1237535-78-2|5-Fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one| Ambeed

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Quality Control of [ 1237535-78-2 ] Purity: 97% SDS Specification

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Product Details of [ 1237535-78-2 ]

CAS No. :	1237535-78-2
Formula :	C₈H₇FN₂O
M.W :	166.15
SMILES Code :	O=C1NC2=C(C(F)=CC=N2)CC1
MDL No. :	MFCD19703686
InChI Key :	NOGFPJHXTCXVDA-UHFFFAOYSA-N
Pubchem ID :	46853239

Safety of [ 1237535-78-2 ]

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

Application In Synthesis of [ 1237535-78-2 ]

* 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 [ 1237535-78-2 ]

[ 1237535-78-2 ] Synthesis Path-Downstream 1~35

1
[ 1237535-78-2 ]
[ 220640-10-8 ]
[ 1237535-80-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 3h;	Method 1 A mixture of (7R)-7-amino-5,6,7,8-tetrahydronaphthalen-2-ol hydrobromide (16.7 g, 68.2 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (11.36 g, 64.95 mmol), and cesium carbonate (63.49 g, 194.9 mmol) in DMF (216 mL) was stirred at 140 C. for 2 h. The reaction was not complete, so additional (7R)-7-amino-5,6,7,8-tetrahydronaphthalen-2-ol hydrobromide (1.70 g, 6.82 mmol) was added. After an additional 1 h at 140 C., the reaction mixture was cooled to rt, and carefully treated with a solution of HCl (1 M). The reaction mixture was then diluted with DCM and filtered through Celite. The phases were separated and the aqueous phase was brought to pH 7 by the addition of a solution of NaOH (1.0 M). The brown precipitate was then removed by filtration through Celite, and the filtrate was washed with DCM. The aqueous phase was then brought to pH 14 by addition of a solution of NaOH (1.0 M) and an off-white precipitate formed. This suspension was treated with solid NaCl and stirred for 1 h. The solid was isolated by filtration and dried under vacuum to give a 17.7 g of an off-white solid (88% yield). LC/MS: (AA) ES+ 310. 1H NMR (400 MHz, d6 DMSO) delta: 10.47 (s, 1H), 7.94 (d, 1H), 7.12 (d, 1H), 6.85-6.81 (m, 2H), 6.26 (d, 1H), 3.03-2.96 (m, 1H), 2.89 (t, 2H), 2.85-2.79 (m, 1H), 2.76-2.66 (m, 1H), 2.51 (t, 2H), 2.44-2.38 (m, 1H), 1.90-1.84 (m, 1H), 1.65 (br s, 2H), and 1.50-1.40 (m, 1H).

References: [1]Patent: US2010/197924,2010,A1 .Location in patent: Page/Page column 13.

2
[ 3054-95-3 ]
[ 1237535-77-1 ]
[ 1237535-78-2 ]

