[ CAS No. 56008-20-9 ] {[proInfo.proName]}

Name: 56008-20-9|3,6,6-Trimethyl-6,7-dihydro-1H-indol-4(5H)-one|95%
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SKU: A281123
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Quality Control of [ 56008-20-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 56008-20-9 ]

Product Details of [ 56008-20-9 ]

CAS No. :	56008-20-9	MDL No. :	MFCD08060464
Formula :	C₁₁H₁₅NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	REGIWYJKSKEPMU-UHFFFAOYSA-N
M.W :	177.24	Pubchem ID :	24820798
Synonyms :

Calculated chemistry of [ 56008-20-9 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.55
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	52.97
TPSA :	32.86 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.93 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.96
Log Po/w (XLOGP3) :	2.04
Log Po/w (WLOGP) :	2.48
Log Po/w (MLOGP) :	1.42
Log Po/w (SILICOS-IT) :	3.5
Consensus Log Po/w :	2.28

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.51
Solubility :	0.549 mg/ml ; 0.0031 mol/l
Class :	Soluble
Log S (Ali) :	-2.36
Solubility :	0.777 mg/ml ; 0.00438 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.75
Solubility :	0.0313 mg/ml ; 0.000177 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.2

Safety of [ 56008-20-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 56008-20-9 ]

* 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.

Upstream synthesis route of [ 56008-20-9 ]
Downstream synthetic route of [ 56008-20-9 ]

[ 56008-20-9 ] Synthesis Path-Upstream 1~6

1
[ 17280-41-0 ]
[ 126-81-8 ]
[ 56008-20-9 ]

Yield	Reaction Conditions	Operation in experiment
52%	With acetic acid; zinc In waterReflux	Step 1. Synthesis of 3,6,6-trimethyl-6,7-dihydro-lH-indole-4(5H)-on [formula 6-2]Anti-pyruvic aldehyde- 1-oxime [formula 6-1] (0.50 g, 5.74 mmol) and 5,5-dimethyl- 1,3-cyclohexandion [formula 6-7] (0.80 g, 5.74 mmol) were dissolved in acetic acid (35 mL) and H₂0 (15 mL) . Thereto, zinc powder (0.75 g, 11.5 mmol) was added slowly maintaining room temperature. The reaction mixture was refluxed with stirring, concentrated under reduced pressure and extracted with CH₂C1₂ and brine, of which pH was adjusted to 6 using saturated NaHC0₃. The reaction mixture was extracted with CH₂C1₂; organic layer was dried over anhydrous MgS0₄ and filtered. Residue was concentrated under reduced pressure and purified by column chromatography (Si0₂; hexane/ethylacetate, 1/3) to yield the title compound as yellow solid (4.9 g, 52 percent).
45%	With zinc In water; acetic acid at 20℃; Heating / reflux	To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5, 5-dimethyl-l, 3-cyclohexanedione (16.1 g, 1 eq) in HOAc- H₂O (7:3, 200 mL) was added zinc powder (14.95 g, 2 eq) slowly with cooling by a water bath at room temperature. The mixture then was refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL) . The pH was adjusted to ca. 6 with saturated aqueous NaHCO₃, then the mixture was extracted with dichloromethane (3x200 mL) . The organic layers were combined, dried overNa₂SO₄, filtered, concentrated. The crude product was purified by flash chromatography eluting with 5percent ethyl acetate in dichloromethane. The combined organic fractions were concentrated, triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give the pure title compound (9 g, 45percent yield) as a solid. LCMS m/z: (M+H) = 178.1.
45%	Stage #1: With acetic acid; zinc In water at 20℃; Heating / reflux Stage #2: With sodium hydrogencarbonate In dichloromethane; water	To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5,5-dimethyl-1,3-cyclohexanedione (16.1 g, 1 eq) in HOAc-H₂O (7:3, 200 mL), was added zinc powder (14.95 g, 2 eq) slowly cooling with a water bath at room temperature. The mixture was refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL). The pH was adjusted to ca. 6 with saturated aqueous NaHCO₃, then extracted with dichloromethane (3.x.200 mL). The organic layers were combined, dried over Na₂SO₄, filtered, concentrated to give crude product. This was purified by flash chromatography, eluting with 5percent ethyl acetate in dichloromethane to give expected product, which was triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give pure title compound (9 g, 45percent yield) as a solid.

45%

With acetic acid; zinc In water at 20℃; Heating / reflux

Example 1; 3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one; To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5,5-dimethyl-1,3-cyclohexanedione (16.1 g, 1 eq) in HOAc-H₂O (7:3, 200 mL), was added zinc powder (14.95 g, 2 eq) slowly cooling with a water bath at room temperature. The mixture was refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL). The pH was adjusted to ca. 6 with saturated aqueous NaHCO₃, then extracted with dichloromethane (3.x.200 mL). The organic layers were combined, dried over Na₂SO₄, filtered, concentrated to give crude product. This was purified by flash chromatography, eluting with 5percent ethyl acetate in dichloromethane to give expected product, which was triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give pure title compound (9 g, 45percent yield) as a solid.

