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Product Details of [ 959163-01-0 ]

CAS No. :	959163-01-0	MDL No. :	MFCD18452001
Formula :	C₈H₉ClN₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	184.62	Pubchem ID :	-
Synonyms :

Safety of [ 959163-01-0 ]

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Application In Synthesis of [ 959163-01-0 ]

* 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.

Downstream synthetic route of [ 959163-01-0 ]

[ 959163-01-0 ] Synthesis Path-Downstream 1~15

1
[ 959162-99-3 ]
[ 959163-01-0 ]

Yield	Reaction Conditions	Operation in experiment
89%	With manganese(IV) oxide In dichloromethane at 20℃;	B1 Example B1 To a solution of (6-chloro-4-(ethylamino)pyridin-3-yl)methanol (2.5 g, 13.4 mmol) in DCM (30 mL) was added MnO2 (5.8 g, 67 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 6-chloro-4-(ethylamino)nicotinaldehyde (2.2 g, 89% yield). 1H NMR (400 MHz, CDCl3): δ 9.82 (s, 1H), 8.51 (br s, 1H), 8.27 (s, 1H), 6.56 (s, 1H), 3.28 (m, 2H), 1.31 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 185.0 [M+H]+.
89%	With manganese(IV) oxide In dichloromethane at 20℃;	B1 General procedure: To a solution of (6-chloro-4-( ethylamino )pyridin-3-yl)methanol (2.5 g, 13.4 mmol)in DCM (30 mL) was added Mn02 (5.8 g, 67 mmol) and the reaction mixture was stirred atRT overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo togive 6-chloro-4-(ethylamino)nicotinaldehyde (2.2 g, 89% yield). 1H NMR (400 MHz,CDCb): b 9.82 (s, 1 H), 8.51 (br s, 1 H), 8.27 (s, 1 H), 6.56 (s, 1 H), 3.28 (m, 2 H), 1.31 (t, J= 7.2 Hz, 3 H); MS (ESI) m/z: 185.0 [M + H(
89%	With manganese(IV) oxide In dichloromethane at 20℃; for 8h;

87%	With Dess-Martin periodane In tetrahydrofuran at 0 - 20℃; for 5h;	2 Scheme 1 compound 5 (4.3 g, 23.0 mmol) was dissolved in THF (80 mL). To this mixture was added Dess-Martin periodinane (14.6 g, 34.5 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 5h. TLC showed the reaction was completely. The reaction mixture was quenched with aq. Na2S203 and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2S04 and concentrated to give a crude residue that was purified by silica gel chromatography (PE/EA = 10/1) to give scheme 1 compound 6 (3.7 g, yield: 87.0%) as a pale yellow solid.
84%	With manganese(IV) oxide In tetrahydrofuran; dichloromethane at 20℃; Inert atmosphere;	1.3 Step 3: Synthesis of 6-chloro-4-(ethylamino)nicotinaldehyde Step 3: Synthesis of 6-chloro-4-(ethylamino)nicotinaldehyde (6-chloro-4-(ethylamino)pyridin-3-yl)methanol(4.2 g, 22.5 mmol) was dissolved in a mixted solvent of dichloromethane (50 mL) and tetrahydrofuran (50 mL), and then MnO2 (23.5 g, 270 mmol) was added. The reaction solution was stirred overnight at room temperature, filtrated and washed with ethyl acetate. The filtrate was concentrated to obtain 6-chloro-4-(ethylamino)nicotinaldehyde (3.5 g, yield: 84%). MS m/z (ESI): 185.0 [M+H]+.
4 g	With manganese(IV) oxide In tetrahydrofuran; dichloromethane at 20℃; for 12h;	3.3 Synthesis of 6-chioro-4-(ethylamino)nicotinaldehyde (Notebook: SP-0010571-035) Step 3: Synthesis of 6-chloro-4-(ethylamino)nicotinaldehyde (Notebook: SP-0010571-035) A mixture of (6-chloro-4-(ethylamino)pyridin-3-yl)methanol (4.4 g, 23.7 mmol) and manganese(IV) oxide (20.5 g, 236.6 mmol) in DCM (250 mL) and THF (50 mL) was stirred at RT for 12 h. LCMS showed the reaction was completed. The solid was filtered off, and the filtrate was concentrated to give 6-chloro-4-(ethylamino)nicotinaldehyde (4.0 g) as a light yellow solid, which was directly used in next step without the further purification. MS (ES+) C8H9ClN2O requires: 184, 186, found: 187, 189 [M+H]+.
4.0 g	With manganese(IV) oxide In tetrahydrofuran; dichloromethane at 20℃; for 12h;	3.3 Step 3: Synthesis of 6-chloro-4-(ethylamino)nicotinaldehyde (Notebook: SP-0010571-035) A mixture of (6-chloro-4-(ethylamino)pyridin-3-yl)methanol (4.4 g, 23.7 mmol) and manganese(IV) oxide (20.5 g, 236.6 mmol) in DCM (250 mL) and THF (50 mL) was stirred at RT for 12 h. LCMS showed the reaction was completed. The solid was filtered off, and the filtrate was concentrated to give 6-chloro-4-(ethylamino)nicotinaldehyde (4.0 g) as a light yellow solid, which was directly used in next step without the further purification. MS (ES+) C8H9ClN2O requires: 184, 186, found: 187, 189 [M+H]+
	With manganese(IV) oxide In dichloromethane at 20℃; for 2h;	1.e; 1 (6-chloro-4-ethylamino-pyridin-3-yl)-methanol (1.40 g, 8.1 mmol) is dissolved in 40 ml DCM and 7.0g MnO2 (81 mmol) is added. The reaction is stirred at RT for 2 hours. Then the reaction solution goes through a celite plug and washed by EA. After removing the solvent under the vacuum, the crude product is purified by flash chromatography using EA/Hexane (3:7). The final product 6-chloro-4-ethylamino-pyridine-3-carbaldehyde is a white solid, 1.30g.

