1354961-13-9|tert-Butyl 5-chloro-2,4-difluorobenzoate| Ambeed

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Quality Control of [ 1354961-13-9 ] Purity: 97% SDS Specification

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Product Details of [ 1354961-13-9 ]

CAS No. :	1354961-13-9
Formula :	C₁₁H₁₁ClF₂O₂
M.W :	248.65
SMILES Code :	O=C(OC(C)(C)C)C1=CC(Cl)=C(F)C=C1F
MDL No. :	MFCD28665067
Boiling Point :	No data available
InChI Key :	JXZKTDJNUFYICB-UHFFFAOYSA-N
Pubchem ID :	58042499

Safety of [ 1354961-13-9 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H301-H311-H331
Precautionary Statements:	P261-P264-P270-P271-P280-P302+P352-P304+P340-P310-P330-P361-P403+P233-P405-P501
Class:	6.1
UN#:	2810
Packing Group:	Ⅲ

Application In Synthesis of [ 1354961-13-9 ]

* 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 [ 1354961-13-9 ]

[ 1354961-13-9 ] Synthesis Path-Downstream 1~35

1
[ 1354961-13-9 ]
[ 1355063-69-2 ]

References: [1]Patent: US2012/10183,2012,A1 .

2
[ 1354961-13-9 ]
[ 1355067-28-5 ]
[ 1355067-24-1 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	A mixture of 5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-ol (PREPARATION WO 2012007869A2, 2.59 g, 10.0 mmol), <strong>[1354961-13-9]tert-butyl 5-chloro-2,4-difluorobenzoate</strong> (PREPARATION WO2012007883A1, 2.48 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol) in anhydrous N,N-dimethylformamide (20 mL) was stirred at ambient temperature for 16 h followed by filtration. The residue was washed with ethyl acetate (100 mL). The filtrate was washed with saturated solution of ammonium chloride (3 x 20 mL), brine (3 x 20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue was purified via silica gel column chromatography eluting with ethyl acetate in hexanes using 10-30% gradient to afford the title compound (3.30 g, 70% yield) as a pale yellow gum: MS (ES+) m/z 487.9, 489.9 (M + 1).
61%	With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 3h;Inert atmosphere;	Potassium carbonate (3.02 g, 21.85 mmol) was added portionwise to a suspension of <strong>[1354961-13-9]tert-butyl 5-chloro-2,4-difluorobenzoate</strong> (Preparation 59, 2.26 g, 9.09 mmol), 5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-ol (Preparation 73, 2.25 g, 8.67 mmol) in DMSO (13.5 mL). The mixture was stirred at room temperature under nitrogen for 3 hours. tert-butyl methyl ether (50.0 mL) was added and the mixture was washed with water (3×50.0 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was suspended with heptane (20.0 mL) and concentrated in vacuo. The resulting solid was suspended in heptane (20.0 mL) and heated to 90 C. until full dissolution. The mixture was cooled with stirring and the residual solid collected by filtration. The filtrate was concentrated in vacuo and the resulting solid was suspended in heptane (10.0 mL) and heated to 90 C. until dissolution. The mixture was again cooled with stirring and the residual solid collected by filtration. The two crops were combined to yield the title compound as a white solid (2.58 g, 5.29 mmol, 61%):1H NMR (400 MHz, d6-DMSO): δ 1.52 (s, 9H), 4.93 (t, 2H), 6.50-6.78 (m, 1H), 7.08 (d, 1H), 7.95 (d, 1H), 8.08-8.14 (m, 2H).LCMS Rt=3.41 minutes MS m/z 522 [MH]+

References: [1]Patent: WO2014/8458,2014,A2 .Location in patent: Paragraph 0330-0331.
[2]Patent: US2012/10183,2012,A1 .Location in patent: Page/Page column 58.

