[ CAS No. 1201676-03-0 ]

Name: 1201676-03-0|4,6-Dichloro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one|95%
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Quality Control of [ 1201676-03-0 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 1201676-03-0 ]

CAS No. :	1201676-03-0	MDL No. :	MFCD16658728
Formula :	C₇H₄Cl₂N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	203.03 g/mol	Pubchem ID :	46899909
Synonyms :

Calculated chemistry of of [ 1201676-03-0 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	49.21
TPSA :	41.99 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) :	-6.39 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.52
Log Po/w (XLOGP3) :	1.62
Log Po/w (WLOGP) :	1.1
Log Po/w (MLOGP) :	1.11
Log Po/w (SILICOS-IT) :	2.62
Consensus Log Po/w :	1.59

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.49
Solubility :	0.658 mg/ml ; 0.00324 mol/l
Class :	Soluble
Log S (Ali) :	-2.11
Solubility :	1.56 mg/ml ; 0.00769 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.75
Solubility :	0.0358 mg/ml ; 0.000176 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.83

Safety of [ 1201676-03-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1201676-03-0 ]

* 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 [ 1201676-03-0 ]
Downstream synthetic route of [ 1201676-03-0 ]

[ 1201676-03-0 ] Synthesis Path-Upstream 1~2

1
[ 1201676-02-9 ]
[ 1201676-03-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	With ammonium hydroxide In tetrahydrofuran at 20℃; for 18 h;	A mixture of 3-bromomethyl-2,6-dichloroisonicotinic acid ethyl ester (13.4 g, 42.7 mmol), tetrahydrofuran (100 ml_), and ammonium hydroxide (300 ml. of 28-30percent ammonia) is stirred at room temperature for 18 h. The solvents are then removed by rotary evaporation. The nearly dry solid is treated with a small amount of water. The salmon-colored solid is isolated by filtration, washed with small amounts of water and then diethyl ether, and dried under vacuum. Filtration of the cooled filtrate yields additional salmon-colored solid (7.47g, 36.8 mmol, 86percent). MS(ESI) m/z 203.2 (M+1 ). ¹H NMR (400 MHz, DMSOd₆) δ ppm 9.29 (br. s., 1 H), 7.83 (s, 1 H), 4.45 (s, 2 H).

Reference： [1] Patent: WO2009/150230, 2009, A1, . Location in patent: Page/Page column 180-181
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 15, p. 5422 - 5438

2
[ 137520-99-1 ]
[ 1201676-03-0 ]

Reference： [1] Patent: WO2009/150230, 2009, A1,

[ 1201676-03-0 ] Synthesis Path-Downstream 1~23

1
[ 1201676-03-0 ]
[ 57260-71-6 ]
[ 1201676-04-1 ]
[ 1201676-05-2 ]

Yield	Reaction Conditions	Operation in experiment
63%	With triethylamine; In 1,4-dioxane; at 120℃; for 40.0h;	4,6-Dichloro-2,3-dihydro-pyrrolo[3,4-c]pyridin-1-one (5.63 g, 27.7 mmol), te/f-butyl piperazine-1-carboxylate (7.75 g, 41.6 mmol), triethylamine (14.Og, 139 mmol), and dioxane (50 ml.) are stirred at 120 0C in a 350 ml. sealed tube for 16 h. To the cooled down reaction mixture are then added more te/f-butyl piperazine-1-carboxylate (5.2 g, 27.7 mmol) and triethylamine (2.83 g, 28.0 mmol). The vessel is sealed again and stirred at 120 0C for 24 h. The reaction mixture is then cooled to ambient temperature, and a light-pink solid is isolated by filtration (6.18 g, 17.5 mmol, 63%). MS(ESI) m/z 353.15 (M+1 ). 1H NMR (400 MHz, DMSOd6) delta ppm 9.04 (s, 1 H), 6.89 (s, 1 H), 4.57 (s, 2 H), 3.61 - 3.54 (m, 4 H), 3.47 - 3.41 (m, 4 H), 1.42 (s, 9 H).D. 4-(4-Chloro-1 -oxo-2,3-dihydro-1 H-pyrrolo[3,4-c]pyridin-6-yl)-piperazine-1 -carboxylic acid terf-butyl ester. <n="184"/> The title compound is typically obtained from the dioxane filtrate after isolation of 4- (6-chloro-1 -oxo-2,3-dihydro-1 /-/-pyrrolo[3,4-c]pyridin-4-yl)-piperazine-1 -carboxylic acid tert- butyl ester. The dioxane is removed by rotary evaporation. Treatment with methanol yields a light yellow solid which is isolated by filtration. MS(ESI) m/z 353.30 (M+1 ). 1H NMR (400 MHz, DMSOd6) delta ppm 8.93 (s, 1 H), 7.01 (s, 1 H), 4.28 (s, 2 H), 3.58 - 3.53 (m, 4 H), 3.45 - 3.40 (m, 4 H), 1.42 (S, 9 H).

