453562-71-5|1-(6-Amino-3,3-dimethylindolin-1-yl)ethanone| Ambeed

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Quality Control of [ 453562-71-5 ] Purity: 98% SDS Specification

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Product Details of [ 453562-71-5 ]

CAS No. :	453562-71-5
Formula :	C₁₂H₁₆N₂O
M.W :	204.27
SMILES Code :	CC(N1CC(C)(C)C2=C1C=C(N)C=C2)=O
MDL No. :	MFCD07636699
InChI Key :	FDFKETITWKJRNI-UHFFFAOYSA-N
Pubchem ID :	21865176

Safety of [ 453562-71-5 ]

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

Application In Synthesis of [ 453562-71-5 ]

* 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 [ 453562-71-5 ]

[ 453562-71-5 ] Synthesis Path-Downstream 1~28

1
[ 453562-71-5 ]
[ 859826-43-0 ]
[ 144-55-8 ]
[ 871107-54-9 ]

Yield	Reaction Conditions	Operation in experiment
	In ethyl acetate; acetonitrile;	D. 1-(6-(7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ylamino)-3,3-dimethylindolin-1-yl)ethanone A mixture of 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (40 mg, 0.14 mmol), <strong>[453562-71-5]1-(6-amino-3,3-dimethylindolin-1-yl)ethanone</strong> (60 mg, 0.29 mmol), and acetonitrile (3 mL) was heated in a sealed tube via microwave at 180 C. for 60 min. The mixture was treated with EtOAc (50 mL) and saturated aqueous sodium bicarbonate. The organic layer was separated and washed with brine, dried (Na2SO4), and evaporated. The residue was purified by flash chromatography over silica gel to give an off-white solid (50 mg). MS: M+H=449.5 & 451.3 (M+1); 1H NMR (DMSO-d6) δ 8.53 (s, 1H), 8.34 (s, 1H), 8.24 (dd, J=4.4, 1.6 Hz, 1H), 8.23 (d, J=1.6 Hz, 1H), 7.86 (dd, J=8.0, 1.6 Hz, 1H), 7.38 (dd, J=8.0, 1.6 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.03 (dd, J=8.0, 4.8 Hz, 1H), 4.34 (s, 2H), 3.86 (s, 2H), 3.67 (t, J=5.6 Hz, 2H), 2.79 (t, J=5.6 Hz, 2H), 2.16 (s, 3H), 1.30 (s, 6H).

References: [1]Patent: US2005/277643,2005,A1 .

2
[ 453562-71-5 ]
[ 659731-42-7 ]