Reference： [1] Patent: WO2013/62344, 2013, A1, . Location in patent: Page/Page column 87
[2] Patent: WO2006/91963, 2006, A1, . Location in patent: Page/Page column 84; 89
[3] Patent: US2008/269193, 2008, A1, . Location in patent: Page/Page column 39
[4] Journal of Medicinal Chemistry, 2009, vol. 52, # 14, p. 4288 - 4305
[5] Patent: US2007/207984, 2007, A1, . Location in patent: Page/Page column 23

2
[ 126-81-8 ]
[ 306-44-5 ]
[ 56008-20-9 ]

Yield	Reaction Conditions	Operation in experiment
52%	With acetic acid; zinc In waterReflux	Anti-pyruvic aldehyde-1-oxime [formula 6-1] (0.50 g, 5.74 mmol) and 5,5-dimethyl-1,3-cyclohexandion [formula 6-7] (0.80 g, 5.74 mmol) were dissolved in acetic acid (35 mL) and H₂O (15 mL). Thereto, zinc powder (0.75 g, 11.5 mmol) was added slowly maintaining room temperature. The reaction mixture was refluxed with stirring, concentrated under reduced pressure and extracted with CH₂Cl₂ and brine, of which pH was adjusted to 6 using saturated NaHCO₃. The reaction mixture was extracted with CH₂Cl₂; organic layer was dried over anhydrous MgSO₄ and filtered. Residue was concentrated under reduced pressure and purified by column chromatography (SiO₂; hexane/ethylacetate, 1/3) to yield the title compound as yellow solid (4.9 g, 52percent).
45%	With acetic acid; zinc In waterReflux	Example 1 3,6,6-Trimethyl-1,5,6,7-tetrahydro-indo1-4-one (Intermediate 1) To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5,5-dimethyl-1,3-cyclohexanedione (16.1 g, 1 eq) in HOAc-H₂O (7:3, 200 mL) is added zinc powder (14.95 g, 2 eq) slowly with cooling by a water bath at room temperature. The mixture is then refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL). The pH is adjusted to ca. 6 with saturated aqueous NaHCO₃, then the mixture is extracted with dichloromethane (3*200 mL). The organic layers are combined, dried over Na₂SO₄, filtered, concentrated. The crude product is purified by flash chromatography eluting with 5percent ethyl acetate in dichloromethane. The combined organic fractions are concentrated, triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give the pure title compound (9 g, 45percent yield) as a solid. LCMS m/z: (M+H)=178.1.

Reference： [1] Patent: US2014/315889, 2014, A1, . Location in patent: Paragraph 0417-0419; 0463-0465
[2] Patent: US2015/329493, 2015, A1, . Location in patent: Paragraph 0228; 0232; 0233

3
[ 37711-24-3 ]
[ 56008-20-9 ]

Reference： [1] Australian Journal of Chemistry, 1990, vol. 43, # 5, p. 825 - 837
[2] Bulet. Soc. chim. Romania, vol. 10, p. 134[3] Chem. Zentralbl., 1929, vol. 100, # I, p. 2185

4
[ 126-81-8 ]
[ 56008-20-9 ]

Reference： [1] Bulet. Soc. chim. Romania, vol. 10, p. 134[2] Chem. Zentralbl., 1929, vol. 100, # I, p. 2185

5
[ 31915-82-9 ]
[ 126-81-8 ]
[ 56008-20-9 ]

Reference： [1] Journal and Proceedings of the Royal Society of New South Wales, 1932, vol. 66, p. 477,481

6
[ 129689-88-9 ]
[ 56008-20-9 ]

Reference： [1] Australian Journal of Chemistry, 1990, vol. 43, # 5, p. 825 - 837
[2] Bulet. Soc. chim. Romania, vol. 10, p. 134[3] Chem. Zentralbl., 1929, vol. 100, # I, p. 2185

[ 56008-20-9 ] Synthesis Path-Downstream 1~86

1
[ 50-00-0 ]
[ 56008-20-9 ]
3,6,6,3',6',6'-hexamethyl-1,5,6,7,1',5',6',7'-octahydro-2,2'-methanediyl-bis-indol-4-one [ No CAS ]

Reference： [1]Buletinul Societatii de Chimie din Romania,vol. 10,p. 141
Chemisches Zentralblatt,1929,vol. 100,p. 2186

2
[ 56008-20-9 ]
[ 100-34-5 ]
3,6,6-trimethyl-6,7-dihydro-5<i>H</i>-indole-2,4-dione-2-phenylhydrazone [ No CAS ]

Reference： [1]Buletinul Societatii de Chimie din Romania,vol. 10,p. 141
Chemisches Zentralblatt,1929,vol. 100,p. 2186

3
[ 56008-20-9 ]
[ 122-51-0 ]
3,6,6,3',6',6',3'',6'',6''-nonamethyl-1,5,6,7,1',5',6',7',1'',5'',6'',7''-dodecahydro-2,2',2''-methanetriyl-tris-indol-4-one [ No CAS ]

Reference： [1]Buletinul Societatii de Chimie din Romania,vol. 10,p. 141
Chemisches Zentralblatt,1929,vol. 100,p. 2186

