[ CAS No. 1173081-96-3 ] {[proInfo.proName]}

Name: 1173081-96-3|3-(Aminomethyl)-4,6-dimethylpyridin-2(1H)-one hydrochloride|95%
Brand: Ambeed
SKU: A714837
Price: 10.0 USD
Availability: InStock
Rating: 96 (32 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

DV 2D 3D

3d Animation Molecule Structure of 1173081-96-3

Structure of 1173081-96-3 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 1173081-96-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1173081-96-3 ]

SDS Specification

Alternatived Products of [ 1173081-96-3 ]

Product Details of [ 1173081-96-3 ]

CAS No. :	1173081-96-3	MDL No. :	MFCD09053337
Formula :	C₈H₁₃ClN₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZMDPNGUJHPRAMG-UHFFFAOYSA-N
M.W :	188.65	Pubchem ID :	43810451
Synonyms :

Calculated chemistry of [ 1173081-96-3 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.38
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	51.63
TPSA :	58.88 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.94 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.72
Log Po/w (WLOGP) :	1.1
Log Po/w (MLOGP) :	0.71
Log Po/w (SILICOS-IT) :	1.99
Consensus Log Po/w :	0.9

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.77
Solubility :	3.22 mg/ml ; 0.0171 mol/l
Class :	Very soluble
Log S (Ali) :	-1.53
Solubility :	5.51 mg/ml ; 0.0292 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.73
Solubility :	0.347 mg/ml ; 0.00184 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.84

Safety of [ 1173081-96-3 ]

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 [ 1173081-96-3 ]

* 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 [ 1173081-96-3 ]
Downstream synthetic route of [ 1173081-96-3 ]

[ 1173081-96-3 ] Synthesis Path-Upstream 1~8

1
[ 769-28-8 ]
[ 1173081-96-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogenchloride; hydrogen; palladium(II) hydroxide In methanol; water at 20℃; for 26 h; Inert atmosphere	To a solution of 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (10.0 g, 67.5 mmol) in MeOH (1.50 L) and conc. HCl (30 mL) was added 10percent Pd(OH)₂ (19 g) under N₂ atmosphere. The N₂ gas was displaced by H₂ gas and the mixture was stirred for 26 hours at RT under hydrogen atmosphere. The H₂ gas was displaced by N₂ gas. The mixture was filtered through Celite, washed with MeOH and concentrated. The residue was triturated with EtOH, collected with Buchner funnel, and dried under vacuum pressure to give the titled compound as a white solid (11.5 g, 90percent). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 11.86 (brs, 1H), 5.98 (s, 1H), 3.78 (m, 2H), 2.20 (s, 3H), 2.16 (s, 3H).
51 g	Stage #1: for 48 h; Stage #2: With hydrogenchloride In water	Intermediate 83-(Aminomethyl)-4,6-dim pyridinone hydrochloridePalladium on carbon (10percent) (3.24 g) was charged into a 2L dry Parr bottle and a small amount of acetic acid was added. Next added 4,6-dimethyl-2-oxo-l,2-dihydro- pyridine- 3-carbonitrile (30 g , 202.7 mmol), sodium acetate (30.75 g, 375.0 mmol), platinum oxide (0.218 g), and acetic acid (1 L).. The bottle was capped, placed on Parr apparatus, and shaken under an atmosphere of H₂ (100 psi) for 2 days. The reaction mixture was filtered.The solvent was removed to give a residue, which was treated with 150 mL of cone. HCl, and the formed solids were filtered. The yellow filtrate was concentrated . To the crude compound was added 30 mL of cone. HCl and 150 mL EtOH, the contents cooled to 0 °C, and stirred at 0 °C for 2h. The formed solids were filtered, washed with cold EtOH, ether, and dried. The product was collected as 36 g. This batch was combined with other batches prepared on smaller scales and triturated with ether to give 51 g of pure compound.. 1H NMR (400 MHz, DMSO- ₆) ? ppm 11.85 (br s,l H) 8.13 (br s, 3 H) 5.93 - 6.01 (m, 1 H) 3.72 - 3.80 (m, 2 H) 2.22 (s, 3 H) 2.16 (s, 3 H).
36g	With platinum(IV) oxide; palladium 10% on activated carbon; hydrogen; sodium acetate In acetic acid for 48 h;	Palladium on carbon (10percent) (3.24 g) was charged into a 2 L dry Parr bottle and asmall amount of acetic acid was added. Next added 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (30 g, 202.7 mmol), sodium acetate (30.75 g, 375.0 mmol),platinum oxide (0.218 g), and acetic acid (1 L) .. The bottle was capped, placed on Parrapparatus, and shaken under an atmosphere ofH2 (100 psi) for 2 days. The reaction mixture was filtered. The solvent was removed to give a residue, which was treated with150 mL of cone. HCl, and the formed solids were filtered. The yellow filtrate wasconcentrated. To the crude compound was added 30 mL of cone. HCl and 150 mL EtOH,the contents cooled to 0 °C, and stirred at 0 oc for 2h. The formed solids were filtered,washed with cold EtOH, ether, and dried. The product was collected as 36 g. This batchwas combined with other batches prepared on smaller scales and triturated with ether togive 51 g of pure compound. IH NMR (400 MHz, DMSO-d6) 8 ppm 11.85 (br s,l H) 8.13(br s, 3 H) 5.93-6.01 (m, 1 H) 3.72-3.80 (m, 2 H) 2.22 (s, 3 H) 2.16 (s, 3 H).