Reference： [1]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - US8461179, 2013, B1 Location in patent: Page/Page column 63
[2]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - WO2013/184119, 2013, A1 Location in patent: Paragraph 0192
[3]Zhang, Xiaomeng; Wang, Yazhou; Ji, Jianfeng; Si, Dongjuan; Bao, Xueting; Yu, Zhuangzhuang; Zhu, Yueyue; Zhao, Liwen; Li, Wei; Liu, Jian [Journal of Medicinal Chemistry, 2022, vol. 65, # 11, p. 7595 - 7618]
[4]Current Patent Assignee: MANNKIND CORP; Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Pharma (in: Sumitomo Chemical) - WO2014/52365, 2014, A1 Location in patent: Page/Page column 165; 167
[5]Current Patent Assignee: ABBISKO THERAPEUTICS - EP3792261, 2021, A1 Location in patent: Paragraph 0077; 0084-0085
[6]Current Patent Assignee: BLUEPRINT MEDICINES CORP - US2015/197519, 2015, A1 Location in patent: Paragraph 0153; 0158; 0159
[7]Current Patent Assignee: BLUEPRINT MEDICINES CORP - US9695165, 2017, B2 Location in patent: Page/Page column 44; 46
[8]Current Patent Assignee: IRM LLC - WO2007/136465, 2007, A2 Location in patent: Page/Page column 33-34

2
[ 959163-01-0 ]
[ 858972-17-5 ]
[ 1012878-78-2 ]

