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Structure of 3874-54-2

Chemical Structure| 3874-54-2

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Product Details of [ 3874-54-2 ]

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

Safety of [ 3874-54-2 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Computational Chemistry of [ 3874-54-2 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

17.07 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.2
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

2.59
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

3.45
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

3.1
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

3.78
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.02

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.79
Solubility 0.323 mg/ml ; 0.00161 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-2.6
Solubility 0.507 mg/ml ; 0.00253 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-4.46
Solubility 0.00696 mg/ml ; 0.0000347 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

Yes
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-5.68 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

1.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.44

Application In Synthesis of [ 3874-54-2 ]

* 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.

  • Downstream synthetic route of [ 3874-54-2 ]

[ 3874-54-2 ] Synthesis Path-Downstream   1~6

  • 1
  • [ 37663-44-8 ]
  • [ 3874-54-2 ]
  • [ 56657-97-7 ]
  • 2
  • [ 313369-67-4 ]
  • [ 3874-54-2 ]
  • [ 313368-91-1 ]
YieldReaction ConditionsOperation 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+).
  • 3
  • [ 313368-85-3 ]
  • [ 3874-54-2 ]
  • [ 313368-91-1 ]
YieldReaction ConditionsOperation 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.
  • 4
  • C14H19N3*2ClH [ No CAS ]
  • [ 3874-54-2 ]
  • [ 313368-91-1 ]
YieldReaction ConditionsOperation 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).
  • 5
  • C14H19N3*C20H19NO7 [ No CAS ]
  • [ 3874-54-2 ]
  • [ 313368-91-1 ]
YieldReaction ConditionsOperation 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.
  • 6
  • [ 313368-85-3 ]
  • [ 3874-54-2 ]
  • 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-((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)phenyl)butan-1-one [ No CAS ]
 

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