[ CAS No. 952664-69-6 ] {[proInfo.proName]}

Name: 952664-69-6|2-Bromo-5-fluoro-4-nitroaniline|97%
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SKU: A138185
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Quality Control of [ 952664-69-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 952664-69-6 ]

Product Details of [ 952664-69-6 ]

CAS No. :	952664-69-6	MDL No. :	MFCD22381005
Formula :	C₆H₄BrFN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PKDUOURYTVRBLI-UHFFFAOYSA-N
M.W :	235.01	Pubchem ID :	57488513
Synonyms :

Calculated chemistry of [ 952664-69-6 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	47.33
TPSA :	71.84 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.41 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.22
Log Po/w (XLOGP3) :	1.86
Log Po/w (WLOGP) :	2.51
Log Po/w (MLOGP) :	1.48
Log Po/w (SILICOS-IT) :	0.12
Consensus Log Po/w :	1.44

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.77
Solubility :	0.396 mg/ml ; 0.00169 mol/l
Class :	Soluble
Log S (Ali) :	-2.99
Solubility :	0.241 mg/ml ; 0.00102 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.56
Solubility :	0.65 mg/ml ; 0.00277 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	3.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.14

Safety of [ 952664-69-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 952664-69-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 952664-69-6 ]
Downstream synthetic route of [ 952664-69-6 ]

[ 952664-69-6 ] Synthesis Path-Upstream 1~3

1
[ 2369-13-3 ]
[ 952664-69-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: With bromine; acetic acid In chloroform at 0 - 20℃; for 2 h; Stage #2: With sodium hydroxide In chloroform; water at 0℃;	To a mixture of 3-fluoro-4-nitroaniline (6.5 g, 42.2 mmol) in AcOH (80 mL) and chloroform (25 mL) was added dropwise Br₂(2.15 mL, 42.2 mmol) at 0° C. After addition, the resulting mixture was stirred at room temperature for 2 h and then poured into ice water. The mixture was basified with aqueous NaOH (10percent) to pH 8.0-9.0 under cooling and then extracted with EtOAc (50 mL.x.3). The combined organic layers were washed with water (80 mL.x.2) and brine (100 mL), dried over Na₂SO₄and concentrated under reduced pressure to give 2-bromo-5-fluoro-4-nitroaniline (9 g, 90percent). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.26 (d, J=8.0, Hz, 1H), 7.07 (brs, 2H), 6.62 (d, J=9.6 Hz, 1H).
90%	With bromine In chloroform; acetic acid	2-Bromo-5-fluoro-4-nitroaniline To a mixture of 3-fluoro-4-nitroaniline (6.5 g, 42.2 mmol) in AcOH (80 mL) and chloroform (25 mL) was added dropwise Br₂ (2.15 mL, 42.2 mmol) at 0° C. After addition, the resulting mixture was stirred at room temperature for 2 h and then poured into ice water. The mixture was basified with aqueous NaOH (10percent) to pH ~8.0-9.0 under cooling and then extracted with EtOAc (50 mL3). The combined organic layers were washed with water (80 mL2) and brine (100 mL), dried over Na₂SO₄ and concentrated under reduced pressure to give 2-bromo-5-fluoro-4-nitroaniline (9 g, 90percent). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.26 (d, J=8.0, Hz, 1H), 7.07 (brs, 2H), 6.62 (d, J=9.6 Hz, 1H).
90%	With bromine; acetic acid In chloroform at 0 - 20℃; for 2 h;	To a mixture of 3-fluoro-4-nitroaniline (6.5 g, 42.2 mmol) in AcOH (80 mL) and chloroform (25 mL) was added dropwise Br₂ (2.15 mL, 42.2 mmol) at 0° C. After addition, the resulting mixture was stirred at room temperature for 2 h and then poured into ice water. The mixture was basified with aqueous NaOH (10percent) to pH˜8.0-9.0 under cooling and then extracted with EtOAc (50 mL3). The combined organic layers were washed with water (80 mL2) and brine (100 mL), dried over Na₂SO₄ and concentrated under reduced pressure to give 2-bromo-5-fluoro-4-nitroaniline (9 g, 90percent). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.26 (d, J=8.0, Hz, 1H), 7.07 (brs, 2H), 6.62 (d, J=9.6 Hz, 1H).

