[ CAS No. 1146699-66-2 ] {[proInfo.proName]}

Name: 1146699-66-2|(R)-2-((4-Chloro-N-(2-fluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)phenyl)sulfonamido)-5,5,5-trifluoropentanamide|98+%
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Quality Control of [ 1146699-66-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1146699-66-2 ]

Product Details of [ 1146699-66-2 ]

CAS No. :	1146699-66-2	MDL No. :	MFCD13195458
Formula :	C₂₀H₁₇ClF₄N₄O₄S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XEAOPVUAMONVLA-QGZVFWFLSA-N
M.W :	520.89	Pubchem ID :	46883536
Synonyms :	BMS-708163	Chemical Name :	(R)-2-((4-Chloro-N-(2-fluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)phenyl)sulfonamido)-5,5,5-trifluoropentanamide

Calculated chemistry of [ 1146699-66-2 ]

Physicochemical Properties

Num. heavy atoms :	34
Num. arom. heavy atoms :	17
Fraction Csp3 :	0.25
Num. rotatable bonds :	10
Num. H-bond acceptors :	11.0
Num. H-bond donors :	1.0
Molar Refractivity :	112.31
TPSA :	127.77 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.65 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.45
Log Po/w (XLOGP3) :	3.98
Log Po/w (WLOGP) :	6.53
Log Po/w (MLOGP) :	2.66
Log Po/w (SILICOS-IT) :	3.44
Consensus Log Po/w :	3.81

Druglikeness

Lipinski :	1.0
Ghose :	None
Veber :	0.0
Egan :	1.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-5.29
Solubility :	0.00269 mg/ml ; 0.00000517 mol/l
Class :	Moderately soluble
Log S (Ali) :	-6.36
Solubility :	0.000225 mg/ml ; 0.000000432 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-7.59
Solubility :	0.0000133 mg/ml ; 0.0000000255 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	3.0
Synthetic accessibility :	3.86

Safety of [ 1146699-66-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1146699-66-2 ]

* 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.

Upstream synthesis route of [ 1146699-66-2 ]
Downstream synthetic route of [ 1146699-66-2 ]

[ 1146699-66-2 ] Synthesis Path-Upstream 1~4

1
[ 1146699-70-8 ]
[ 122-51-0 ]
[ 1146699-66-2 ]