4
[ 56008-20-9 ]
3,6,6-trimethyl-4,5,6,7-tetrahydro-indole [ No CAS ]

Reference： [1]Buletinul Societatii de Chimie din Romania,vol. 10,p. 141
Chemisches Zentralblatt,1929,vol. 100,p. 2186

5
[ 56008-20-9 ]
3,6,6-trimethyl-4,5,6,7-tetrahydro-indole [ No CAS ]
bis-(3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-ylidene)-hydrazine [ No CAS ]

Reference： [1]Buletinul Societatii de Chimie din Romania,vol. 10,p. 141
Chemisches Zentralblatt,1929,vol. 100,p. 2186

6
[ 129689-88-9 ]
[ 56008-20-9 ]

Reference： [1]Australian Journal of Chemistry,1990,vol. 43,p. 825 - 837
[2]Buletinul Societatii de Chimie din Romania,vol. 10,p. 134
Chemisches Zentralblatt,1929,vol. 100,p. 2185

7
[ 31915-82-9 ]
[ 126-81-8 ]
[ 56008-20-9 ]

Reference： [1]Journal and Proceedings - Royal Society of New South Wales,1932,vol. 66,p. 477,481

8
[ 56008-20-9 ]
[ 61810-29-5 ]
[ 129689-90-3 ]

Reference： [1]Australian Journal of Chemistry,1990,vol. 43,p. 825 - 837

11
4-oxo-3.6.6-trimethyl-4.5.6.7-tetrahydro-indole-carboxylic acid-⁽²⁾ [ No CAS ]
[ 56008-20-9 ]

Reference： [1]Buletinul Societatii de Chimie din Romania,vol. 10,p. 134
Chemisches Zentralblatt,1929,vol. 100,p. 2185

12
[ 56008-20-9 ]
[ 64-17-5 ]
[ 7803-57-8 ]
3,6,6-trimethyl-4,5,6,7-tetrahydro-indole [ No CAS ]
bis-(3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-ylidene)-hydrazine [ No CAS ]

Reference： [1]Buletinul Societatii de Chimie din Romania,vol. 10,p. 141
Chemisches Zentralblatt,1929,vol. 100,p. 2186

13
[ 1009036-29-6 ]
[ 56008-20-9 ]
1-(4-Amino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%	With sodium hydride; In ISOPROPYLAMIDE; at 160℃; for 0.333333h;Microwave irradiation;	A solution of 7-Fluoro-quinazolin-4-ylamine (0.2203 g, 1.35 mmol), 6,6,6,-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.286 g, 1.62 mmol) and NaH (60% suspension in mineral oil, 0.081 g, 2.025 mmol) in dimethylacetamide (5 mL) is microwaved at 160 C. for 20 min. The reaction mixture is poured onto a saturated solution of NH4Cl (5 mL), and the aqueous phase is extracted with EtOAc (3×). The combined organic layers are washed with brine, dried over MgSO4, and evaporated to dryness. Purification of the crude material by column chromatography (5% MeOH in CH2Cl2) affords 1-(4-Amino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.1131 g, 26%). LC/MS m/z=321 [M+H]+.

Reference： [1]Patent: US2008/70935,2008,A1 .Location in patent: Page/Page column 45
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2550 - 2554

14
[ 214045-86-0 ]
[ 56008-20-9 ]
1-(3-chloro-isoquinolin-6-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9%	With sodium hydride; In N,N-dimethyl-formamide; at 160℃; for 0.333333h;Microwave irradiation;	Example 14 1-(3-chloro-isoquinolin-6-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one; To a solution of <strong>[214045-86-0]1-chloro-6-fluoro-isoquinoline</strong> (0.0847 g, 0.47 mmol) in DMF (2 mL) are added pyrrole (0.1 g, 0.56 mmol) and NaH (0.028 g, 0.71 mmol). The reaction mixture is microwaved at 160 C. for 20 min. The reaction mixture is cooled to RT, and treated with NH4Cl (satd. aq., 2 mL). The aqueous phase is extracted with EtOAc (2×). The combined organic layers are washed with brine, and dried over MgSO4. The solvent is evaporated and the residue is dried under vacuum. Purification of the crude material using a Biotage column (0-50% EtOAc/hexanes) affords 0.014 g (9%) of 1-(3-chloro-isoquinolin-6-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one. LC/MS m/z=339 [M+H]+, RT=4.01 min.

Reference： [1]Patent: US2008/70935,2008,A1 .Location in patent: Page/Page column 49

15
[ 1009034-73-4 ]
[ 56008-20-9 ]
1-(1-Amino-4-bromo-isoquinolin-6-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With sodium hydride; In N,N-dimethyl-formamide; at 120℃; for 0.666667h;Microwave irradiation;	Example 18 1-(1-Amino-4-bromo-isoquinolin-6-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (Compound 9); To a solution of 1-amino-4-bromo-6-fluoro-isoquinoline (0.029 g, 0.12 mmol) in DMF (1 mL) are added 3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.042 g, 0.24 mmol) and NaH (0.01 g, 0.24 mmol). The reaction mixture is microwaved at 120 C. for 40 min, cooled to RT, and treated with NH4Cl (satd. aq, 2 mL). The aqueous phase is extracted with EtOAc (2×). The combined organic layers are washed with brine, and dried over MgSO4. The solvent is evaporated and the residue is dried under vacuum. Purification of the crude material using a Biotage column (0-10% MeOH/CH2Cl2) affords 0.0118 g (25%) of 1-(1-Amino-4-bromo-isoquinolin-6-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one. LC/MS m/z=399 [M+H]+.