Yield	Reaction Conditions	Operation in experiment
65%		In a 500ml three-necked round bottom flask equipped with an overhead stirrer, was combined l-acetyl-3,3-dimethyl-2,3-dihydro-lH-indol-6-amine A.8(6.98g, 34.22 mmol) [Chen, G., J. Adams, et al. WO 2002066470 p263] with 30ml of ice/water. The solution was cooled in an ice bath before concentrated HCl (6.8ml, 81.60 mmol) was added. A solution OfNaNO2 (2.48g, 35.93 mmol) dissolved in 30ml of water was added drop wise over a period of 10 minutes. After 30minutes a solution of KI (11.36g, 68.44 mmol) dissolved in 70ml of chloroform was added via an addition funnel over a period of 0.5hr. Then the brownish solution was stirred at room temperature until gas evolution ceased. Partitioned the solution in a separation funnel, and washed the organic layer with saturated NaHCO3, followed by 5% Na2S2O3. The organics were dried over MgSO4 before being concentrated under vacuum to 1/10th the volume. Purified the residue obtained by chromatography on silica eluting with 20% hexane/dichloromethane. The fractions containing the product were combined and concentrated under vacuum to give l-acetyl-6-iodo-3,3-dimethyl-2,3-dihydro-lH-indole A.9 (6.95g, 65%) as a tan colored solid.1H NMR (500 MHz, (CD)3SO) δ 8.39 (s, IH), 7.37 (d, J = 7.8Hz, IH), 7.08 (d, J = 7.8Hz, IH), 3.85 (s, 2H), 2.16 (s, 3H), 1.29 (s, 6H); ESI MS: M + H+ 316.0 m/z.
	With hydrogenchloride; potassium iodide; sodium nitrite; In water; at 0 - 20℃; for 1.08333h;	Example 4;l Synthesis of 1-(6-odo-3,3-dimethylindolin-1-yl)ethanonβ; To a suspension of <strong>[453562-71-5]1-(6-amino-3,3-dimethylindolin-1-yl)ethanone</strong> (2.000 g, 9.791 mmol) in concentrated hydrochloric acid (20.00 ml, 548.5 mmol) at 0 was added ice (15 g) followed by a solution of sodium nitrite (0.7769 g, 11.26 mmol) in water (15 mL). After 45 min, a solution of potassium iodide (3.251 g, 19.58 mmol) in water (15 mL) was added dropwise. After 5 min, the mixture was allowed to warm to RT. After 1 hr, CH2CI2 (ca. 100 mL) and water (ca.25 mL) were added. The aqueous fraction was extracted 2x with CH2CI2. The combined organic fractions were washed with saturated NaHCO3 followed by 10% NaS2O3 and brine. After drying with Na2SO4, the deep red solution was concentrated in vacuo and purified by silica gel chromatography using 10-60% hexanes:EtOAc to afford 1-(6-iodo-3,3-dimethylindolin-1-yl)ethanone as an orange oil that solidified upon standing. M+H+ = 316.0.
		Example 5Synthesis of 1-(6-iodo-3,3-dimethylindolin-1-yl)ethanoneTo a suspension of <strong>[453562-71-5]1-(6-amino-3,3-dimethylindolin-1-yl)ethanone</strong> (2.00O g, 9.791 mmol) in concentrated HCI (20.00 ml, 548.5 mmol) at O0C was added ice (15 g) followed by a solution of sodium nitrite (0.7769 g, 11.26 mmol) in water (15 mL). After 45 min, a solution of potassium iodide (3.251 g, 19.58 mmol) in water (15 mL) was added dropwise. After 5 min, the mixture was allowed to warm to RT. After 1 hr, CH2CI2 (ca. 100 mL) and water (ca.25 mL) were added. The aqueous fraction was extracted 2x with DCM. The combined organic fractions were washed with saturated NaHCO3 followed by 10% NaS2O3 and brine. After drying <n="36"/>with Na2SO4, the deep red solution was concentrated in vacuo and purified by silica gel chromatography using 10-60% hexanes: EtOAc to afford 1-(6-iodo-3,3- dimethylindolin-1-yl)ethanone as an orange oil that solidified upon standing. Found M+H+ = 316.0.

In a 500 mL three-necked round bottom flask equipped with an overhead stirrer, was combined l-(6-amino-3,3-dimethylindolin-1-yl)ethanone (6.98g, 34.22 mmol) with 30 mL of ice/water. The solution was cooled in an ice bath before concentrated HCl (6.8 mL, 81.60 mmol) was added. A solution OfNaNO2 (2.48 g, 35.93 mmol) dissolved in 30 mL of water was added drop wise over a period of 10 min. After 30min a solution of KI (11.36 g, 68.44 mmol) dissolved in 70 mL of CHCl3 was added via an addition funnel over a period of 0.5 h. Then the brownish solution was stirred at rt until gas evolution ceased. Partitioned the solution in a separation funnel, and washed the organic layer with saturated NaHCθ3, followed by 5% Na2S2Os. The organics were dried over MgSO4 before being concentrated under vacuum to 1/10th the volume. This was purified by column chromatography on silica eluting with 20% hexane/DCM. The fractions containing the product were combined and concentrated under vacuum to give 1- (6-iodo-3,3-dimethylindolin-1-yl)ethanone as a tan colored solid. Mass Spectrum (ESI)m/e = 316.0 (M + 1).