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 5422 - 5438
[2]Patent: WO2009/150230,2009,A1 .Location in patent: Page/Page column 181

2
[ 1201676-03-0 ]
5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)-pyrazine hydrochloride [ No CAS ]
[ 1201676-08-5 ]

Yield	Reaction Conditions	Operation in experiment
65%	With triethylamine; In 1,4-dioxane; at 120℃; for 40.0h;	A mixture of <strong>[1201676-03-0]4,6-dichloro-2,3-dihydro-pyrrolo[3,4-c]pyridin-1-one</strong> (0.655 g, 3.23 mmol), triethylamine (2.61 g, 25.8 mmol), and 5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3- a]pyrazine hydrochloride (0.544 g, 3.39 mmol) in dioxane (7.5 ml.) is stirred in a 48 ml_ sealed tube at 12O0C for 16 h. Additional 5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-a]pyrazine hydrochloride (0.500 g, 3.11 mmol) is added to the mixture, which is heated again at 12O0C for 24 h. A light yellow powder is isolated by filtration of the room temperature reaction mixture (0.61 1 g, 2.10 mmol, 65%). MS(ESI) m/z 291.18 (M+1 ). 1H NMR (400 MHz, DMSOd6) delta ppm 9.1 1 (s, 1 H), 8.50 (s, 1 H), 7.01 (s, 1 H), 4.97 (s, 2 H), 4.68 (s, 2 H), 4.19 (t, J=5.31 Hz, 2 H), 4.01 (t, J=5.43 Hz, 2 H).

Reference： [1]Patent: WO2009/150230,2009,A1 .Location in patent: Page/Page column 184-185

3
[ 1201676-02-9 ]
[ 1201676-03-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	With ammonium hydroxide; In tetrahydrofuran; at 20℃; for 18.0h;	A mixture of 3-bromomethyl-2,6-dichloroisonicotinic acid ethyl ester (13.4 g, 42.7 mmol), tetrahydrofuran (100 ml_), and ammonium hydroxide (300 ml. of 28-30% ammonia) is stirred at room temperature for 18 h. The solvents are then removed by rotary evaporation. The nearly dry solid is treated with a small amount of water. The salmon-colored solid is isolated by filtration, washed with small amounts of water and then diethyl ether, and dried under vacuum. Filtration of the cooled filtrate yields additional salmon-colored solid (7.47g, 36.8 mmol, 86%). MS(ESI) m/z 203.2 (M+1 ). 1H NMR (400 MHz, DMSOd6) delta ppm 9.29 (br. s., 1 H), 7.83 (s, 1 H), 4.45 (s, 2 H).

Reference： [1]Patent: WO2009/150230,2009,A1 .Location in patent: Page/Page column 180-181
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 5422 - 5438

4
[ 1201676-03-0 ]
[ 1201676-10-9 ]
[ 1201676-09-6 ]

Yield	Reaction Conditions	Operation in experiment
31%	With triethylamine; In 1,4-dioxane; at 120℃; for 68.0h;	A mixture of <strong>[1201676-03-0]4,6-dichloro-2,3-dihydro-pyrrolo[3,4-c]pyridin-1-one</strong> (1.19 g, 5.87 mmol), triethylamine (2.97 g, 29.3 mmol), and crude trifluoroacetic acid salt of piperidine-4- carboxylic acid isobutyl amide [obtained by stirring 4-isobutylcarbamoyl-piperidine-1- carboxylic acid te/f-butyl ester (2.63 g, 8.80 mmol) in dichloromethane (20 mL) and trifluoroacetic acid (6 mL) for 1.5 hours, then removing solvents by rotary evaporation] in dioxane (10 mL) is heated in a 75 mL sealed tube at 120 0C for 68 h. Filtration of room temperature mixture does not lead to separation of regioisomers. The filtrate is concentrated down to dryness by rotary evaporation, dissolved into ethyl acetate, and then washed with water and brine. The organic layer is dried over sodium sulfate, filtered and concentrated down to dryness by rotary evaporation. This residue is then combined with solids from first filtration and eluted through a silica gel column (80:20 ethyl acetate / heptane, then 100% ethyl acetate, then 95:5 ethyl acetate / methanol). The more polar regioisomer (TLC <n="189"/>solvents: 90:10 ethyl acetate / methanol) is concentrated down to dryness by rotary evaporation, then treated with a small amount of methanol. The pink solid is isolated by filtration (0.647 g, 1.84 mmol, 31 %). MS(ESI) m/z 351.20 (M+1 ). 1H NMR (400 MHz, DMSOd6) delta ppm 9.00 (s, 1 H), 7.79 (t, J=5.81 Hz, 1 H), 6.84 (s, 1 H), 4.54 (s, 2 H), 4.19 (d, J=13.39 Hz, 2 H), 3.09 - 2.92 (m, 2 H), 2.86 (dd, J=6.57, 6.06 Hz, 2 H), 2.48 - 2.36 (m, 1 H), 1.79 - 1.71 (m, 2 H), 1.71 - 1.52 (m, 3 H), 0.82 (d, J=6.82 Hz, 6 H).