Yield	Reaction Conditions	Operation in experiment
47%	With N-ethyl-N,N-diisopropylamine;di-mu-chlorobis[5-hydroxy-2-[1-(hydroxyimino)ethyl]phenyl]palladium(II) dimer; In water; N,N-dimethyl-formamide; at 140℃; for 5h;	Step 3 Preparation of 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one A round bottom flask was charged with tert-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate (20.0 g, 59.2 mmol), 3,3-diethoxy-1-propene (13.5 mL, 88.7 mmol), DMF (150 mL), water (50 mL), DIPEA (15.4 mL, 88.7 mmol) and Pd catalyst 1 (Corma, A.; Garcia, H.; Leyva, A. Tetrahedron 61, 9848, 2005) (480 mg, 0.827 mmol) and the reaction mixture was stirred in an oil bath at 140 C. After 5 h, the reaction mixture was cooled in a refrigerator for 2 days. The precipitate was isolated by filtration, washed with diethyl ether, and dried to give 3.25 g of pink needles. The filtrate was concentrated to give a reddish semi-solid. This material was redissolved in DCM, and the solution was passed through 200 g of SiO2. Concentration of the resulting solution provided a red/orange residue which was recrystallized from 2-propanol (150 mL) to give 9.4 g of a pink solid. Purification of this pink solid by column chromatography (SiO2, elution with 0-75% EtOAc/DCM) provided 1.41 g of a white powder. Overall, 4.66 g of final productproduct was isolated (47% yield). LC/MS: (FA) ES+ 167. 1H NMR (300 MHz, d6 DMSO): delta 10.67 (s, 1H), 8.13-8.08 (m, 1H), 6.93-6.88 (m, 1H), 2.87 (t, 2H), and 2.51 (t, 2H). This reaction may also be carried out under the same conditions using Pd(OAc)2 as catalyst, both in the presence or absence of tri-o-tolylphosphine as ligand. In a method analogous to that described for 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one, 5-chloro-3,4-dihydro-1,8-naphthyridin-2(1H)-one was prepared from 2,4-dichloropyridine. LC/MS: (AA) ES+ 183. 1H NMR (400 MHz, d6 DMSO): delta 10.68 (s, 1H), 8.07-8.06 (m, 1H), 7.13-7.11 (m, 1H), 2.96 (t, 2H), and 2.55 (t, 2H).
47%	With N-ethyl-N,N-diisopropylamine;Pd catalyst; In N,N-dimethyl-formamide; at 140℃; for 5h;	Step 3: 5-fluoro-3,4-dihydro-l,8-naphthyridin-2(lH)-one Intermediate-28 [00201] A round bottom flask was charged with f erf-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate (Int-27, 20 g, 59.2 mmol), 3,3-diethoxy-l-propene (13.5 mL, 88.7 mmol), NN-dimethylformamide (150 mL), water (50 mL), NN-diisopropylethylamine (15.4 mL, 88.7 mmol) and the Pd catalyst ("Palladacyle 1" from Corma et. al. Tetrahedron 2005, 61(41):9848; 480 mg, 0.827 mmol) and the reaction mixture was warmed to 140 C. After 5 h, the reaction mixture was cooled in a refrigerator for 2 days. The resulting precipitate was isolated by suction filtration, washed with diethyl ether, and dried to give 3.25 g of pink needles. The filtrate was concentrated to give a reddish semi-solid. This material was redissolved in methylene chloride and the solution was passed through 200 g of silica. Concentration of the resulting solution provided a red/orange residue which was recrystallized from 2-propanol (150 mL) to give 9.4 g of a pink solid. Purification of this pink solid by column chromatography (Si02} elution with 0-75% ethyl acetate in methylene chloride) provided 1.41 g of a white powder, Overall, 4.66 g of 5-fluoro-3,4- dihydro-l,8-naphthyridin-2(lH)-one was isolated (47% yield). LC-MS: (FA) ES+ 167; NMR (400 MHz, <¾-DMSO) 5 ppm 10.7 (s, 1 H), 8.1 1 (dd, J = 8.5, 5.7 Hz, 1 H), 6.91 (dd, J = 8.8, 5.7 Hz, H), 2.91- 2.85 (m, 2 H), 2.55-2.50 (m, 2 H).
47%	With N-ethyl-N,N-diisopropylamine;Palladacyle 1; In N,N-dimethyl-formamide; at 140℃; for 5h;	Step 3: 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one Intermediate 31 A round bottom flask was charged with tert-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate (Int-30, 20 g, 59.2 mmol), 3,3-diethoxy-1-propene (13.5 mL, 88.7 mmol), N,N-dimethylformamide (150 mL), water (50 mL), N,N-diisopropylethylamine (15.4 mL, 88.7 mmol) and the Pd catalyst ("Palladacyle 1? from Corma et. al., Tetrahedron 2005, 61(41):9848; 480 mg, 0.827 mmol) and the reaction mixture was warmed to 140 C. After 5 h, the reaction mixture was cooled in a refrigerator for 2 days. The resulting precipitate was isolated by suction filtration, washed with diethyl ether, and dried to give 3.25 g of pink needles. The filtrate was concentrated to give a reddish semi-solid. This material was redissolved in methylene chloride and the solution was passed through 200 g of silica. Concentration of the resulting solution provided a red/orange residue which was recrystallized from 2-propanol (150 mL) to give 9.4 g of a pink solid. Purification of this pink solid by column chromatography (SiO2, elution with 0-75% ethyl acetate in methylene chloride) provided 1.41 g of a white powder. Overall, 4.66 g of 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one was isolated (47% yield). LC-MS: (FA) ES+ 167; 1H NMR (400 MHz, d6-DMSO) delta ppm 10.7 (s, 1H), 8.11 (dd, J=8.5, 5.7 Hz, 1H), 6.91 (dd, J=8.8, 5.7 Hz, 1H), 2.91-2.85 (m, 2H), 2.55-2.50 (m, 2H).