Yield	Reaction Conditions	Operation in experiment
90%	With trifluoroacetic acid In acetonitrile at 40 - 50℃;	Step C. (2R)-2-[[(4-Chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide (R)-2-(4-Chloro-N-(2-fluoro-4-(N'-hydroxycarbamimidoyl)benzyl)-phenylsulfonamido)-5,5,5-trifluoropentanamide (246 g) was charged to a reactor followed by dry acetonitrile (509 mL), triethyl orthoformate (120 mL), and trifluoroacetic acid (7 mL). The solution was heated to 40-50° C. until the reaction was complete by HPLC (<0.15 relative AP starting material). Methanol (1.48 L) was charged in one portion, followed by water (1.034 L), keeping the batch at 45-50° C. The batch was then cooled to 15-20° C. and filtered. The cake was washed with 2:6:5 MeCN:MeOH:water and tray dried under vacuum at 50-60° C., giving the title compound as a white solid (228 g, 90percent yield). ¹H NMR, (CDCl₃, 300 MHz) δ: 1.40-1.58 (m, 1H) 1.75-1.90 (m, 1H) 1.92-2.07 (m, 1H) 2.10 -2.26 (m, 1H) 4.37 (dd, J=8.67, 6.22 Hz, 1H) 4.48 (d, J=15.64 Hz, 1H) 4.64 (d, J=15.82 Hz, 1H) 5.54 (s, 1H) 6.33 (s, 1H) 7.44-7.54 (m, 2H) 7.62 (t, J=7.72 Hz, 1H) 7.68-7.76 (m, 3H) 7.85 (dd, J=7.91, 1.51 Hz, 1H) 8.76 (s, 1H). ¹³C NMR, (DMSO-d₆, 75 MHz) δ: 170.34, 167.75, 165.80, 159.64 (d, J=244.5 Hz, 1C), 138.19, 137.64, 131.25 (d, J=3.75 Hz, 1C), 129.31, 129.23, 129.05 (d, J=14.25 Hz, 1C), 126.74 (q, J=274.5 Hz, 1C), 126.91, 126.80, 123.12 (d, J=3.75 Hz, 1C), 113.7 (d, J=24.0 Hz, 1C), 57.92, 41.38 (d, J=4.5 Hz, 1C), 30.04 (d, J=30.0 Hz, 1C), 22.90. ¹⁹F NMR, (CDCl₃, 282 MHz) δ: -116.3, -66.5. IR (KBr): 3454, 334, 3286, 2952, 1705, 1432, 1325, 1260, 1167, 1084, 828 cm^-1. Anal. Calcd. for C₂₀H₁₇ClF₄N₄O₄S Calc. C, 46.11; H, 3.29; N, 10.71; S, 6.15; F, 14.58; Cl, 6.80. Found C, 46.06; H, 3.24; N, 10.71; S, 6.25; F, 14.60; Cl, 6.88.
69.3%	With boron trifluoride diethyl etherate In 1,1-dichloroethane at 70℃; for 1 h;	Step C. (2R)-2-[[(4-Chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide; To a solution of (R)-2-(4-chloro-N-(4-cyano-2-fluorobenzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide (6.5 g, 13.6 mmol) in EtOH (70 mL) was added NH₂OH (50percent in H₂O, 2.6 mL 40.8 mmol). The resulting mixture was stirred at 80° C. under nitrogen for 1 h and then cooled to rt. The solvents were evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water and dried over Na₂SO₄. Evaporation of the solvent gave a white solid which was recrystallized from EtOAc and hexanes to afford the intermediate amide oxime as a white solid (6.93 g, quantitative yield). To a mixture of the intermediate (R)-2-(4-chloro-N-(2-fluoro-4-(N'-hydroxycarbamimidoyl)benzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide (6.93 g, 13.6 mmol) and triethyl orthoformate (6.77 mL, 40.8 mmol) in dichloroethane (30 mL) was added BF₃.OEt₂(0.17 mL, 1.36 mmol). The resulting mixture was stirred at 70° C. for 1 h and then cooled to room temperature. Chromatography (silica gel, biotage, 40+M column, 3percent to 80percent EtOAc in hexanes, 651 mL) provided the title compound as a white solid. (4.9 g, 69.3percent yield). The above 4.9 g of product was combined with a second lot of 9.8 g of (2R)-2-[[(4-chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide (prepared by the procedure described in Example 1). To the combined lots (14.7 g) was added isopropyl alcohol (75 mL). The mixture was refluxed until almost complete dissolution, and then filtered. The filtrate was stirred at rt for 16 h. and filtered. A white fine crystalline white solid was obtained after drying to a constant mass to afford (2R)-2-[[(4-chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide (13.7 g). ¹H NMR (CDCl₃, 500 MHz) δ 8.77 (s, 1H), 7.90 (dd, J=8.0, 1.5 Hz, 1H), 7.77-7.71 (m, 3H), 7.64 (dd, J=7.5, 7.5 Hz, 1H), 7.51 (d, J=8.5 Hz, 2H), 6.34 (s, 1H), 5.28 (s, 1H), 4.66 (d, J=15.6 Hz, 1H), 4.51 (d, J=15.6 Hz, 1H), 4.39 (dd, J=8.9, 6.3 Hz, 1H), 2.25-1.82 (m, 3H), 1.54-1.47 (m, 1H); ESI MS m/z 521 [C₂₀H₁₇ClF₄N₄O₄S+H]⁺.

