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Chemical Structure| 137973-76-3

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Product Details of [ 137973-76-3 ]

CAS No. :137973-76-3
Formula : C26H23ClN2O3
M.W : 446.93
SMILES Code : CC1=C(C=CC=C1)C(=O)NC1=CC(C)=C(C=C1)C(=O)N1CCCC(=O)C2=C1C=CC(Cl)=C2
MDL No. :MFCD19440797
InChI Key :VENGMROMZOKURN-UHFFFAOYSA-N
Pubchem ID :11362843

Safety of [ 137973-76-3 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 137973-76-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 32
Num. arom. heavy atoms 18
Fraction Csp3 0.19
Num. rotatable bonds 5
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 130.54
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

66.48 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

3.46
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

4.97
Log Po/w (WLOGP)?

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

5.26
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.

4.09
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

5.57
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

4.67

Water Solubility

Log S (ESOL):?

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

-5.83
Solubility 0.000664 mg/ml ; 0.00000148 mol/l
Class?

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

Moderately soluble
Log S (Ali)?

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

-6.1
Solubility 0.000351 mg/ml ; 0.000000786 mol/l
Class?

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

Poorly 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

-8.98
Solubility 0.000000465 mg/ml ; 0.000000001 mol/l
Class?

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

Poorly 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

No
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

No
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

Yes
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

Yes
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

No
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

Yes
Log Kp (skin permeation)?

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

-5.5 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

0.0
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

0.0 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<2.0
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)

3.04

Application In Synthesis of [ 137973-76-3 ]

* 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 [ 137973-76-3 ]

[ 137973-76-3 ] Synthesis Path-Upstream   1~2

  • 1
  • [ 137973-76-3 ]
  • [ 150683-30-0 ]
YieldReaction ConditionsOperation in experiment
96% at 0℃; for 2 h; 7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1- benzazepine (19.0g, 42.51mmol) was dissolved in methanol (200ml) in a solvent, at 0 for Conditional batch of sodium borohydride (2.42g, 63.77mmol), after the addition was complete stirring was continued for 2h, TLC the reaction was complete. The reaction mixture was poured into water, extracted with methylene chloride, dried over anhydrous sodium sulfate, filtration and vacuum distillation of crude with methanol: petroleum ether (2: 1) and recrystallized to give a white solid tolvaptan (18.33g , 96.0percent).
94% at 20℃; for 5 h; The compound (X) (20.0 g, 44.75 mmol) was dissolved in methanol (200 mL), sodium borohydride (3.39 g, 89.50 mmol) was added at room temperature and stirred for 5 h at room temperature. The reaction solution was poured into an ice-water bath (100 mL), quenched, the methanol was removed, the residue was extracted with dichloromethane (3 x 100 mL), the organic phases were combined and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulphate , Filtered and evaporated under reduced pressure to give a crude product which was recrystallized from methanol: petroleum ether (2: 1) to give tolvaptan as a white solid (18.89 g, 94percent).
94.2% With sodium bis(2-methoxyethoxy)aluminium dihydride In tetrahydrofuran at -5 - 20℃; 5 g of the compound of Formula II is added to a 100 mL three-necked bottle,Then add 25mL of tetrahydrofuran,Stir and dissolveCool down to -5 ~ 0 °C,Temperature control -5 ~ 0 °C,1.73g of a 70wtpercent solution of sodium dihydrobis(2-methoxyethoxy)aluminate in toluene was added dropwise.After the completion of heating up to 10 ~ 20 °C,The reaction was stirred for 2 h.When the HPLC reaction is complete,Temperature control 10 ~ 20 °C,Add 50mL of water,There is a solid precipitated,Continue stirring for 1-2 hours, suction filtration, filter cake recrystallized with aqueous methanol,Drying under reduced pressureA white crystal of tolvaptan 4.73 g was obtained with a yield of 94.2percent.HPLC purity was 99.97percent, dechlorination impurity IV was not detected.
92% for 1 h; To a 1 L reactor was added 7-chloro-1- [2-methyl-4 - [(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine .0 g, 179.00 mmol) and methanol (675 ml), and the mixture was stirred for 30 minutes. Sodium borohydride (2.37 g, 62.65 mmol) was added to the reaction mixture and stirred for 1 hour. Thereafter, 0.5percent dilute hydrochloric acid (232 ml) was gradually added to the reaction mixture, and the mixture was gradually cooled at room temperature. When crystals were precipitated, the reaction mixture was filtered, and the resulting filtrate was dried under reduced pressure to obtain 7-chloro-5-hydroxy-1- [2-methyl-4- (2- methylbenzoylamino) benzoyl ] -2,3,4,5-tetrahydro-1 H-1-benzazepine (73.9 g, 92percent).
91.2% With sodium tetrahydroborate In methanol; water at 25℃; for 1 h; 7-chloro-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-5 oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (25 gm.) was suspended in methanol (600 ml) & water (180 ml) and then added sodium borohydride (2.95 gm.) at 25° C. and the reaction mixture was stirred for 1hr. To the reaction mixture was added hydrochloric acid (150 ml). Then the reaction mixture was stirred for 2 hours. The solid obtained was collected by filtration and dried to give 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (22.8 gm). Yield—91.2percent; Purity (HPLC)—98.92percent; Dehalogenated Impurity—0.01percent
79.6% at 15 - 30℃; for 1 h; 10.0 g of intermediate compound IV,110ml of methanol into 250ml reaction flask, stirring, less than 15 under the conditions of adding 0.56g NaBH4, heated to 30 reaction,The solid gradually precipitated. After 1h, the sample TLC showed no raw material. After 2h, 0.75percent hydrochloric acid was added dropwise to terminate the reaction. After stirring for 0.5h, the mixture was cooled to 0 ° C and stirred for 2h. The mixture was filtered to obtain 9.0g of a white solid. The resulting solid methanol and water were recrystallized, filtered,Drying in vacuo at 60 ° C for 8 hours afforded 8.0 g of a white solid with a yield of 79.6percent HPLC purity of 99.9percent.
57 g
Stage #1: With sodium tetrahydroborate In methanol at 20℃; for 1 h;
Stage #2: With hydrogenchloride In water
Example 5
Preparation of Tolvaptan
7-Chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (63 gm) as obtained in example 4 was dissolved in methanol (570 ml) and then added sodium borohydride (2.07 gm) at room temperature.
The reaction mass was stirred for 1 hour and pH of the reaction mass was adjusted to 6.0 to 7.0 with hydrochloric acid solution (1percent, 630 ml).
The separated solid was filtered and dried to obtain 57 gm of tolvaptan.