51 g

Stage #1: for 48 h; Inert atmosphere
Stage #2: With hydrogenchloride In ethanol; water at 0℃; for 2 h; Inert atmosphere

Palladium on carbon (10percent) (3.24 g) was charged into a 2L dry Parr bottle and a small amount of acetic acid was added. Next added 4,6-dimethyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (30 g, 202.7 mmol), sodium acetate (30.75 g, 375.0 mmol), platinum oxide (0.218 g), and acetic acid (1 L). The bottle was capped, placed on Parr apparatus, and shaken under an atmosphere of H₂(100 psi) for 2 days. The reaction mixture was filtered. The solvent was removed to give a residue, which was treated with 150 mL of conc. HCl, and the formed solids were filtered. The yellow filtrate was concentrated. To the crude compound was added 30 mL of conc. HCl and 150 mL EtOH, the contents cooled to 0° C., and stirred at 0° C. for 2 h. The formed solids were filtered, washed with cold EtOH, ether, and dried. The product was collected as 36 g. This batch was combined with other batches prepared on smaller scales and triturated with ether to give 51 g of pure compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.85 (br s, 1H) 8.13 (br s, 3H) 5.93-6.01 (m, 1H) 3.72-3.80 (m, 2H) 2.22 (s, 3H) 2.16 (s, 3H).

Reference： [1] Patent: US2014/107122, 2014, A1, . Location in patent: Paragraph 0154; 0155
[2] Patent: WO2011/140324, 2011, A1, . Location in patent: Page/Page column 143
[3] Patent: WO2011/140325, 2011, A1, . Location in patent: Page/Page column 141-142
[4] Patent: WO2013/39988, 2013, A1, . Location in patent: Page/Page column 50-51
[5] Patent: WO2013/173441, 2013, A2, . Location in patent: Page/Page column 43; 44
[6] Patent: US2014/256739, 2014, A1, . Location in patent: Paragraph 0725
[7] Patent: WO2014/151142, 2014, A1,
[8] Patent: WO2015/23915, 2015, A1,

2
[ 1616288-77-7 ]
[ 1173081-96-3 ]

Yield	Reaction Conditions	Operation in experiment
55%	With hydrogenchloride In water at 100℃; for 6 h;	A solution of tert-butyl [(2-methoxy-4,6-dimethylpyridin-3-yl)methyl]carbamate (Cpd U, 140 g, 0.52 mol) in 6N HCl (500 mL) was heated at 100° C. and stirred for six hours. The reaction mixture was concentrated and the residue was re-crystallized with EtOH to afford the title compound (Cpd V, 77 g, 55percent) as hydrochloride salts. ¹H NMR (400 MHz, D₂O) δ 6.31 (s, 1H), 4.11 (s, 2H), 2.31-2.30 (s, 6H); MS 175.1 [M+Na].

