1201923-48-9|(S)-tert-Butyl (1-(1,3-dioxoisoindolin-2-yl)-3-(3-fluorophenyl)propan-2-yl)carbamate| Ambeed

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Quality Control of [ 1201923-48-9 ] Purity: 95% SDS Specification

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Product Details of [ 1201923-48-9 ]

CAS No. :	1201923-48-9
Formula :	C₂₂H₂₃FN₂O₄
M.W :	398.43
SMILES Code :	O=C(OC(C)(C)C)N[C@@H](CC1=CC=CC(F)=C1)CN(C(C2=C3C=CC=C2)=O)C3=O
MDL No. :	MFCD28359281
InChI Key :	TWQAEDUMDUDFGX-INIZCTEOSA-N
Pubchem ID :	58282788

Safety of [ 1201923-48-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 1201923-48-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	29
Num. arom. heavy atoms	12
Fraction Csp3	0.32
Num. rotatable bonds	8
Num. H-bond acceptors	5.0
Num. H-bond donors	1.0
Molar Refractivity	109.33
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	75.71 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	3.35
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	3.72
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.6
Log P_o/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.	3.24
Log P_o/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	3.79
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.54

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-4.43
Solubility	0.0147 mg/ml ; 0.000037 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.	-5.0
Solubility	0.00397 mg/ml ; 0.00000997 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	-6.59
Solubility	0.000102 mg/ml ; 0.000000256 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	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	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	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	Yes
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.09 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	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<3.0
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)	3.34

Application In Synthesis of [ 1201923-48-9 ]

* 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.

Downstream synthetic route of [ 1201923-48-9 ]

[ 1201923-48-9 ] Synthesis Path-Downstream 1~28

1
[ 136918-14-4 ]
[ 944470-56-8 ]
[ 1201923-48-9 ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20 - 25℃; for 1.0h;	To a solution of 1 ,1-dimethylethyl [(1 S)-2-(3-fluorophenyl)-1-(hydroxymethyl)ethyl]carbamate (7.0 g, 26.0 mmol), triphenylphosphine (8.18 g, 31.2 mmol) and phthalimide (4.21 g, 28.6 mmol) in THF (150 ml.) at 25 C was added diisopropyl azodicarboxylate (7.58 ml_, 39.0 mmol). After stirring at RT for 1 h, the reaction solution was concentrated under vacuum and the residue triturated with Et2O (100 ml.) and filtered to give the crude product (22 g) as a white solid which was used directly without further purification: LCMS (ES) m/z 399 (M+H)+.
	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20 - 25℃; for 1.0h;	To a solution of 1 ,1-dimethylethyl [(1 S)-2-(3-fluorophenyl)-1- (hydroxymethyl)ethyl]carbamate (7.0 g, 26.0 mmol), triphenylphosphine (8.18 g, 31.2 mmol) and phthalimide (4.21 g, 28.6 mmol) in THF (150 ml.) at 25 0C was added diisopropyl azodicarboxylate (7.58 ml_, 39.0 mmol). After stirring at RT for 1 h, the reaction solution was concentrated under vacuum and the residue triturated with Et2O (100 ml.) and filtered to give the crude product (22 g) as a white solid which was used directly without further purification: LCMS (ES) m/z 399 (M+H)+.
	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 2.0h;	Step B 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione [1.0]-hydrogen chloride To a solution of tert-butyl[(1S)-1-(3-fluorobenzyl)-2-hydroxyethyl]carbamate (9.40 g, 34.9 mmol), triphenylphosphine (9.15 g, 34.9 mmol), and phthalimide (5.14 g, 34.9 mmol) in tetrahydrofuran (100 mL, 1000 mmol) at room temperature was added diethyl azodicarboxylate (17.9 mL, 45.4 mmol). The reaction was stirred at room temperature for 2 hr and then concentrated under reduced pressure. The residue was purified by combi-flash chromatography eluted with EtOAc/hexane (0-40%) to give the desired intermediate. LCMS found: 399.0 (M+1). To the solution of the purified intermediate in methanol (20 mL, 400 mmol) was added 4.0 M hydrogen chloride in dioxane (30 mL, 100 mmol). The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure to give 3.1 g (26% total yield for the two steps) of the final product, 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione [1.0]-Hydrogen chloride, as white solid. LC/MS found: 299.0 (M+H)+.