Reference： [1]Patent: US2008/70935,2008,A1 .Location in patent: Page/Page column 50

16
[ 1009034-82-5 ]
[ 56008-20-9 ]
[ 1009034-84-7 ]

Yield	Reaction Conditions	Operation in experiment
40%	With sodium hydride; In N,N-dimethyl-formamide; at 120℃; for 0.666667h;Microwave irradiation;	Example 22 1-amino-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-isoquinoline-4-carbonitrile; To a solution of 1-amino-6-fluoro-isoquinoline-4-carbonitrile (0.109 g, 0.58 mmol) in DMF (5 mL) are added pyrrole (0.15 g, 0.87 mmol) and NaH (0.035 g, 0.87 mmol). The reaction mixture is microwaved at 120 C. for 40 min. The reaction mixture is cooled to RT, and treated with H2O (10 mL). The aqueous phase is extracted with EtOAc (2×). The combined organic layers are washed with brine, and dried over MgSO4. The solvent is evaporated and the residue is dried under vacuum. Purification of the crude material using a Biotage column (0-20% MeOH/CH2Cl2) affords 0.08 g (40%) of 1-amino-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-isoquinoline-4-carbonitrile. LC/MS m/z=345 [M+H]+, RT=2.98 min.

Reference： [1]Patent: US2008/70935,2008,A1 .Location in patent: Page/Page column 51

17
Cyclopropyl-(7-fluoro-quinazolin-4-yl)-amine [ No CAS ]
[ 56008-20-9 ]
1-(4-Cyclopropylamino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; at 100℃; for 0.416667h;Microwave irradiation;	Example 34 1-(4-Cyclopropylamino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one; 3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.177 g, 1 mmol), sodium hydride (60% in oil, 40 mg, 1 mmol), Cyclopropyl-(7-fluoro-quinazolin-4-yl)-amine (0.20 g, 1 mmol), and N,N-dimethylformamide are sealed in a microwave vessel and irradiated at 100 degrees Celsius for 1500 seconds. The mixture is extracted with ethyl acetate and washed with water. The organic phase is dried over magnesium sulfate, filtered concentrated, and chromatographed to afford 0.2 g of 1-(4-Cyclopropylamino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one as a solid (55%). LC/MS m/z=361 [M+H]+.

Reference： [1]Patent: US2008/70935,2008,A1 .Location in patent: Page/Page column 54

18
[ 56008-20-9 ]
7-fluoroquinazolin-2-amine [ No CAS ]
1-(2-Amino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With sodium hydride; In N,N-dimethyl-formamide; at 150℃; for 0.416667h;Microwave irradiation;	3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.65 g, 3.68 mmol), sodium hydride (60% in oil, 0.177 g, 4.4 mmol), 7-fluoroquinazolin-2-amine (0.60 g, 3.68 mmol), and N,N-dimethylformamide are sealed in a microwave vessel and irradiated at 150 degrees Celsius for 1500 seconds. The mixture is purified by column chromatography and recrystallized from dichloromethane/hexane, affording 0.96 g of 1-(2-Amino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (81%). LC/MS m/z=321 [M+H]+.

Reference： [1]Patent: US2008/70935,2008,A1 .Location in patent: Page/Page column 55
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2550 - 2554

19
[ 56008-20-9 ]
2-amino-7-fluoro-4-methylquinazoline [ No CAS ]
1-(2-amino-4-methylquinazolin-7-yl)-3,6,6-trimethyl-6,7-dihydro-1H-indol-4(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With sodium hydride; In N,N-dimethyl-formamide; at 150℃; for 0.416667h;Microwave irradiation;	3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.7 g, 4 mmol), sodium hydride (60% in oil, 0.20 g, 4.8 mmol), 7-Fluoro-4-methyl-quinazolin-2-ylamine (0.7 g, 4 mmol), and N,N-dimethylformamide are heated at 150 degrees Celsius for 2 h. The mixture is extracted with ethyl acetate/water. The organic layer is dried and concentrated. The residue is purified by column chromatography, affording 0.9 g of a solid 1-(2-Amino-4-methyl-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (68%). LC/MS m/z=335 [M+H]+.