Reference： [1] Patent: US2014/179667, 2014, A1, . Location in patent: Paragraph 0786; 0790

3
[ 771579-27-2 ]
[ 1173081-96-3 ]

Reference： [1] ACS Medicinal Chemistry Letters, 2012, vol. 3, # 12, p. 1091 - 1096

4
[ 123-54-6 ]
[ 1173081-96-3 ]

Reference： [1] Patent: US2014/107122, 2014, A1,
[2] Patent: WO2014/151142, 2014, A1,
[3] Patent: WO2015/23915, 2015, A1,

5
[ 14237-71-9 ]
[ 1173081-96-3 ]

Reference： [1] Patent: US2014/179667, 2014, A1,

6
[ 65515-39-1 ]
[ 1173081-96-3 ]

Reference： [1] Patent: US2014/179667, 2014, A1,

7
[ 46002-83-9 ]
[ 1173081-96-3 ]

Reference： [1] Patent: US2014/179667, 2014, A1,

8
[ 1173081-96-3 ]
[ 1403254-99-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: With triethylamine In dimethyl sulfoxide at 15 - 25℃; for 0.5 h; Stage #2: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dimethyl sulfoxide at 20℃; for 16 h; Stage #3: With triethylamine In water; dimethyl sulfoxide at 19 - 30℃; for 4 h;	N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-4-methyl-4 '-(morpholinomethyl)- [1,1 '-biphenyl] -3-carboxamide (Compound I) A mixture of 5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'- (morpho linomethyl)-[ 1,1 '-biphenyl] -3 -carboxylic acid (540 g, 1.23 mol) and 3-(aminomethyl)- 4,6-dimethyl-dihydro-pyridin-2(lH)-one hydrochloride (279 g, 1.48 mol) was suspended in DMSO (2.70 L) and treated with triethylamine (223 ml, 1.60 mol). The mixture was stirred at 25 °C for 30 min and treated with EDC-HC1 (354 g, 1.85 mol) and HOBT hydrate (283 g, 1.85 mol). The reaction mixture was stirred at rt for 16 h. After addition of triethylamine (292 ml, 2.09 mol), the mixture was cooled to 15 °C, diluted with water (10.1 L) maintaining the temperature below 30 °C, and stirred at 19-25 °C for 4 h. The resulting precipitate was filtered, washed twice with water (2.70 L), and dried under vacuum to give a crude product (695 g, wt-wt analysis = 78percent). For the further purification of the product, recrystallization was conducted. A crude product (20.00 g, 34.92 mmol) was suspended in a mixture of ethanol (190 ml) and water (10.00 ml) and heated to 75°C until a clear solution was obtained. The solution was allowed to cool to rt overnight. The precipitate was filtered, washed twice with a mixture of ethanol (30.0 ml) and water (30.0 ml), and dried under vacuum at 35 °C to give the title compound as an off white solid (14.0 g, 70percent recovery from the crude and 90percent> yield based on wt-wt assay).

Reference： [1] Patent: WO2015/57859, 2015, A1, . Location in patent: Paragraph 093; 094

[ 1173081-96-3 ] Synthesis Path-Downstream 1~88

1
[ 769-28-8 ]
[ 1173081-96-3 ]

