1190861-43-8|6-Bromo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one| Ambeed

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Quality Control of [ 1190861-43-8 ] Purity: 97% SDS Specification

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Product Details of [ 1190861-43-8 ]

CAS No. :	1190861-43-8
Formula :	C₁₂H₁₂BrNO₂
M.W :	282.13
SMILES Code :	O=C1NC2=C(C=CC(Br)=C2)C13CCOCC3
MDL No. :	MFCD19703313
InChI Key :	WGDOZEMHDIATQE-UHFFFAOYSA-N
Pubchem ID :	66953489

Safety of [ 1190861-43-8 ]

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

Computational Chemistry of [ 1190861-43-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	6
Fraction Csp3	0.42
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	67.52
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.33 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.29
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	1.66
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.88
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.	2.12
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	3.06
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.2

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.91
Solubility	0.345 mg/ml ; 0.00122 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.	-2.08
Solubility	2.35 mg/ml ; 0.00834 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	-4.58
Solubility	0.00751 mg/ml ; 0.0000266 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	Yes
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	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	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.84 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<0.0
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)	2.57

Application In Synthesis of [ 1190861-43-8 ]

* 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 [ 1190861-43-8 ]

[ 1190861-43-8 ] Synthesis Path-Downstream 1~35

1
[ 1190861-47-2 ]
[ 1190861-43-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogenchloride; In 1,4-dioxane; at 20℃; for 5h;	A mixture of tert-butyl 6-bromo-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-1-carboxylate (preparation 8b, 4.20 g, 11.0 mmol) and a 5M solution of hydrogen chloride in 1,4-dioxane (25 mL) was stirred at room temperature. After 5 hours, the mixture was concentrated in vacuo to give the title compound (3.20 g, 98%) as a pale pink solid. LRMS (m/z): 278/280 (M-1)+. 1H-NMR delta (DMSO-d6): 1.71 (m, 4H), 3.81 (m, 2H), 4.01 (m, 2H), 6.98 (d, J=1.65 Hz, 1H), 7.14 (dd, J=7.97 Hz, J=1.65 Hz, 1H), 7.47 (d, J=7.97 Hz, 1H), 10.55 (s, NH).
98%	With hydrogenchloride; In 1,4-dioxane; at 20℃; for 5h;	A mixture of tert-butyl 6-bromo-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-1-carboxylate (preparation 6b, 4.20 g, 11.0 mmol) and a 5M solution of hydrogen chloride in 1,4-dioxane (25 mL) was stirred at room temperature. After 5 hours, the mixture was concentrated in vacuo to give the title compound (3.20 g, 98%) as a pale pink solid. LRMS (m/z): 278/280 (M-1)+. 1H-NMR delta (DMSO-d6): 1.71 (m, 4H), 3.81 (m, 2H), 4.01 (m, 2H), 6.98 (d, J=1.65 Hz, 1H), 7.14 (dd, J=7.97 Hz, J=1.65 Hz, 1H), 7.47 (d, J=7.97 Hz, 1H), 10.55 (s, NH).

References: [1]Patent: EP2108641,2009,A1 .Location in patent: Page/Page column 32-33.
[2]Patent: EP2113503,2009,A1 .Location in patent: Page/Page column 24.

3
[ 1190861-43-8 ]
[ 73183-34-3 ]
[ 1190861-50-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 90℃; for 16h;Inert atmosphere;	An oven dried resealable Schlenk tube was charged with <strong>[1190861-43-8]6-bromo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one</strong> (preparation 8, 0.10 g, 0.35 mmol), bis(pinacolato)diboron (0.18 g, 0.71 mmol), potassium acetate (0.07 g, 0.70 mmol) and dimethylsulphoxide (1 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.02 g, 0.02 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in an oil bath at 90 C. After 16h, the mixture was cooled and ethyl acetate was added. The organic layer was washed with water, dried (MgSO4) and evaporated. The mixture was filtered through a silica cartridge eluding with hexanes/ethyl acetate to give the title compound in quantitative yield as a pale-yellow oily residue, which was used without further purification. LRMS (m/z): 330 (M+1)+. 1H-NMR delta (CDCl3): 1.35 (m, 12H), 1.89-1.91 (m, 4H), 3.91-3.95 (m, 2H), 4.23-4.27 (m, 2H), 7.33 (s, 1 H), 7.40 (d, J = 7.5 Hz, 1 H), 7.56 (d, J = 7.5 Hz, 1H), 7.77 (brs, 1H).
100%	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 90℃; for 16h;Inert atmosphere;	An oven dried resealable Schlenk tube was charged with <strong>[1190861-43-8]6-bromo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one</strong> (preparation 6, 0.10 g, 0.35 mmol), bis(pinacolato)diboron (0.18 g, 0.71 mmol), potassium acetate (0.07 g, 0.70 mmol) and dimethylsulphoxide (1 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.02 g, 0.02 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in an oil bath at 90 C. After 16h, the mixture was cooled and ethyl acetate was added. The organic layer was washed with water, dried (MgSO4) and evaporated. The mixture was filtered through a silica cartridge eluting with hexanes/ethyl acetate to give the title compound in quantitative yield as a pale-yellow oily residue, which was used without further purification. LRMS (m/z): 330 (M+1)+. 1H-NMR delta (CDCl3): 1.35 (m, 12H), 1.89-1.91 (m, 4H), 3.91-3.95 (m, 2H), 4.23-4.27 (m, 2H), 7.33 (s, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.77 (br s, 1H).