References: [1]Patent: US2010/197924,2010,A1 .Location in patent: Page/Page column 11-12.
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 1836 - 1846.
[3]Patent: WO2011/146591,2011,A1 .Location in patent: Page/Page column 76.
[4]Patent: US2012/15942,2012,A1 .Location in patent: Page/Page column 54.

3
[ 1237535-78-2 ]
(2S)-N-[3-[(isopropylamino)methyl]-5-(trifluoromethyl)-phenyl]-7-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxamide hydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1836 - 1846.

4
[ 1237535-78-2 ]
C₃₅H₃₉F₃N₄O₅ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1836 - 1846.

5
[ 1237535-78-2 ]
(2S)-N-[3-(2-aminopropan-2-yl)-5-(trifluoromethyl)phenyl]-7-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxamide hydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1836 - 1846.

6
[ 1237535-78-2 ]
C₃₄H₃₇F₃N₄O₅ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1836 - 1846.

7
[ 1237535-78-2 ]
[ 1274816-87-3 ]
[ 1274816-88-4 ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1836 - 1846.

8
[ 1237535-76-0 ]
[ 1237535-78-2 ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1836 - 1846.
[2]Patent: WO2011/146591,2011,A1 .
[3]Patent: US2012/15942,2012,A1 .

9
[ 34941-91-8 ]
[ 1237535-78-2 ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1836 - 1846.
[2]Patent: WO2011/146591,2011,A1 .
[3]Patent: US2012/15942,2012,A1 .

10
[ 1137826-05-1 ]
[ 1237535-78-2 ]
[ 1350750-76-3 ]

Yield	Reaction Conditions	Operation in experiment
		Step 4: 6-(7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-4-yloxy)quinoline-3-carboxylic acidIntermediate-29 [00202] 5-fluoro-3,4-dihydro-l,8-naphthyridin-2(lH)-one (Int-28, 120 mg, 0.72 mmol), 6- hydroxyquinoline-3-carboxylic acid (1.5 mg, 0.794 mmol), and cesium carbonate (706 mg, 2.17 mmol) were weighed into a microwave vial. N,N-Dimethylformamide (3.5 mL) was added and the vial was sealed and heated in a microwave at 150 C for 4 h. The vial was opened and water was added (5 mL). The resulting clear solution was neutralized by the addition of IN HC1 and washed with ethyl acetate. The washed aqueous phase was acidified to pH 3 and pure product was collected by suction filtration. LC-MS: (FA) ES+ 336; ]H NMR (400 MHz, i/6-DMSO) delta ppm 13.55 (s, 1 H), 10.60 (s, 1 H), 9.27 (d, J = 2.1 Hz, 1 H), 8.94 (d, J = 1.9 Hz, 1 H), 8.17 (d, J = 9.1 Hz, 1 H), 8.07-8.02 (m, 1 H), 7.85 (d, J = 2.7 Hz, I H), 7.74 (dd, J = 9.1, 2.8 Hz, 1 H), 6.52 (d, J = 5.7 Hz, 1 H), 2.92 (t, J = 7.7, 7.7 Hz, 2 H), 2.54 (dd, J = 8.3, 7.1 Hz, 2 H).

References: [1]Patent: WO2011/146591,2011,A1 .Location in patent: Page/Page column 76-77.

11
[ 1237535-78-2 ]
[ 1274816-87-3 ]
(S)-7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yloxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With caesium carbonate; In ISOPROPYLAMIDE; at 150℃; for 1h;Microwave irradiation; Sealed vial;	Step 4: (S)-7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yloxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid Intermediate 325-Fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one (Int-31, 50 mg, 0.301 mmol), (2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (63.6 mg, 0.331 mmol), and cesium carbonate (294 mg, 0.903 mmol) were weighed into a microwave vial (2-5 mL) followed by N,N-dimethylacetamide (1.4 mL). The vial was sealed and the resulting mixture was stirred for 1 h at 150 C. under microwave irradiation. The contents of the vial were cooled to room temperature, water (5 mL) was added and the resulting mixture was stirred for a few minutes. The clear solution was neutralized by addition of 1N HCl and the resulting suspension was filtered through a Celite pad. The solid residue was washed with methanol then the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (2-10% methanol in methylene chloride gradient) to provide 52 mg of product as a colorless solid (41%). The enantiomeric purity of this product was assessed by chiral HPLC (85% ee). Column: IA 4.6×250 mm Elute: 100/0.1 EtOH/TFA; 0.5 mL/min 10 uL injection 50 min. LC-MS: (FA) ES+ 339; 1H NMR (400 MHz, d6-DMSO) delta ppm 12.33 (s, 1H), 10.49 (s, 1H), 8.00-7.90 (m, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.87 (dd, J=8.2, 2.5 Hz, 1H), 6.28 (d, J=5.8 Hz, 1H), 2.98-2.74 (m, 5H), 2.71-2.61 (m, 1H), 2.57-2.51 (m, 3H), 2.14-2.06 (m, 1H), 1.73 (dddd, J=13.0, 10.0, 9.9, 6.7 Hz, 1H).