3
[ 1354961-13-9 ]
[ 6294-93-5 ]
[ 1354961-11-7 ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 18h;	To a stirred solution of <strong>[1354961-13-9]tert-butyl 5-chloro-2,4-difluorobenzoate</strong> (Preparation 51, 200 mg, 0.80 mmol) in DMSO (4 mL) was added K2CO3 (333 mg, 2.41 mmol) followed by 4-chloro-3-(trifluoromethyl)phenol (190 mg, 0.97 mmol) and the reaction stirred at room temperature for 18 h. Water (10 mL) and EtOAc (15 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (15 mL). The combined organic extracts were washed with brine (15 mL), dried (MgSO4) filtered and the solvent removed under reduced pressure to give the title compound (245 mg, 72%) as a solid.1H NMR (CDCl3, 400 MHz): δ 1.58 (9H, s), 6.66 (1H, d), 7.14 (1H, dd), 7.36 (1H, d), 7.54 (1H, d) and 8.00 (1H, d).

References: [1]Patent: US2012/10207,2012,A1 .Location in patent: Page/Page column 46.

4
[ 1354961-13-9 ]
[ 1354955-70-6 ]

References: [1]Patent: US2012/10207,2012,A1 .

5
[ 1354961-13-9 ]
[ 1354960-86-3 ]

References: [1]Patent: US2012/10207,2012,A1 .

6
[ 24424-99-5 ]
5-chloro-2,4-difluorobenzoic acid [ No CAS ]
[ 1354961-13-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With dmap; In tert-butyl alcohol; at 50℃; for 16h;	5-chloro-2,4-difluorobenzoic acid (190 g, 986.8 mol) and N,N-dimethylpyridin-4-amine (12.05 g, 0.0986 mol) were dissolved tert-butanol (1 L). Di-tert-butyl dicarbonate (445 g, 2.039 mol) was added and the reaction heated to 50 C. for 16 hours. The solvent was concentrated in vacuo and the crude was taken up in ethyl acetate (300 mL). The organic layer was washed subsequently with a solution of hydrochloric acid (1 M, 300 mL), aqueous brine (2×150 mL) and an aqueous solution of saturated sodium hydrogen carbonate. The organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo to give title compound as a dark orange oil (243 g, 99%).1H NMR (400 MHz; CDCl3): δ 1.61 (s, 9H), 6.97 (dd, 1H), 7.96 (dd, 1H)LC Rt=7.032 minutes.
90%	dmap; In tert-butyl alcohol; at 45℃; for 64h;Inert atmosphere;	Di-tert-butyl dicarbonate (22.7 g, 104 mmol) was added portionwise followed by N,N-dimethylpyridin-4-amine (0.635 g, 5.20 mmol) to a solution of 5-chloro-2,4-difluorobenzoic acid (10.0 g, 51.9 mmol) in tert-butanol (140.0 mL). The mixture stirred at 45 C. under nitrogen for 64 hours. The solvent was concentrated in vacuo and then EtOAc (50.0 mL) was added. The mixture was washed with an aqueous solution of hydrochloric acid (1.0 M, 50.0 mL), then with a saturated aqueous solution of sodium hydroxide (1.0 M, 50.0 mL), and finally with brine (50.0 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was filtered through a pad of silica eluting with a 30% solution of EtOAc in heptane to afford the title compound as a colourless oil (11.6 g, 90%):1H NMR (400 MHz, d6-DMSO): δ 1.50 (s, 9H), 7.62-7.67 (m, 1H), 7.94-7.98 (m, 1H).LCMS Rt=2.98 minutes

References: [1]Organic Process Research and Development,2019,vol. 23,p. 1829 - 1840.
[2]Patent: US2012/10207,2012,A1 .Location in patent: Page/Page column 46.
[3]Journal of Medicinal Chemistry,2019,vol. 62,p. 908 - 927.
[4]Patent: US2012/10183,2012,A1 .Location in patent: Page/Page column 55.