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 7667 - 7685.
[2]Patent: WO2009/158011,2009,A1 .Location in patent: Page/Page column 30.
[3]Patent: WO2008/11109,2008,A2 .Location in patent: Page/Page column 37.
[4]Patent: WO2008/8493,2008,A2 .Location in patent: Page/Page column 34-35.
[5]Patent: WO2010/151737,2010,A2 .Location in patent: Page/Page column 61-62.

3
[ 453562-68-0 ]
[ 453562-71-5 ]

Yield	Reaction Conditions	Operation in experiment
94%	With hydrogen;5% Pd(II)/C(eggshell); In tetrahydrofuran; at 60℃; under 1551.49 Torr; for 6h;	Example 6; Preparation of 1-(6-amino-3,3-dimethyl-indolin-1-1y)ethanone; [0073](1 eq.) (3 eq.) (5 wt%) (1 eq.)[0074] l-(3, 3-Dimethyl-6-nitroindoline-ly)ethanone (Example 5, 50 g), 5% Pd/C (1 g, 50% wet) and THF (200 mL) were charged to a 400 mL hydrogenation reactor. The slurry was degassed with vacuum/hydrogen three times and stirred for 6 h at 60 0C under hydrogen (30 PSI). The resulting mixture was filtered through a thin layer of Celite and the cake was washed with THF (150 mL x 2). The filtrate and washes were combined and concentrated in vacuo, followed by addition of toluene (150 mL). The product was isolated by filtration and the wet cake was washed with D.I. water (100 mL x 2) and 50 mL toluene to afford l-(6-amino-3, 3-dimethyl-indolin-l-yl)ethanone (38.5 g, 94% yield, >99.9 A%, 100 wt%).
61%	Pd-C; In methanol;	DC-8; 1-(6-Amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone 10% Pd-C (0.2 g) was added to a suspension of 1-(3,3-dimethyl-6-nitroindolin-1-yl)ethanone (2.1 g, 9 mmol) in MeOH (20 mL). The reaction was stirred under H2 (40 psi) at room temperature overnight. Pd-C was filtered off and the filtrate was concentrated under vacuum to give a crude product, which was purified by column chromatography to yield 1-(6-amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (DC-8) (1.3 g, 61%).
61%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; under 2068.65 Torr;	10% Pd-C (0.2 g) was added to a suspension of 1-(3,3-dimethyl-6-nitroindolin-1-yl)ethanone (2.1 g, 9 mmol) in MeOH (20 mL). The reaction was stirred under H2 (40 psi) at room temperature overnight. Pd-C was filtered off and the filtrate was concentrated under vacuum to give a crude product, which was purified by column chromatography to yield 1-(6-amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (DC-8) (1.3 g, 61%).