84%	Stage #1: With bromine In acetic acid at 0 - 5℃; for 2 h; Stage #2: With sodium carbonate In water; acetic acid	To a solution of 3-fluoro-4-nitroaniline (56 g, 0.36 mol) in acetic acid (500 mL) was added drop-wise bromine (17.7 mL, 0.36 mol) over 1 hour. The reaction mixture was stirred for 1 hour at 0-5 °C in an ice bath. The reaction mixture was basified with saturated Na₂CO₃ and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to yield a residue that was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 10 : 1) to give the 2-bromo-5-fluoro-4-nitroaniline ( 45.6 g, 84 percent ) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.29 (d, J = 7.6 Hz, 1 H), 653 (d, J = 12.4 Hz, 1 H), 4.94 (br s, 2 H).
61%	With bromine; acetic acid In chloroform at 0℃; for 2.33 h;	Step 1214 15[00168] methyl 2.2-difluorobenzo[d1[1.31dioxole-5-carboxylate: To a solution of 3- fluoro-4-nitroaniline (6.5 g, 41.64 mmol, 1.00 equiv) in chloroform (25 mL) and AcOH (80 mL) was added Bn (6.58 g, 41.17 mmol, 1.00 equiv.) dropwise with stirring at 0 °C in 20 min. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 150 mL of water/ice. The pH value of the solution was adjusted to 9 with sodium hydroxide (10 percent). The resulting solution was extracted with 3 x 50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x 50 mL of water and 2 x 50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was re-crystallized from PE/EA (10: 1) to afford 6 g (61percent) of 2-bromo-5-fluoro-4-nitroaniline as a yellow solid.
50%	With N-Bromosuccinimide In ethyl acetate at 22℃;	Synthesis of 2-bromo-5-fluoro-4-nitroaniline A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22° C. At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap. The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight. The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50° C. overnight with N₂ bleed until constant weight was achieved. A yellowish tan solid was isolated (50percent yield, 97.5percent AUC).Other impurities were a bromo-regioisomer (1.4percent AUC) and a di-bromo adduct (1.1percent AUC). NMR (500 MHz, DMSO) δ 8.19 (1H, d, J=8.1 Hz), 7.06 (br. s, 2H), 6.64 (d, 1H, J=14.3 Hz).
50%	With N-Bromosuccinimide In ethyl acetate at 22℃;	Synthesis of 2-bromo-5-fluoro-4-nitroaniline A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22° C. At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap. The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight. The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50° C. overnight with N₂ bleed until constant weight was achieved. A yellowish tan solid was isolated (50percent yield, 97.5percent AUC).Other impurities were a bromo-regioisomer (1.4percent AUC) and a di-bromo adduct (1.1percent AUC). ¹H NMR (500 MHz, DMSO) δ 8.19 (1H, d, J=8.1 Hz), 7.06 (br. s, 2H), 6.64 (d, 1H, J=14.3 Hz).
50%	With N-Bromosuccinimide In ethyl acetate at 22℃;	A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22 °C. At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap. The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight. The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50 °C overnight with N₂ bleed until constant weight was achieved. A yellowish tan solid was isolated (50percent yield, 97.5percent AUC). Other impurities were a bromo-regioisomer (1.4percent AUC) and a di-bromo adduct (1.1percent AUC). ¹H NMR (500 MHz, DMSO) δ 8.19 (1 H, d, J= 8.1 Hz), 7.06 (br. s, 2 H), 6.64 (d, 1 H, J= 14.3 Hz).

Reference： [1] Patent: US2007/244159, 2007, A1, . Location in patent: Page/Page column 112-113
[2] Patent: US2011/98311, 2011, A1,
[3] Patent: US2015/231142, 2015, A1, . Location in patent: Paragraph 1640; 1979
[4] Patent: WO2010/53471, 2010, A1, . Location in patent: Page/Page column 56-57
[5] Patent: WO2016/109362, 2016, A1, . Location in patent: Paragraph 00168
[6] Patent: US2013/143918, 2013, A1, . Location in patent: Paragraph 0201
[7] Patent: US2013/116238, 2013, A1, . Location in patent: Paragraph 0288; 0289
[8] Patent: WO2014/14841, 2014, A1, . Location in patent: Paragraph 00327
[9] Patent: WO2011/119984, 2011, A1, . Location in patent: Page/Page column 50
[10] Patent: WO2013/185112, 2013, A1, . Location in patent: Paragraph 00580

2
[ 128-08-5 ]
[ 2369-13-3 ]
[ 952664-69-6 ]