Reference： [1] Patent: US2009/111858, 2009, A1, . Location in patent: Page/Page column 23
[2] Patent: US2009/111858, 2009, A1, . Location in patent: Page/Page column 19-20
[3] ACS Medicinal Chemistry Letters, 2010, vol. 1, # 3, p. 120 - 124

2
[ 1146699-64-0 ]
[ 1146699-67-3 ]
[ 1146699-66-2 ]

Yield	Reaction Conditions	Operation in experiment
50%	With hydroxylamine; tetra-(n-butyl)ammonium iodide; caesium carbonate In acetonitrile at 15 - 35℃;	Step B, Procedure 2 To a suitable vessel was added (R)-2-(4-chlorophenylsulfonamido)-5,5,5-trifluoropentanamide (2.68 kg, 7.77 mol, 1 eq), 3-(4-(bromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole (2.00 kg, 7.78 mol, 1 eq), cesium carbonate (1.65 kg, 5.06 mol, 0.65 eq), tetrabutylammonium iodide (0.29 kg, 0.78 mol, 0.1 eq) and acetonitrile (12.0 L 4.5 L/kg). The reaction was heated to 35° C. until complete by HPLC (3-(4-(bromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole <0.5 relative AP by HPLC). The reaction was cooled to 15° C. and water (10.72 L, 4 L/kg) was added with stirring followed by glacial acetic acid (0.22 kg) to bring the pH of the reaction to <6.5. The stirring was stopped and the phases were separated (the top layer contained the product). To the product rich layer was added toluene (26.8 kg, 31 L, 10 kg/kg) followed by brine solution (20percent w/w, 6.39 kg, 2 L/kg) and the layers were separated (the top layer contained the product). The mixture was distilled at ~50° C. under vacuum (200 mbar) until acetonitrile was removed. The concentration was adjusted with additional toluene if needed after distillation to ensure total volume in the reactor was ~10 L/kg. Isopropyl alcohol (0.48 kg, 0.2 L/kg) was charged and the batch was cooled to 15° C. to initiate crystallization. The resulting slurry was filtered and washed with cold toluene (18.65 kg, 21.56 L, 8 L/kg). The crude cake was tray dried under vacuum at 50° C. until loss on drying was <1.0percent. The dry cake was added to a 100 L reactor along with isopropyl alcohol (27.34 kg, 34.8 L, 13 L/kg) and hydroxylamine (50percent aqueous solution, 0.05 kg, 1.51 mol, 0.2 eq). The mixture was heated to 65° C. and monitored by HPLC until (R)-2-(4-chloro-N-(4-cyano-2-fluorobenzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide was <0.4 AP. The reaction was then distilled (pot temperature ~50° C., vacuum 300 mbar) until reaction volume was ~60percent of original. Acetonitrile (5.36 kg, 2 L/kg) was charged and the reaction temperature was increased to 70° C. to achieve complete dissolution. Water (11.26 L, 4.2 L/kg) was charged slowly while keeping the reaction temperature >65° C. The reaction was cooled to 15° C. over 2 hours and crystallization occurred. The slurry was filtered and washed with cold aqueous isopropyl alcohol (2:1 IPA:water by volume). The cake was dried in a vacuum oven until loss on drying was <1percent. The product was then recrystallized by dissolving in acetonitrile (2 L/kg based on weight of input of dried cake) and methanol (6 L/kg) and then heated to 50° C. Water (4 L/kg) was added slowly, keeping the reaction temperature >50° C. The reaction was cooled to 15° C. over 2 hours. The resulting slurry was filtered and washed with a solution of methanol:acetonitrile:water (6:2:4, 5 L/kg) to give (2R)-2-[[(4-chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide (2.02 kg, 50percent yield) as a white solid.

Reference： [1] Patent: US2009/111858, 2009, A1, . Location in patent: Page/Page column 21-22
[2] Patent: US2009/111858, 2009, A1, . Location in patent: Page/Page column 20-21

3
[ 1186196-25-7 ]
[ 1146699-67-3 ]
[ 1146699-66-2 ]

