Structure of 3874-54-2
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 3874-54-2 |
Formula : | C10H10ClFO |
M.W : | 200.64 |
SMILES Code : | O=C(C1=CC=C(F)C=C1)CCCCl |
MDL No. : | MFCD00001007 |
InChI Key : | HXAOUYGZEOZTJO-UHFFFAOYSA-N |
Pubchem ID : | 19750 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.3 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 51.0 |
TPSA ? Topological Polar Surface Area: Calculated from |
17.07 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.2 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.59 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.45 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.1 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.78 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.02 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.79 |
Solubility | 0.323 mg/ml ; 0.00161 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.6 |
Solubility | 0.507 mg/ml ; 0.00253 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.46 |
Solubility | 0.00696 mg/ml ; 0.0000347 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
Yes |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.68 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.44 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.15 g (75%) | With hydrogenchloride; potassium iodide; triethylamine; In 1,4-dioxane; dichloromethane; water; toluene; | EXAMPLE 261 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone A mixture of 3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (3.20 g, 14 mmol), 4-chloro-4'-fluoro-butyrophenone (4.21 g, 21 mmol), triethylamine (3 mL), potassium iodide (3.48 g, 21 mmol), dioxane (25 mL), and toluene (25 mL) was stirred and refluxed for 15 h under an atmosphere of nitrogen and then evaporated under reduced pressure to remove the volatiles. The residue was triturated with a small volume of dichloromethane and decanted from the insoluble material. The process was repeated two more times and the combined dichloromethane solutions was added to 0.5N solution of hydrogen chloride in ether(200 mL). The salt that separated was filtered off, washed with ether, dissolved immediately in a minimum quantity of water and the solution extracted with ether. The ether extract was discarded and aqueous layer basified with 10% aqueous sodium hydroxide. The resulting mixture was extracted with dichloromethane (2*) and the extract dried over magnesium sulfate and stripped of the solvent under reduced pressure to yield 4.15 g (75%) of a highly viscous brown liquid. 1H NMR (CDCl3, 300 MHz) delta 1.79-2.13 (m, 6H), 2.21-2.32 (m, 1H), 2.32-2.44 (m, 2H), 2.60-2.71 (m, 1H), 2.75-2.92 (m, 2H), 2.86 (s, 3H), 2.98 (t, J=7.3 Hz, 2H), 3.04-3.16 (m, 1H), 3.16-3.35 (m, 2H), 3.55-3.64 (m, 1H), 6.39 (d, J=8.1 Hz, 1H), 6.50 (d, J=8.1 Hz, 1H), 6.64 (t, J=7.7 Hz, 1H), 7.12 (t, 2H), 8.01 (m, 2H) ppm. MS (CI): 394 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 9: Production of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-lH- pyrido- [3 ',4' :4,5] -pyrrolo [1 ,2,3-de] quinoxalin-8-(7H)-yI)-l -(4-fluorophenyl)-l- butanone; A suspension of (6bR, 10aS)-3-methyl-2,3,6b,9, 10, 1 Oa-hexahydro- 1 H- pyrido-[3',4':4,5]-pyrtauolo[l,2,3-de]quinoxaline (ca. 11.8g, ca.50mmol), 4-chloro-4'- flurobutyrophenone (15.Og, 74.8mmol), triethylamine (3OmL, 214mmol), and potassium iodide (12.6g, 76mmol) in dioxane (65 ml) and toluene (65 ml) is heated to reflux for 7 hours. After filtration and evaporation of the solvent, 200 ml of DCM is added. The DCM solution is washed with brine, dried (Na2SO4) and concentrated to approximately 55 ml. The concentrated solution is added dropwise to 600 ml of 0.5N HCl ether solution. The solid is filtered off and washed with ether and then dissolved in water. The resulting aqueous solution is basifed with 2N NaOH and extracted with DCM. The DCM layers are combined, washed with brine (2x200mL) and dried (Na2SO4). Evaporation of the solvent and chromatography of the residue over silica gel gives 4-((6bR, 10aS)-3-methyl-2,3,6b,9, 10, 1 Oa-hexahydro- 1 H-pyrido-[3 ',4' :4,5]- pyrrolo[ 1 ,2,3-de]quinoxalin-8-(7H)-yl)- 1 -(4-fluorophenyl)- 1 -butanone.