	With hydrogen;palladium 10% on activated carbon; In methanol;	l-(3,3-Dimeth.Yl-6-nitro-2,3-dihydro-indol-l-Yl)ethanone (250mg) was dissolved in MeOH (20 mL), the mixture was bubbledwith H2 for 10 min. 10% Pd/C (50 mg) was added and themixture was stirred under H2 overnight. The mixture wasfiltered through Celite and concentrated in vacuo. Thecrude material was purified by flash chromatography onsilica gel with 1:1 EtOAc:CH2Cl2 to afford the titlecompound as a white crystalline material. MS: 205 (M+l).Calc'd. for Ci2H16N20-204 .27 .
	With H2; In methanol; ethyl acetate;	EXAMPLE 133 Step A-Preparation of 1-acetyl-6-amino-3,3-dimethylindoline 1-Acetyl-3,3-dimethyl-6-nitroindoline (250 mg) was dissolved in MeOH (20 mL), the mixture was bubbled with H2 for 10 min. 10% Pd/C (50 mg) was added and the mixture was stirred under H2 overnight. The mixture was filtered through Celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 1:1 EtOAc:CH2Cl2 to afford the title compound as a white crystalline material. MS: 205 (M+1). Calc'd. for C12H16N2O-204.27.
	With hydrogen;palladium 10% on activated carbon; In ethanol; under 760.051 Torr; for 3h;	C. 1-(6-amino-3,3-dimethylindolin-1-yl)ethanone A mixture of 1-(3,3-dimethyl-6-nitroindolin-1-yl)ethanone (300 mg), 10% Pd-C (50 mg), and EtOH (50 mL) was stirred under hydrogen atmosphere (1 atm) for 3 h. The catalyst was filtered out and the filtrate was concentrated to give a light yellow solid (260 mg). MS: M+H=205.
	Pd-C; In ethanol;	C. 1-(6-Amino-3,3-dimethylindolin-1-yl)ethanone A mixture of 1-(3,3-dimethyl-6-nitroindolin-1-yl)ethanone (300 mg, 1.3 mmol), 10% Pd-C (50 mg), and EtOH (50 mL) was stirred under H2 (1 atm) for 3 h. After that the catalyst was filtered off and the filtrate was concentrated to give a light yellow solid (260 mg). MS: M+H=205 (M+1);
	With H2; In methanol; ethyl acetate;	Step A-Preparation of 1-acetyl-6-amino-3,3-dimethylindoline 1-Acetyl-3,3-dimethyl-6-nitroindoline (250 mg) was dissolved in MeOH (20 mL), the mixture was bubbled with H2 for 10 min. 10% Pd/C (50 mg) was added and the mixture was stirred under H2 overnight. The mixture was filtered through Celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 1:1 EtOAc:CH2Cl2 to afford the title compound as a white crystalline material. MS: 205 (M+1). Calc'd. for C12H16N2O-204.27.
	With hydrogen;palladium 10% on activated carbon; In ethanol; at 25℃; under 2250.23 Torr; for 1.16667h;	Stage f: 1-acetyl-3,3-dimethylindolin-6-amine 1.46 g of 10% palladium on charcoal, 8.8 g of 1-acetyl-3,3-dimethyl-6-nitroindoline obtained in stage e) below and 110 mL of ethanol are placed in a hydrogenation reactor. After reacting for one hour 10 minutes at 3 bar at a temperature of 25 C., the reaction medium is filtered through paper and concentrated under reduced pressure to give 6.9 g of 1-acetyl-3,3-dimethylindolin-6-amine in the form of a brown solid, the characteristics of which are as follows: LCMS: RT=1.12 min; m/z=205 [M+H]+
	With hydrogen;palladium 10% on activated carbon; In methanol;	Step A-Preparation of 1-acetyl-6-amino-3,3-dimethylindoline 1-Acetyl-3,3-dimethyl-6-nitroindoline (250 mg) was dissolved in MeOH (20 mL), the mixture was bubbled with H2 for 10 min. 10% Pd/C (50 mg) was added and the mixture was stirred under H2 overnight.The mixture was filtered through Celite and concentrated in vacuo.The crude material was purified by flash chromatography on silica gel with 1:1 EtOAc:CH2Cl2 to afford the title compound as a white crystalline material. MS: 205 (M+1). Calc'd. for C12H16N2O-204.27.
	With hydrogen;palladium 10% on activated carbon; In methanol;	Preparation LXXIX: [1-ACETYL-6-AMINO-3,] 3-dimethylindoline [1- (3,] 3-dimethyl-6-nitro-2, [3-DIHYDRO-INDOL-1-] yl) ethanone (250 mg) was dissolved in MeOH (20 mL), the mixture was bubbled with [H2] for 10 min. 10% Pd/C (50 mg) was added and the mixture was stirred under [H2] overnight. The mixture was filtered through Celte and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 1: 1 EtOAc: CH2Cl2 to afford the title compound as a white crystalline material. MS: 205 [(M+1).] [CALC'D.] for C12H16N2O-204. 27.
	With hydrogen;palladium 10% on activated carbon; In methanol;	l-(3,3-Dimethyl-6-nitro-2,3-dihydro-indol-l-yl)ethanone (250 mg) was dissolved in MeOH (20 mL), the mixture was bubbled with H2 for 10 min. 10% Pd/C (50 mg) was added and the mixture was stirred under H2 overnight. The mixture was filtered through Celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 1:1 EtOAc:CH2Cl2 to afford the title compound as a white crystalline material. MS: 205 (M+l). Calc'd. for Ci2H16N2O-204.27.
	With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; at 50℃; under 2585.81 Torr; for 0.133333h;	A Parr hydrogenation unit was charged with l-(3,3-dimethyl-6-nitroindolin-1-yl)- ethanone (450 g, 1.92 mol), THF (1.8 L), and 10% Pd/C (20.3 g). The unit was purged with nitrogen twice then agitated. The unit was pressurized with 50 psi hydrogen and the agitation was continued until absorption ceased. Hydrogen absorption was exothermic. The temperature was maintained below 50 C during the reaction. The reaction was monitored by GC. After 8 min, the unit was purged with nitrogen. The mixture was filtered through a Celite pad and washed the pad with THF (100 mL x 1). The filtrate was concentrated under reduced pressure to 1A total volume and cooled to 0 C. To the mixture was added heptane (800 mL x 1) and the mixture was stirred at 0 C for 45 min. The resulting precipitate was collected by filtration, washed the solid with heptane (150 mL x 1), and dried at 50 C under reduced pressure to give l-(6-amino-3,3- dimethylindolin- 1 -yl)ethanone.