Yield	Reaction Conditions	Operation in experiment
96.9%		Add 5.0g (0.034mol) to a 500mL single-mouth bottle4,6-dimethyl-3-cyanopyrimidin-2-one,250mL of methanol, not fully soluble,25mL 25% ammonia water,About 5.0g of nickel, replaced by argon three times,The hydrogen was replaced three times, and the temperature was raised to 50 C. After 11 h of reaction, the TLC reaction was complete.Stop the reaction and filter the solution through diatomaceous earth.The filtrate was evaporated to dryness to give 6.3 g, m.Dissolve the product with methanol,Placed in an ice salt bath,20mL of 4N hydrochloric acid ethanol solution was added dropwise with stirring.After the drop,After stirring for 1 h in an ice bath, a large amount of white solid was precipitated, which was filtered with suction to give a white solid.Wash twice with ethanol, suction filtration,Dry to give 5.0 g of a white solid.The yield was 96.9%.
90%	With hydrogenchloride; hydrogen; palladium(II) hydroxide; In methanol; water; at 20℃; for 26h;Inert atmosphere;	To a solution of 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (10.0 g, 67.5 mmol) in MeOH (1.50 L) and conc. HCl (30 mL) was added 10% Pd(OH)2 (19 g) under N2 atmosphere. The N2 gas was displaced by H2 gas and the mixture was stirred for 26 hours at RT under hydrogen atmosphere. The H2 gas was displaced by N2 gas. The mixture was filtered through Celite, washed with MeOH and concentrated. The residue was triturated with EtOH, collected with Buchner funnel, and dried under vacuum pressure to give the titled compound as a white solid (11.5 g, 90%). 1H NMR (400 MHz, DMSO-d6): delta ppm 11.86 (brs, 1H), 5.98 (s, 1H), 3.78 (m, 2H), 2.20 (s, 3H), 2.16 (s, 3H).
85%		Dissolve 10% Pd/C (324 mg) in a small amount of acetic acid.Add raw material SI (3 · 00g, 20 · 25mmol), AcONa(3 · 08g, 37 · 55mmol), Pt02 (30mg) and 100mL of acetic acid were hydrogenated at 100 psi H2.After 48 hours, the diatomaceous earth was filtered, the solvent was evaporated, 15 mL of concentrated hydrochloric acid was added, and then filtered, the filtrate was sifted, and 3 mL of concentrated hydrochloric acid and 15 mL of absolute ethanol were added, and the mixture was stirred under ice bath. After a period of time, solids were precipitated, after 2 hours. Filtration, cold ethanol wash, cold ether wash, yellowish white solid S2(3.258, yield 85%)

