1303587-99-6|2-Chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine| Ambeed

CAS No. :	1303587-99-6
Formula :	C₆H₆ClN₃O
M.W :	171.58
SMILES Code :	ClC1=NC=C2OCCNC2=N1
MDL No. :	MFCD20688597
InChI Key :	GYQORXHFUXETMQ-UHFFFAOYSA-N
Pubchem ID :	73554181

Safety of [ 1303587-99-6 ]

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

Application In Synthesis of [ 1303587-99-6 ]

* 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 [ 1303587-99-6 ]

[ 1303587-99-6 ] Synthesis Path-Downstream 1~55

1
[ 1303587-99-6 ]
[ 1423-26-3 ]
[ 1303588-00-2 ]

Yield	Reaction Conditions	Operation in experiment
52%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 120℃; for 12h;Inert atmosphere; sealed tube;	2-Chloro-7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazine (68; 1.41 g, 8.22 mmol), 3- (trifluoromethyl)phenylboronic acid (1.87 g, 9.86 mmol), Pd(PPh3)4 (475 mg, 0.411 mmol), Na2C03 (2.09 g, 19.7 mmol) and dioxane/water(4:l, 35 ml) were added to a sealed tube and filled with nitrogen. Then the mixture was heated to 120 C for 12 hours. After cooling, CH2CI2 (100 mL) was added and the mixture was passed through a pad of Na2SO

References: [1]Patent: WO2011/59839,2011,A1 .Location in patent: Page/Page column 92.

2
[ 943995-31-1 ]
[ 106-93-4 ]
[ 1303587-99-6 ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate; In dichloromethane; for 4h;Reflux;	4-Amino-2-chloropyrimidin-5-ol (67; 3.75 g, 25.8 mmol) was taken up in CH2CI2 (2500 mL) along with 1,2-dibromoethane (4.85 g, 25.8 mmol) and 2C03 (10.68 g, 77.4 mmol). The resulting reaction mixture was refluxed for 4 h. The solid in the mixture was removed by filtration. The filtrate was concentrated, and the residue was purified by column chromatography to obtain 2-chloro-7,8-dihydro-6H-pyrimido[5,4-b][l ,4]oxazine (68; 3.18 g, 72% yield). MS (ESI) calcd for C6H6C1N30: 171.58; found 173 [M+H].

References: [1]Patent: WO2011/59839,2011,A1 .Location in patent: Page/Page column 92.

3
[ 1303587-99-6 ]
[ 1303585-77-4 ]

References: [1]Patent: WO2011/59839,2011,A1 .

4
[ 1303587-99-6 ]
[ 100-39-0 ]
8-benzyl-2-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%		To a stirred solution of 2-chloro-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (50 mg, 0.29 mmol) in DMF (0.25 mL) under argon atmosphere were added sodium hydride (35 mg, 0.87 mmol) at 0 C. After stirring for 5 mins, benzyl bromide (0.035 mL, 0.29 mmol) was added to the reaction mixture at RT and stirred for 2 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (10 mL) and extracted with 5% MeOH/ CH2C12 (2 x 5 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 2% MeOH: CH2C12 to afford 8-benzyl-2-chloro-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazine (75 mg, 98%) as an off-white solid. ?H-NMR (DMSO-d6, 400 MHz): oe 7.70 (s, 1H), 7.33-7.21 (m, 5H), 4.78 (s, 2H), 4.20-4.17 (m, 2H), 3.50-3.48 (m, 2H); LCMS: 262.3 (M+1); (column; X-Select CSH C-18 (50 x 3.0 mm, 3.5 jim); RT 4.10 mm. 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 5% MeOH/ CH2C12 (Rf 0.7).
98%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 2h;Inert atmosphere;	Synthesis of 8-benzyl-2-chloro-7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazine [0420] To a stirred solution of 2-chloro-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine 1 (50 mg, 0.29 mmol) in DMF (0.25 mL) under argon atmosphere was added sodium hydride (35 mg, 0.87 mmol) at 0 C. After stirring for 5 mins, benzyl bromide (0.035 mL, 0.29 mmol) was added to the reaction mixture at RT and stirred for 2 h. After consumption of the starting materials (monitored by TLC), the reaction was diluted with water (10 mL) and extracted with 5% MeOH/ CH2CI2 (2 x 5 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 2% MeOH: CH2CI2 to afford 8-benzyl-2-chloro-7, 8-dihydro- 6H-pyrimido [5, 4-b] [1, 4] oxazine (75 mg, 98%) as an off-white solid. 1H-NMR (DMSO-<, 400 MHz): delta 7.70 (s, 1H), 7.33-7.21 (m, 5H), 4.78 (s, 2H), 4.20-4.17 (m, 2H), 3.50-3.48 (m, 2H); LCMS: 262.3 (M+l); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 mupiiota); RT 4.10 min. 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 5% MeOH/ CH2C12 (R 0.7).

References: [1]Patent: WO2015/66696,2015,A1 .Location in patent: Paragraph 0323.
[2]Patent: WO2015/66697,2015,A1 .Location in patent: Paragraph 0420.

