109229-22-3|6-Benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one| Ambeed

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Quality Control of [ 109229-22-3 ] Purity: 98% SDS Specification

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Product Details of [ 109229-22-3 ]

CAS No. :	109229-22-3
Formula :	C₁₄H₁₅N₃O
M.W :	241.29
SMILES Code :	O=C1C(CN(CC2=CC=CC=C2)CC3)=C3N=CN1
MDL No. :	MFCD09835497
InChI Key :	PVNGDFHKRAIVTC-UHFFFAOYSA-N
Pubchem ID :	135592935

Safety of [ 109229-22-3 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Application In Synthesis of [ 109229-22-3 ]

* 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.

Downstream synthetic route of [ 109229-22-3 ]

[ 109229-22-3 ] Synthesis Path-Downstream 1~35

1
[ 159660-85-2 ]
[ 463-52-5 ]
[ 109229-22-3 ]

Yield	Reaction Conditions	Operation in experiment
	In 2-methoxy-ethanol;Heating / reflux;	In Scheme 53, commercially available compound (1) is allowed to react with [FORMAMIDINE,] for example, [FORMAMIDINE] acetate, at elevated temperatures to give cyclic compound (2). Compound (2) is alkylated at N-3 to give compound (3), and the benzyl protecting group is removed to give compound (4). Compound (4) may be used to prepare 6- (3-substituted prop-2-ynyl) compounds of Formula I such as compound (5) or, alternatively, carbonylated derivatives of Formula I such as compound (6).

References: [1]Patent: WO2004/14384,2004,A2 .Location in patent: Page/Page column 198-199.

2
[ 3473-63-0 ]
[ 1454-53-1 ]
[ 109229-22-3 ]

Yield	Reaction Conditions	Operation in experiment
61.4%		6-Benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one A mixture of ethyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride (50.0 g, 0.168 mol), formamidine acetate (16.2 g, 0.201 mol), 4.37 M of sodium methoxide in methanol (190 mL) and methanol (200 mL, 5 mol) was heated to 85 C. for 16 hour in a 350 ml sealed reaction vessel. The mixture was allowed to cool and reduced in vacuo. The residue was dissolved in 1N NaOH (150 ml) and poured over ice. Glacial acetic acid was added to the mixture until the pH of the mixture was 7 and a tan solid precipitated out. the solid was filtered, washed with water and cold ether, and dried on high vacuum to yield the title compound as a tan solid. (26.2 g, 61.4%). MS: M+H=242.2. 1H NMR (DMSO-d6): delta 2.29 (t, 5.8 Hz, 2H); 2.61 (t, 5.8 Hz, 2H); 3.26 (s, 2H); 3.64 (s, 2H); 7.21-7.36 (m, 6H); 7.96 (s, 1H).
61.4%		Intermediate 16-Benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one A mixture of ethyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride (50.0 g, 0.168 mol), formamidine acetate (16.2 g, 0.201 mol), 4.37 M of sodium methoxide in methanol (190 mL) and methanol (200 mL) was heated at 85 C. for 16 hour in a 350 mL sealed reaction vessel. The mixture was allowed to cool and concentrated in vacuo. The residue was dissolved in 1N NaOH (150 mL) and poured over ice. Glacial acetic acid was added to the mixture until the pH of the mixture was 7 and a tan solid precipitated out. The solid was filtered, washed with water and cold ether, and dried on high vacuum to yield the title compound as a tan solid (26.2 g, 61.4%).LC-MS: 242.2 [M+1]+; 1H NMR (400 MHz, DMSO-d6): delta 2.29 (t, 2H, J=5.8 Hz), 2.61 (t, 2H, J=5.8 Hz), 3.26 (s, 2H), 3.64 (s, 2H), 7.21-7.36 (m, 6H), 7.96 (s, 1H).
61.4%		INTERMEDIATE 1 6-Benzyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4(3H)-one[00273] A mixture of ethyl l-benzyl-4-oxopiperidine-3-carboxylate hydrochloride (50.0 g,0.168 mol), formamidine acetate (16.2 g, 0.201 mol), 4.37 M of sodium methoxide in methanol (190 mL) and methanol (200 mL) was heated at 85 0C for 16 hour in a 350 mL sealed reaction vessel. The mixture was allowed to cool and concentrated in vacuo. The residue was dissolved in IN NaOH (150 mL) and poured over ice. Glacial acetic acid was added to the mixture until the pH of the mixture was 7 and a tan solid precipitated out. The solid was filtered, washed with water and cold ether, and dried on high vacuum to yield the title compound as a tan solid (26.2 g, 61.4 %).MS: 242.2 [M+l]+; 1H NMR (400 MHz, DMSO-d6): 2.29 (t, 2H, J = 5.8 Hz), 2.61 (t, 2H, J = 5.8 Hz), 3.26 (s, 2H), 3.64 (s, 2H), 7.21-7.36 (m, 6H), 7.96 (s, IH).