Yield	Reaction Conditions	Operation in experiment
45%	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 2 h;	Step D. (R)-2-(4-chloro-N-(2-fluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide To a solution of sulfonamide (R)-2-(4-chlorophenylsulfonamido)-5,5,5-trifluoropentanamide (130 mg, 0.37 mmol) in DMF (2 mL) was added Cs₂CO₃ (241 mg, 0.74 mmol) and 3-(4-bromomethyl-3-fluoro-benzyl)-1,2,4-oxadiazole (257 mg, 0.48 mmol). The reaction was stirred at room temperature for 2 h, diluted with water (50 mL), and extracted with EtOAc (250 mL). The combined organic extract was washed with water (250 mL) and brine (50 mL) and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 0-55percent EtOAc/hexanes) to provide the title oxadiazole compound (92 mg, 45percent) as a white solid: mp 66-68° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.77 (s, 1H), 7.90 (dd, J=8.0, 1.5 Hz, 1H), 7.77-7.71 (m, 3H), 7.64 (dd, J=7.5, 7.5 Hz, 1H), 7.51 (d, J=8.5 Hz, 2H), 6.34 (s, 1H), 5.28 (s, 1H), 4.66 (d, J=15.6 Hz, 1H), 4.51 (d, J=15.6 Hz, 1H), 4.39 (dd, J=8.9, 6.3 Hz, 1H), 2.25-1.82 (m, 3H), 1.54-1.47 (m, 1H); ESI MS m/z 521 [C₂₀H₁₇ClF₄N₄O₄S+H]⁺; HPLC 98.9percent (AUC), t_R=19.4 min.

Reference： [1] Patent: US2009/111858, 2009, A1, . Location in patent: Page/Page column 4; 19

4
[ 1146699-70-8 ]
[ 1146699-66-2 ]

Reference： [1] Patent: US2009/111858, 2009, A1, . Location in patent: Page/Page column 20-21

[ 1146699-66-2 ] Synthesis Path-Downstream 1~6

1
[ 1146699-70-8 ]
[ 122-51-0 ]
[ 1146699-66-2 ]