References: [1]Patent: WO2010/71828,2010,A2 .Location in patent: Page/Page column 15-16.
[2]Patent: US2011/98311,2011,A1 .
[3]Patent: US2015/231142,2015,A1 .Location in patent: Paragraph 0656.
[4]Patent: WO2006/12374,2006,A1 .Location in patent: Page/Page column 162.
[5]Patent: US2003/125339,2003,A1 .
[6]Patent: US2006/258689,2006,A1 .Location in patent: Page/Page column 35; 36.
[7]Patent: US2005/277643,2005,A1 .
[8]Patent: US6878714,2005,B2 .
[9]Patent: US2009/82379,2009,A1 .Location in patent: Page/Page column 23.
[10]Patent: US2003/225106,2003,A1 .Location in patent: Page 51; 80; 126.
[11]Patent: WO2004/5279,2004,A2 .Location in patent: Page 120.
[12]Patent: WO2007/48070,2007,A2 .Location in patent: Page/Page column 120.
[13]Patent: WO2010/151737,2010,A2 .Location in patent: Page/Page column 45.

4
[ 453562-71-5 ]
[ 118-48-9 ]
[ 645418-60-6 ]

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide; at 150℃; for 6h;	Example 9 [N- (1-ACETYL-3,] 3-dimethyl-2, [3-DIHYDRO-LH-INDOL-6-YL)-2-] [ [(QUINOLIN-4-YLMETHYL)-AMINO]-BENZAMIDE] Step A: Preparation of [N- (1-ACETYL-3,] 3-dimethyl-2,3- [DIHYDRO-LH-INDOL-6-YL)-2-AMINO-BENZAMIDE] A mixture of 1- (6-amino-3, 3-dimethyl-2,3-dihydro- indol-1-yl)-ethanone (1.02 g, 5 mmol) and isatoic anhydride (0. 85 g, 5.2 mmol) in DMSO (5 mL) was heated to 150 [C] for 6 h. After cooling to RT, the mixture was suspended in a [NAHC03] solution (40 mL) and extracted with [CH2CL2] [(20] mL x 3). The organic solution was combined and concentrated in vacuo. The residue was purified via flash chromatography on silica gel (EtOAc: hexanes 9: 2) to give the desired compound as an off-white solid.

References: [1]Patent: WO2004/5279,2004,A2 .Location in patent: Page 128.