Reference： [1]Patent: WO2009/150230,2009,A1 .Location in patent: Page/Page column 186-187

5
[ 1201676-03-0 ]
[ 1201674-76-1 ]

Reference： [1]Patent: WO2009/150230,2009,A1

6
[ 1201676-03-0 ]
[ 1201674-74-9 ]

Reference： [1]Patent: WO2009/150230,2009,A1

7
[ 1201676-03-0 ]
[ 1201674-77-2 ]

Reference： [1]Patent: WO2009/150230,2009,A1

8
[ 1201676-03-0 ]
[ 1201676-06-3 ]

Reference： [1]Patent: WO2009/150230,2009,A1

9
[ 1201676-03-0 ]
[ 1201676-07-4 ]

Reference： [1]Patent: WO2009/150230,2009,A1

10
[ 1201676-03-0 ]
[ 1201676-10-9 ]
[ 1201674-78-3 ]

Reference： [1]Patent: WO2009/150230,2009,A1

11
[ 137520-99-1 ]
[ 1201676-03-0 ]

Reference： [1]Patent: WO2009/150230,2009,A1

12
[ 126689-01-8 ]
[ 1201676-03-0 ]
6-chloro-4-cyclopropyl-2H,3H-pyrrolo[3,4-c]pyridin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 16h;Inert atmosphere;	A solution of 4,6-dichloro-2H,3H-pyrrolo[3,4-c]pyridin-l-one (1.0 g, 4.9 mmol, 1 eq.), 2- cyclopropyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.0 mL, 11 mmol, 2.2 eq.), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (0.80 g, 1.0 mmol, 0.2 eq.) and potassium carbonate (3.4 g, 25 mmol, 5 eq.) in dioxane-water (10: 1 v/v, 15 mL) was degassed and heated at 80 C for 16 hours. After cooling the mixture, it was diluted with water and extracted with 15% isopropanol in chloroform (3x). The combined organic layers were dried, filtered and concentrated. The product was purified chromatography B to afford the title compound (0.44 g, 42%) as a white solid.

Reference： [1]Patent: WO2019/148005,2019,A1 .Location in patent: Paragraph 2644

13
bromo(cyclopropyl)zinc [ No CAS ]
[ 1201676-03-0 ]
4,6-dicyclopropyl-2H,3H-pyrrolo[3,4-c]pyridin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91 mg	With 2?-(dicyclohexylphophanyl)-N2,N2,N6,N6-tetramethyl[1,1?-biphenyl]-2,6-diamine; palladium diacetate; In tetrahydrofuran; at 65 - 75℃; for 18.0h;	A mixture of 4,6-dichloro-lH,2H,3H-pyrrolo[3,4-c]pyridin-l-one (200 mg, 1.0 mmol, 1 eq), bromo(cyclopropyl)zinc (5.9 mL of 0.5M solution in THF, 2.7 mmol, 3 eq), palladium (II) acetate (22 mg, 0.1 mmol, 0.1 eq), 2'-(dicyclohexylphosphanyl)-N2,N2,N6,N6-tetramethyl-[l,r- biphenyl] -2,6-diamine (86 mg, 0.2 mmol, 0.2 eq) and THF (2 mL) was heated at 65 - 75 C for 18 h. After cooling to rt, the reaction was subject to aqueous work-up and chromatography on silica gel to afford 91 mg of the title compound as an off-white solid.

Reference： [1]Patent: WO2019/148005,2019,A1 .Location in patent: Paragraph 2172; 2619

14
[ 1201676-03-0 ]
4-cyclopropyl-6-((S)-1-((R)-4,4-difluoro-3-methylpiperidin-1-yl)ethyl)-2-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one [ No CAS ]
4-cyclopropyl-6-((R)-1-((R)-4,4-difluoro-3-methylpiperidin-1-yl)ethyl)-2-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / water; 1,4-dioxane / 16 h / 80 °C / Inert atmosphere 2.1: palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; potassium phosphate / 1,4-dioxane / 3 h / 105 °C / Inert atmosphere 3.1: bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 100 °C 4.1: hydrogenchloride / water; methanol / 1 h 5.1: triethylamine / methanol / 0.02 h / 100 °C / Microwave irradiation 5.2: 5 h / 80 - 200 °C / Microwave irradiation