[0096] Alternative to the use of dioxane, the reaction may be carried out in 3- pentanone. To a 5 L, three-necked, round-bottomed flask equipped with a mechanical stirrer, a N2 inlet, a reflux condenser, and a temperature probe is charged with 230 g of (6bR, 10aS)-3-methyl-2,3,6b,9, 10, 1 Oa-hexahydro- 1 H-pyrido-[3 ',4' :4,5]-pyrrolo[l ,2,3- dejquinoxaline (1 mol), 249.78 g of KI (1.5 mol, 1.5 equiv), 194.12 g OfPr2NEt (1.5 mol, 1.5 equiv), 301.76 g of 4-chloro-4'-fluorobutyrophenone (1.5 mol, 1.5 equiv), and 2300 mL of 3-pentanone. The resultant mixture is then heated at 95 0C (internal temperature) for 17 h, and then is checked by HPLC for reaction completion. The batch is then cooled to ca. 10 0C with an ice bath, and then is added 5% NaOH solution (2300 mL). The separated aqueous layer is then extracted with EtOAc (2300 mL). The <n="95"/>combined organic layer is filtered through a pad of silica gel (1 15 g) that is pre-packed with EtOAc. The silica gel is then flushed with EtOAc (2300 mL). The combined filtrate is concentrated under reduced pressure to afford a dark brown liquid. To the liquid is then added EtOAc (2300 mL), and is added 1.5 N HCl solution (2300 mL). The batch is stirred at rt for ca. 20 min, and layers are cut. The separated organic layer is extracted with 1.5 N HCl solution (1150 mL), and the layers are separated. The combined aqueous layer is cooled in an ice bath to ca. 10 0C, and is added EtOAc (2300 mL). To the stirring mixture is then added 25% NaOH solution (1000 mL) through an addition funnel while maintaining the internal temperature under 25 0C. The resultant mixture is stirred in an ice bath for ca. 20 min, and the layers are separated. The aqueous layer shows a pH between 11 to 12 by pH paper. The aqueous layer is back extracted with EtOAc (1 150 mL), and the layers are cut. The combined organic layer is washed with brine (1150 mL), dried over Na2SO4 (230 g), filtered, and concentrated in vacuo to afford 368.8 g of a dark brown liquid. The crude free base is stored under N2 in a dark cold room. | ||
Example 9: Production of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-lH- pyrido- [3 ',4' :4,5] -pyrrolo [1 ,2,3-de] quinoxalin-8-(7H)-yI)-l -(4-fluorophenyl)-l- butanone; A suspension of (6bR, 10aS)-3-methyl-2,3,6b,9, 10, 1 Oa-hexahydro- 1 H- pyrido-[3',4':4,5]-pyrtauolo[l,2,3-de]quinoxaline (ca. 11.8g, ca.50mmol), 4-chloro-4'- flurobutyrophenone (15.Og, 74.8mmol), triethylamine (3OmL, 214mmol), and potassium iodide (12.6g, 76mmol) in dioxane (65 ml) and toluene (65 ml) is heated to reflux for 7 hours. After filtration and evaporation of the solvent, 200 ml of DCM is added. The DCM solution is washed with brine, dried (Na2SO4) and concentrated to approximately 55 ml. The concentrated solution is added dropwise to 600 ml of 0.5N HCl ether solution. The solid is filtered off and washed with ether and then dissolved in water. The resulting aqueous solution is basifed with 2N NaOH and extracted with DCM. The DCM layers are combined, washed with brine (2x200mL) and dried (Na2SO4). Evaporation of the solvent and chromatography of the residue over silica gel gives 4-((6bR, 10aS)-3-methyl-2,3,6b,9, 10, 1 Oa-hexahydro- 1 H-pyrido-[3 ',4' :4,5]- pyrrolo[ 1 ,2,3-de]quinoxalin-8-(7H)-yl)- 1 -(4-fluorophenyl)- 1 -butanone.[0096] Alternative to the use of dioxane, the reaction may be carried out in 3- pentanone. To a 5 L, three-necked, round-bottomed flask equipped with a mechanical stirrer, a N2 inlet, a reflux condenser, and a temperature probe is charged with 230 g of (6bR, 10aS)-3-methyl-2,3,6b,9, 10, 1 Oa-hexahydro- 1 H-pyrido-[3 ',4' :4,5]-pyrrolo[l ,2,3- dejquinoxaline (1 mol), 249.78 g of KI (1.5 mol, 1.5 equiv), 194.12 g OfPr2NEt (1.5 mol, 1.5 equiv), 301.76 g of 4-chloro-4'-fluorobutyrophenone (1.5 mol, 1.5 equiv), and 2300 mL of 3-pentanone. The resultant mixture is then heated at 95 0C (internal temperature) for 17 h, and then is checked by HPLC for reaction completion. The batch is then cooled to ca. 10 0C with an ice bath, and then is added 5% NaOH solution (2300 mL). The separated aqueous layer is then extracted with EtOAc (2300 mL). The <n="95"/>combined organic layer is filtered through a pad of silica gel (1 15 g) that is pre-packed with EtOAc. The silica gel is then flushed with EtOAc (2300 mL). The combined filtrate is concentrated under reduced pressure to afford a dark brown liquid. To the liquid is then added EtOAc (2300 mL), and