6
[ 453562-71-5 ]
N-(1-acetyl-3,3-dimethylindolin-6-yl){2-[(4-pyridylmethyl)-amino](3-pyridyl)}-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step B-Preparation of N-(1-acetyl-3,3-dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide The titled compound was prepared from <strong>[453562-71-5]1-acetyl-6-amino-3,3-dimethylindoline</strong> (Step A) by the method described in Example 82.

References: [1]Patent: US2003/125339,2003,A1 .

7
[ 453562-71-5 ]
[ 914612-37-6 ]
[ 914611-07-7 ]

Yield	Reaction Conditions	Operation in experiment
		D. 1-{6-[6-(3-chloro-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-3,3-dimethyl-2,3-dihydro-indol-1-yl}-ethanone A mixture of <strong>[453562-71-5]1-(6-amino-3,3-dimethylindolin-1-yl)ethanone</strong> (80 mg), 4-chloro-6-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (80 mg), and CH3CN (5 mL) was run in a Microwave Reactor at 180 C. for 1 h. After cooling, the mixture was treated with sat. aq. Na2CO3 and extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column to give a light yellow solid (75 mg). 1H NMR (d6-DMSO): 8.61 (s, 1H), 8.34 (s, 1H), 8.28 (dd, 1H, J=4.8, 1.6 Hz), 8.19 (d, 1H, J=1.6 Hz), 7.88 (dd, 1H, J=8.0, 1.6 Hz), 7.35 (dd, 1H, J=8.0, 2.0 Hz), 7.15 (d, 1H, J=8.0 Hz), 7.07 (dd, 1H, J=8.0, 4.8 Hz), 4.38 (s, 2H), 3.86 (s, 2H), 3.61 (t, 2H, J=5.6 Hz), 2.87 (t, 2H, J=5.6 Hz), 2.16 (s, 3H), 1.30 (s, 6H).

References: [1]Patent: US2006/258689,2006,A1 .Location in patent: Page/Page column 35; 36.

8
[ 453562-71-5 ]
[ 15028-41-8 ]
[ 530-62-1 ]
[ 945103-85-5 ]