		Intermediate 1 3-(Aminomethyl)-4,6-dimethyl-2(lH)-pyridinone hydrochloride Palladium on carbon (10%) (3.24 g) was charged into a 2L dry Parr bottle and a small amount of acetic acid was added. Next added 4,6-dimethyl-2-oxo-l ,2-dihydro- pyridine-3- carbonitrile (30 g , 202.7 mmol), sodium acetate (30.75 g, 375.0 mmol), platinum oxide (0.218 g), and acetic acid (1 L).. The bottle was capped, placed on Parr apparatus, and shaken under an atmosphere of ¾ (100 psi) for 2 days. The reaction mixture was filtered. The solvent was removed to give a residue, which was treated with 150 mL of cone. HCl, and the formed solids were filtered. The yellow filtrate was concentrated . To the crude compound was added 30 mL of cone. HCl and 150 mL EtOH, the contents cooled to 0 C, and stirred at 0 C for 2h. The formed solids were filtered, washed with cold EtOH, ether, and dried. The product was collected as 36 g. This batch was combined with other batches prepared on smaller scales and triturated with ether to give 51 g of pure compound.. 1H NMR (400 MHz, DMSO- 6) delta ppm 1 1.85 (br s, l H) 8.13 (br s, 3 H) 5.93 - 6.01 (m, 1 H) 3.72 - 3.80 (m, 2 H) 2.22 (s, 3 H) 2.16 (s, 3 H).
		Intermediate 13-(Aminomethyl)-4,6-dimethyl-2(l//)-pyridinone hydrochloride Palladium on carbon (10%) (3.24 g) was charged into a 2L dry Parr bottle and a small amount of acetic acid was added. Next added 4,6-dimethyl-2-oxo- 1 ,2-dihydro- pyridine-3-carbonitrile (30 g , 202.7 mmol), sodium acetate (30.75 g, 375.0 mmol), platinum oxide (0.218 g), and acetic acid (1 L).. The bottle was capped, placed on Parr apparatus, and shaken under an atmosphere of H2 (100 psi) for 2 days. The reaction mixture was filtered. The solvent was removed to give a residue, which was treated with 150 mL of cone. HC1, and the formed solids were filtered. The yellow filtrate was concentrated . To the crude compound was added 30 mL of cone. HC1 and 150 mL EtOH, the contents cooled to 0 C, and stirred at 0 C for 2h. The formed solids were filtered, washed with cold EtOH, ether, and dried. The product was collected as 36 g. This batch was combined with other batches prepared on smaller scales and triturated with ether to give 51 g of pure compound.. lH NM (400 MHz, DMSO-
51 g		Intermediate 83-(Aminomethyl)-4,6-dim pyridinone hydrochloridePalladium on carbon (10%) (3.24 g) was charged into a 2L dry Parr bottle and a small amount of acetic acid was added. Next added 4,6-dimethyl-2-oxo-l,2-dihydro- pyridine- 3-carbonitrile (30 g , 202.7 mmol), sodium acetate (30.75 g, 375.0 mmol), platinum oxide (0.218 g), and acetic acid (1 L).. The bottle was capped, placed on Parr apparatus, and shaken under an atmosphere of H2 (100 psi) for 2 days. The reaction mixture was filtered.The solvent was removed to give a residue, which was treated with 150 mL of cone. HCl, and the formed solids were filtered. The yellow filtrate was concentrated . To the crude compound was added 30 mL of cone. HCl and 150 mL EtOH, the contents cooled to 0 C, and stirred at 0 C for 2h. The formed solids were filtered, washed with cold EtOH, ether, and dried. The product was collected as 36 g. This batch was combined with other batches prepared on smaller scales and triturated with ether to give 51 g of pure compound.. 1H NMR (400 MHz, DMSO- 6) ? ppm 11.85 (br s,l H) 8.13 (br s, 3 H) 5.93 - 6.01 (m, 1 H) 3.72 - 3.80 (m, 2 H) 2.22 (s, 3 H) 2.16 (s, 3 H).