Yield	Reaction Conditions	Operation in experiment
90%	With trifluoroacetic acid; In acetonitrile; at 40 - 50℃;Product distribution / selectivity;	Step C. (2R)-2-[[(4-Chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide (R)-2-(4-Chloro-N-(2-fluoro-4-(N'-hydroxycarbamimidoyl)benzyl)-phenylsulfonamido)-5,5,5-trifluoropentanamide (246 g) was charged to a reactor followed by dry acetonitrile (509 mL), triethyl orthoformate (120 mL), and trifluoroacetic acid (7 mL). The solution was heated to 40-50 C. until the reaction was complete by HPLC (<0.15 relative AP starting material). Methanol (1.48 L) was charged in one portion, followed by water (1.034 L), keeping the batch at 45-50 C. The batch was then cooled to 15-20 C. and filtered. The cake was washed with 2:6:5 MeCN:MeOH:water and tray dried under vacuum at 50-60 C., giving the title compound as a white solid (228 g, 90% yield). 1H NMR, (CDCl3, 300 MHz) delta: 1.40-1.58 (m, 1H) 1.75-1.90 (m, 1H) 1.92-2.07 (m, 1H) 2.10 -2.26 (m, 1H) 4.37 (dd, J=8.67, 6.22 Hz, 1H) 4.48 (d, J=15.64 Hz, 1H) 4.64 (d, J=15.82 Hz, 1H) 5.54 (s, 1H) 6.33 (s, 1H) 7.44-7.54 (m, 2H) 7.62 (t, J=7.72 Hz, 1H) 7.68-7.76 (m, 3H) 7.85 (dd, J=7.91, 1.51 Hz, 1H) 8.76 (s, 1H). 13C NMR, (DMSO-d6, 75 MHz) delta: 170.34, 167.75, 165.80, 159.64 (d, J=244.5 Hz, 1C), 138.19, 137.64, 131.25 (d, J=3.75 Hz, 1C), 129.31, 129.23, 129.05 (d, J=14.25 Hz, 1C), 126.74 (q, J=274.5 Hz, 1C), 126.91, 126.80, 123.12 (d, J=3.75 Hz, 1C), 113.7 (d, J=24.0 Hz, 1C), 57.92, 41.38 (d, J=4.5 Hz, 1C), 30.04 (d, J=30.0 Hz, 1C), 22.90. 19F NMR, (CDCl3, 282 MHz) delta: -116.3, -66.5. IR (KBr): 3454, 334, 3286, 2952, 1705, 1432, 1325, 1260, 1167, 1084, 828 cm-1. Anal. Calcd. for C20H17ClF4N4O4S Calc. C, 46.11; H, 3.29; N, 10.71; S, 6.15; F, 14.58; Cl, 6.80. Found C, 46.06; H, 3.24; N, 10.71; S, 6.25; F, 14.60; Cl, 6.88.
69.3%	With boron trifluoride diethyl etherate; In 1,1-dichloroethane; at 70℃; for 1.0h;Product distribution / selectivity;	Step C. (2R)-2-[[(4-Chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide; To a solution of (R)-2-(4-chloro-N-(4-cyano-2-fluorobenzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide (6.5 g, 13.6 mmol) in EtOH (70 mL) was added NH2OH (50% in H2O, 2.6 mL 40.8 mmol). The resulting mixture was stirred at 80 C. under nitrogen for 1 h and then cooled to rt. The solvents were evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water and dried over Na2SO4. Evaporation of the solvent gave a white solid which was recrystallized from EtOAc and hexanes to afford the intermediate amide oxime as a white solid (6.93 g, quantitative yield). To a mixture of the intermediate (R)-2-(4-chloro-N-(2-fluoro-4-(N'-hydroxycarbamimidoyl)benzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide (6.93 g, 13.6 mmol) and triethyl orthoformate (6.77 mL, 40.8 mmol) in dichloroethane (30 mL) was added BF3.OEt2 (0.17 mL, 1.36 mmol). The resulting mixture was stirred at 70 C. for 1 h and then cooled to room temperature. Chromatography (silica gel, biotage, 40+M column, 3% to 80% EtOAc in hexanes, 651 mL) provided the title compound as a white solid. (4.9 g, 69.3% yield). The above 4.9 g of product was combined with a second lot of 9.8 g of (2R)-2-[[(4-chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide (prepared by the procedure described in Example 1). To the combined lots (14.7 g) was added isopropyl alcohol (75 mL). The mixture was refluxed until almost complete dissolution, and then filtered. The filtrate was stirred at rt for 16 h. and filtered. A white fine crystalline white solid was obtained after drying to a constant mass to afford (2R)-2-[[(4-chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide (13.7 g). 1H NMR (CDCl3, 500 MHz) delta 8.77 (s, 1H), 7.90 (dd, J=8.0, 1.5 Hz, 1H), 7.77-7.71 (m, 3H), 7.64 (dd, J=7.5, 7.5 Hz, 1H), 7.51 (d, J=8.5 Hz, 2H), 6.34 (s, 1H), 5.28 (s, 1H), 4.66 (d, J=15.6 Hz, 1H), 4.51 (d, J=15.6 Hz, 1H), 4.39 (dd, J=8.9, 6.3 Hz, 1H), 2.25-1.82 (m, 3H), 1.54-1.47 (m, 1H); ESI MS m/z 521 [C20H17ClF4N4O4S+H]+.

Reference： [1]Patent: US2009/111858,2009,A1 .Location in patent: Page/Page column 23
[2]Patent: US2009/111858,2009,A1 .Location in patent: Page/Page column 19-20
[3]ACS Medicinal Chemistry Letters,2010,vol. 1,p. 120 - 124

2
[ 1146699-64-0 ]
[ 1146699-67-3 ]
[ 1146699-66-2 ]