55%	With sodium methylate; In methanol; at 70℃; for 18.0h;	To a solution of ethyl l-benzyl-4-oxopiperidine-3-carboxylate hydrochloride (1.0 g, 3.4 mmol) and formamidine acetate (0.420 g, 4.03 mmol) in MeOH (6.7 mL) was added NaOMe in MeOH (4.6 ml, 20 mmol) and the resulting suspension was stirred at 70 C for 18 h. The mixture was cooled to RT and concentrated under reduced pressure. The residue was partitioned between water (1 mL) and 3: 1 CHCh:iPrOH (3 mL). The layers were separated and the organic layer was washed with brine (1 mL), dried over Na2S04 and concentrated under reduced pressure to afford the title compound (444 mg, 55%) as a light yellow solid.MS (ES+) C14H15N3O requires: 241, found: 242 [M+H]+.
	With sodium alcoholate; In ethanol; for 2.0h;Reflux;	Step A:l-Benzyl-3-ethoxycarbonyl-4-piperidone hydrochloride (12.89 g, 43.3 mmol) was suspended in a sodium methoxide solution in methanol (25 % wt/wt, 50 mL, 216. 2 mmol) and formamidine acetate (5.4 g, 51.9 mmol) was added to the mixture. The reaction mixture was refluxed until all of the starting material was consumed (2 h). The methanol was removed under reduced pressure, and the resulting white solid was dissolved in a 3/1 mixture of chloroform / isopropanol. The mixture was washed with water and brine, dried over Na2S04, filtered and evaporated to give the desired product as a white solid (9.4 g). MS (ESEI): 242.1 [M+l]+
	With sodium alcoholate; In water; for 2.0h;Reflux;	l-Ben2yl-3-ethoxycarbonyl-4-piperidone hydrochloride (12.89 g, 43.3 mmol) was suspended in a sodium methoxide solution in methanol (25 % wt wt, 50 mL, 216. 2 mmol) and formamidine acetate (5.4 g, 51.9 mmol) was added to the mixture. The reaction mixture was refluxed until all of the starting material was consumed (2 h). The methanol was removed under reduced pressure, and the resulting white solid was dissolved in a 3/1 mixture of chloroform / isopropanol. The mixture was washed with water and brine, dried over Na2SC>4, filtered and evaporated to give the desired product as a white solid (9.4 g). MS (ESEI): 242.1 [M+l]?

References: [1]Patent: US2006/258689,2006,A1 .Location in patent: Page/Page column 22; 23; 27; 28.
[2]Patent: US2008/275037,2008,A1 .Location in patent: Page/Page column 22.
[3]Patent: WO2008/123963,2008,A1 .Location in patent: Page/Page column 44.
[4]Patent: WO2018/218197,2018,A2 .Location in patent: Paragraph 0337; 0338.
[5]Patent: WO2011/103715,2011,A1 .Location in patent: Page/Page column 38.
[6]Patent: WO2011/106276,2011,A1 .Location in patent: Page/Page column 38.

3
[ 109229-22-3 ]
[ 914612-23-0 ]

