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[ CAS No. 869886-67-9 ] {[proInfo.proName]}

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Chemical Structure| 869886-67-9
Chemical Structure| 869886-67-9
Structure of 869886-67-9 * Storage: {[proInfo.prStorage]}
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Product Details of [ 869886-67-9 ]

CAS No. :869886-67-9 MDL No. :MFCD22628898
Formula : C21H22Cl2N4O2 Boiling Point : -
Linear Structure Formula :- InChI Key :KSERXGMCDHOLSS-LJQANCHMSA-N
M.W : 433.33 Pubchem ID :11719003
Synonyms :
BVD-523;VRT752271

Calculated chemistry of [ 869886-67-9 ]

Physicochemical Properties

Num. heavy atoms : 29
Num. arom. heavy atoms : 17
Fraction Csp3 : 0.24
Num. rotatable bonds : 8
Num. H-bond acceptors : 3.0
Num. H-bond donors : 4.0
Molar Refractivity : 116.42
TPSA : 90.04 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.03 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.05
Log Po/w (XLOGP3) : 4.1
Log Po/w (WLOGP) : 4.15
Log Po/w (MLOGP) : 2.36
Log Po/w (SILICOS-IT) : 4.75
Consensus Log Po/w : 3.68

Druglikeness

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

Water Solubility

Log S (ESOL) : -5.02
Solubility : 0.00418 mg/ml ; 0.00000965 mol/l
Class : Moderately soluble
Log S (Ali) : -5.7
Solubility : 0.000871 mg/ml ; 0.00000201 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -8.15
Solubility : 0.0000031 mg/ml ; 0.0000000071 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 3.0
Synthetic accessibility : 3.59

Safety of [ 869886-67-9 ]

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 [ 869886-67-9 ]

* 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 [ 869886-67-9 ]
  • Downstream synthetic route of [ 869886-67-9 ]