Reference： [1]Patent: US2008/70935,2008,A1 .Location in patent: Page/Page column 55
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2550 - 2554

20
[ 56008-20-9 ]
[ 129689-93-6 ]

Reference： [1]Australian Journal of Chemistry,1990,vol. 43,p. 825 - 837

21
[ 56008-20-9 ]
[ 129715-51-1 ]

Reference： [1]Australian Journal of Chemistry,1990,vol. 43,p. 825 - 837

22
[ 37711-24-3 ]
[ 56008-20-9 ]

Reference： [1]Australian Journal of Chemistry,1990,vol. 43,p. 825 - 837
[2]Buletinul Societatii de Chimie din Romania,vol. 10,p. 134
Chemisches Zentralblatt,1929,vol. 100,p. 2185

23
[ 126-81-8 ]
[ 56008-20-9 ]

Reference： [1]Buletinul Societatii de Chimie din Romania,vol. 10,p. 134
Chemisches Zentralblatt,1929,vol. 100,p. 2185

24
[ 17280-41-0 ]
[ 126-81-8 ]
[ 56008-20-9 ]

Yield	Reaction Conditions	Operation in experiment
52%	With acetic acid; zinc; In water;Reflux;	Step 1. Synthesis of 3,6,6-trimethyl-6,7-dihydro-lH-indole-4(5H)-on [formula 6-2]Anti-pyruvic aldehyde- 1-oxime [formula 6-1] (0.50 g, 5.74 mmol) and 5,5-dimethyl- 1,3-cyclohexandion [formula 6-7] (0.80 g, 5.74 mmol) were dissolved in acetic acid (35 mL) and H20 (15 mL) . Thereto, zinc powder (0.75 g, 11.5 mmol) was added slowly maintaining room temperature. The reaction mixture was refluxed with stirring, concentrated under reduced pressure and extracted with CH2C12 and brine, of which pH was adjusted to 6 using saturated NaHC03. The reaction mixture was extracted with CH2C12; organic layer was dried over anhydrous MgS04 and filtered. Residue was concentrated under reduced pressure and purified by column chromatography (Si02; hexane/ethylacetate, 1/3) to yield the title compound as yellow solid (4.9 g, 52 %).
45%	With zinc; In water; acetic acid; at 20℃;Heating / reflux;	To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5, 5-dimethyl-l, 3-cyclohexanedione (16.1 g, 1 eq) in HOAc- H2O (7:3, 200 mL) was added zinc powder (14.95 g, 2 eq) slowly with cooling by a water bath at room temperature. The mixture then was refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL) . The pH was adjusted to ca. 6 with saturated aqueous NaHCO3, then the mixture was extracted with dichloromethane (3x200 mL) . The organic layers were combined, dried overNa2SO4, filtered, concentrated. The crude product was purified by flash chromatography eluting with 5% ethyl acetate in dichloromethane. The combined organic fractions were concentrated, triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give the pure title compound (9 g, 45% yield) as a solid. LCMS m/z: (M+H) = 178.1.
45%		To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5,5-dimethyl-1,3-cyclohexanedione (16.1 g, 1 eq) in HOAc-H2O (7:3, 200 mL), was added zinc powder (14.95 g, 2 eq) slowly cooling with a water bath at room temperature. The mixture was refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL). The pH was adjusted to ca. 6 with saturated aqueous NaHCO3, then extracted with dichloromethane (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, concentrated to give crude product. This was purified by flash chromatography, eluting with 5% ethyl acetate in dichloromethane to give expected product, which was triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give pure title compound (9 g, 45% yield) as a solid.

45%

With acetic acid; zinc; In water; at 20℃;Heating / reflux;

Example 1; 3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one; To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5,5-dimethyl-1,3-cyclohexanedione (16.1 g, 1 eq) in HOAc-H2O (7:3, 200 mL), was added zinc powder (14.95 g, 2 eq) slowly cooling with a water bath at room temperature. The mixture was refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL). The pH was adjusted to ca. 6 with saturated aqueous NaHCO3, then extracted with dichloromethane (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, concentrated to give crude product. This was purified by flash chromatography, eluting with 5% ethyl acetate in dichloromethane to give expected product, which was triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give pure title compound (9 g, 45% yield) as a solid.

Reference： [1]Patent: WO2013/62344,2013,A1 .Location in patent: Page/Page column 87
[2]Patent: WO2006/91963,2006,A1 .Location in patent: Page/Page column 84; 89
[3]Patent: US2008/269193,2008,A1 .Location in patent: Page/Page column 39
[4]Journal of Medicinal Chemistry,2009,vol. 52,p. 4288 - 4305
[5]Patent: US2007/207984,2007,A1 .Location in patent: Page/Page column 23