7
[ 1000339-94-5 ]
[ 1354961-13-9 ]
[ 1354962-92-7 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 19.0h;	To a mixture of tert-butyl 5-chloro-2,4-difluorobenzoate (WO2012007883A1, 1.17 g, 4.72 mmol) and <strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (1.02 g, 4.80 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added potassium carbonate (1.31 g, 9.45 mmol). The mixture was stirred at ambient temperature for 19 h. The reaction mixture was then diluted with diethyl ether (200 mL), washed with saturated aqueous sodium bicarbonate (2 chi 200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to afford the title compound as a white solid (2.02 g, 97%): FontWeight="Bold" FontSize="10" H NMR (300 MHz, CDC13) delta 7.98 (d, J= 13 Hz, 1H), 7.34-7.31 (m, 1H), 7.12 (d, J= 2.9 Hz, 1H), 6.93 (dd, J= 2.9, 9.0 Hz, 1H), 6.68 (d, J= 10.8 Hz, 1H), 1.57 (s, 9H); MS (ES+) m/z 440.9, 441.9 (M + 1).
75%	With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 18.0h;	<strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (22.6 g, 0.106 mol) and tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 51, 26.4 g, 0.106 mol) were dissolved in dimethlysulfoxide (105 mL). Then potassium carbonate (29.4 g, 0.213 mol) was added portionwise to the mixture, which was stirred at room temperature for 18 hours. The reaction mixture was dropped into iced water (500 mL) and stirred vigorously for 4 hours. The resulting solid was collected by filtration then taken up in isopropanol (75 mL) and water (15 mL). The reaction was heated to 55 C., then cooled down to room temperature. The resulting solid was collected by filtration to yield the title compound as an off-white white solid (35.3 g, 75%).1H NMR (400 MHz; CDCl3): delta 1.62 (s, 9H), 6.72 (d, 1H), 6.97 (dd, 1H), 7.16 (d, 1H), 7.35-7.38 (m, 1H), 8.02 (d, 1H)LC Rt=8.637 minutes.

References: [1]Patent: WO2014/8458,2014,A2 .Location in patent: Paragraph 0300-0301.
[2]Patent: US2012/10207,2012,A1 .Location in patent: Page/Page column 56.

8
[ 1354961-13-9 ]
[ 1354955-46-6 ]

References: [1]Patent: US2012/10207,2012,A1 .

9
[ 1354961-13-9 ]
[ 1354962-93-8 ]

References: [1]Patent: US2012/10207,2012,A1 .
[2]Patent: WO2014/8458,2014,A2 .

10
[ 1354961-13-9 ]
[ 1355067-26-3 ]

References: [1]Patent: US2012/10183,2012,A1 .

11
[ 1354961-13-9 ]
[ 1446444-52-5 ]

References: [1]Patent: WO2013/102826,2013,A1 .

12
[ 1354961-13-9 ]
[ 1446444-71-8 ]

References: [1]Patent: WO2013/102826,2013,A1 .

13
[ 95-77-2 ]
[ 1354961-13-9 ]
[ 1446444-70-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 16h;	fert-Butyl 5-chloro-2,4-difluorobenzoate (WO2012007861 , 1 .60 g, 6.44 mmol) and potassium carbonate (1 .69 g, 12.26 mmol) were added to a solution of 3,4- dichlorophenol (1 g, 6.13 mmol) in DMSO (30 mL). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (100 mL) then washed with water (100 mL). The organic layer was dried over MgSO and the filtrate was evaporated to give the title compound as an orange gum (2.40 g, 100% yield). 1H NMR (400 MHz, CDCI3): δ 1 .58 (s, 9H), 6.65 (d, 1 H), 6.90 (dd, 1 H), 7.14 (d, 1 H), 7.46 (d, 1 H), 7.98 (d, 1 H) ppm. 19F NMR (376 MHz, CDCI3): δ -107.1 1 (s) ppm. LCMS Rt = 4.45 minutes

References: [1]Patent: WO2013/102826,2013,A1 .Location in patent: Page/Page column 92; 93.

14
[ 1354961-13-9 ]
[ 1533431-19-4 ]

References: [1]Patent: WO2014/8458,2014,A2 .