Yield	Reaction Conditions	Operation in experiment
68%	With potassium carbonate In N,N-dimethyl-formamide at 80℃;	A38 Example A38 A solution of Example B1 (6.0 g, 0.033 mol), ethyl 2-(3-amino-4-fluorophenyl)acetate (6.4 g, 0.033 mol) and K2CO3 (9.17 g, 0.066 mol) in DMF (100 mL) was heated to 80° C. overnight. The reaction mixture was poured into the water and extracted with EtOAc (3). The combined extracts were washed with brine (3), dried (MgSO4), concentrated in vacuo and purified by chromatography to provide 3-(3-amino-4-fluorophenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1H)-one (7.0 g, 68% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.07 (s, 1H), 7.67 (s, 1H), 7.13 (dd, J=8.8, 2.0 Hz, 1H), 7.02 (dd, J=11.6, 8.4 Hz, 1H), 6.80 (m, 1H), 5.20 (s, 2H), 4.25 (q, J=6.8 Hz, 2H), 1.19 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 318.2 [M+H]+.
68%	With potassium carbonate In N,N-dimethyl-formamide at 80℃;	A38 Example A38: A solution of Example B1 (6.0 g, 0.033 mol), ethyl2-(3-amino-4-fluorophenyl)acetate (6.4 g, 0.033 mol) and K2C03 (9.17 g, 0.066 mol) in DMF (100 mL)was heated to 80°C overnight. The reaction mixture was poured into the water and extractedwith EtOAc (3x). The combined extracts were washed with brine (3x), dried (MgS04),concentrated in vacuo and purified by chromatography to provide 3-(3-amino-4-fluorophenyl)-7 -chloro-1-ethyl-1 ,6-naphthyridin-2(1H)-one (7 .0 g, 68% yield). 1 H NMR(400 MHz, DMSO-d6): 8 8.75 (s, 1 H), 8.07 (s, 1 H), 7.67 (s, 1 H), 7.13 (dd, J = 8.8, 2.0 Hz, 1H), 7.02 (dd, J = 11.6, 8.4 Hz, 1 H), 6.80 (m, 1 H), 5.20 (s, 2 H), 4.25 (q, J = 6.8 Hz, 2 H),1.19 (t, J = 6.8 Hz, 3 H); MS (ESI) m/z: 318.2 [M+H(

Reference： [1]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - US8461179, 2013, B1 Location in patent: Page/Page column 51
[2]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - WO2013/184119, 2013, A1 Location in patent: Paragraph 0152

3
[ 959163-01-0 ]
[ 1442471-26-2 ]
[ 1442470-52-1 ]

Yield	Reaction Conditions	Operation in experiment
89%	With aluminum oxide; potassium fluoride In N,N-dimethyl acetamide for 2h; Sonication;	A13 Example A13 A mixture of Example C5 (2.191 g, 7.94 mmol), Example B1 (1.538 g, 8.33 mmol) and KF on alumina (40 wt %) (9.22 g, 63.5 mmol) in DMA (40 mL) was sonicated for 2 h. The mixture was filtered through a shallow bed of silica gel and rinsed well with EtOAc. The filtrate was washed with satd. NaHCO3 (1), 5% LiCl (2), then brine (1*), dried (MgSO4), and concentrated to dryness to afford 3-(5-amino-2-bromo-4-fluorophenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1H)-one (2.793 g, 89% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 8.77 (s, 1H), 8.00 (s, 1H), 7.74 (s, 1H), 7.37 (d, 1H), 6.77 (d, 1H), 5.45 (s, 2H), 4.27 (q, 2H), 1.20 (t, 3H); MS (ESI) m/z: 398.0 [M+H]+.
89%	With 40% potassium fluoride/alumina In N,N-dimethyl acetamide for 2h; Sonication;	A13 Example A13: A mixture of Example CS (2.191 g, 7.94 mmol), Example B1(1.538 g, 8.33 mmol) and KF on alumina (40 wt%) (9.22 g, 63.5 mmol) in DMA (40 mL)was sonicated for 2 h. The mixture was filtered through a shallow bed of silica gel and rinsedwell with EtOAc. The filtrate was washed with satd. NaHC03 (1x), 5% LiCl (2x), then brine(1x), dried (MgS04), and concentrated to dryness to afford 3-(5-amino-2-bromo-4-fluorophenyl)-7 -chloro-1-ethyl-1 ,6-naphthyridin-2(1H)-one (2. 793 g, 89% yield) as a brownsolid. 1H NMR (400 MHz, DMSO-d6): 8 8.77 (s, 1 H), 8.00 (s, 1 H), 7.74 (s, 1 H), 7.37 (d, 1H), 6.77 (d, 1 H), 5.45 (s, 2 H), 4.27 (q, 2 H), 1.20 (t, 3 H); MS (ESI) m/z: 398.0 [M+Ht.