References: [1]Patent: EP2108641,2009,A1 .Location in patent: Page/Page column 33.
[2]Patent: EP2113503,2009,A1 .Location in patent: Page/Page column 24.

4
[ 1190861-43-8 ]
[ 1202765-56-7 ]

Yield	Reaction Conditions	Operation in experiment
73%		LiAIH4 (0.54 g, 14.18 mmol) was added portion wise at 0C to a solution of 178a (1.6 g, 5.67 mmol) in THF (500 mL). The reaction mixture was heated at 80C for 4 h, cooled, then sequentially quenched with water (0.54 mL), 20% NaOH solution (0.54 mL) and water (1.08 mL) and stirred for 1H at RT. The mixture was filtered through a plug of celite and the filter was rinsed with DCM/MeOH = 4: 1 (3x 50 mL). The filtrate was evaporated and the residue was purified by flash column chromatography [silica gel; hexane /EtOAc 4:1 ]. Light yellow solid. Yield: 1.1 g (73%). HPLC (method 1 ): Rt = 3.27 min, m/z [M+H]+ = 270.2 (MW calc. 268.15).
64%		A heterogeneous mixture of 6-bromo-2',3',5',6'-tetrahydrospiro[indole-3,4l-pyran]-2(lH)-one A.99 (3.5 g, 12.4 mmol) in toluene (25 mL) was stirred at 80 0C. To the heated mixture was added a solution of Red- Al (65% in toluene, 11.6 mL, 37.2 mmol) and the mixture was stirred at 800C. After 50 min, the mixture was cooled to 0 0C and quenched with 2 N of aqueous NaOH (31 mL, 62 mmol) with stirring. The mixture was extracted with ethyl acetate (100 mL, 2 times). The combined extracts were washed with brine (100 mL, 3 times), dried (Na2SO4), filtered, and concentrated under reduced pressure to give a green solid. The product was purified by silica gel column chromatography using using 0 to 100% gradient of dichloromethane-methanol-NH4OH (89:9:1) in dichloromethane) to give 6-bromo- 1,2,2',3',5',6'-hexahydrospiro[indole-3,4'-pyran] A.100 (2.13 g, 64%) as a yellow solid: 1H NMR (500 MHz, DMSO-dbeta) delta ppm 6.91 - 6.99 (1 H, m), 6.66 (1 H, dd, J=7.8, 1.7 Hz), 6.59 (1 <n="63"/>H, d, J=I .7 Hz), 5.85 (1 H, s), 3.70 - 3.87 (2 H, m), 3.36 - 3.51 (4 H, m), 1.65 - 1.84 (2 H, m), 1.39 - 1.57 (2 H, m); ESI-MS m/z 268.0 [(M+l) (79Br)] and 270.0 [(M+l) (81Br)].
	With sodium bis(2-methoxyethoxy)aluminium dihydride; In toluene; at 80℃; for 0.833333h;	A heterogeneous mixture of 6-bromo-2',3',5',6'-tetrahydrospiro[indoline-3,4'- pyran]-2-one (3.5 g, 12.4 mmol) in toluene (25 mL) was stirred at 80 C. To the heated mixture was added a solution of Red- Al (65% in toluene, 11.6 mL, 37.2 mmol) and the mixture was stirred at 80 C for 50 min. After this time the mixture was cooled to 0 C and quenched with a 2 N solution of aqueous NaOH (31 mL, 62 mmol). The mixture was extracted with EtOAc (2 x 100 mL). The combined extracts were washed with brine (3 x 100 mL), dried over Na2SO4, filtered, and evaporated in vacuo. The resulting residue was purified by column chromatography (0 to 100% gradient OfDCM-MeOH-NH4OH (89:9:1) in DCM) to give 6-bromo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran] as a yellow solid. Mass Spectrum (ESI) m/e 268 [(M+l) (79Br)] and 270 [(M+l) (81Br)].