Yield	Reaction Conditions	Operation in experiment
79%	With N,N-dimethyl-formamide; trichlorophosphate; In acetonitrile; at 70℃; for 16.0h;	To a solution of the product from the previous step (100 mg, 0.414 mmol) in acetonitrile (1.7 mL) was added POCb (68 mu, 0.72 mmol) and DMF (13 mu, 0.17 mmol) and the resulting mixture was stirred at 70 C for 4 h. Additional POCI3 (113 mu, 1.2 mmol) was added and the mixture was stirred at 70 C for 12 h. The mixture was concentrated and the residue was taken up in CH2CI2 (10 mL) and partitioned with aqueous sat. NaHC03 (2 mL). The aqueous layer was extracted with CH2CI2 (3 x 3 mL) and the combined organic layers were washed with NaHC03 (1 mL), brine (1 mL), dried over Na2S04, filtered and concentrated. The residue was purified via silica gel chromatography (0 - 10 % MeOH in CH2CI2) to afford the title compound (85 mg, 79 % yield) as a brown liquid.MS (ES+) C14H14CIN3 requires: 259, found: 260 [M+H]+.
57.8%		6-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine A mixture of <strong>[109229-22-3]6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one</strong> (5.0 g, 0.02 mol), phosphoryl chloride (3.30 mL, 0.035 mol) and acetonitrile (80 mL) and DMF (catalytic amount) was heated to at 70 C. for 1 hour. The mixture was reduced in vacuo and the remaining black residue was taken up in dichloromethane (250 ml) and poured over ice. The mixture was carefully neutralized with the addition of solid sodium bicarbonate. The layers were separated and the organic dried over sodium sulfate and reduced in vacuo. The mixture was chromatographed using an ethyl acetate:hexanes (0-100%) gradient on an isco flash chromatography system. The combined pure fractions were reduced in vacuo to yield the title compound as a yellow oil (3 g, 57.8%). MS: M+H=260. 1H NMR (DMSO-d6): delta 8.80 (s, 1H). 7.40-7.24 (m, 5H), 3.76 (s, 2H), 3.57 (s, 2H), 2.92 (t, 2H), 2.80 (t, 2H).
57.8%		Intermediate 26-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine A mixture of <strong>[109229-22-3]6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one</strong> (5.0 g, 0.02 mol), phosphoryl chloride (3.30 mL, 0.035 mol) and acetonitrile (80 mL) and DMF (catalytic amount) was heated at 70 C. for 1 hour. The mixture was concentrated in vacuo and the remaining black residue was taken up in dichloromethane (250 mL) and poured over ice. The mixture was carefully neutralized with the addition of solid sodium bicarbonate. The organic layer was separated and dried over sodium sulfate and concentrated in vacuo. The mixture was purified by silica gel column with EtOAc/hexane (0-100%) to yield the title compound as a yellow oil (3 g, 57.8%). LC-MS: 260 [M+1]+; 1H NMR (400 MHz, DMSO-d6): delta 8.80 (s, 1H), 7.40-7.24 (m, 5H), 3.76 (s, 2H), 3.57 (s, 2H), 2.92 (t, 2H), 2.80 (t, 2H).

57.8%		INTERMEDIATE 26-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine[00274] A mixture of <strong>[109229-22-3]6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one</strong> (5.0 g,0.02 mol), phosphoryl chloride (3.30 mL, 0.035 mol) and acetonitrile (80 mL) and DMF (catalytic amount) was heated at 70 0C for 1 hour. The mixture was concentrated in vacuo and the remaining black residue was taken up in dichloroniethane (250 mL) and poured over ice. The mixture was carefully neutralized with the addition of solid sodium bicarbonate. The organic layer was separated and dried over sodium sulfate and concentrated in vacuo. The mixture was purified by silica gel column with EtOAc/hexane (0-100%) to yield the title compound as a yellow oil (3 g, 57.8%). MS: 260 [M+l]+; 1H NMR (400 MHz, DMSO-d6): 8.80 (s, IH), 7.40-7.24 (m, 5H), 3.76 (s, 2H), 3.57 (s, 2H), 2.92 (t, 2H), 2.80 (t, 2H).
	With trichlorophosphate;N,N-dimethyl-formamide; In acetonitrile; for 3.0h;Reflux;	A mixture of <strong>[109229-22-3]6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one</strong> 1 from Intermediate I, step A(5.0 g, 0.02 mol), phosphorous oxychloride (3.30 mL, 0.035 mol) and acetonitrile (80 mL) and DMF (catalytic amount) was heated at reflux for 3 hours. Then the solvents were reduced in vacuum and the remaining black residue was taken up in dichloromethane (250 mL) and poured over ice. The mixture was carefully neutralized with the addition of solid sodium bicarbonate to pH~8. The layers were separated and the organic was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography to yield compound 2 as a yellow oil (3 g). MS (ESEI): 242.1 [M+l]+ ] NMR (DMSO-d6): delta 8.80 (s, 1Eta).7.40-7.24 (m, 5H), 3.76 (s, 2H), 3.57 (s, 2H), 2.92 (t, 2H), 2.80 (t, 2H).
		A mixture of 6-benzyl-5f6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one 1 from Intermediate I, step A (5.0 g, 0.02 mol), phosphorous oxychloride (3.30 mL, 0.035 mol) and acetonitrile (80 mL) and DMF (catalytic amount) was heated at reflux for 3 hours. Then the solvents were reduced in vacuum and the remaining black residue was taken up in dichloromethane (250 mL) and poured over ice. The mixture was carefully neutralized with the addition of solid sodium bicarbonate to pH~8. The layers were separated and the organic was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography to yield compound 2 as a yellow oil (3 g). MS (ESEI): 242.1 [M+lf ¾ NMR (DMSO-d6): 8 8.80 (s, 1Eta).7.40-7.24 (m, 5H), 3.76 (s, 2H), 3.57 (s, 2H), 2.92 (t, 2H), 2.80 (t, 2H).