Reference： [1]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - US8461179, 2013, B1 Location in patent: Page/Page column 40
[2]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - WO2013/184119, 2013, A1 Location in patent: Paragraph 0125

4
[ 872046-08-7 ]
[ 959163-01-0 ]
[ 1588423-94-2 ]

Yield	Reaction Conditions	Operation in experiment
38%	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 48h; Inert atmosphere;	53 A mixture of Scheme 40 compound 1 (4.5 g, 24.45 mmol), Scheme 40 compound 2 (7.3 g, 36.70 mmol) and K2C03 (10.2 g, 73.35 mmol) in dry DMF (100 mL) was heated to 100 °C under nitrogen atmosphere for 48 h. After TLC showed the starting material was completely consumed, the reaction mixture was cooled to RT and diluted with EtOAc (100 mL), washed with water (2 x 30 mL) and brine (20 mL) then dried over Na2S04 and concentrated. The resulting residue was purified by flash chromatography on silica gel (eluting with petroleum ether/EtOAc 100/0 gradually increasing to 70/30) to give Scheme 40 compound 3 (3.0 g, 38%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.81 (s, 1H), 8.28 (s, 1H), 7.79 (s, 1H), 7.61-7.46 (m, 1H), 7.24 (t, J= 8.0 Hz, 2H), 4.29 (m, 2H), 1.22 (t, J= 7.0 Hz, 5H). MS [ESI, MH+] = 321.02.

Reference： [1]Current Patent Assignee: MANNKIND CORP; Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Pharma (in: Sumitomo Chemical) - WO2014/52365, 2014, A1 Location in patent: Page/Page column 256-257

5
[ 959163-01-0 ]
[ 54551-83-6 ]
[ 1588423-83-9 ]

Yield	Reaction Conditions	Operation in experiment
10.4%	Stage #1: methyl 2-(2,6-dichlorophenyl)acetate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5h; Stage #2: 6-chloro-4-ethylamino-pyridine-3-carbaldehyde In tetrahydrofuran at -60 - 20℃;	46 As shown in scheme 35, scheme 35 compound 4 was prepared in the same manner showed before. The solution of 4,6-dichloro-nicotinic acid ethyl ester (2.86 g, 13.04 mmol) in THF (25 mL) was cooled to -78 °C in a flask. LDA (2 M, 7 mL, 13.92 mmol) was added dropwised into the flask. After the addition, the reaction mixture was stirred for another 30 min at -78 °C. The solution of scheme 35 compound 4 (800 mg, 4.35 mmol) in THF (8 mL) was added dropwise into the flask slowly to maintain the reaction temperature below -60 °C. After the addition, the reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was quenched with saturated aqueous NH4C1, and extracted with DCM. The combined DCM was dried over anhydrous Na2S04 and concentrated to give a crude residue that was purified by silica gel column chromatography (PE/EA = 10/1) to give scheme 35 compound 5 (160 mg, yield: 10.4%) as a white solid.

Reference： [1]Current Patent Assignee: MANNKIND CORP; Sumitomo Chemical (w/o Dongwoo Fine-Chem); Sumitomo Pharma (in: Sumitomo Chemical); SUMITOMO CHEMICAL COMPANY LIMITED - WO2014/52365, 2014, A1 Location in patent: Page/Page column 244-245

6
[ 39931-77-6 ]
[ 959163-01-0 ]
[ 1588424-05-8 ]

Yield	Reaction Conditions	Operation in experiment
63%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 48h;Inert atmosphere;	A mixture of 6-chloro-4-(ethyl amino) nicotinaldehyde (Scheme 1 compound 6) (1.0 g, 5.45 mmol), ethyl 2-(pyridin-3-yl) acetate (600 mg, 3.63 mmol) and K2C03 (1.5 g, 10.9 mmol) in dry DMF (6 mL) was heated to 100 C under nitrogen atmosphere for 48 h. After TLC showed the starting material was completely consumed, the reaction mixture was cooled to RT, diluted with EtOAc (3 x 30 mL), washed with water (2 x 10 mL) and brine (10 mL) then dried over Na2S04 and concentrated to give a residue which was purified by flash chromatography on silica gel (eluting with petroleum ether/EtOAc 100/0 gradually increasing to 80/20) to give 7-chloro-l-ethyl-3-(pyridin-3-yl)-l,6-naphthyridin-2(lH)-one (600 mg, 63%) as a light yellow solid. 1H NMR (400 MHz, CDC13): delta 8.86 (d, J= 2.4 Hz, 1H), 8.71- 8.54 (m, 2H), 8.12 (dt, J= 7.8, 2.1 Hz, 1H), 7.88 (s, 1H), 7.40 (dd, J= 7.9, 4.8 Hz, 1H), 7.27 (s, 1H), 4.34 (m, 2H), 1.42 (t, J= 7.1 Hz, 3H). MS [ESI, MH+] = 286.0.