With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20 - 25℃;

b) 1 , 1 -dimethylethyl {(1 S)-2-(1 ,3-dioxo-1 ,3-dihydro-2H-isoindol-2-yl)-1 -[(3- fluorophenyl)methyl]ethyl}carbamate <n="31"/> To a solution of 1 ,1-dimethylethyl [(1 S)-2-(3-fluorophenyl)-1-(hydroxymethyl)ethyl]carbamate (7.0 g, 26.0 mmol), triphenylphosphine (8.18 g, 31.2 mmol) and phthalimide (4.21 g, 28.6 mmol) in THF (150 ml.) at 25 C was added diisopropyl azodicarboxylate (7.58 ml_, 39.0 mmol). After stirring at RT for 1 h, the reaction solution was concentrated under vacuum and the residue triturated with Et2O (100 ml.) and filtered to give the crude product (22 g) as a white solid which was used directly without further purification: LCMS (ES) m/z 399 (M+H)+.

References: [1]Patent: WO2009/158371,2009,A1 .Location in patent: Page/Page column 33; 34.
[2]Patent: WO2009/158372,2009,A1 .Location in patent: Page/Page column 30.
[3]Patent: US2013/96144,2013,A1 .Location in patent: Paragraph 0248-0250.
[4]Drugs of the Future,2014,vol. 39,p. 541 - 546.
[5]Patent: WO2009/158374,2009,A2 .Location in patent: Page/Page column 29; 30.

2
[ 1201923-48-9 ]
[ 1202237-87-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 20℃; for 12.0h;	To a solution of 1 ,1-dimethylethyl 1 ,1-dimethylethyl {(1 S)-2-(1 ,3-dioxo-1 ,3-dihydro-2/-/-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}carbamate (9.0 g, 22.6 mmol) in DCM (200 ml.) at RT was added 4M HCI in dioxane (56 ml_, 226 mmoles). After 12h, the solution was filtered and washed with DCM (50 ml.) affording the title compound (7.8 g,99%) as a white HCI salt: LCMS (ES) m/z 349 (M+H)+.
99%	With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 20℃; for 12.0h;	To a solution of 1 ,1-dimethylethyl 1 ,1-dimethylethyl {(1 S)-2-(1 ,3-dioxo-1 ,3-dihydro- 2/-/-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}carbamate (9.0 g, 22.6 mmol) in DCM (200 mL) at RT was added 4M HCI in dioxane (56 mL, 226 mmoles). After 12h, the solution was filtered and washed with DCM (50 mL) affording the title compound (7.8 g, 99%) as a white HCI salt: LCMS (ES) m/z 349 (M+H)+.
3.1 g	With hydrogenchloride; In 1,4-dioxane; methanol; at 20℃; for 2.0h;	Step B 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione [1.0]-hydrogen chloride To a solution of tert-butyl[(1S)-1-(3-fluorobenzyl)-2-hydroxyethyl]carbamate (9.40 g, 34.9 mmol), triphenylphosphine (9.15 g, 34.9 mmol), and phthalimide (5.14 g, 34.9 mmol) in tetrahydrofuran (100 mL, 1000 mmol) at room temperature was added diethyl azodicarboxylate (17.9 mL, 45.4 mmol). The reaction was stirred at room temperature for 2 hr and then concentrated under reduced pressure. The residue was purified by combi-flash chromatography eluted with EtOAc/hexane (0-40%) to give the desired intermediate. LCMS found: 399.0 (M+1). To the solution of the purified intermediate in methanol (20 mL, 400 mmol) was added 4.0 M hydrogen chloride in dioxane (30 mL, 100 mmol). The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure to give 3.1 g (26% total yield for the two steps) of the final product, 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione [1.0]-Hydrogen chloride, as white solid. LC/MS found: 299.0 (M+H)+.