25
[ 56008-20-9 ]
[ 36282-26-5 ]
[ 908111-21-7 ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium hydride; In N,N-dimethyl-formamide; at 55℃; for 1h;	The title compound of Example 1 (9.8 g, 55.3 itimol) and 2- bromo-4-fluorobenzonitrile (13.27 g, 66.4 mmol) were dissolved in anhydrous dimethylformamide (DMF, 300 mL) . To this was added sodium hydride (95%, 2.79 g, 111 mmol) and the reaction was stirred at 55 0C for 1 hour. The reaction mixture was cooled to room temperature and water was added. A tan solid precipitated which was filtered, washed with water and ether and then dried in vacuo (16.5 g, 84%). LCMS m/z: (M+H) = 358.1
84%	With sodium hydride; In N,N-dimethyl-formamide; at 55℃; for 1h;	Example 2; 2-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrile; The title compound of Example 1 (9.8 g, 55.3 mmol) and 2-bromo-4-fluorobenzonitrile (13.27 g, 66.4 mmol) were dissolved in anhydrous dimethylformamide (DMF, 300 mL). To this was added sodium hydride (NaH, 95%, 2.79 g, 111 mmol) and the reaction was stirred at 55 C. for 1 hour. The reaction mixture was cooled to room temperature and water was added. A tan solid precipitated which was filtered, washed with water and ether and then dried in vacuo (16.5 g, 84%). MS m/z: (M+H)=358.1.
	With sodium hydride; In N,N-dimethyl-formamide; at 55℃; for 1h;	10235] Thetitle compound of Example 1 (9.8g, 55.3 mmol) and 2-bromo-4-fluorobenzonitrile (13.27 g, 66.4 mmol) are dissolved in anhydrous dimethylformamide (DMF, 300 mL). To this is added sodium hydride (95%, 2.79 g, 111 mmol) and the reaction is stirred at 550 C. for 1 hour. The reaction mixture is cooled to room temperature and water is added. A tan solid precipitated which is filtered, washed with water and ether and then dried in vacuo.

Reference： [1]Patent: WO2006/91963,2006,A1 .Location in patent: Page/Page column 84; 90
[2]Journal of Medicinal Chemistry,2009,vol. 52,p. 4288 - 4305
[3]Patent: US2007/207984,2007,A1 .Location in patent: Page/Page column 23
[4]Patent: US2015/329493,2015,A1 .Location in patent: Paragraph 0228; 0234; 0235

26
[ 56008-20-9 ]
[ 1073973-23-5 ]
[ 1073973-24-6 ]

Yield	Reaction Conditions	Operation in experiment
39%	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 0 - 100℃; for 96h;microwave cap;	Potassium carbonate (1.21 g, 8.75 mmol) was added to a solution of 4-bromo-2-fluoro-6-(S-tetrahydro-furan-3-ylamino)-benzonitrile (0.5 g, 1.75 mmol) and 3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.31 g, 1.75 mmol) in 1,4-dioxane (6 mL). The solution was degassed under N2. The flask was then cooled at 0 C. and connected to a vacuum line. The vacuum was pulled until the solvent started bubbling. The degassing/vacuum cycle was repeated 2 times. Then N,N'-dimethylethylenediamine (0.27 mL, 2.54 mmol) and CuI (0.5 g, 2.63 mmol) were added. The degassing/vacuum cycle was performed 3 times. The rubber septum was replaced by a microwave cap. The solution was degassed one more time, and placed in an oil bath at 100 C. The reaction mixture was stirred at 100 C. for 4 days. The reaction mixture was filtered through a pad of Celite, and the filter pad was rinsed with EtOAc. The solvent was removed under reduced pressure. Purification of the residue using a Biotage column eluted with 0-50% MeOH/CH2Cl2 afforded 0.263 g (39%) of 2-fluoro-6-(S-tetrahydro-furan-3-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrile. LC/MS: m/z=382 [M+H]+. 1H NMR (DMSO, 20 C., 400 MHz) δ (ppm) 7.73-7.69 (m, 2H), 7.44 (d, 1H), 6.55 (d, 1H), 6.46 (s, 1H), 4.46 (b, 1H), 3.87-3.70 (m, 7H), 2.97 (s, 3H), 2.74 (s, 2H), 2.49 (s, 2H), 0.98 (s, 6H)

Reference： [1]Patent: US2008/269193,2008,A1 .Location in patent: Page/Page column 40

27
[ 56008-20-9 ]
[ 1073973-35-9 ]
[ 1073973-63-3 ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 0 - 100℃;Sealed;	To a stirred solution of 2-((1S,2S)-2-benzyloxy-cyclopentylamino)-4-bromo-6-fluoro-bezonitrile (1.48 g) and 3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.56 g) in dioxane (15 mL) were added K2CO3 (2.64 g). The suspension was freezed in ice-bath and degassed by pump/backfill of N2 3 times. Then CuI (1.1 g) and N,N'-dimethylethylenediamine (0.6 mL) were added. The reaction mixture was degassed again for 3 times with backfill of N2. Then the sealed reaction mixture was stirred at 100 C. overnight. The reaction mixture was filtered through a celite pad, washed by EtOAc, concentrated to give a gum (LCMS m/z M+H=486.3). That was dissolved in EtOH-DMSO (4:1, 50 mL), then 1N NaOH aq (10 mL), and H2O2 (3 mL) were added and the mixture stirred at RT for 4 h. The reaction mixture was concentrated and poured into Sat'd NH4Cl aq. (250 mL), extracted by EtOAc (3×150 mL), dried over Na2SO4, filtered, concentrated to give a gum, which was purified by Biotage chromatography, eluted by 30% EtOAc in hexane to give 2-fluoro-6-((1S,2S)-2-benzyloxy-cyclopentylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide (1.2 g, 63% for 2 steps). LCMS (M+H) m/z=504.3.