Reference： [1]Patent: WO2014/52365,2014,A1 .Location in patent: Page/Page column 275

7
[ 40061-54-9 ]
[ 959163-01-0 ]
[ 1588424-08-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 48h;Inert atmosphere;	A mixture of 6-chloro-4-(ethyl amino) nicotinaldehyde (Scheme 1 compound 6) (620 mg, 3.36 mmol), ethyl 2-(2-chlorophenyl)-acetate (800 mg, 4.04 mmol) and K2CO3 (1.39 g, 10.08 mmol) in dry DMF (lOmL) was heated to 100 C under nitrogen atmosphere for 48 h. After TLC showed the starting material was completely consumed, the reaction mixture was cooled to RT, diluted with EtOAc (100 mL), washed with water (2 x 30 mL) and brine (20 mL) then dried over Na2S04 and concentrated to give a residue which was purified by flash chromatography on silica gel (eluting with petroleum ether/EtOAc 100/0 gradually increasing to 70/30) to give 7-chloro-3-(2-chlorophenyl)-l -ethyl- l,6-naphthyridin-2(lH)-one (1.10 g, 85%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): delta 8.79 (s, 1H), 8.10 (s, 1H), 7.77 (s, 1H), 7.50 (d, J= 44.7 Hz, 4H), 4.29 (m, 2H), 1.22 (t, J= 6.7 Hz, 3H). MS [ESI, MH+] = 319.04.

Reference： [1]Patent: WO2014/52365,2014,A1 .Location in patent: Page/Page column 279

8
[ 959163-01-0 ]
[ 3215-64-3 ]
[ 1588424-18-3 ]

Yield	Reaction Conditions	Operation in experiment
45%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;Inert atmosphere;	A mixture of 6-chloro-4-(ethyl amino) nicotinaldehyde (Scheme 1 compound 6) (1.20 g, 6.52 mmol), <strong>[3215-64-3]2-<strong>[3215-64-3](2,6-dichlorophenyl)acetonitrile</strong></strong> (1.57 g, 8.47 mmol) and K2C03 (2.70 g, 19.56 mmol) in dry DMF (12 mL) was heated to 100 C under nitrogen atmosphere for 16 h. After TLC showed the starting material was completely consumed, the reaction mixture was cooled to RT, diluted with EtOAc (100 mL), washed with water (2 x 30 mL) and brine (20 mL) then dried over Na2S04 and concentrated to give a residue which was purified by flash chromatography on silica gel (eluting with petroleum ether/EtOAc 100/0 gradually increasing to 70/30) to give 7-chloro-3-(2,6-dichlorophenyl)-l-ethyl-l,6-naphthyridin-2(lH)-imine (1.5 g, 45%) as a black gummy solid. 1H NMR (400 MHz, DMSO-d6): delta 8.45 (d, J= 4.7 Hz, 1H), 7.66 (d, J= 8.1 Hz, 2H), 7.56 (t, J= 7.2 Hz, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 6.85 (d, J= 10.0 Hz, 1H), 4.30 (s, 2H), 1.22-1.16 (m, 3H). MS [ESI, MH+] = 352.05.

Reference： [1]Patent: WO2014/52365,2014,A1 .Location in patent: Page/Page column 296

9
[ 959163-01-0 ]
[ 500912-18-5 ]
[ 1588424-20-7 ]

