 2017, A,
[12] Patent: US2018/105527, 2018, A1,
  • 2
  • [ 124-41-4 ]
  • [ 226409-94-5 ]
  • [ 226410-00-0 ]
YieldReaction ConditionsOperation in experiment
77% at 0 - 20℃; for 2 h; 5-methyl-3,4-dihydro-2H-pyrrole (4 g, 0.05 mol) was dissolved in THF (120 mL) and N-chlorosuccinimide (51.4 g, 0.39 mol) was slowly added at 0 ° C and refluxed for 15 minutes. The reaction mixture was stirred at 70 & lt; After stirring for two and a half hours, the THF was removed under reduced pressure, extracted three times with dichloromethane and washed with brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to obtain 4,4-dichloro-5- (trichloromethyl) -3,4-dihydro-2H-pyrrole.It was used immediately for the next reaction without further purification. 4,4-Dichloro-5- (trichloromethyl) -3,4-dihydro-2H-pyrrole (2 ) (12 g, 0.05 mol) To methanol (100 mL) was added And dissolved in sodium methoxide (NaOMe) (28 wtpercent methanol) (16 g, 0.29 mol) is slowly added dropwise at 0 . The reaction mixture was reacted at room temperature for 2 hours, extracted three times with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The reaction mixture was purified by flash column chromatography (n-hexane: ethyl acetate = 5: 1) Purification yielded 6.5 g (0.04 mol, 77percent yield) of brown solid compound methyl 3-chloro-lH-pyrrole-2-carboxylate.
91.3 g at 20℃; for 2 h; Cooling with ice Intermediate 1: Methyl 3-chloro-lH-pyrrole-2-carboxylate At 55-60 °C with vigorous stirring to a mixture of NCS (107 g, 800 mmol) in THF (250 mL) in a 2 L flask was added 5-methyl-3,4-dihydro-2H-pyrrole (8.3 g, 100 mmol) in one-portion. After addition, the reaction spontaneously heated to reflux for about 5 min, then reacted at 60-70 °C for another 1.5 hours. After cooled to r.t., hexane (300 mL) and water (300 mL) were added to the mixture. The organic layer was separated, collected and concentrated. The residue was used in the next step without further purification. To a mixture of the crude 4,4-dichloro-5-(trichloromethyl)-3,4-dihydro-2H-pyrrole (240 g, 941 mmol) in MeOH (2 L) in an ice-bath was added a solution of NaOMe (324 g, 6 mol) in MeOH (1.5 L) drop-wise over an hour. After addition, the mixture was stirred at r.t. for another one hour. Then 2N HCl aq. was added to adjust its pH to 2 and the resulting was stirred at room temperature for 15 minutes. The mixture was concentrated and diluted with EtOAc (2.5 L) and water (2 L). The organic layer was separated, concentrated and purified by column chromatography eluting with EtOAc/PE and then crystallize upon standing. Methyl 3-chloro-lH-pyrrole-2-carboxylate was obtained as an orange solid (91.3 g, yield: 61percent). MS (m/z): 160.1 (M+H)+ . 1H NMR (400 MHz, DMSO-de) δ 12.05 (s, 1H), 6.98 (m, 1H), 6.21 (t, / = 2.6 Hz, 1H), 3.75 (s, 3H).
91.3 g at 20℃; for 2 h; Cooling with ice To a mixture of the crude 4,4-dichloro-5-(trichloromethyl)-3,4-dihydro-2H-pyrrole (240 g, 941 mmol) in MeOH (2 L) in an ice-bath was added a solution of NaOMe (324 g, 6 mol) in MeOH (1.5 L) drop-wise over an hour. After addition, the mixture was stirred at r.t. for another one hour. Then 2N HCl aq. was added to adjust its pH to 2 and the resulting was stirred at room temperature for 15 minutes. The mixture was concentrated and diluted with EtOAc (2.5 L) and water (2 L). The organic layer was separated, concentrated and purified by column chromatography eluting with EtOAc/PE and then crystallize upon standing. Methyl 3-chloro-1H-pyrrole-2-carboxylate was obtained as an orange solid (91.3 g, yield: 61percent). MS (m/z): 160.1 (M+H)+ . 1HNMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 6.98 (m, 1H), 6.21 (t, J= 2.6 Hz, 1H), 3.75 (s, 3H). Intermediate 2: Ethyl 3-bromo-1H-pyrrole-2-carboxylate
91.3 g
Stage #1: at 20℃; for 1 h; Cooling with ice
Stage #2: With hydrogenchloride In water at 20℃; for 0.25 h;
To a mixture of the crude 4,4-dichloro-5-(trichloromethyl)-3,4-dihydro-2H-pyrrole (240 g, 941 mmol) in MeOH (2 L) in an ice-bath was added a solution of NaOMe (324 g, 6 mol) in MeOH (1.5 L) drop-wise over an hour. After addition, the mixture was stirred at r.t. for another one hour. Then 2N HCl aq. was added to adjust its pH to 2 and the resulting was stirred at room temperature for 15 minutes. The mixture was concentrated and diluted with EtOAc (2.5 L) and water (2 L). The organic layer was separated, concentrated and purified by column chromatography eluting with EtOAc/PE and then crystallize upon standing. Methyl 3-chloro-1H-pyrrole-2-carboxylate was obtained as an orange solid (91.3 g, yield: 61percent). MS (m/z): 160.1 (M+H)+ . 1HNMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 6.98 (m, 1H), 6.21 (t, J= 2.6 Hz, 1H), 3.75 (s, 3H). Intermediate 2: Ethyl 3-bromo-1H-pyrrole-2-carboxylate