Yield	Reaction Conditions	Operation in experiment
50%	With hydroxylamine; tetra-(n-butyl)ammonium iodide; caesium carbonate; In acetonitrile; at 15 - 35℃;Product distribution / selectivity;	Step B, Procedure 2 To a suitable vessel was added (R)-2-(4-chlorophenylsulfonamido)-5,5,5-trifluoropentanamide (2.68 kg, 7.77 mol, 1 eq), 3-(4-(bromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole (2.00 kg, 7.78 mol, 1 eq), cesium carbonate (1.65 kg, 5.06 mol, 0.65 eq), tetrabutylammonium iodide (0.29 kg, 0.78 mol, 0.1 eq) and acetonitrile (12.0 L 4.5 L/kg). The reaction was heated to 35 C. until complete by HPLC (3-(4-(bromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole <0.5 relative AP by HPLC). The reaction was cooled to 15 C. and water (10.72 L, 4 L/kg) was added with stirring followed by glacial acetic acid (0.22 kg) to bring the pH of the reaction to <6.5. The stirring was stopped and the phases were separated (the top layer contained the product). To the product rich layer was added toluene (26.8 kg, 31 L, 10 kg/kg) followed by brine solution (20% w/w, 6.39 kg, 2 L/kg) and the layers were separated (the top layer contained the product). The mixture was distilled at ~50 C. under vacuum (200 mbar) until acetonitrile was removed. The concentration was adjusted with additional toluene if needed after distillation to ensure total volume in the reactor was ~10 L/kg. Isopropyl alcohol (0.48 kg, 0.2 L/kg) was charged and the batch was cooled to 15 C. to initiate crystallization. The resulting slurry was filtered and washed with cold toluene (18.65 kg, 21.56 L, 8 L/kg). The crude cake was tray dried under vacuum at 50 C. until loss on drying was <1.0%. The dry cake was added to a 100 L reactor along with isopropyl alcohol (27.34 kg, 34.8 L, 13 L/kg) and hydroxylamine (50% aqueous solution, 0.05 kg, 1.51 mol, 0.2 eq). The mixture was heated to 65 C. and monitored by HPLC until (R)-2-(4-chloro-N-(4-cyano-2-fluorobenzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide was <0.4 AP. The reaction was then distilled (pot temperature ~50 C., vacuum 300 mbar) until reaction volume was ~60% of original. Acetonitrile (5.36 kg, 2 L/kg) was charged and the reaction temperature was increased to 70 C. to achieve complete dissolution. Water (11.26 L, 4.2 L/kg) was charged slowly while keeping the reaction temperature >65 C. The reaction was cooled to 15 C. over 2 hours and crystallization occurred. The slurry was filtered and washed with cold aqueous isopropyl alcohol (2:1 IPA:water by volume). The cake was dried in a vacuum oven until loss on drying was <1%. The product was then recrystallized by dissolving in acetonitrile (2 L/kg based on weight of input of dried cake) and methanol (6 L/kg) and then heated to 50 C. Water (4 L/kg) was added slowly, keeping the reaction temperature >50 C. The reaction was cooled to 15 C. over 2 hours. The resulting slurry was filtered and washed with a solution of methanol:acetonitrile:water (6:2:4, 5 L/kg) to give (2R)-2-[[(4-chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide (2.02 kg, 50% yield) as a white solid.
	With tetra-(n-butyl)ammonium iodide; caesium carbonate; In acetonitrile; at 38℃;Product distribution / selectivity;	Step B, Procedure 1 A suitable vessel was charged with 3-(4-(bromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole (492.14 g, 1.10 equiv, 1.914 mol), (R)-2-(4-chlorophenylsulfonamido)-5,5,5-trifluoropentanamide (600 g, 1.00 equiv; 1.74 mol) cesium carbonate (312.22 g, 0.55 equiv; 0.98 mol), tetra-n-butylammonium iodide (64.29 g, 0.10 equiv; 0.17 mmoles), and acetonitrile (9 mL/g; 5.4 L). The jacket was heated to 40 C. (internal 38 C.). The reaction was monitored by HPLC until (R)-2-(4-chlorophenylsulfonamido)-5,5,5-trifluoropentanamide was <5 AP. The vessel was cooled to an internal temperature of 20 C. and water (5.4 L) was added. The phases were separated and the product rich layer was on the top. The bottom layer was discarded. Water (3.7 L) was charged over 18 minutes, and the reaction was held for 20 h at 20 C. and then filtered. Water (6 L) was added to the vessel and agitated to assist in transfer of solid stuck to agitator and vessel walls. The crude cake was washed once with the water used to rinse the reactor. The crude cake was dried in trays under vacuum at 50 C. The dry, crude cake weighed 699 g. The cake was transferred to a 10 L reactor and THF was charged (2.025 L) followed by hydroxylamine solution (50% in water) (42.97 mL, 0.40 equiv, 0.696 mol). The reactor jacket was heated to 40 C. The reaction was monitored by HPLC until (R)-2-(4-chloro-N-(4-cyano-2-fluorobenzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide was <0.4 AP. The reaction was cooled to 20 C., water (2 L) was added and the reaction was stirred at 20 C. for 30 minutes. The phases were separated and the organic phase was treated with heptane (8 L) while stirring and the reaction oiled, then precipitated. The slurry was allowed to stand at 20 C. for 2 h, and the reaction was filtered and the cake was washed with heptane (2 L). The crude cake was tray dried under vacuum at 40-50 C. and weighed 613 g after drying to <1% loss on drying. The crude product was transferred back to the vessel along with MeOH (3.678 L) and MeCN (1.226 L). The jacket was heated to 60 C. (internal 52 C.) to effect complete dissolution, and water (2.023 L) was added at that temperature slowly, maintaining an internal temperature of >50 C. When water addition was complete, the solution was cooled to an internal temperature of 15 C. over 4 hours while crystallization occurred. Additional water was charged to the reactor (400 mL) and the reaction was filtered and the mother liquor was returned to the vessel. The mother liquor was agitated for 2 minutes to free any stuck product in the vessel. The crude cake was washed with mother liquor followed by heptanes (1.500 L). The product was tray dried under vacuum at 40-50 C. until loss on drying was <0.5% to give (2R)-2-[[(4-Chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide as a shiny, off white solid (577.6 g, 63.76% yield.).