Reference： [1]Patent: US2008/269193,2008,A1 .Location in patent: Page/Page column 45; 55

28
[ 56008-20-9 ]
4-bromo-2-fluoro-6-(trans-4-hydroxy-cyclohexylamino)-benzonitrile [ No CAS ]
4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-2-fluoro-6-(4-hydroxy-cyclohexylamino)-benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 0 - 100℃; for 17h;	4-Bromo-2-fluoro-6-(4-hydroxy-cyclohexylamino)-benzonitrile (1.74 g, 5.56 mmol), 3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (1 g, 5.56 mmol), and K2CO3 (3.84 g, 27.8 mmol) are dissolved in 1,4-dioxane (16 mL). The reaction mixture is degassed by 3 freeze (0 C.)/pump/thaw cycles under N2. Then, N,N'-dimethylethylenediamine (0.87 mL, 8.1 mmol) and CuI (1.6 g, 8.34 mmol) are added and the reaction is again degassed by three more freeze/pump/thaw cycles. The reaction mixture is then heated to 100 C. for 17 hours. After cooling, the reaction is filtered through Celite, washed with EtOAc (3×20 mL), concentrated and purified via Biotage column (0-50% EtOAc in Hex) to give 4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-2-fluoro-6-(4-hydroxy-cyclohexylamino)-benzonitrile (1.78 g; 78% yield). LC/MS: m/z=409 [M+H]+.

Reference： [1]Patent: US2008/269193,2008,A1 .Location in patent: Page/Page column 49-50

29
[ 56008-20-9 ]
[ 1194-02-1 ]
C₁₈H₁₈N₂O [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4288 - 4305
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 3382 - 3400
[3]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 1338 - 1342

30
7-Fluoro-2-methyl-quinazolin-4-ylamine [ No CAS ]
[ 56008-20-9 ]
1-(4-Amino-2-methyl-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2550 - 2554

31
5,7-difluoroquinazolin-4-amine [ No CAS ]
[ 56008-20-9 ]
1-(4-Amino-5-fluoro-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2550 - 2554

32
7,8-difluoroquinazolin-4-amine [ No CAS ]
[ 56008-20-9 ]
[ 1009034-62-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2550 - 2554

33
[ 56008-20-9 ]
C₁₂H₁₄FN₃O [ No CAS ]
1-(4-amino-8-butoxyquinazolin-7-yl)-3,6,6-trimethyl-6,7-dihydro-1H-indol-4(5H)-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2550 - 2554

34
[ 56008-20-9 ]
C₁₂H₁₅FN₄ [ No CAS ]
1-(4-amino-8-(butylamino)quinazolin-7-yl)-3,6,6-trimethyl-6,7-dihydro-1H-indol-4(5H)-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2550 - 2554

35
[ 56008-20-9 ]
C₁₂H₁₄FN₃S [ No CAS ]
1-(4-amino-8-(butylthio)quinazolin-7-yl)-3,6,6-trimethyl-6,7-dihydro-1H-indol-4(5H)-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2550 - 2554

36
[ 56008-20-9 ]
C₁₁H₁₀FN₃S [ No CAS ]
1-(8-(allylthio)-4-aminoquinazolin-7-yl)-3,6,6-trimethyl-6,7-dihydro-1H-indol-4(5H)-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2550 - 2554

37
[ 56008-20-9 ]
C₁₀H₁₁FN₄S [ No CAS ]
1-(4-amino-8-(2-aminoethylthio)quinazolin-7-yl)-3,6,6-trimethyl-6,7-dihydro-1H-indol-4(5H)-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2550 - 2554

38
[ 56008-20-9 ]
C₁₀H₁₁FN₄S [ No CAS ]
1-(2,4-diamino-5-(ethylthio)quinazolin-7-yl)-3,6,6-trimethyl-6,7-dihydro-1H-indol-4(5H)-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2550 - 2554

39
[ 56008-20-9 ]
C₉H₈FN₃O [ No CAS ]
1-(4-amino-5-methoxyquinazolin-7-yl)-3,6,6-trimethyl-6,7-dihydro-1H-indol-4(5H)-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2550 - 2554

40
[ 56008-20-9 ]
[ 119584-78-0 ]
1-(2,4-Diamino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2550 - 2554

41
[ 56008-20-9 ]
[ 2417-72-3 ]
[ 1432509-59-5 ]

Yield	Reaction Conditions	Operation in experiment
34%		Step 2. Synthesis of methyl 4-((3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-lH-indole-l-yl)methyl)benzoate [formula 6-3]3,6,6-trimethyl-6,7-dihydro-lH-indole-4(5H)-on [formula 6-2] (0.23 g, 1.29 mmol) was dissolved DMF. Thereto, NaH (0.062 g, 2.56 mmol) was added slowly at room temperature.After 5 minutes stirring, methyl 4-(bromethyl)benzoate was added and stirred at room temperature for 4 hours -After-the completion of reaction7the "reaction mixmfe^wa^ extracTed with ethyl acetate and saturated NH4C1 aqueous solution, the organic layer was dried over anhydrous MgS04 and filtered. Filtrate was concentrated under reduced pressure and purified by column chromatography (Si02; hexane/ethylacetate, 7/3) to yield the title compound as white solid (0.14 g, 34 %).
34%		3,6,6-trimethyl-6,7-dihydro-1H-indole-4(5H)-on [formula 6-2] (0.23 g, 1.29 mmol) was dissolved DMF. Thereto, NaH (0.062 g, 2.56 mmol) was added slowly at room temperature. After 5 minutes stirring, methyl 4-(bromethyl)benzoate was added and stirred at room temperature for 4 hours. After the completion of reaction, the reaction mixture was extracted with ethyl acetate and saturated NH4Cl aqueous solution, the organic layer was dried over anhydrous MgSO4 and filtered. Filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2; hexane/ethylacetate, 7/3) to yield the title compound as white solid (0.14 g, 34%).