15
[ 1355066-42-0 ]
[ 1354961-13-9 ]
tert-butyl 5-chloro-4-((5-chloro-6-isobutoxypyridin-3-yl)oxy)-2-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 16h;	To a mixture of 5-chloro-6-isobutoxypyridin-3-ol (Preparation 13, 0.32 g, 1.56 mmol) and <strong>[1354961-13-9]tert-butyl 5-chloro-2,4-difluorobenzoate</strong> (Preparation WO2012007883 A, 10.39 g, 1.56 mmol) in anhydrous dimethyl sulfoxide (5 mL) was added potassium carbonate (0.431 g, 3.12 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The mixture was diluted with ethyl acetate (100 mL) and water (10 mL) was added. The organic phase was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give the title compound as pale yellow solid (0.51 g, 76%). The compound was used without further purification in the next step. To a mixture of /ert-butyl 5-chloro-4-((5-chloro-6- isobutoxypyridin-3-yl)oxy)-2-fluorobenzoate (0.51 g, 1.19 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (4 mL) and the reaction mixture was stirred for 16 hours at room temperature. After concentration in vacuo, the residue was triturated in diethyl ether/hexanes (1: 1, 5 mL) to give the title compound as an off-white solid (0.38 g, 84% yield): NMR (300 MHz, CDC13) δ 10.04 (br s, 1H), 8.10 (d, J= 7.3 Hz, 1H), 7.94 (d, J= 2.4 Hz, 1H), 7.51 (d, J= 2.4 Hz, 1H), 6.54 (d, J= 11.2 Hz, 1H), 4.12 (d, J= 6.5 Hz, 2H), 2.19-2.07 (m, 1H), 1.04 (d, J = 6.7 Hz, 6H); MS (ES-) m/z 372.1, 374.1 (M-l).

References: [1]Patent: WO2014/8458,2014,A2 .Location in patent: Paragraph 0326-0327.

16
[ 1354961-13-9 ]
[ 110860-92-9 ]
[ 1533431-93-4 ]

Yield	Reaction Conditions	Operation in experiment
7%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;	A mixture of 5,6-dichloropyridin-3-ol (PREPARATION 15, 3.28 g, 20.0 mmol), <strong>[1354961-13-9]tert-butyl 5-chloro-2,4-difluorobenzoate</strong> (PREPARATION WO 2012007883, 4.96 g, 20.0 mmol) and potassium carbonate (4.15 g, 30.0 mmol) in anhydrous N,N-dimethylformamide (30 mL) was stirred at ambient temperature for 6 h followed by filtration. The residue was washed with ethyl acetate (100 mL). The filtrate was washed with saturated solution of ammonium chloride (3 x 20 mL), brine (3 x 20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue was purified via silica gel column chromatography eluting with ethyl acetate in hexanes using 10-30% gradient to afford the title compound (0.51 g, 7% yield) as a colourless solid: NMR (300 MHz, CDC13) δ 8.09 (d, J= 2.7 Hz, 1H), 8.00 (d, J= 7.3 Hz, 1H), 7.41 (d, J= 2.7 Hz, 1H), 6.74 (d, J= 10.4 Hz, 1H), 1.58 (s, 9H).

References: [1]Patent: WO2014/8458,2014,A2 .Location in patent: Paragraph 0332-0333.

17
[ 1354961-13-9 ]
[ 1159825-50-9 ]
benzyl 3-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With caesium carbonate; In dimethyl sulfoxide; at 70℃; for 16h;	To a solution of benzyl 3- (hydroxymethyl) -8-azabicyclo [3.2.1] octane-8-carboxylate (1.92 g, 7.00 mmol) in anhydrous dimethylsulfoxide (15 mL) was added cesium carbonate (5.69 g, 10.50 mmol) and tert-butyl 5-chloro-2, 4-difluorobenzoate (1.82 g, 7.35 mmol) . The reaction mixture was stirred at 70 for 16 hours cooled to ambient temperature and acidified to pH 1 with 5aqueous hydrochloric acid solution and extracted with ethyl acetate (2 x 15 mL) , the combined organics were washed with brine (15 mL) dried over anhydrous sodium sulfate filtered and concentrated in vacuo. Purification of the residue by column chromatography (0 to 10 gradient of ethyl acetate in hexanes) afforded the title compound (2.00 g, 54) : 1H NMR (300 MHz, CDCl3) d 7.85 (d, J 7.6 Hz, 1H) , 7.39-7.26 (m, 5H) , 6.56 (d, J 12.1 Hz, 1H) , 5.13 (s, 2H) , 4.46-4.28 (m, 2H) , 3.81-3.73 (m, 2H) , 2.54-2.32 (m, 1H) , 2.03-1.96 (m, 4H) , 1.79-1.65 (m, 4H) , 1.60-1.51 (m, 9H) MS (ES+) m/z 504.2, 506.2 (M + 1) .