6.5 g at 0 - 20℃; for 2 h; 5-methyl-3,4-dihydro-2H-pyrrole(1) (4 g, 0.05 mol) was dissolved in THF (120 ml), to which N-chlorosuccinimide (51.4 g, 0.39 mol) was slowly added at 0° C. The mixture was stirred for 15 minutes, followed by reflux for 2.5 hours. THF was eliminated under reduced pressure. Extraction was performed with dichloromethane. The organic layer was washed with saturated brine, separated, dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure. The obtained compound 4,4-dichloro-5-(trichloromethyl)-3,4-dihydro-2H-pyrrole(2) was used for the next reaction without purification. 4,4-dichloro-5-(trichloromethyl)-3,4-dihydro-2H-pyrrole(2) (12 g, 0.05 mol) was dissolved in methanol (100 ml), to which sodium methoxide (NaOMe) (28 wt percent methanol solution) (16 g, 0.29 mol) was slowly added at 0° C., followed by reaction at room temperature for 2 hours. Extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, separated, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, eluent: hexane/ethyl acetate, 5/1) to give 6.5 g of the target compound methyl 3-chloro-1H-pyrrole-2-carboxylate(3) as a brown solid (0.04 mmol, yield: 77percent). (0560) 1H NMR (300 MHz, CDCl3) δ 9.11 ( br s, 1H, NH), 6.87 (t, J=2.7 Hz, 1H), 6.26 (t, J=2.7 Hz, 1H), 3.90 (s, 3H).

Reference: [1] Patent: KR2017/74381, 2017, A, . Location in patent: Paragraph 0223-0226
[2] Patent: US2013/267521, 2013, A1, . Location in patent: Paragraph 1077
[3] Patent: WO2014/15675, 2014, A1, . Location in patent: Page/Page column 35; 36
[4] Patent: WO2014/15523, 2014, A1, . Location in patent: Page/Page column 31
[5] Patent: WO2014/15830, 2014, A1, . Location in patent: Page/Page column 37
[6] Patent: WO2014/154723, 2014, A1, . Location in patent: Page/Page column 42
[7] Patent: US2018/105527, 2018, A1, . Location in patent: Paragraph 0558-0560
  • 3
  • [ 226409-94-5 ]
  • [ 226410-00-0 ]
YieldReaction ConditionsOperation in experiment
83% for 1.5 h; Reflux 4,4-Dichloro-5-(trichloromethyl)-3,4-dihydro-2H-pyrrole (47.4 mmol, 1.0 equiv.) was added to a solution of sodium methanolate (284.5 mmol, 6.0 equiv.) in methanol (126 ml), and the mixture was heated for 1.5 h at boiling temperature. The reaction mixture was cooled to 25° C., the solvent was concentrated under reduced pressure, the residue was taken up in diethyl ether (470 ml), and the mixture was stirred for 30 min. The resulting solid (sodium chloride) was filtered out, and the filtrate was dried over K2CO3 and concentrated under reduced pressure. The residue was taken up in DCM (600 ml), extracted with 2 N HCl (2.x.150 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude product was used in the next step without being purified further. Yield: 83percent
Reference: [1] Patent: US2010/222324, 2010, A1, . Location in patent: Page/Page column 48
[2] Tetrahedron, 1999, vol. 55, # 13, p. 4133 - 4152
[3] Journal of Medicinal Chemistry, 2010, vol. 53, # 22, p. 7967 - 7978
[4] Patent: EP2612848, 2013, A1, . Location in patent: Paragraph 0280; 0281; 0283
[5] Patent: US2015/111887, 2015, A1,
  • 4
  • [ 226409-98-9 ]
  • [ 226410-00-0 ]
YieldReaction ConditionsOperation in experiment
2.5 g With hydrogenchloride In dichloromethane; water for 0.166667 h; To a solution of 5-methyl-3,4-dihydro-2H-pyrrole (2.50 g, 30.0 mmol) in CCl4 (100 mL) was added N-chlorosuccinimide (32.00 g, 240 mmol), and the mixture was then heated to reflux for 72 hours. The reaction mixture was cooled to 0° C. The formed precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (100 mL), followed by the addition of sodium methoxide (9.80 g, 180 mmol). The resulting suspension was heated to reflux and stirred for 1.5 h. The solvent was evaporated, and the residue was suspended in ether. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) and 2 M HCl (100 mL). The biphasic solution was stirred for 10 min. The organic layer was separated, dried over MgSO4, filtered and evaporated. The crude oil was subjected to chromatography purification on silica gel eluting with EtOAc and Hexanes to afford the title compound (2.5 g, 52percent) as an orange solid. MS (ES+) C6H6ClNO2 requires: 159. found: 160 [M+H]+.
Reference: [1] Tetrahedron, 1999, vol. 55, # 13, p. 4133 - 4152
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 22, p. 7967 - 7978
[3] Patent: US2015/111887, 2015, A1, . Location in patent: Paragraph 0192; 0193
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