References: [1]Patent: US2012/15942,2012,A1 .Location in patent: Page/Page column 54-55.

12
[ 1237535-78-2 ]
[ 1274816-87-3 ]
C₂₄H₂₉N₃O₅ [ No CAS ]

References: [1]Patent: US2012/15942,2012,A1 .

13
[ 1237535-78-2 ]
(±)-exo-ethyl 5-hydroxy-3-methyl-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylate [ No CAS ]
(±)-exo-ethyl 3-methyl-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The mixture of the product from step H (90 mg, 0.38 mmol), 5-fluoro-3,4-dihydro-l,8- naphthyridin-2(lH)-one (64 mg, 0.38 mmol) and cesium carbonate (188 mg, 0.58mmol) in DMF (5 mL) was stirred at 120 C for 2 hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2x20 mL). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was used in next step without further purification.
	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	The mixture of the product from step H (90 mg, 0.38 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (64 mg, 0.38 mmol) and cesium carbonate (188 mg, 0.58 mmol) in DMF (5 mL) was stirred at 120 C. for 2 hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2*20 mL). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was used in next step without further purification.

References: [1]Patent: WO2013/97224,2013,A1 .Location in patent: Page/Page column 75.
[2]Patent: US2015/45355,2015,A1 .Location in patent: Paragraph 0378; 0395-0396.

14
[ 1237535-78-2 ]
(±)-exo-ethyl 4-chloro-5-hydroxy-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylate [ No CAS ]
(±)-exo-ethyl 4-chloro-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
320 mg	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The mixture of the product from step A (577 mg, 2.3 mmol), 5-fluoro-3,4-dihydro-l,8- naphthyridin-2(lH)-one (377 mg, 2.3 mmol) and cesium carbonate (1.1 g, 3.4 mmol) in DMF (20 mL) was stirred at 120 C for 2 hrs. The reaction was diluted with water (40 mL) and extracted with ethyl acetate (2x30 mL). The combined organic phase was washed with brine (40 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE = 1 :5 ~ 1 : 1) to afford the title compound (320 mg, 80%) as a white solid
320 mg	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	The mixture of the product from step A (577 mg, 2.3 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (377 mg, 2.3 mmol) and cesium carbonate (1.1 g, 3.4 mmol) in DMF (20 mL) was stirred at 120 C. for 2 hrs. The reaction was diluted with water (40 mL) and extracted with ethyl acetate (2*30 mL). The combined organic phase was washed with brine (40 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE=1:5-1:1) to afford the title compound (320 mg, 80%) as a white solid.

References: [1]Patent: WO2013/97224,2013,A1 .Location in patent: Page/Page column 77.
[2]Patent: US2015/45355,2015,A1 .Location in patent: Paragraph 0402; 0405-0406.

15
[ 1237535-78-2 ]
(±)-exo-ethyl 3-hydroxy-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylate [ No CAS ]
(±)-exo-ethyl 3-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The mixture of the product from step E (2.0 g, 9 mmol), 5-fluoro-3,4-dihydro-l,8- naphthyridin-2(lH)-one (1.5 g, 9 mmol) and cesium carbonate (6 g, 18mmol) in DMF (30 mL) was stirred at 120 C for 2hours. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (2x40 mL). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE = 1 :5 ~ 1 : 1) to obtain the title compound (1.4 g, 42%) as a white solid.
42%	With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	The mixture of the product from step E (2.0 g, 9 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (1.5 g, 9 mmol) and cesium carbonate (6 g, 18 mmol) in DMF (30 mL) was stirred at 120 C. for 2 hours. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (2*40 mL). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE=1:5-1:1) to obtain the title compound (1.4 g, 42%) as a white solid.

References: [1]Patent: WO2013/97224,2013,A1 .Location in patent: Page/Page column 36.
[2]Patent: US2015/45355,2015,A1 .Location in patent: Paragraph 0216; 0227-0228.

16
[ 1237535-78-2 ]
(±)-exo-5-((1-(6-hydroxy-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one [ No CAS ]