Yield	Reaction Conditions	Operation in experiment
		Stage g: 3-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethylimidazolidine-2,4-dione A solution of 6.6 g of 1,1'-carbonylbis(1H-imidazole) and 460 mg of 1H-imidazole in 50 mL of tetrahydrofuran is stirred under argon and cooled in an ice bath at 0 C. To this solution is added a suspension of 6.9 g of <strong>[453562-71-5]1-acetyl-3,3-dimethylindolin-6-amine</strong> obtained in stage f) below in 50 mL of tetrahydrofuran. After stirring for one hour, 9.5 mL of triethylamine and 5.2 g of methyl 2-methylalaninate hydrochloride are added and the mixture is stirred for two hours at room temperature and then refluxed for 17 hours. After cooling to room temperature, the mixture is diluted with 800 mL of water and the precipitate formed is filtered off, washed with four times 25 mL of water and with three times 15 mL of diethyl ether and then dried to give 8 g of 3-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethylimidazolidine-2,4-dione in the form of a beige-coloured solid, the characteristics of which are as follows: LCMS: RT=3.19 min; m/z=316 [M+H]+; m/z=314 [M-H]-
		Steps A • and B:5,17 mmol ' of 1,1' -Carbonyldimidazole and 0,86- -mmo. ofimidazole are dissolved in 10 ml THF and cooled'to 0C. Asolution of 'the aromatic amine . (4,31 mmol ) in a .suitable'amount of THF' '(5 to 10 ml) is added over .15 mini..The.reaction mixture "is allowed to 'reach RT and stirred, f.oranother 2h. Then 4,3 'mmol of Net3 and 4,3 mmol .of ..2-'amino-2-methyl-propionic = acid methyl. ester ' .acid•hydrochlorid are added and ' the resulting mixture -,isstirred''until completion of the reaction. After theevaporation of the solvent ' the crude product is pure,enough • for ' the next step. Example 293- (l-Acetyl-3, 3-dimethyl-2, 3-dihydro-lH-indol-6-yl) -5, 5-• dimethyl-1- [2- (pyrazin-2- ylamino) -pyridin-4-ylmethyl] -• imi-dazoridine-2, 4-dione• Start-ing /from 1- (6^Amino-3, 3'-dimethyl-2, 3-dihydro-indol-1-yl) -ethanohe in step • A and' using steps,, B, C, D .arid* Ewith 2-aminopyrazine•M+H+ measured =• 50-0.24LC/MS retention time [min] =1.3.3- Example 7la ' .- . . , .3-(l-Acetyl-3,3-dimethyl-2,3-dihydro-lH-indol-6-yl)-5,5-dimethyl-imidazolidine-2,4- dione To a ' solution." of -838 mg d'i-imidazol-1-yl-methanone..and 58. mg imidazole in 10 ml • tetrahydrofuran a solution of 880 mg • 1-(6-amino-3f3-dimethyl-2,3-dihydro-indol-l-yl)-ethanone in 5 ml tetrahydrofuran was slowly added at 0C. After stirring at 0C for 90 minutes. 0.60 ml triethylamine and 661 mg 2-amino-2-methyl-propionic acid methyl- ester hydrochloride were added and the reaction mixture was allowed to warirv up to room temperature. After, 2 hours stirring at room temperature the solution was •heated for 6 hours at - 70C.' After cooling to ,room temperature'the solvent of the mixture was removed under reduced pressure and • the residue was purified by flash chromatography on silica gel with a n-heptane/ ethylacetate gradient. The fractions -containing the product were combined .and evaporated to yield a white solid.Yield: 920 mg'M+H-f- measured = 3161H-NMR (400 MHz, DMSO/TMS) : d = 8.50 (s, 1H) ; 7.93 (s, 1H);'7.33 (d, 1H) ; 6.97. - (dd, • 1H) ; 3.90 (s, 2H) ; 2.17 (s, 3H); 1.50 (s, 6H); 1.33 (s, 6H)

References: [1]Patent: US2009/82379,2009,A1 .Location in patent: Page/Page column 22-23.
[2]Patent: WO2006/10642,2006,A1 .Location in patent: Page/Page column 79; 81; 94-95.

9
[ 5414-19-7 ]
[ 453562-71-5 ]
[ 1259511-93-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In methanol; at 150℃; for 2.5h;Sealed tube;	A mixture of l-(6-amino-3,3-dimethylindolin-1-yl)ethanone (5 g, 24.5mmol), 1- bromo-2-(2-bromoethoxy)ethane (6.25 g, 26.9 mmol), and Na2CO3 (5.19 g, 49 mmol) in MeOH (25 mL) was heated to 150 C in a sealed tube. After 2.5 h, the mixture was cooled to rt. The reaction mixture was diluted with water (100 mL). The resulting solid was filtered, washed with water (300 mL), and dried in the air to give l-(3,3-dimethyl-6-morpholinoindolin-1-yl)ethanone as a grey solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 7.74 (1 H, s), 7.06 (1 H, d, J=8.1 Hz), 6.61 (1 H, dd, J=8.2, 2.1 Hz), 3.82 (2 H, s), 3.67 - 3.76 (4 H, m), 2.95 - 3.06 (4 H, m), 2.13 (3 H, s), 1.26 (6 H, s). Mass Spectrum (ESI) m/e = 275.2 (M + 1).

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 7667 - 7685.
[2]Patent: WO2010/151737,2010,A2 .Location in patent: Page/Page column 46.

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References: [1]Patent: US2011/98311,2011,A1 .
[2]Patent: US2015/231142,2015,A1 .

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References: [1]Patent: US2011/98311,2011,A1 .
[2]Patent: US2015/231142,2015,A1 .

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