[ 869886-67-9 ] Synthesis Path-Upstream   1~16

  • 1
  • [ 663611-73-2 ]
  • [ 869886-90-8 ]
  • [ 869886-67-9 ]
YieldReaction ConditionsOperation in experiment
78.81%
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at -20 - 25℃; Inert atmosphere; Large scale
Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at -30 - 25℃; Large scale
In Step 4, a dry and clean 50 L flask was purged with nitrogen for 20 mi DMF (30.20 kg) was charged into the 50 L flask reactor. Then the stirrer was started. Maintaining the temperature at 15-25°C, ASYM-112394 (3.22 kg, 2.76 kg after corrected) was added into the mixture. The mixture was stirred until the solid dissolved completely. The mixture was cooled to -10 to -20°C and 1-hydroxybenzotriazole hydrate (2.10 kg) was added into the mixture at -10 to -20°C. Then EDCI (2.41 kg) was added into the mixture in five portions at an interval of about 5-10 mm. The mixture was cooled to -20 to -30°C and ASYM-111888 (Asymchem) (1.96 kg) was added into the mixture at -20 to -30°C. Then DIEA (1.77 kg) was added into the mixture at the rate of 3-4 kg/h. The mixture was heated to 15-25°C at the rate of 5-10°C/h. The mixture was reacted at 15-25°C. After 6-8 h,the mixture was sampled and analyzed by HPLC every 2-4 h until the content of ASYM-112394 was 2percent. The mixture was cooled to 0-10°C and the reaction mixture was quenched with a solution which was prepared from ethyl acetate (28.80 kg) in purified water (12.80 kg) at 0-10°C. The mixture was extracted three times with ethyl acetate (28.80 kg). For each extraction the mixture was stirred for 20-30 mm and settled for 20-30 mm before separation. The organic phases were combined and washed twice with purified water (12.80 kg). The mixture was stirred for 20-30 mm and settled for 20-30 mm before separation for each time. Then the obtained organic phase was filtered through an in-line fluid filter. The filtrate was transferred into a 300 L glass-lined reactor. The mixture was washed twice with a 5percent acetic acid solution, which was prepared from acetic acid (2.24 kg) in purified water (42.50 kg). The solution was added at the rate of 10-20 kg/h. The organic phase was washed twice with a sodium carbonate solution, which was prepared from sodium carbonate (9.41 kg) in purified water (48.00 kg). The organic phase was washed twice with a sodium chloride solution, which was prepared from sodium chloride (16.00 kg) in purified water (44.80 kg). The organic phase was transferred into a 300 L glass-lined reactor. Anhydrous sodium sulfate (9.70 kg) was added into the mixture and the mixture was stirred for 2-4 h at 15-30°C. The mixture was filtered with a nutsche filter, which was pre-loaded with about 1 cm thick silica gel (7.50 kg). The filter cake was soaked and washed with ethyl acetate (14.40 kg) before filtration. The filtrates were combined and the combined filtrate was added into a 72 L flask through an in-line fluid filter. The mixture was concentrated at T40°C under reduced pressure (P-0.08 MPa) until 3-4 L remained. Then MTBE (4.78 kg) was added into the mixture. The mixture was cooled to 0-10°C for crystallization with stirring. After 1 h, the mixture was sampled and analyzed by wtpercentevery 1-2 h until the wtpercent of the mother liquor was 5percent or the change of wtpercent between consecutive samples was 1percent. The mixture was filtered with a vacuum filter flask and the filter cake was dried in the tray drier under nitrogen at 30-40°C until KF0.5percent. 3.55 kg of product was recovered as an off-white solid at 100percent purity.2e(°)9.1 ±0.210.0 ± 0.210.2 ± 0.211.4± 0.212.5 ± 0.212.7 ± 0.213.3 ± 0.215.2 ± 0.215.4 ± 0.216.0 ± 0.217.1 ±0.217.6 ± 0.218.2 ± 0.218.8 ± 0.219.2 ± 0.219.5 ± 0.2d space (A)9.690 ± 0.2128.869 ± 0.1788.664 ± 0.1697.742 ± 0.1357.066±0.1126.956 ± 0.1096.637 ± 0.0995.833 ± 0.0765.769 ± 0.0755.531 ± 0.0695.173 ± 0.0605.038 ± 0.0574.876 ± 0.0534.723 ± 0.0504.624 ± 0.0484.556 ± 0.046Intensity (percent)12275258215469384212100[0234] The resulting 4-(5-Chloro-2-isopropylam inopyridin-4-yl)-1 H-pyrrole-2- carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide free base was analyzed by XRPD (FIG. 1). Peaks shown in FIG. 1 are listed in Table 2, prominent peaks are listed in Table 3.Table 2: XRPD peaks observed for 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 Hpyrrole-2-carboxyl ic acid [1 -(3-ch lorophenyl)-2-hydroxyethyl]am ide free base.20.3 ± 0.220.5 ± 0.221.4± 0.221.7 ± 0.221.9± 0.223.1 ±0.223.3 ± 0.223.6 ± 0.224.3 ± 0.225.2 ± 0.225.6 ± 0.226.6 ± 0.227.0 ± 0.227.7 ± 0.227.9 ± 0.228.2 ± 0.228.7 ± 0.228.9 ± 0.229.2 ± 0.230.2 ± 0.230.6 ± 0.24.381 ± 0.0434.327 ± 0.0424.145 ± 0.0384.102 ± 0.0374.057 ± 0.0373.847 ± 0.0333.812 ± 0.0323.774 ± 0.0323.653 ± 0.0303.530 ± 0.0283.476 ± 0.0273.355 ± 0.0253.297 ± 0.0243.214 ± 0.0233.191 ± 0.0223.159 ± 0.0223.106 ± 0.0213.083 ± 0.0213.057 ± 0.0202.957 ± 0.0192.923 ± 0.019141244111213252611923713103949149Table 3: Prominent XRPD peaks for 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 Hpyrrole-2-carboxyl ic acid [1 -(3-ch lorophenyl)-2-hydroxyethyl]am ide free base.2e(°)9.1 ±0.212.5 ± 0.215.2 ± 0.215.4 ± 0.2d space (A)9.690 ± 0.2127.066±0.1125.833 ± 0.0765.769 ± 0.075Intensity (percent)1225154619.2 ± 0.219.5 ± 0.220.3 ± 0.220.5 ± 0.221.4± 0.221.7 ± 0.221.9± 0.223.1 ±0.223.3 ± 0.223.6 ± 0.224.3 ± 0.227.7 ± 0.227.9 ± 0.230.2 ± 0.24.624 ± 0.0484.556 ± 0.0464.381 ± 0.0434.327 ± 0.0424.145 ± 0.0384.102 ± 0.0374.057 ± 0.0373.847 ± 0.0333.812 ± 0.0323.774 ± 0.0323.653 ± 0.0303.214 ± 0.0233.191 ± 0.0222.957 ± 0.01912100141244111213252611131014[0235]FT-IR was performed onisopropylaminopyridin-4-yI)-1 H-pyrrole-2-carboxylica sample of 4-(5-Chloro-2-acid [1 -(3-chlorophenyl)-2-Position (cm1)681712748783807827857878Intensity0.01 740.00250.00140.00580.0010.00820.00450.00069hydroxyethyl]amide free base as described in Example 1 (FIG. 2). Observed peaks from FIG. 2 are listed in Table 4.Table 4: Observed FT-IR peaks for 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 Hpyrrole-2-carboxyl ic acid [1 -(3-ch lorophenyl)-2-hydroxyethyl]am ide free base.Position (cm1) Intensity897 0.00067916 0.00056932 0.0008996 0.00041040 0.000741080 0.00691101 0.000811126 0.000961145 0.00141170 0.00271197 0.00111208 0.00281235 0.00131255 0.00151268 0.00211294 0.00131350 0.00181364 0.0021385 0.000771398 0.000771439 0.00171451 0.00141466 0.00191487 0.00891504 0.00331523 0.00651533 0.00631568 0.00211603 0.01081629 0.00622927 0.000242974 0.000283235 0.000523405 0.00026Position (cm1) Intensity; DSC was performed on a sample of 4-(5-Chloro-2- isopropylam inopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2- hydroxyethyl]amide free base as described in Example 1 (FIG. 3) and showed an endotherm having an onset temperature of approximately 184°C.
78.81% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at -30 - 25℃; Inert atmosphere; Large scale [0151] In Step 4, a dry and clean 50 L flask was purged with nitrogen for 20 mm. DMF (30.20 kg) was charged into the 50 L flask reactor. Then the stirrer was started. Maintaining the temperature at 15-25°C, ASYM-112394 (3.22 kg, 2.76 kgafter corrected) was added into the mixture. The mixture was stirred until the solid dissolved completely. The mixture was cooled to -10 to -20°C and 1-hydroxybenzotriazole hydrate (2.10 kg) was added into the mixture at -10 to -20°C. Then EDCI (2.41 kg) was added into the mixture in five portions at an interval of about 5-10 mm. The mixture was cooled to -20 to -30°C and ASYM-1 11888 (Asymchem) (1.96 kg) was added into the mixture at -20 to -30°C. Then DIEA (1 .77 kg) was added into the mixture at the rate of 3-4 kg/h. The mixture was heated to 15-25°C at the rate of 5-10°C/h. The mixture was reacted at 15-25°C. After 6-8 h, the mixture was sampled and analyzed by HPLC every 2-4 h until the content of ASYM-112394 was 2percent. The mixture was cooled to 0-10°C and the reaction mixture was quenched with a solution which was prepared from ethyl acetate (28.80 kg) in purified water (12.80 kg) at 0-10°C. The mixture was extracted three times with ethyl acetate (28.80 kg). For each extraction the mixture was stirred for 20-30 mm and settled for 20-30 mm before separation. The organic phases were combined and washed twice with purified water (12.80 kg). The mixture was stirred for 20-30 mm and settled for 20-30 mm before separation for each time. Then the obtained organic phase was filtered through an in-line fluid filter. The filtrate was transferred into a 300 L glass-lined reactor. The mixture was washed twice with a 5percent acetic acid solution, which was prepared from acetic acid (2.24 kg) in purified water (42.50 kg). The solution was added at the rate of 10-20 kg/h. The organic phase was washed twice with a sodium carbonate solution, which was prepared from sodium carbonate (9.41 kg) in purified water (48.00 kg). The organic phase was washed twice with a sodium chloride solution, which was prepared from sodium chloride (16.00 kg) in purified water (44.80 kg). The organic phase was transferred into a 300 L glass-lined reactor. Anhydrous sodium sulfate (9.70 kg) was added into the mixture and the mixture was stirred for 2-4 h at 15-30°C. The mixture was filtered with a nutsche filter, which was pre-loaded with about 1 cm thick silica gel (7.50 kg). The filter cake was soaked and washed with ethyl acetate (14.40 kg) before filtration. The filtrates were combined and the combined filtrate was added into a 72 L flask through an in-line fluid filter. The mixture was concentrated at T40°C under reduced pressure (P-0.08 MPa) until 3-4 L remained. Then MTBE (4.78 kg) was added into the mixture. The mixture was cooled to 0-10°C for crystallization with stirring. After 1 h, the mixture was sampled and analyzed by wtpercent every 1-2 h until the wtpercent of the mother liquor was 5percent or the change of wtpercent between consecutive samples was 1 percent. The mixture was filtered with a vacuum filter flask and the filter cake was dried in the tray drier under nitrogen at 30-40°C until KF0.5percent. 3.55 kg of product was recovered as an off-white solid at 100percent purity.
64% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 20℃; 4-(5-Chloro- 2-isopropylaminopyridin-4-yl)-lH-pyrrole-2-carboxylic acid [1-(3- chlorophenyl) -2-hydroxyethyl] amide: To a suspension of 4-(5-chloro-2- isopropylaminopyridin-4-yl)-lH-pyrrole-2-carboxylic acid (1.93 g, 6.9 mmol, 1.0 equivalent) in DMF (5.0 mL) was added EDCI (1.45 g, 7.6 mmol, 1.1 equivalents), HOBt (0.94 g, 6.9 mmol, 1.0 equivalent) and (S)-3-chlorophenylglycynol (1.58 g, 7.6 mmol, 1.1 equivalents). Diisopropylethylamine (2.7 mL) was then added and the resulting mixture was stirred a room temperature overnight. The mixture was then poured into water and extracted with ethyl acetate. After drying over sodium sulfate, the solvent was removed and the crude was adsorbed on silica gel. Purification was effected by flash chromatography on silica, eluting with mixtures of hexanes/acetone (from 80: 20 to 60: 40) to afford the title compound as white solid (1.9 g, 64percent). Rt(min) 4.981s. FIA MS: 433.1 ES+; 431.2 ES-. (at)HNMR (CD30D) 8 1.31 (d, 6H), 3.85 (in, 3H), 5.15 (t, 1H), 7.01 (s, 1H), 7.25 (m, 3H), 7.4 (s, 1H), 7.45 (s, 1H), 7.7 (s, 1H), 7.95 (s, 1H).
Reference: [1] Patent: WO2016/123574, 2016, A1, . Location in patent: Paragraph 0233; 0234; 0235; 0236
[2] Patent: WO2016/123581, 2016, A1, . Location in patent: Paragraph 146; 0151; 0152; 0153; 0154
[3] Patent: WO2005/113541, 2005, A1, . Location in patent: Paragraph 0089
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Reference: [1] Patent: WO2016/123574, 2016, A1,
[2] Patent: WO2016/123581, 2016, A1,
[3] Patent: WO2005/113541, 2005, A1,
[4] Patent: WO2005/113541, 2005, A1,
[5] Patent: WO2005/113541, 2005, A1,
[6] Patent: WO2005/113541, 2005, A1,
  • 3
  • [ 869886-87-3 ]
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Reference: [1] Patent: WO2016/123574, 2016, A1,
[2] Patent: WO2016/123581, 2016, A1,
[3] Patent: WO2005/113541, 2005, A1,
[4] Patent: WO2005/113541, 2005, A1,
[5] Patent: WO2005/113541, 2005, A1,
[6] Patent: WO2005/113541, 2005, A1,
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  • [ 869886-90-8 ]
  • [ 620616-08-2 ]
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Reference: [1] Patent: WO2005/113541, 2005, A1, . Location in patent: Paragraph 0090
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  • [ 869886-85-1 ]
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Reference: [1] Patent: WO2005/113541, 2005, A1,
[2] Patent: WO2005/113541, 2005, A1,
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Reference: [1] Patent: WO2005/113541, 2005, A1,
[2] Patent: WO2005/113541, 2005, A1,
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Reference: [1] Patent: WO2005/113541, 2005, A1,
[2] Patent: WO2005/113541, 2005, A1,
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  • [ 869886-84-0 ]
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Reference: [1] Patent: WO2005/113541, 2005, A1,
[2] Patent: WO2005/113541, 2005, A1,
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  • [ 869886-86-2 ]
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Reference: [1] Patent: WO2005/113541, 2005, A1,
[2] Patent: WO2005/113541, 2005, A1,
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Reference: [1] Patent: WO2005/113541, 2005, A1,
[2] Patent: WO2005/113541, 2005, A1,
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Reference: [1] Patent: WO2005/113541, 2005, A1,
[2] Patent: WO2005/113541, 2005, A1,
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Reference: [1] Patent: WO2005/113541, 2005, A1,
[2] Patent: WO2005/113541, 2005, A1,
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Reference: [1] Patent: WO2005/113541, 2005, A1,
[2] Patent: WO2005/113541, 2005, A1,
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  • [ 869886-88-4 ]
  • [ 869886-67-9 ]
Reference: [1] Patent: WO2016/123574, 2016, A1,
[2] Patent: WO2016/123581, 2016, A1,
[3] Patent: WO2005/113541, 2005, A1,
[4] Patent: WO2005/113541, 2005, A1,
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  • [ 869886-89-5 ]
  • [ 869886-67-9 ]
Reference: [1] Patent: WO2005/113541, 2005, A1,
[2] Patent: WO2005/113541, 2005, A1,
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  • [ 869886-92-0 ]
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Reference: [1] Patent: WO2005/113541, 2005, A1,
[2] Patent: WO2005/113541, 2005, A1,
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