is added 1.5 N HCl solution (2300 mL). The batch is stirred at rt for ca. 20 min, and layers are cut. The separated organic layer is extracted with 1.5 N HCl solution (1150 mL), and the layers are separated. The combined aqueous layer is cooled in an ice bath to ca. 10 0C, and is added EtOAc (2300 mL). To the stirring mixture is then added 25% NaOH solution (1000 mL) through an addition funnel while maintaining the internal temperature under 25 0C. The resultant mixture is stirred in an ice bath for ca. 20 min, and the layers are separated. The aqueous layer shows a pH between 11 to 12 by pH paper. The aqueous layer is back extracted with EtOAc (1 150 mL), and the layers are cut. The combined organic layer is washed with brine (1150 mL), dried over Na2SO4 (230 g), filtered, and concentrated in vacuo to afford 368.8 g of a dark brown liquid. The crude free base is stored under N2 in a dark cold room. | ||
With triethylamine; potassium iodide; In 1,4-dioxane; toluene; for 7h;Reflux; | A suspension of (6bR,l0aS)-3-methyl-2,3,6b,7,8,9,l0,l0a-octahydro-lH- pyrido-[3?,4?:4,5]-pyrrolo[l,2,3-de]quinoxaline (ca. 11.8g, ca.50mmol), 4-chloro-4?- fluorobutyrophenone (15. Og, 74.8mmol), triethylamine (30mL, 2l4mmol), and potassium iodide (12.6g, 76mmol) in dioxane (65 ml) and toluene (65 ml) is heated to reflux for 7 hours. After filtration and evaporation of the solvent, 200 ml of DCM is added. The DCM solution is washed with brine, dried (Na2S04) and concentrated to approximately 55 ml. The concentrated solution is added dropwise to 600 ml of 0.5N HC1 in ether solution. The solid is filtered off and washed with ether and then dissolved in water. The resulting aqueous solution is basified with 2N NaOH and extracted with DCM. The DCM layers are combined, washed with brine (2x200mL) and dried (Na2S04). Evaporation of the solvent and chromatography of the residue over silica gel gives 4-((6bR,l0aS)-3-methyl-2,3,6b,9,l0,l0a-hexahydro-lH-pyrido-[3?,4?:4,5]- pyrrolo[l,2,3-de]quinoxalin-8-(7H)-yl)-l-(4-fluorophenyl)-l-butanone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With triethylamine; potassium iodide; In toluene; for 14h;Inert atmosphere; | 1.82 g (6.0 mmol) formula (II) 2HC1 substance is suspended in 20 ml toluene, then 1.81 g (9.0 mmol) 4-chloro-4'-fluoro butyrophenone, 5.04 ml (36.1 mmol) triethylamine and 1.50 g (9.0 mmol) dried potassium iodide are added to it. The suspension reaction mixture is then boiled for 14 hours in an argon atmosphere. After cooling the reaction mixture is filtered and the filtered out solid material is washed with toluene. The organic phase is extracted with 20 ml water, then with 20 ml saturated NaCl solution, dried over MgS04, filtered and evaporated. The raw product obtained is cleaned on silica gel using flash chromatography and dichloromethane eluent. 0.93 g (39%) formula (I) substance is obtained (light brown oil). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triethylamine; potassium iodide; sodium hydroxide; In toluene; for 14h;Inert atmosphere; | 6.15 g (10 mmol) formula (VI) compound is dissolved in 20 ml 5% NaOH solution and then the solution is extracted with toluene (20 ml, 2 c 15 ml). The unified toluene phase is dehydrated using azeotropic distillation. 3.01 g (15 mmol) 4-chloro-4'-fluoro butyrophenone, 5.86 ml (42.5 mmol) triethylamine and 2.49 g (15 mmol) dried potassium iodide is added to the 20 ml toluene solution obtained in this way. The reaction mixture is boiled for 14 hours in an argon atmosphere, then cooled and filtered. The filtrate is extracted with 10 ml water and 10 ml cone. NaCl solution, dried over Na2S04, filtered and evaporated. The residue to cleaned with flash chromatography on silica gel with a CH2CI2 - MeOH eluent. 2.68 g (68%) lumateperone (brown oil) is obtained.[a]D24 = -36,8 (c = 0.853, CHCI3). IR (film): 1737, 1686, 1616, 1597, 1504, 1326, 1156 cm 1. 1H-NMR (CDCh, 400 MHz): 8.00 (~dd, J = 5.5 Hz, J2 = 8.9 Hz, 2H), 7.12 (~t, J= 8.7 Hz, 2H), 6.64 (m, 1H), 6.51 (m, 1H), 6.40 (m, 1H), 3.59 (m, 1H), 3.30 (m, 1H), 3.26 (m, 1H),3.19 (m, 1H), 3.08 (m, 1H), 2.98 (t, J= 12 Hz, 2H), 2.86 (s, 3H), 2.84 (m, 1H), 2.82 (m, 1H), 2.65 (m, 1H), 2.39 (m, 2H), 2.24 (m, 1H), 1.98 (m, 1H), 1.95 (m, 2H), 1.89 (m, 1H), 1.82 (m, 1H) ppm. |
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