With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 20℃;

c) 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1 H-isoindole-1 ,3(2H)-dioneTo a solution of 1 ,1-dimethylethyl 1 ,1-dimethylethyl {(1 S)-2-(1 ,3-dioxo-1 ,3-dihydro- 2/-/-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}carbamate (9.0 g, 22.6 mmol) in DCM (200 ml.) at RT was added 4M HCI in dioxane (56 ml_, 226 mmoles). After 12h, the solution was filtered and washed with DCM (50 ml.) affording the title compound (7.8 g, 99%) as a white HCI salt: LCMS (ES) m/z 349 (M+H)+.

References: [1]Patent: WO2009/158371,2009,A1 .Location in patent: Page/Page column 34.
[2]Patent: WO2009/158372,2009,A1 .Location in patent: Page/Page column 30.
[3]Patent: US2013/96144,2013,A1 .Location in patent: Paragraph 0248-0250.
[4]Patent: WO2009/158374,2009,A2 .Location in patent: Page/Page column 30.

3
[ 114873-01-7 ]
[ 1201923-48-9 ]

References: [1]Drugs of the Future,2014,vol. 39,p. 541 - 546.
[2]Patent: US2013/96144,2013,A1 .
[3]Patent: WO2009/158371,2009,A1 .
[4]Patent: WO2009/158374,2009,A2 .

4
[ 1201923-48-9 ]
[ 1386982-03-1 ]

References: [1]Patent: US2012/184542,2012,A1 .

5
[ 136918-14-4 ]
[(S)-2-(3-fluoro-phenyl)-1-hydroxymethyl-ethyl]carbamic acid tert-butyl ester [ No CAS ]
[ 1201923-48-9 ]

Yield	Reaction Conditions	Operation in experiment
67.2%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 0.5h;Cooling with ice;	To an ice cooled mixture of [(S)-2-(3-fluoro-phenyl)-1-hydroxymethyl-ethyl]carbamic acid tert-butyl ester (1.214 g, 4.5 mmol), triphenyl phosphine (1.359 g, 5.18 mmol), phthalimide (0.762 g, 5.18 mmol) and tetrahydrofuran (15 mL) was added a solution of diisopropyldiazodicarboxylate (1.048 g, 5.18 mmol) in tetrahydrofuran (5 mL). The mixture was stirred for 30 minutes at room temperature and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with dichloromethane-ethyl acetate (90:10) to give [(S)-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(3-fluoro-phenyl)-ethyl]carbamic acid tert-butyl ester as a white solid. (Yield 1.205 g, 67.2%).

References: [1]Patent: US2012/184542,2012,A1 .Location in patent: Page/Page column 106.

6
[ 1201923-48-9 ]
[ 1386982-02-0 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; In dichloromethane; at 20℃; for 1.0h;	A mixture [(S)-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(3-fluoro-phenyl)-ethyl]carbamic acid tert-butyl ester (1.203 g, 3 mmol) and trifluoroacetic acid-dichloromethane (15 mL, 2:1) was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give crude 2-[(S)-2-amino-3-(3-fluoro-phenyl)-propyl]-isoindole-1,3-dione trifluoroacetic acid salt. (Yield 1.516, 123%).

References: [1]Patent: US2012/184542,2012,A1 .Location in patent: Page/Page column 107.

7
[ 1201923-48-9 ]
[ 1386982-05-3 ]

References: [1]Patent: US2012/184542,2012,A1 .

8
[ 1201923-48-9 ]
[ 1386982-06-4 ]

References: [1]Patent: US2012/184542,2012,A1 .

9
[ 1201923-48-9 ]
[ 1386982-07-5 ]

References: [1]Patent: US2012/184542,2012,A1 .

10
[ 1201923-48-9 ]
[ 1386980-58-0 ]

References: [1]Patent: US2012/184542,2012,A1 .

11
[ 1201923-48-9 ]
3-amino-N-[(S)-1-aminomethyl-2-(3-fluoro-phenyl)ethyl]-4-chloro-benzamide [ No CAS ]

References: [1]Patent: US2012/184542,2012,A1 .

12
[ 1201923-48-9 ]
[ 1430058-10-8 ]