Reference： [1]Patent: WO2013/62344,2013,A1 .Location in patent: Page/Page column 87; 88; 98
[2]Patent: US2014/315889,2014,A1 .Location in patent: Paragraph 0419-0421; 0465-0467

42
[ 56008-20-9 ]
[ 1432508-44-5 ]

Reference： [1]Patent: US2014/315889,2014,A1
[2]Patent: WO2013/62344,2013,A1

43
[ 56008-20-9 ]
[ 1595029-04-1 ]
[ 1595027-99-8 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3382 - 3400

44
[ 56008-20-9 ]
C₁₄H₁₆FNO [ No CAS ]
[ 1595028-02-6 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3382 - 3400

45
[ 56008-20-9 ]
C₁₅H₁₈FNO [ No CAS ]
[ 1595028-04-8 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3382 - 3400

46
[ 56008-20-9 ]
C₁₄H₁₆FNO₂ [ No CAS ]
[ 1595028-06-0 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3382 - 3400

47
[ 56008-20-9 ]
C₁₃H₁₄FNO [ No CAS ]
[ 1595028-08-2 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3382 - 3400

48
[ 56008-20-9 ]
C₁₃H₁₆FNO [ No CAS ]
[ 1595028-10-6 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3382 - 3400

49
[ 56008-20-9 ]
C₁₃H₁₆FNO [ No CAS ]
[ 1595028-12-8 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3382 - 3400

50
[ 56008-20-9 ]
C₁₆H₁₄FNO [ No CAS ]
[ 1595028-14-0 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3382 - 3400

51
[ 56008-20-9 ]
C₁₅H₁₂FNO [ No CAS ]
[ 1595028-16-2 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3382 - 3400

52
[ 56008-20-9 ]
C₁₅H₁₁F₂NO [ No CAS ]
[ 1595028-18-4 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3382 - 3400

53
[ 56008-20-9 ]
C₁₅H₁₁F₂NO [ No CAS ]
[ 1595028-20-8 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3382 - 3400

54
[ 56008-20-9 ]
C₁₆H₁₄FNO₂ [ No CAS ]
[ 1595028-22-0 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3382 - 3400

55
[ 56008-20-9 ]
[ 1194-02-1 ]
4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3382 - 3400
[2]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 1338 - 1342

56
[ 126-81-8 ]
[ 306-44-5 ]
[ 56008-20-9 ]

Yield	Reaction Conditions	Operation in experiment
52%	With acetic acid; zinc; In water;Reflux;	Anti-pyruvic aldehyde-1-oxime [formula 6-1] (0.50 g, 5.74 mmol) and 5,5-dimethyl-1,3-cyclohexandion [formula 6-7] (0.80 g, 5.74 mmol) were dissolved in acetic acid (35 mL) and H2O (15 mL). Thereto, zinc powder (0.75 g, 11.5 mmol) was added slowly maintaining room temperature. The reaction mixture was refluxed with stirring, concentrated under reduced pressure and extracted with CH2Cl2 and brine, of which pH was adjusted to 6 using saturated NaHCO3. The reaction mixture was extracted with CH2Cl2; organic layer was dried over anhydrous MgSO4 and filtered. Residue was concentrated under reduced pressure and purified by column chromatography (SiO2; hexane/ethylacetate, 1/3) to yield the title compound as yellow solid (4.9 g, 52%).
45%	With acetic acid; zinc; In water;Reflux;	Example 1 3,6,6-Trimethyl-1,5,6,7-tetrahydro-indo1-4-one (Intermediate 1) To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5,5-dimethyl-1,3-cyclohexanedione (16.1 g, 1 eq) in HOAc-H2O (7:3, 200 mL) is added zinc powder (14.95 g, 2 eq) slowly with cooling by a water bath at room temperature. The mixture is then refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL). The pH is adjusted to ca. 6 with saturated aqueous NaHCO3, then the mixture is extracted with dichloromethane (3*200 mL). The organic layers are combined, dried over Na2SO4, filtered, concentrated. The crude product is purified by flash chromatography eluting with 5% ethyl acetate in dichloromethane. The combined organic fractions are concentrated, triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give the pure title compound (9 g, 45% yield) as a solid. LCMS m/z: (M+H)=178.1.

Reference： [1]Patent: US2014/315889,2014,A1 .Location in patent: Paragraph 0417-0419; 0463-0465
[2]Patent: US2015/329493,2015,A1 .Location in patent: Paragraph 0228; 0232; 0233

57
[ 56008-20-9 ]
C₁₈H₁₈N₂O₂ [ No CAS ]