Reference： [1]Patent: US2009/111858,2009,A1 .Location in patent: Page/Page column 21-22
[2]Patent: US2009/111858,2009,A1 .Location in patent: Page/Page column 20-21

3
[ 1186196-25-7 ]
[ 1146699-67-3 ]
[ 1146699-66-2 ]

Yield	Reaction Conditions	Operation in experiment
45%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2.0h;Product distribution / selectivity;	Step D. (R)-2-(4-chloro-N-(2-fluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide To a solution of sulfonamide (R)-2-(4-chlorophenylsulfonamido)-5,5,5-trifluoropentanamide (130 mg, 0.37 mmol) in DMF (2 mL) was added Cs2CO3 (241 mg, 0.74 mmol) and 3-(4-bromomethyl-3-fluoro-benzyl)-1,2,4-oxadiazole (257 mg, 0.48 mmol). The reaction was stirred at room temperature for 2 h, diluted with water (50 mL), and extracted with EtOAc (250 mL). The combined organic extract was washed with water (250 mL) and brine (50 mL) and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 0-55% EtOAc/hexanes) to provide the title oxadiazole compound (92 mg, 45%) as a white solid: mp 66-68 C.; 1H NMR (500 MHz, CDCl3) delta 8.77 (s, 1H), 7.90 (dd, J=8.0, 1.5 Hz, 1H), 7.77-7.71 (m, 3H), 7.64 (dd, J=7.5, 7.5 Hz, 1H), 7.51 (d, J=8.5 Hz, 2H), 6.34 (s, 1H), 5.28 (s, 1H), 4.66 (d, J=15.6 Hz, 1H), 4.51 (d, J=15.6 Hz, 1H), 4.39 (dd, J=8.9, 6.3 Hz, 1H), 2.25-1.82 (m, 3H), 1.54-1.47 (m, 1H); ESI MS m/z 521 [C20H17ClF4N4O4S+H]+; HPLC 98.9% (AUC), tR=19.4 min.