36g	With platinum(IV) oxide; palladium 10% on activated carbon; hydrogen; sodium acetate; In acetic acid; under 5171.62 Torr; for 48h;	Palladium on carbon (10%) (3.24 g) was charged into a 2 L dry Parr bottle and asmall amount of acetic acid was added. Next added 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (30 g, 202.7 mmol), sodium acetate (30.75 g, 375.0 mmol),platinum oxide (0.218 g), and acetic acid (1 L) .. The bottle was capped, placed on Parrapparatus, and shaken under an atmosphere ofH2 (100 psi) for 2 days. The reaction mixture was filtered. The solvent was removed to give a residue, which was treated with150 mL of cone. HCl, and the formed solids were filtered. The yellow filtrate wasconcentrated. To the crude compound was added 30 mL of cone. HCl and 150 mL EtOH,the contents cooled to 0 C, and stirred at 0 oc for 2h. The formed solids were filtered,washed with cold EtOH, ether, and dried. The product was collected as 36 g. This batchwas combined with other batches prepared on smaller scales and triturated with ether togive 51 g of pure compound. IH NMR (400 MHz, DMSO-d6) 8 ppm 11.85 (br s,l H) 8.13(br s, 3 H) 5.93-6.01 (m, 1 H) 3.72-3.80 (m, 2 H) 2.22 (s, 3 H) 2.16 (s, 3 H).
51 g		Palladium on carbon (10%) (3.24 g) was charged into a 2L dry Parr bottle and a small amount of acetic acid was added. Next added 4,6-dimethyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (30 g, 202.7 mmol), sodium acetate (30.75 g, 375.0 mmol), platinum oxide (0.218 g), and acetic acid (1 L). The bottle was capped, placed on Parr apparatus, and shaken under an atmosphere of H2 (100 psi) for 2 days. The reaction mixture was filtered. The solvent was removed to give a residue, which was treated with 150 mL of conc. HCl, and the formed solids were filtered. The yellow filtrate was concentrated. To the crude compound was added 30 mL of conc. HCl and 150 mL EtOH, the contents cooled to 0 C., and stirred at 0 C. for 2 h. The formed solids were filtered, washed with cold EtOH, ether, and dried. The product was collected as 36 g. This batch was combined with other batches prepared on smaller scales and triturated with ether to give 51 g of pure compound. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.85 (br s, 1H) 8.13 (br s, 3H) 5.93-6.01 (m, 1H) 3.72-3.80 (m, 2H) 2.22 (s, 3H) 2.16 (s, 3H).
5 g		The titledproduct was obtained from carbonitrile B7c according to the general procedure describedpreviously for the reduction reaction of carbonitrile as a light yellow solid (6.3 g). The crude product was dissolved with menthol in ice bath below 0 C, the 4 N hydrogenchloride ethanol solution (20 mL) was added dropwise. The stirring was continued for 60min, and the solid filtered off and washed with ethanol. After drying, hydrochloride saltwas obtained as a white solid (5.0 g, 97%). 1H NMR (600 MHz, DMSO-d6) delta (ppm): 11.84(br, 1H), 8.04 (s, 3H), 5.97 (s, 1H), 3.77 (s, 2H), 2.21 (s, 3H), 2.16 (s, 3H). Compounds B1~B5were obtained from different carbonitrile (B6a-c, B7a-b) to provide the correspondingproducts according to the general procedure described previously for the reductionreaction of carbonitrile.