Reference： [1] Patent: US2012/15999, 2012, A1,

3
[ 952664-69-6 ]
[ 1152311-62-0 ]

Reference： [1] Patent: WO2011/119984, 2011, A1,
[2] Patent: US2013/143918, 2013, A1,
[3] Patent: WO2013/185112, 2013, A1,
[4] Patent: WO2014/14841, 2014, A1,
[5] Patent: US2015/231142, 2015, A1,
[6] Patent: US2013/116238, 2013, A1,

[ 952664-69-6 ] Synthesis Path-Downstream 1~63

1
[ 2369-13-3 ]
[ 952664-69-6 ]

Yield	Reaction Conditions	Operation in experiment
90%		To a mixture of 3-fluoro-4-nitroaniline (6.5 g, 42.2 mmol) in AcOH (80 mL) and chloroform (25 mL) was added dropwise Br2 (2.15 mL, 42.2 mmol) at 0° C. After addition, the resulting mixture was stirred at room temperature for 2 h and then poured into ice water. The mixture was basified with aqueous NaOH (10percent) to pH 8.0-9.0 under cooling and then extracted with EtOAc (50 mL.x.3). The combined organic layers were washed with water (80 mL.x.2) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give 2-bromo-5-fluoro-4-nitroaniline (9 g, 90percent). 1H-NMR (400 MHz, DMSO-d6) delta 8.26 (d, J=8.0, Hz, 1H), 7.07 (brs, 2H), 6.62 (d, J=9.6 Hz, 1H).
90%	With bromine; In chloroform; acetic acid;	2-Bromo-5-fluoro-4-nitroanilineTo a mixture of 3-fluoro-4-nitroaniline (6.5 g, 42.2 mmol) in AcOH (80 mL) and chloroform (25 mL) was added dropwise Br2 (2.15 mL, 42.2 mmol) at 0° C.After addition, the resulting mixture was stirred at room temperature for 2 h and then poured into ice water.The mixture was basified with aqueous NaOH (10percent) to pH ~8.0-9.0 under cooling and then extracted with EtOAc (50 mL3).The combined organic layers were washed with water (80 mL2) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give 2-bromo-5-fluoro-4-nitroaniline (9 g, 90percent).1H-NMR (400 MHz, DMSO-d6) delta 8.26 (d, J=8.0, Hz, 1H), 7.07 (brs, 2H), 6.62 (d, J=9.6 Hz, 1H).
90%	With bromine; acetic acid; In chloroform; at 0 - 20℃; for 2h;	To a mixture of 3-fluoro-4-nitroaniline (6.5 g, 42.2 mmol) in AcOH (80 mL) and chloroform (25 mL) was added dropwise Br2 (2.15 mL, 42.2 mmol) at 0° C. After addition, the resulting mixture was stirred at room temperature for 2 h and then poured into ice water. The mixture was basified with aqueous NaOH (10percent) to pH?8.0-9.0 under cooling and then extracted with EtOAc (50 mL3). The combined organic layers were washed with water (80 mL2) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give 2-bromo-5-fluoro-4-nitroaniline (9 g, 90percent). 1H-NMR (400 MHz, DMSO-d6) delta 8.26 (d, J=8.0, Hz, 1H), 7.07 (brs, 2H), 6.62 (d, J=9.6 Hz, 1H).