Reference： [1]Patent: US2009/111858,2009,A1 .Location in patent: Page/Page column 4; 19

4
[ 1146699-70-8 ]
[ 1146699-66-2 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; water; acetonitrile; at 15 - 52℃; for 4.0h;Product distribution / selectivity;	Step B, Procedure 1 A suitable vessel was charged with 3-(4-(bromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole (492.14 g, 1.10 equiv, 1.914 mol), (R)-2-(4-chlorophenylsulfonamido)-5,5,5-trifluoropentanamide (600 g, 1.00 equiv; 1.74 mol) cesium carbonate (312.22 g, 0.55 equiv; 0.98 mol), tetra-n-butylammonium iodide (64.29 g, 0.10 equiv; 0.17 mmoles), and acetonitrile (9 mL/g; 5.4 L). The jacket was heated to 40 C. (internal 38 C.). The reaction was monitored by HPLC until (R)-2-(4-chlorophenylsulfonamido)-5,5,5-trifluoropentanamide was <5 AP. The vessel was cooled to an internal temperature of 20 C. and water (5.4 L) was added. The phases were separated and the product rich layer was on the top. The bottom layer was discarded. Water (3.7 L) was charged over 18 minutes, and the reaction was held for 20 h at 20 C. and then filtered. Water (6 L) was added to the vessel and agitated to assist in transfer of solid stuck to agitator and vessel walls. The crude cake was washed once with the water used to rinse the reactor. The crude cake was dried in trays under vacuum at 50 C. The dry, crude cake weighed 699 g. The cake was transferred to a 10 L reactor and THF was charged (2.025 L) followed by hydroxylamine solution (50% in water) (42.97 mL, 0.40 equiv, 0.696 mol). The reactor jacket was heated to 40 C. The reaction was monitored by HPLC until (R)-2-(4-chloro-N-(4-cyano-2-fluorobenzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide was <0.4 AP. The reaction was cooled to 20 C., water (2 L) was added and the reaction was stirred at 20 C. for 30 minutes. The phases were separated and the organic phase was treated with heptane (8 L) while stirring and the reaction oiled, then precipitated. The slurry was allowed to stand at 20 C. for 2 h, and the reaction was filtered and the cake was washed with heptane (2 L). The crude cake was tray dried under vacuum at 40-50 C. and weighed 613 g after drying to <1% loss on drying. The crude product was transferred back to the vessel along with MeOH (3.678 L) and MeCN (1.226 L). The jacket was heated to 60 C. (internal 52 C.) to effect complete dissolution, and water (2.023 L) was added at that temperature slowly, maintaining an internal temperature of >50 C. When water addition was complete, the solution was cooled to an internal temperature of 15 C. over 4 hours while crystallization occurred. Additional water was charged to the reactor (400 mL) and the reaction was filtered and the mother liquor was returned to the vessel. The mother liquor was agitated for 2 minutes to free any stuck product in the vessel. The crude cake was washed with mother liquor followed by heptanes (1.500 L). The product was tray dried under vacuum at 40-50 C. until loss on drying was <0.5% to give (2R)-2-[[(4-Chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide as a shiny, off white solid (577.6 g, 63.76% yield.).

Reference： [1]Patent: US2009/111858,2009,A1 .Location in patent: Page/Page column 20-21

5
C₁₄H₁₄F₄N₄O₂ [ No CAS ]
[ 98-60-2 ]
[ 1146699-66-2 ]

Yield	Reaction Conditions	Operation in experiment
90.8%	With triethylamine; In tetrahydrofuran;Heating;	Compound 10 (50·0 g, 144 mmol), TEA (51.1 g, 505 mmol), p-chlorobenzenesulfonyl chloride 2 (54.9 g, 260 mmol) and tetrahydrofuran (500 mL).Heating and stirring; Water (5000 mL) was added, the temperature was lowered, filtered and dried to give BMS-708163 (68.3 g, 90.8%).

Reference： [1]Patent: CN108640886,2018,A .Location in patent: Paragraph 0006; 0015; 0017

6
C₉H₄FN₃O [ No CAS ]
[ 1146699-66-2 ]

Reference： [1]Patent: CN108640886,2018,A

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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. 1146699-66-2 ] {[proInfo.proName]}

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[ 1146699-66-2 ] Synthesis Path-Upstream 1~4

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