Reference： [1]Patent: CN109320499,2019,A .Location in patent: Paragraph 0124; 0127; 0128; 0153; 0154; 0155; 0157
[2]Patent: US2014/107122,2014,A1 .Location in patent: Paragraph 0154; 0155
[3]New Journal of Chemistry,2020,vol. 44,p. 2247 - 2255
[4]Patent: CN110016014,2019,A .Location in patent: Paragraph 0104-0106
[5]Patent: WO2011/140324,2011,A1 .Location in patent: Page/Page column 143
[6]Patent: WO2011/140325,2011,A1 .Location in patent: Page/Page column 141-142
[7]Patent: WO2013/39988,2013,A1 .Location in patent: Page/Page column 50-51
[8]Patent: WO2013/173441,2013,A2 .Location in patent: Page/Page column 43; 44
[9]Patent: US2014/256739,2014,A1 .Location in patent: Paragraph 0725
[10]Patent: WO2014/151142,2014,A1
[11]Patent: WO2015/23915,2015,A1
[12]Molecules,2020,vol. 25

2
[ 1173081-96-3 ]
[ 1346575-77-6 ]
6-(2-aminoethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxamide hydrochloride [ No CAS ]

Reference： [1]Patent: WO2011/140324,2011,A1

3
[ 1173081-96-3 ]
[ 1346575-77-6 ]
[ 1346576-81-5 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	b) 6-(2-Aminoethyl)-N-[(4,6-dimethyl-2-oxo-l,2-dihydro-3-pyridinyl)methyl]-3-methyl-l- (1 -methylethyl)- lH-indole-4-carboxamide hydrochloride salt To a stirred suspension of 6-[2-([(l,l-dimethylethyl)oxy]carbonyl}amino)ethyl]-3- methyl- l-(l-methylethyl)-lH-indole-4-carboxylic acid (500 mg, 1.387 mmol), 3- (aminomethyl)-4,6-dimethyl-2(lH)-pyridinone HC1 salt (340 mg, 1.802 mmol), HO At (245 mg, 1.800 mmol) in DMF (20 mL) was added N-methylmorpholine (200 mu, 1.819 mmol) and EDC free base (280 mg, 1.804 mmol). The reaction was stirred overnight at RT. LCMS showed that the reaction was complete. The reaction was evaporated to dryness and purified by silica gel chromatography (Analogix, SF25-40g, 0 to 10% CH2C12 / 20%(5% NH4OH in MeOH) in CH2C12). The pure fractions were combined and evaporated to dryness. Triturated with 50%) MeOH in water, filtered and dried under vacuum to give the Boc protected product as an off- white solid. The Boc protected product was suspended in a small volume of MeOH (2 mL) and treated with 4 N HC1 in dioxane (25 mL) and stirred at RT for 1 hr. LCMS showed that the reaction was complete. The reaction was evaporated to dryness, triturated with Et20, filtered and dried under vacuum to give the product 6-(2-aminoethyl)-N-[(4,6- dimethyl-2-oxo- 1 ,2-dihydro-3 -pyridinyl)methyl]-3 -methyl- 1 -( 1 -methylethyl)- 1 H-indole-4- carboxamide (460 mg, 1.067 mmol, 77% yield) as an off-white solid. 1H NMR (400MHz ,DMSO-d6 + D20) delta 8.05 (t, J= 5.2 Hz, 1 H), 8.00 (br. s., 2 H), 7.39 (d, J= 1.0 Hz, 1 H),7.25 (s, 1 H), 6.86 (d, J= 1.3 Hz, 1 H), 5.93 (s, 1 H), 4.69 (dt, J= 6.6, 13.3 Hz, 1 H), 4.34 (d, J= 5.1 Hz, 2 H), 3.06 (dd, J= 5.8, 7.6 Hz, 2 H), 3.01 - 2.91 (m, 2 H), 2.25 (s, 3 H), 2.13 (s, 3H), 2.12 (s, 3 H), 1.41 (d, J= 6.8 Hz, 6 H). MS(ES)+ m/e 394.9 [M+H]+.
	With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	To a stirred suspension of 6-[2-([(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylic acid (500 mg, 1.387 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone HCl salt (340 mg, 1.802 mmol), HOAt (245 mg, 1.800 mmol) in DMF (20 mL) was added N-methylmorpholine (200 muL, 1.819 mmol) and EDC free base (280 mg, 1.804 mmol). The reaction was stirred overnight at RT. LCMS showed that the reaction was complete. The reaction was evaporated to dryness and purified by silica gel chromatography (Analogix, SF25-40g, 0 to 10% CH2Cl2/20% (5% NH4OH in MeOH) in CH2Cl2). The pure fractions were combined and evaporated to dryness. Triturated with 50% MeOH in water, filtered and dried under vacuum to give the Boc protected product as an off-white solid. The Boc protected product was suspended in a small volume of MeOH (2 mL) and treated with 4 N HCl in dioxane (25 mL) and stirred at RT for 1 hr. LCMS showed that the reaction was complete. The reaction was evaporated to dryness, triturated with Et2O, filtered and dried under vacuum to give the product 6-(2-aminoethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxamide (460 mg, 1.067 mmol, 77% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6+D2O) delta 8.05 (t, J=5.2 Hz, 1H), 8.00 (br. s., 2H), 7.39 (d, J=1.0 Hz, 1H), 7.25 (s, 1H), 6.86 (d, J=1.3 Hz, 1H), 5.93 (s, 1H), 4.69 (dt, J=6.6, 13.3 Hz, 1H), 4.34 (d, J=5.1 Hz, 2H), 3.06 (dd, J=5.8, 7.6 Hz, 2H), 3.01-2.91 (m, 2H), 2.25 (s, 3H), 2.13 (s, 3H), 2.12 (s, 3H), 1.41 (d, J=6.8 Hz, 6H). MS(ES)+ m/e 394.9 [M+H]+.