Yield	Reaction Conditions	Operation in experiment
61%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;Inert atmosphere;	A mixture of 6-chloro-4-(ethyl amino) nicotinaldehyde (Scheme 1 compound 6) (1.7 g, 9.32 mmol), Scheme 56 compound 4 (2.0 g, 12.11 mmol) and K2C03 (3.8 g, 27.96 mmol) in dry DMF (10 mL) was heated to 100 C under nitrogen atmosphere for 16 h. After TLC showed the starting material was completely consumed, the reaction mixture was cooled to RT, diluted with EtOAc (2 x 50 mL), washed with water (2 x 20 mL) and brine (10 mL) then dried over Na2S04 and concentrated to give a residue which was purified by flash chromatography on silica gel (eluting with petroleum ether/EtOAc 100/0 gradually increasing to 60/40) to give 7-chloro-l-ethyl-3-(2-fluoro-6-methoxyphenyl)-l,6-naphthyridin-2(lH)- imine (800 mg, 26%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): delta 8.41 (s, 1H), 7.51 (q, J= 8.0 Hz, 1H), 7.41 (d, J= 10.6 Hz, 2H), 7.07-6.92 (m, 2H), 4.26 (m, 2H), 3.77 (d, J = 2.4 Hz, 3H), 1.22-1.16 (m, 3H). MS [ESI, MH+] = 332.09.

Reference： [1]Patent: WO2014/52365,2014,A1 .Location in patent: Page/Page column 299-300

10
[ 959163-01-0 ]
[ 1261760-73-9 ]
[ 1588424-25-2 ]

Yield	Reaction Conditions	Operation in experiment
50%	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 16h; Inert atmosphere;	67 A mixture of 6-chloro-4-(ethylamino) nicotinaldehyde (Scheme 1 compound 6) (800 mg, 4.34 mmol), Scheme 59 compound 5 (1.19 g, 6.52 mmol) and K2C03 (1.79 g, 13.04 mmol) in dry DMF (10 mL) was heated to 100 °C under nitrogen atmosphere for 16 h. After TLC showed the starting material was completely consumed, the reaction mixture was cooled to RT, diluted with EtOAc (100 mL), washed with water (2 x 30 mL) and brine (20 mL) then dried over Na2S04 and concentrated to give a residue which was purified by flash chromatography on silica gel (eluting with petroleum ether/EtOAc 100/0 gradually increasing to 70/30) to give Scheme 59 compound 6 (1.0 g, 55%) as a brown solid. MS [ESI, MH+] = 350.4.

Reference： [1]Current Patent Assignee: Sumitomo Pharma (in: Sumitomo Chemical); SUMITOMO CHEMICAL COMPANY LIMITED; MANNKIND CORP; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - WO2014/52365, 2014, A1 Location in patent: Page/Page column 306; 308

11
[ 57382-97-5 ]
[ 959163-01-0 ]
[ 1588424-46-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 100℃;	11.A Method A Scheme 1 compound 6 (leq) was dissolved in anhydrous DMF and added Thiophen-2-yl-acetic acid ethyl ester (1.1 eq) and K2CO3 (3.0 eq). The mixture was stirred at 100 °C overnight. TLC showed the starting material was consumed completely. The reaction mixture was diluted with H20 and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na2S04, concentrated to give crude residue which was purified by silica gel chromatographyto give intermediate 7-Chloro-l-ethyl-3-thiophen-2-yl- lH-[l ,6]naphthyridin-2-one as yellow solid.

12
[ 959163-01-0 ]
[ 10272-07-8 ]
ethyl 2-chloro-5-((3,5-dimethoxyphenylamino)methyl)-N-ethylpyridin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: 6-chloro-4-ethylamino-pyridine-3-carbaldehyde; 3.5-dimethoxyaniline In methanol at 20℃; for 4h; Stage #2: With sodium cyanoborohydride; acetic acid In methanol at 20℃; for 16h;	3.4 Synthesis of ethyl 2-chloro-5-((3,5-dimethoxyphenylamino)methyl)-N-ethylpyridin-4- amine Step 4: Synthesis of ethyl 2-chloro-5-((3,5-dimethoxyphenylamino)methyl)-N-ethylpyridin-4-amine A mixture of 6-chloro-4-(ethylamino)nicotinaldehyde (700 mg, 3.8 mmol), 3,5-dimethoxyaniline (872 mg, 5.7 mmol) in MeOH (10 mL) was stirred at 20° C. for 4 h. After that, sodium cyanoborohydride (718 mg, 11.4 mmol) and acetic acid (5 mL) was added to the mixture. The resultant mixture was stirred at RT for 16 h. The mixture was diluted with EtOAc (100 mL), washed with water (50 mL) and brine, dried over Na2SO4, filtered and concentrated and purified by silica gel column, eluting with PE:EA (5:1) to get title compound ethyl 2-chloro-5-((3,5-dimethoxyphenylamino)methyl)-N-ethylpyridin-4-amine (1.1 g, 85%) as a white solid. MS (ES+) C16H20ClN3O2 requires: 321, found: 322 [M+H]+.