References: [1] Patent: CN105315169, 2016, A, . Location in patent: Paragraph 0170; 0211; 0212.
[2] Patent: CN105753735, 2016, A, . Location in patent: Paragraph 0181; 0221; 0222.
[3] Patent: CN107663171, 2018, A, . Location in patent: Paragraph 0023; 0024; 0025; 0026; 0027; 0028.
[4] Patent: JP2018/12690, 2018, A, . Location in patent: Paragraph 0031; 0032.
[5] Patent: US2015/112059, 2015, A1, . Location in patent: Paragraph 0027.
[6] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 23, p. 6455 - 6458.
[7] Patent: CN106883175, 2017, A, . Location in patent: Paragraph 0019; 0020.
[8] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 8, p. 1743 - 1754.
[9] Patent: WO2012/46244, 2012, A1, . Location in patent: Page/Page column 9.
[10] Patent: US2013/190490, 2013, A1, . Location in patent: Paragraph 0066.
  • 2
  • [ 137973-76-3 ]
  • [ 150683-30-0 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With sodium tetrahydroborate In methanol for 1 h;
Stage #2: With hydrogenchloride In methanol; water at 20℃;
Example 2; Preparation of 7-chloro-5-hydroxy- l-[2-methyl-4-(2-methyl- benzoylamino)benzoyl]-2,3,4,5-tetrahydro- IH- 1-benzazepine; 7-Chloro-l-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2, 3,4,5- tetrahydro-lH-l-benzazepin-5-one (3.2 g, 7.1 mM) is suspended in methanol (27 mL), and thereto is added at one time crystalline sodium borohydride (96 mg = 2.5 mM), and the mixture is reacted for about one hours. To the reaction mixture is added dropwise 0.5percent diluted hydrochloric acid (9.3 mL), and the mixture is stirred at room temperature and then cooled. The precipitated crystals are separated by filtration, and dried at room temperature to give the desired 7- chloro-5-hydroxy- 1 - [2 -methyl-4- (2 -methylbenzoylamino) benzoyl] - 2,3,4,5-tetrahydro- IH- 1-benzazepine (2.97 g) as white powder (Yield 92 percent, Mp 224.5-225.5°C). The pure 7-chloro-5-hydroxy-l-[2-methyl-4~(2-methylbenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro- IH- 1-benzazepine is obtained by recrystallizing the above product from methanol/ water (4 : 1). The product thus obtained is while crystalline powder (yield of recrystallization, 90 percent, purity more than 99.5 percent, Mp 226-227.5°C). The 7-chloro-5-hydroxy-l-[2-methyl-4-(2-methylbenzoylamino)- benzoyl]-2,3,4,5-tetrahydro- IH- 1-benzazepine thus obtained has the following physical data; (1) NMR spectrum data, (2) IR spectrum data, (3) MS spectrum data and (4) powder X-ray diffraction spectrum data. (1) NMR spectrum: 1H NMR (300MHz, DMSO-d6): major conformational isomer δ= 1.49 (br EPO <DP n="35"/>ddd, J= I 1.3Hz, J= I 1.3Hz, J= I 1.3Hz, IH), 1.74 (br d, J= I 1.3Hz, IH), 1.95 (br ddd, J= I 1.3Hz, J= I 1.3Hz, J=I 1.3Hz, IH), 2.11 (br d, J= I 1.3Hz, IH), 2.34 (s, 6H), 2.68 (br dd, J= I 1.3Hz, J= I 1.3Hz, IH), 4.64 (br d, J=I 1.3Hz, IH), 4.90 (br d, J= 11.3Hz, IH), 5.70 (br d, J=4.6Hz, IH), 6.74 (d, J=8.2Hz, IH), 6.76 (d, J= 10. IHz, IH), 7.05 (dd, J=8.2Hz, J=2.3Hz, IH), 7.25-7.29 (m, 3H), 7.37 (dd, J=7.3Hz, J=7.3Hz, IH), 7.41 (d, J=7.3Hz, IH), 7.50 (d, J=2.3Hz, IH), 7.60 (s, IH), 10.2 (s, IH)(2) IR spectrumIR (KBr): 3397, 3221, 2926, 1657, 1622, 1609, 1395, 1304, 1094, 866, 827, 745 cm-1(3) MS spectrumMS (FAB): m/z = 449 (MH+); (4) Powder X-ray diffraction spectrum 2Ψ = 4.7, 15.4, 18.7, 21.7, 23.5°. The purity is measured by high performance liquid chromatography (HPLC) under the following conditions:Detector: Ultraviolet absorptiometer (UV 254 nm), column: YMC- Pack ODS-A A-312, column temperature: around 25°C, mobile phase: acetonitrile/ water/ phosphoric acid solution (500 : 500 : 1) or acetonitrile/water/phosphoric acid solution (700 : 300 : 1).
References: [1] Patent: WO2007/26971, 2007, A2, . Location in patent: Page/Page column 33-36.
 