Reference： [1]Patent: WO2011/140324,2011,A1 .Location in patent: Page/Page column 125-126
[2]Patent: US2014/256739,2014,A1 .Location in patent: Paragraph 0668

4
[ 1173081-96-3 ]
[ 1346575-81-2 ]
[ 1346575-34-5 ]

Yield	Reaction Conditions	Operation in experiment
64.9%	With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 20℃; for 4h;Inert atmosphere;	c) 6-{3-[(Dimethylamino)methyl]-4-fluorophenyl}-N-[(4,6-dimethyl-2-oxo-l,2-dihydro-3- pyridinyl)methyl] -3 -meth l- 1 -( 1 -methylethyl)- 1 H-indole-4-carboxamide To a stirred suspension of 6- {3-[(dimethylamino)methyl]-4-fluorophenyl} -3-methyl-1-(1 -methylethyl)- lH-indole-4-carboxylic acid (210 mg, 0.570 mmol), 3-(aminomethyl)-4,6- dimethyl-2(lH)-pyridinone HCl salt (140 mg, 0.742 mmol) and HO At (100 mg, 0.735 mmol) in DMF (15 mL) was added N-methylmorpholine (82 mu, 0.746 mmol) and EDC free base (110 mg, 0.709 mmol). The reaction was stirred for 4 h at RT and concentrated to near dryness under vacuum. Water was added till the product ppt. out. The suspension was triturated, filtered, rinsed with cold water water then dried under vacuum to give the product 6- {3-[(dimethylamino)methyl]-4-fluorophenyl} -N-[(4,6-dimethyl-2-oxo- 1 ,2-dihydro-3- pyridinyl)methyl] -3 -methyl- 1-(1 -methylethyl)- lH-indole-4-carboxamide (186 mg, 0.370 mmol, 64.9% yield) as a light tan solid.1H NMR (400MHz ,DMSO-d6) delta = 11.47 (br. s., 1 H), 8.15 (t, J= 4.9 Hz, 1 H), 8.04 (d, J= 5.3 Hz, 1 H), 7.90 - 7.86 (m, 1 H), 7.39 (t, J= 9.2 Hz, 1 H), 7.35 (s, 1 H), 7.27 (d, J= 1.3 Hz, 1 H), 5.87 (s, 1 H), 4.88 (dt, J= 6.6, 13.3 Hz, 1 H), 4.36 (d, J= 5.1 Hz, 2 H), 4.26 (br. s., 2 H), 2.69 (s, 6 H), 2.24 (s, 3 H), 2.17 (s, 3 H), 2.11 (s, 3 H),1.44 (d, J= 6.6 Hz, 6 H). MS(ES)+ m/e 503.0 [M+H]+.
64.9%	With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 4h;Inert atmosphere;	To a stirred suspension of 6-{3-[(dimethylamino)methyl]-4-fluorophenyl}-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylic acid (210 mg, 0.570 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone HCl salt (140 mg, 0.742 mmol) and HOAt (100 mg, 0.735 mmol) in DMF (15 mL) was added N-methylmorpholine (82 mul, 0.746 mmol) and EDC free base (110 mg, 0.709 mmol). The reaction was stirred for 4 h at RT and concentrated to near dryness under vacuum. Water was added till the product ppt. out. The suspension was triturated, filtered, rinsed with cold water then dried under vacuum to give the product 6-{3-[(dimethylamino)methyl]-4-fluorophenyl}-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxamide (186 mg, 0.370 mmol, 64.9% yield) as a light tan solid. 1H NMR (400 MHz, DMSO-d6) delta=11.47 (br. s., 1H), 8.15 (t, J=4.9 Hz, 1H), 8.04 (d, J=5.3 Hz, 1H), 7.90-7.86 (m, 1H), 7.39 (t, J=9.2 Hz, 1H), 7.35 (s, 1H), 7.27 (d, J=1.3 Hz, 1H), 5.87 (s, 1H), 4.88 (dt, J=6.6, 13.3 Hz, 1H), 4.36 (d, J=5.1 Hz, 2H), 4.26 (br. s., 2H), 2.69 (s, 6H), 2.24 (s, 3H), 2.17 (s, 3H), 2.11 (s, 3H), 1.44 (d, J=6.6 Hz, 6H). MS(ES)+ m/e 503.0 [M+H]+.

Reference： [1]Patent: WO2011/140324,2011,A1 .Location in patent: Page/Page column 128
[2]Patent: US2014/256739,2014,A1 .Location in patent: Paragraph 0676

5
[ 1173081-96-3 ]
[ 1346703-87-4 ]