5
2-chloro-4-((2-chloroethyl)amino)pyrimidin-5-ol [ No CAS ]
[ 1303587-99-6 ]

Yield	Reaction Conditions	Operation in experiment
67%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;Inert atmosphere;	To a stirred solution of 2-chloro-4-((2-chloroethyl) amino) pyrimidin-5-ol (4 g, 19.23 mmol) in DMF (70 mL) under argon atmosphere was added potassium carbonate (7.96 g, 57.69 mmol) at RT. The reaction mixture was stirred at 100 C for 16 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 40% EtOAc/hexanes to afford 2-chloro-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazine (2.1 g, 67%) as a brown solid. ?H-NMR (DMSO-d6, 400 MHz): oe 8.29 (s, 1H), 7.65 (s, 1H), 4.13-4.10 (m, 2H), 3.46-3.43 (m, 2H); LCMS: 172 (M+1); (column; Eclipse XDB C-18 (150 x 4.6 mm, 5 jim); RT 5.61 mm. 0.05% aq TFA:ACN; 1.0 mL/min); TLC: 60% EtOAc/hexanes (R 0.5).

References: [1]Patent: WO2015/66696,2015,A1 .Location in patent: Paragraph 0322.

6
[ 1303587-99-6 ]
8-benzyl-N-(1-(6-methylpyrimidin-4-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]

References: [1]Patent: WO2015/66696,2015,A1 .

7
[ 1303587-99-6 ]
8-benzyl-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]

References: [1]Patent: WO2015/66696,2015,A1 .

8
[ 1303587-99-6 ]
8-benzyl-N-(1-(2-methoxypyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]

References: [1]Patent: WO2015/66696,2015,A1 .

9
[ 1303587-99-6 ]
N-(1-(6-methylpyrimidin-4-yl)piperidin-4-yl)-8-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]

References: [1]Patent: WO2015/66696,2015,A1 .

10
[ 1303587-99-6 ]
8-(2,2,2-trifluoroethyl)-N-(1-(2-(trifluoromethyl)pyridin-4-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]

References: [1]Patent: WO2015/66696,2015,A1 .

11
[ 1303587-99-6 ]
N-(1-(2-methoxypyridin-4-yl)piperidin-4-yl)-8-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]

References: [1]Patent: WO2015/66696,2015,A1 .

12
[ 353-83-3 ]
[ 1303587-99-6 ]
2-chloro-8-(2,2,2-trifluoroethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 25℃; for 32h;Inert atmosphere;	To a stirred solution of 2-chloro-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (500 mg, 2.92 mmol) in DMF (5 mL) under argon atmosphere were added cesium carbonate (1.9 g, 5.84 mmol) and 1, 1, 1-trifluoro-2-iodoethane (611 mg, 2.92 mmol) at RT. The reaction mixture was stirred for 32 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 20% EtOAc:hexanes to afford 2-chloro-8-(2, 2, 2-trifluoroethyl)-7, 8-dihydro-6H-pyrimido [5, 4- b] [1, 4] oxazine (235 mg, 32%) as an off-white solid. ?H-NMR (CDC13, 500 MHz): oe 7.79 (s, 1H), 4.30-4.28 (m, 2H), 4.27-4.23 (m, 2H), 3.70-3.68 (m, 2H); LCMS: 254.4 (M+1); (column; X-Select CSH C-18 (50 x 3.0 mm, 3.5 jim); RT 3.76 mm. 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 60% EtOAc/hexanes (R1: 0.6).
32%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 32h;Inert atmosphere;	Synthesis of2-chloro-8-(2, 2, 2-trifluoroethyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazine [0414] To a stirred solution of 2-chloro-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (500 mg, 2.92 mmol) in DMF (5 mL) under argon atmosphere were added cesium carbonate (1.9 g, 5.84 mmol) and 1, 1, l-trifluoro-2-iodoethane (611 mg, 2.92 mmol) at RT and the mixture was stirred for 32 h. After consumption of the starting materials (monitored by TLC), the reaction was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 20% EtOAc:hexanes to afford 2-chloro-8-(2, 2, 2-trifluoroethyl)-7, 8-dihydro-6H-pyrimido [5, 4- b] [1, 4] oxazine (235 mg, 32%) as an off-white solid. 1H-NMR (CDC13, 500 MHz): delta 7.79 (s, 1H), 4.30-4.28 (m, 2H), 4.27-4.23 (m, 2H), 3.70-3.68 (m, 2H); LC-MS: 254.4 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 mupiiota); RT 3.76 min. 0.05% Aq TFA: ACN; 0.80 mL/min); TLC: 60% EtOAc:hexanes (R/. 0.6).

References: [1]Patent: WO2015/66696,2015,A1 .Location in patent: Paragraph 0324.
[2]Patent: WO2015/66697,2015,A1 .Location in patent: Paragraph 0414; 0421.

13
2-chloro-5-(2-chloroethoxy)pyrimidin-4-amine [ No CAS ]
[ 1303587-99-6 ]

Yield	Reaction Conditions	Operation in experiment
67%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;Inert atmosphere;	Synthesis of 2-chloro-7 , 8-dihydro-6H-pyrimido [5, 4-b] [I, 4] oxazine [0348] To a stirred solution of 2-chloro-5-(2-chloroethoxy)pyrimidin-4-amine (4 g, 19.23 mmol) in DMF (70 mL) under argon atmosphere was added potassium carbonate (7.96 g, 57.69 mmol) at RT. The reaction mixture was heated to 100 C and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction was diluted with cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 40% EtOAc:hexanes to afford 2-chloro-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazine (2.1 g, 67%) as a brown solid. 1H-NMR (DMSO-< 5, 400 MHz): delta 8.29 (s, 1H), 7.65 (s, 1H), 4.13-4.10 (m, 2H), 3.46-3.43 (m, 2H); TLC: 60% EtOAc:hexanes (R/. 0.5).

References: [1]Patent: WO2015/66697,2015,A1 .Location in patent: Paragraph 0348; 0419.

14
[ 1303587-99-6 ]
C₂₄H₂₁F₃N₆O₂ [ No CAS ]