References: [1]Patent: WO2017/108204,2017,A1 .Location in patent: Page/Page column 133-134.
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 7667 - 7685.
[3]Patent: WO2009/158011,2009,A1 .Location in patent: Page/Page column 61-62.
[4]Patent: WO2010/151737,2010,A2 .Location in patent: Page/Page column 49-50.

5
[ 1202765-53-4 ]
[ 1190861-43-8 ]

Yield	Reaction Conditions	Operation in experiment
72%	With iron; acetic acid; at 100℃; for 2.5h;	Methyl 4-(4-bromo-2-nitrophenyl)-tetrahydro-2H-pyran-4-carboxylate A.98 (6.67 g, 19.4 mmol) was dissolved in acetic acid (97 mL), Fe powder (5.42 g, 96.97 mmol) was added and the resultant mixture was stirred at 100 0C for 2.5 hours. The hot mixture was filtered through a Celite pad and the pad was washed with acetic acid (250 mL). The filtrate was concentrated under reduced pressure to give a dark syrup. The product was purified by silica gel column chromatography using 0 to 100% gradient of ethyl acetate in w-hexane) to give 4.75 g of a reddish-pink solid. The solid was suspended in 50% of ethyl acetate in hexane (20 mL), filtered, and washed with 50% of ethyl acetate in hexane (40 mL) on the filter paper to give 6- bromo-2',31,5',6'-tetrahydrospiro[indole-3,4'-pyran]-2(lH)-one A.99 (3.93 g, 72%) as an orange-pink solid: 1H NMR (500 MHz, DMSO-d6) delta ppm 10.53 (1 H, s), 7.47 (1 H, d, J=7.8 Hz), 7.14 (1 H, dd, J=8.1, 1.0 Hz), 6.98 (1 H, d, J=LO Hz), 3.91 - 4.12 (2 H, m), 3.67 - 3.86 (2 H, m), 1.54 - 1.84 (4 H, m); ESI-MS m/z 282.0 [(M+l) (79Br)] and 284.0 [(M+l) (81Br)].
	With iron; acetic acid; at 100℃; for 2h;	A mixture of the methyl-nitro-methylpropanoate (1 eq) in acetic acid (100 eq) was treated with iron powder (5 eq). The reaction was heated to 100 C for 2 h. After this time the reaction was cooled to rt and filtered over Celite . The Celite was washed with acetic acid and the combined filtrates were evaporated in vacuo. The resulting residue was purified by column chromatography (hexanes:EtOAc, 1 :0 to 0:1) to give the bromo-dimethylpyridinone (or indolinone).; -Bromo-l'^^S^'-tetrahydrospiro^ndoline-S^'-pyranJ-1-onePrepared according to procedure J using methyl 4-(4-bromo-2-nitrophenyl)tetra- hydro-2H-pyran-4-carboxylate (6.67 g, 19.4 mmol), AcOH (97 mL) and Fe powder (5.42 g, 96.97 mmol) and heating the mixture at 100C for 2 h. After purification 6-bromo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one was obtained as an orange solid. Mass Spectrum (ESI) m/e = 282 [(M+l) (79Br)] and 284 [(M+l) (81Br)].

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 7667 - 7685.
[2]Patent: WO2009/158011,2009,A1 .Location in patent: Page/Page column 60-61.
[3]Patent: WO2010/151737,2010,A2 .Location in patent: Page/Page column 35; 49.

6
[ 515135-67-8 ]
[ 1190861-43-8 ]
[ 1190859-96-1 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5270 - 5273.

7
[ 1190861-43-8 ]
[ 1268349-81-0 ]
[ 1190859-98-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5270 - 5273.

8
[ 34270-90-1 ]
[ 99365-40-9 ]
[ 1190861-43-8 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5270 - 5273.

9
[ 100487-82-9 ]
[ 1190861-43-8 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 7667 - 7685.
[2]Patent: WO2009/158011,2009,A1 .

10
[ 1190861-43-8 ]
[ 1259512-03-2 ]