References: [1]Patent: WO2015/78374,2015,A1 .Location in patent: Page/Page column 171; 172.

18
[ 1354961-13-9 ]
[ 142253-56-3 ]
tert-butyl 3-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)methyl)azetidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With caesium carbonate; In dimethyl sulfoxide; at 85℃; for 6h;Inert atmosphere;	To a mixture of tert-butyl 3- (hydroxymethyl) azetidine-1-carboxylate (8.96 g, 47.86 mmol) , tert-butyl 5-chloro-2, 4-difluorobenzoate (14.28 g, 57.43 mmol) in anhydrous dimethylsulfoxide (250 mL) was added cesium carbonate (28.10 g, 86.15 mmol) . The reaction mixture was heated at 85 under nitrogen for 6 hours, cooled to ambient temperature and diluted with ethyl acetate (500 mL) , washed with water (250 mL) , aqueous saturated ammonium chloride solution (2 x 200 mL) and brine (2 x 100 mL) dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (0 -25ethyl acetate in hexanes) to provide the title compound as a colorless solid (19.30 g, 81) :1H NMR (300 MHz, CDCl3) δ 7.83 (d, J 7.7 Hz, 1H) , 6.61 (d, J 11.8 Hz, 1H) , 4.13-4.07 (m, 2H) , 4.40 (d, J 8.4 Hz, 2H) , 3.80 (dd, J 8.6, 5.2 Hz, 2H) , 3.07-2.91 (m, 1H) , 1.53 (s, 9H) , 1.40 (s, 9H) MS (ES+) m/z 416.2, 418.2 (M + 1) .

References: [1]Patent: WO2015/78374,2015,A1 .Location in patent: Page/Page column 649.

19
[ 72351-36-1 ]
[ 1354961-13-9 ]
tert-butyl 4-((1-benzhydrylazetidin-3-yl)methoxy)-5-chloro-2-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With potassium tert-butylate; In dimethyl sulfoxide; at 20℃; for 1h;	To solution of (1-benzhydrylazetidin-3-yl) methanol (1.141 g) and tert-butyl 5-chloro-2, 4-difluoro-benzoate (1.244 g, 90 pure) in DMSO (13.5 mL) at 14 (bath) was added potassium tert-butoxide (0.606 g) . The mixture was stirred at rt for 1 hr. Diluted with EtOAc, the contents were washed with dilute NaHCO3 (2x) and brine (1x) , and dried (Na2SO4) . After filtration and concentration, the crude was purified with silica gel flash chromatography (0-40EtOAc/heptane) to give the product (1.359 g, 63) .

References: [1]Patent: WO2015/78374,2015,A1 .Location in patent: Page/Page column 189.
[2]Journal of Medicinal Chemistry,2021,vol. 64,p. 2953 - 2966.

20
[ 1354961-13-9 ]
[ 143900-43-0 ]
(R)-tert-butyl 3-(4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In dimethyl sulfoxide; at 70℃; for 1h;Inert atmosphere;	To a solution of (R) -tert-butyl 3-hydroxypiperidine-1-carboxylate (10.05 g, 50.00 mmol) and tert-butyl 5-chloro-2, 4-difluorobenzoate (13.02 g, 52.50 mmol) in anhydrous DMSO (200 mL) was added cesium carbonate (40.62 g, 75.00 mmol) . The reaction mixture was stirred at 70 for 1 hour under an atmosphere of nitrogen and then cooled to ambient temperature and quenched by addition of 50 mL of water. The mixture was extracted with ethyl acetate (3 x 100 mL) the organic layers were combined and washed with brine (150 mL) , dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material (22.50 g, 99) was used directly for the next step without further purification: MS (ES+) m/z 430.2, 431.2 (M+1) .