84%		To a solution of 3-fluoro-4-nitroaniline (56 g, 0.36 mol) in acetic acid (500 mL) was added drop-wise bromine (17.7 mL, 0.36 mol) over 1 hour. The reaction mixture was stirred for 1 hour at 0-5 °C in an ice bath. The reaction mixture was basified with saturated Na2CO3 and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue that was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 10 : 1) to give the 2-bromo-5-fluoro-4-nitroaniline ( 45.6 g, 84 percent ) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 8.29 (d, J = 7.6 Hz, 1 H), 653 (d, J = 12.4 Hz, 1 H), 4.94 (br s, 2 H).
61%	With bromine; acetic acid; In chloroform; at 0℃; for 2.33h;	Step 1214 15[00168] methyl 2.2-difluorobenzo[d1[1.31dioxole-5-carboxylate: To a solution of 3- fluoro-4-nitroaniline (6.5 g, 41.64 mmol, 1.00 equiv) in chloroform (25 mL) and AcOH (80 mL) was added Bn (6.58 g, 41.17 mmol, 1.00 equiv.) dropwise with stirring at 0 °C in 20 min. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 150 mL of water/ice. The pH value of the solution was adjusted to 9 with sodium hydroxide (10 percent). The resulting solution was extracted with 3 x 50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x 50 mL of water and 2 x 50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was re-crystallized from PE/EA (10: 1) to afford 6 g (61percent) of 2-bromo-5-fluoro-4-nitroaniline as a yellow solid.
50%	With N-Bromosuccinimide; In ethyl acetate; at 22℃;	Synthesis of 2-bromo-5-fluoro-4-nitroaniline A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22° C. At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap. The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight. The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50° C. overnight with N2 bleed until constant weight was achieved. A yellowish tan solid was isolated (50percent yield, 97.5percent AUC).Other impurities were a bromo-regioisomer (1.4percent AUC) and a di-bromo adduct (1.1percent AUC). NMR (500 MHz, DMSO) delta 8.19 (1H, d, J=8.1 Hz), 7.06 (br. s, 2H), 6.64 (d, 1H, J=14.3 Hz).
50%	With N-Bromosuccinimide; In ethyl acetate; at 22℃;	Synthesis of 2-bromo-5-fluoro-4-nitroaniline A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22° C. At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap. The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight. The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50° C. overnight with N2 bleed until constant weight was achieved. A yellowish tan solid was isolated (50percent yield, 97.5percent AUC).Other impurities were a bromo-regioisomer (1.4percent AUC) and a di-bromo adduct (1.1percent AUC). 1H NMR (500 MHz, DMSO) delta 8.19 (1H, d, J=8.1 Hz), 7.06 (br. s, 2H), 6.64 (d, 1H, J=14.3 Hz).
50%	With N-Bromosuccinimide; In ethyl acetate; at 22℃;	A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22 °C. At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap. The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight. The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50 °C overnight with N2 bleed until constant weight was achieved. A yellowish tan solid was isolated (50percent yield, 97.5percent AUC). Other impurities were a bromo-regioisomer (1.4percent AUC) and a di-bromo adduct (1.1percent AUC). 1H NMR (500 MHz, DMSO) delta 8.19 (1 H, d, J= 8.1 Hz), 7.06 (br. s, 2 H), 6.64 (d, 1 H, J= 14.3 Hz).
	With N-Bromosuccinimide; In ethyl acetate; at 22℃;	00208] Synthesis of 2-bromo-5-fluoro-4-ntroaniline.A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion- wise as to maintain internal temperature of 22 °C. At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap. The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight. The resulting slurry was filtered and the wetcake was washed with 2- propanol, dried in vacuum oven at 50 °C overnight with N2 bleed until constant weight was achieved. A yellowish tan solid was isolated (50percent> yield, 97.5percent AUC). Other impurities were a bromo- regioisomer (1.4percent AUC) and a di-bromo adduct (1.1percent AUC). 1H NMR (500 MHz, DMSO) delta 8.19 (1 H, d, J= 8.1 Hz), 7.06 (br. s, 2 H), 6.64 (d, 1 H, J= 14.3 Hz).
	With N-Bromosuccinimide; In ethyl acetate; at 22℃;	A flask was charged with 3-fluoro-4-nitroanil.ine (1.0 equiv) followed by ethylacetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was addedportion-wise as to maintain an internal temperature of 22 oc. At the end of the reaction, thereaction mixture was concentrated in vacuo on a rotavap. The residue was slmTied in distilledwater (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by'\.Vater workup procedure.) The water was decanted and the solid was slurried in 2-propanol (.5vol) overnight The resulting slurry was filtered and the wetcake was washed with 2-propanol,dried in vacuum oven at 50 cc overnight with N2 bleed until constant weight was achieved. Ayellowish tan solid was isolated (50percent yield, 97.5percent AUC). Other impurities were a bromoregioisomer(1.4percent AUC) and a dibromo adduct (Llpercent AUC). 1H NMR (500 wlliz, DMSO) 88.19 (1 H, d, J ''' 8.1 Hz), 7.06 (br. s, 2 H), 6.64 ( d, I H, J = 14.3 Hz).