Reference： [1]Current Patent Assignee: BLUEPRINT MEDICINES CORP - US2015/197519, 2015, A1 Location in patent: Paragraph 0153; 0160; 0161

13
[ 959163-01-0 ]
[ 10272-07-8 ]
2-chloro-5-((3,5-dimethoxyphenylamino)methyl)-N-ethylpyridin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: 6-chloro-4-ethylamino-pyridine-3-carbaldehyde; 3.5-dimethoxyaniline In methanol at 20℃; for 4h; Stage #2: With sodium cyanoborohydride; acetic acid In methanol at 20℃; for 16h;	3.4 Step 4: Synthesis of ethyl 2-chloro-5-((3,5-dimethoxyphenylamino)methyl)-N-ethylpyridin-4-amine A mixture of 6-chloro-4-(ethylamino)nicotinaldehyde (700 mg, 3.8 mmol), 3,5-dimethoxyaniline (872 mg, 5.7 mmol) in MeOH (10 mL) was stirred at 20° C. for 4 h. After that, sodium cyanoborohydride (718 mg, 11.4 mmol) and acetic acid (5 mL) was added to the mixture. The resultant mixture was stirred at RT for 16 h. The mixture was diluted with EtOAc (100 mL), washed with water (50 mL) and brine, dried over Na2SO4, filtered and concentrated and purified by silica gel column, eluting with PE:EA (5:1) to get title compound ethyl 2-chloro-5-((3,5-dimethoxyphenylamino)methyl)-N-ethylpyridin-4-amine (1.1 g, 85%) as a white solid. MS (ES+) C16H20ClN3O2 requires: 321, found: 322 [M+H]+.

Reference： [1]Current Patent Assignee: BLUEPRINT MEDICINES CORP - US9695165, 2017, B2 Location in patent: Page/Page column 44; 45; 46; 47

14
[ 959163-01-0 ]
[ 1442471-26-2 ]
C₁₆H₁₄BrClFN₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78.6%	With potassium fluoride In N,N-dimethyl acetamide at 20℃; for 2h;	10-12 Example 10 Synthesis of compound represented by formula 6 Dissolve compound 4 (1g, 3.6mmol), compound 5 (668.6mg, 3.6mmol), KF (40% alumina) (420.8mg, 7.2mmol) in DMA (15mL), stir the reaction at room temperature for 2h, and detect the reaction by TLC After completion, the reaction solution was filtered, the filter cake was washed with ethyl acetate, the filtrate was extracted with saturated sodium bicarbonate, washed with saturated brine, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound of formula 6. The yield is 1128 mg, the yield is 78.6%, and the HPLC purity is 98.5%.

Reference： [1]Current Patent Assignee: WUHAN JIUZHOU YUMIN PHARMACEUTICAL TECH - CN112625038, 2021, A Location in patent: Paragraph 0057; 0078-0079; 0080-0081; 0082-0083

15
[ 959163-01-0 ]
[ 6512-32-9 ]
7-chloro-3-(3,5-dimethoxyphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 7h;

Reference： [1]Zhang, Xiaomeng; Wang, Yazhou; Ji, Jianfeng; Si, Dongjuan; Bao, Xueting; Yu, Zhuangzhuang; Zhu, Yueyue; Zhao, Liwen; Li, Wei; Liu, Jian [Journal of Medicinal Chemistry, 2022, vol. 65, # 11, p. 7595 - 7618]

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P378
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Physical hazards
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H200	Unstable explosive
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Health hazards
Code	Phrase
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H310	Fatal in contact with skin
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Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
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H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 959163-01-0 ] {[proInfo.proName]}

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[ 959163-01-0 ] Synthesis Path-Downstream 1~15

Precautionary Statements-General

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