References: [1]Patent: WO2015/78374,2015,A1 .Location in patent: Page/Page column 138.

21
[ 4728-12-5 ]
[ 1354961-13-9 ]
tert-butyl 5-chloro-4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-2-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With potassium tert-butylate; In dimethyl sulfoxide; at 14 - 20℃; for 1h;	Potassium tert-butoxide (7.8 g, 70 mmol) was added to a solution of (2, 2-dimethyl-1, 3-dioxan-5-yl) methanol (9.3 g, 63.7 mmol) and tert-butyl 5-chloro-2, 4-difluorobenzoate (16.6 g, 66.9 mmol) in DMSO (200 mL) at 14 . After stirring at room temperature for1h, the reaction mixture was diluted with water (500 mL) and extracted with EtOAc (200 mL × 3) . The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with petroleum ether/ethylacetate, 5/1) to afford the target compound (16.4 g, yield: 69) as a white solid.

References: [1]Patent: WO2015/78374,2015,A1 .Location in patent: Page/Page column 211.

22
[ 67686-01-5 ]
[ 1354961-13-9 ]
tert-butyl 4-((1-benzylpiperidin-4-yl)methoxy)-5-chloro-2-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%	With potassium tert-butylate; In dimethyl sulfoxide; at 15 - 20℃; for 1h;	Potassium tert-butoxide (135 mg, 1.12 mmol) was added to a mixture of tert-butyl 5-chloro-2, 4-difluorobenzoate (300 mg, 0.93 mmol) and (1-benzylpiperidin-4-yl) methanol (230 g, 1.12 mmol) in DMSO (5 mL) at 15 . After stirring at room temperature for 1 h, the mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate 10/1) to give the desired product (105 mg, 26yield) as an oil. LCMS (ESI) : m/z 434.0 [M+H]+.

References: [1]Patent: WO2015/78374,2015,A1 .Location in patent: Page/Page column 215.

23
[ 1354961-13-9 ]
[ 123855-51-6 ]
tert-butyl 4-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)-methyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium tert-butylate; In dimethyl sulfoxide; at 20℃; for 1h;	Potassium tert-butoxide (6.2 g, 55.6 mmol) was added to a solution of tert-butyl 4-(hydroxymethyl) piperidine-1-carboxylate (10.0 g, 46.3 mmol) and tert-butyl 5-chloro-2, 4-difluorobenzoate (12.6 g, 50.9 mmol) in DMSO (200 mL) . After stirring at room temperature for1h, the reaction mixture was diluted with water (500 mL) and extracted with EtOAc (200 mL × 3) . The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate, from 20/1 to 5/1) to afford the target compound (12.3 g, yield: 60) as a pale yellowliquid. LCMS (ESI) m/z: 331.9. [M-111]+.
60%	With potassium tert-butylate; In dimethyl sulfoxide; at 20℃; for 1h;Inert atmosphere;	Step 1 (0232) Potassium tert-butoxide (6.2 g, 55.6 mmol) was added to a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (10.0 g, 46.3 mmol) and <strong>[1354961-13-9]tert-butyl 5-chloro-2,4-difluorobenzoate</strong> (12.6 g, 50.9 mmol) in DMSO (200 mL). After stirring at room temperature for 1 h, the reaction mixture was diluted with water (500 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate, from 20/1 to 5/1) to afford the target compound (12.3 g, yield: 60%) as a pale yellow liquid. LCMS (ESI) m/z: 331.9. [M-111]+.

References: [1]Patent: WO2015/78374,2015,A1 .Location in patent: Page/Page column 217.
[2]Patent: US2016/340309,2016,A1 .Location in patent: Paragraph 0231; 0232; 0233.
[3]Journal of Medicinal Chemistry,2021,vol. 64,p. 2953 - 2966.

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[ 1354961-13-9 ]
[ 91599-81-4 ]
(R)-tert-butyl 4-((1-benzylpiperidin-3-yl)oxy)-5-chloro-2-fluorobenzoate [ No CAS ]