Reference： [1]Patent: US2007/244159,2007,A1 .Location in patent: Page/Page column 112-113
[2]Patent: US2011/98311,2011,A1
[3]Patent: US2015/231142,2015,A1 .Location in patent: Paragraph 1640; 1979
[4]Patent: WO2010/53471,2010,A1 .Location in patent: Page/Page column 56-57
[5]Patent: WO2016/109362,2016,A1 .Location in patent: Paragraph 00168
[6]Patent: US2013/143918,2013,A1 .Location in patent: Paragraph 0201
[7]Patent: US2013/116238,2013,A1 .Location in patent: Paragraph 0288; 0289
[8]Patent: WO2014/14841,2014,A1 .Location in patent: Paragraph 00327
[9]Patent: WO2011/119984,2011,A1 .Location in patent: Page/Page column 50
[10]Patent: WO2013/185112,2013,A1 .Location in patent: Paragraph 00580

2
[ 952664-69-6 ]
[ 917-92-0 ]
[ 952664-70-9 ]

Yield	Reaction Conditions	Operation in experiment
46%	With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In water; toluene; at 70℃; for 4h;	A mixture of <strong>[952664-69-6]2-bromo-5-fluoro-4-nitroaniline</strong> (9.0 g, 38.4 mmol), 3,3-dimethyl-but-1-yne (9.95 g, 121 mmol), CuI (0.5 g 2.6 mmol), Pd(PPh3)2Cl2 (3.4 g, 4.86 mmol) and Et3N (14 mL, 6.9 mmol) in toluene (100 mL) and water (50 mL) was heated at 70° C. for 4 h. The aqueous layer was separated and the organic layer washed with water (80 mL.x.2) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to dryness. The residue was recrystallized with ether to afford 2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4-nitroaniline (4.2 g, 46percent). 1H-NMR (400 MHz, DMSO-d6) delta 7.84 (d, J=8.4 Hz, 1H), 6.84 (brs, 2H), 6.54 (d, J=14.4 Hz, 1H), 1.29 (s, 9H).
46%	With CuI; triethylamine;Pd(PPh3)2Cl2; In water; toluene;	2-(3,3-Dimethylbut-1-ynyl)-5-fluoro-4-nitroanilineA mixture of <strong>[952664-69-6]2-bromo-5-fluoro-4-nitroaniline</strong> (9.0 g, 38.4 mmol), 3,3-dimethyl-but-1-yne (9.95 g, 121 mmol), CuI (0.5 g 2.6 mmol), Pd(PPh3)2Cl2 (3.4 g, 4.86 mmol) and Et3N (14 mL, 6.9 mmol) in toluene (100 mL) and water (50 mL) was heated at 70° C. for 4 h.The aqueous layer was separated and the organic layer was washed with water (80 mL*2) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to dryness.The residue was recrystallized with ether to afford 2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4-nitroaniline (4.2 g, 46percent).1H-NMR (400 MHz, DMSO-d6) delta 7.84 (d, J=8.4 Hz, 1H), 6.84 (brs, 2H), 6.54 (d, J=14.4 Hz, 1H), 1.29 (s, 9H).
46%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In water; toluene; at 70℃; for 4h;	A mixture of <strong>[952664-69-6]2-bromo-5-fluoro-4-nitroaniline</strong> (9.0 g, 38.4 mmol), 3,3-dimethyl-but-1-yne (9.95 g, 121 mmol), CuI (0.5 g 2.6 mmol), Pd(PPh3)2Cl2 (3.4 g, 4.86 mmol) and Et3N (14 mL, 6.9 mmol) in toluene (100 mL) and water (50 mL) was heated at 70° C. for 4 h. The aqueous layer was separated and the organic layer was washed with water (80 mL*2) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to dryness. The residue was recrystallized with ether to afford 2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4-nitroaniline (4.2 g, 46percent). 1H-NMR (400 MHz, DMSO-d6) delta 7.84 (d, J=8.4 Hz, 1H), 6.84 (brs, 2H), 6.54 (d, J=14.4 Hz, 1H), 1.29 (s, 9H).

Reference： [1]Patent: US2007/244159,2007,A1 .Location in patent: Page/Page column 113
[2]Patent: US2011/98311,2011,A1
[3]Patent: US2015/231142,2015,A1 .Location in patent: Paragraph 1641

3
[ 952664-69-6 ]
[ 204588-77-2 ]
[ 1225589-66-1 ]