Historical Records

Technical Information

• Acyl Group Substitution • Alkyl Halide Occurrence • Baeyer-Villiger Oxidation • Barbier Coupling Reaction • Baylis-Hillman Reaction • Benzylic Oxidation • Birch Reduction • Blanc Chloromethylation • Bucherer-Bergs Reaction • Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions • Chan-Lam Coupling Reaction • Clemmensen Reduction • Complex Metal Hydride Reductions • Corey-Bakshi-Shibata (CBS) Reduction • Corey-Chaykovsky Reaction • Fischer Indole Synthesis • Friedel-Crafts Reaction • General Reactivity • Grignard Reaction • Henry Nitroaldol Reaction • Hiyama Cross-Coupling Reaction • Horner-Wadsworth-Emmons Reaction • Hydride Reductions • Hydrogenolysis of Benzyl Ether • Kinetics of Alkyl Halides • Kumada Cross-Coupling Reaction • Lawesson's Reagent • Leuckart-Wallach Reaction • Mannich Reaction • McMurry Coupling • Meerwein-Ponndorf-Verley Reduction • Passerini Reaction • Paternò-Büchi Reaction • Petasis Reaction • Peterson Olefination • Pictet-Spengler Tetrahydroisoquinoline Synthesis • Preparation of Aldehydes and Ketones • Preparation of Alkylbenzene • Preparation of Amines • Prins Reaction • Reactions of Aldehydes and Ketones • Reactions of Alkyl Halides with Reducing Metals • Reactions of Amines • Reactions of Benzene and Substituted Benzenes • Reformatsky Reaction • Robinson Annulation • Schlosser Modification of the Wittig Reaction • Schmidt Reaction • Specialized Acylation Reagents-Carbodiimides and Related Reagents • Specialized Acylation Reagents-Ketenes • Specialized Acylation Reagents-Vilsmeier Reagent • Stille Coupling • Stobbe Condensation • Substitution and Elimination Reactions of Alkyl Halides • Suzuki Coupling • Tebbe Olefination • Ugi Reaction • Vilsmeier-Haack Reaction • Wittig Reaction • Wolff-Kishner Reduction

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