References: [1]Patent: WO2018/218197,2018,A2 .Location in patent: Paragraph 0337; 0339.
[2]Patent: US2006/258689,2006,A1 .Location in patent: Page/Page column 23; 28.
[3]Patent: US2008/275037,2008,A1 .Location in patent: Page/Page column 23.
[4]Patent: WO2008/123963,2008,A1 .Location in patent: Page/Page column 44.
[5]Journal of Medicinal Chemistry,2008,vol. 51,p. 3124 - 3132.
[6]Patent: WO2011/103715,2011,A1 .Location in patent: Page/Page column 40.
[7]Patent: WO2011/106276,2011,A1 .Location in patent: Page/Page column 40.

4
[ 109229-22-3 ]
[ 756437-41-9 ]

Yield	Reaction Conditions	Operation in experiment
77.6%	With formic acid; triethylamine;palladium dihydroxide; In methanol; at 60 - 65℃; for 3.25h;	A mixture of <strong>[109229-22-3]6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one</strong> (Intermediate 2, 18.0 g, 0.0738 mol), triethylamine (48 mL, 0.34 mol) Palladium hydroxide (10 g, 0.07 mol) in methanol (242 mL, 5.91 mol) was heated to 60 C. Formic acid (7.6 mL, 0.20 mol) was added dropwise to the mixture over a 15 minute period. The mixture was heated at at 65 C. for three hours, allowed to cool, and filtered over Celite. The filtrate was concentrated under reduced vacuum to yield the title compound as a yellow solid which was used directly in the next reaction. (9.62 g, 77.6%). MS:M+H=152.2.
77.6%		INTERMEDIATE 3 4-Chloro-5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidineA. 5,6,7,8-Tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one[00275] A mixture of <strong>[109229-22-3]6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one</strong>(Intermediate 1, 18.0 g, 0.0738 mol), triethylamine (48 mL, 0.34 mol), palladium hydroxide (10 g, 0.07 mol) in methanol (242 mL) was heated to 60 0C. Formic acid (7.6 mL, 0.20 mol) was added dropwise to the mixture over a 15 minute period. The mixture was heated at 65 0C for three hours, allowed to cool, and filtered over Celite. The filtrate was concentrated under vacuum to yield the title compound as a yellow solid which was used as such for the next step (9.62 g, 77.6 %). MS: 152.2 [M+l]+.
	With formic acid; triethylamine;palladium(II) hydroxide; In methanol; at 60℃; for 5.5h;	Step B:To a solution of compound 1 (100 g, 0.415 mol), Pd(OH) 2 (23 g), and TEA (200 g, 2.07 mol) in MeOH(1500 mL) was added HCOOH (50 mL) dropwise at 60C over 30 mins and after addition, the mixture was stirred at 60C for additional 5 hours. The reaction mixture was cooled to room temperature and filtered over Celite. The filtrate was concentrated to yield the title compound 2 (65 g) as a yellow solid which was used directly in the next reaction. MS (ESEI): 152 (M+H)+.

With formic acid; triethylamine;10 wt% Pd(OH)2 on carbon; In methanol; at 60℃; for 5.5h;

To a solution of compound 1 (100 g, 0.415 mol),.Pd(OH)2 (23 g), and TEA (200 g, 2.07 mol) in MeOH (1500 mL) was added HCOOH (50 mL) dropwise at 60*0 over 30 mins and after addition, the mixture was stirred at 60C for additional 5 hours. The reaction mixture was cooled to room temperature and filtered over Celite. The filtrate was concentrated to yield the title compound 2 (65 g) as a yellow solid which was used directly in the next reaction. MS (ESEI): 152 (M+H)+.

References: [1]Patent: US2006/258689,2006,A1 .Location in patent: Page/Page column 23; 27; 38.
[2]Patent: WO2008/123963,2008,A1 .Location in patent: Page/Page column 45.
[3]Patent: WO2011/103715,2011,A1 .Location in patent: Page/Page column 38-39.
[4]Patent: WO2011/106276,2011,A1 .Location in patent: Page/Page column 39.

5
[ 41276-30-6 ]
[ 463-52-5 ]
[ 109229-22-3 ]