Yield	Reaction Conditions	Operation in experiment
56%	With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; at 20 - 80℃;	To a solution of <strong>[952664-69-6]2-bromo-5-fluoro-4-nitroaniline</strong> (23.0 g, 0.1 mol) in Et3N (250 mL) was added benzoic 2,2-dimethylbut-3-ynoic anhydride (59.0 g, 0.29 mol), CuI (1.85 g) andPd(PPh3)2Cl2 (2.3 g) at room temperature. The mixture was stirred at 8O0C overnight. After cooling to room temperature, the reaction was quenched with water and the aqueous layer was extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (10percent ethyl acetate in petroleum ether) to give benzyl 4-(2-amino-4-fluoro-5- nitrophenyl)-2,2-dimethylbut-3-ynoate (20.0 g, 56percent). 1H NMR (400 MHz, CDCl3) 8.05 (d, J = 8.4 Hz, 1 H), 7.39-7.38 (m, 5 H), 6.33 (d, J = 13.2 Hz, 1 H), 5.20 (s, 2 H), 4.89 (br s, 2 H), 1.61 (s, 6 H).

Reference： [1]Patent: WO2010/53471,2010,A1 .Location in patent: Page/Page column 60-61

4
[ 952664-69-6 ]
[ 66476-86-6 ]
[ 1152311-72-2 ]

Yield	Reaction Conditions	Operation in experiment
57%	With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; at 70℃; for 8h;Inert atmosphere;	To a solution of <strong>[952664-69-6]2-bromo-5-fluoro-4-nitroaniline</strong> (45.7 g, 0.19 mol) and ethyl 3,3- dimethylpent-4-ynoate (88.3 g, 0.57 mol) in Et3N (700 mL) was added Pd(PPh3)2Cl2 (13.8 g, 0.02 mol) and CuI (3.6 g, 0.02 mol) under N2. The reaction mixture was stirred at 700C for 8 hours. The reaction mixture was diluted with 500 mL of ethyl acetate and 1500 mL of water. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (500 mLx3), the combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 10: 1) to give ethyl-5-(2-amino-4- fluoro-5- nitrophenyl)-3,3-dimethylpent-4-ynoate (34.5 g, 57 percent). 1H NMR (300 MHz, CDCl3) delta 8.05 (d, J = 8.1Hz, 1 H), 6.36 (d, / = 13.2 Hz, 1 H), 5.60 (brs, 2 H), 4.16 (q, / = 7.2 Hz, 2 H), 2.51 (s, 2 H), 1.40 (s, 6 H), 1.28 (t, J = 7.2 Hz, 3 H).

Reference： [1]Patent: WO2010/53471,2010,A1 .Location in patent: Page/Page column 56-57

5
[ 952664-69-6 ]
2-tert-butyl-6-fluoro-1H-indol-5-amine [ No CAS ]

Reference： [1]Patent: US2011/98311,2011,A1
[2]Patent: US2015/231142,2015,A1

6
[ 952664-69-6 ]
6-tert-butoxy-2-tert-butyl-1H-indol-5-amine [ No CAS ]

Reference： [1]Patent: US2011/98311,2011,A1
[2]Patent: US2015/231142,2015,A1

7
[ 952664-69-6 ]
[ 952664-71-0 ]

Reference： [1]Patent: US2011/98311,2011,A1
[2]Patent: US2015/231142,2015,A1

8
[ 952664-69-6 ]
[ 952664-72-1 ]

Reference： [1]Patent: US2011/98311,2011,A1
[2]Patent: US2015/231142,2015,A1

9
[ 952664-69-6 ]
[ 952664-74-3 ]

Reference： [1]Patent: US2011/98311,2011,A1
[2]Patent: US2015/231142,2015,A1

10
[ 952664-69-6 ]
[ 104-15-4 ]
[ 14618-80-5 ]
[ 1294504-64-5 ]

Yield	Reaction Conditions	Operation in experiment
		[00209] Synthesis of benzylglycolated-4-ammonium-2-bromo-5-fluoroaniline tosylate salt.1) \| ^OBncat. Zn(C104)2-2H20 .(C).[00210] A thoroughly dried flask under N2 was charged with the following: Activated powdered 4A molecular sieves (50 wtpercent based on <strong>[952664-69-6]2-bromo-5-fluoro-4-nitroaniline</strong>), 2-Bromo-5- fluoro-4-nitroaniline (1.0 equiv), zinc perchlorate dihydrate (20 molpercent), and toluene (8 vol). The mixture was stirred at room temperature for NMT 30 min. Lastly, (R)-benzyl glycidyl ether (2.0 equiv) in toluene (2 vol) was added in a steady stream. The reaction was heated to 80 °C (internal temperature) and stirred for approximately 7 hours or until 2-Bromo-5-fluoro-4- nitroaniline was <5percentAUC.[00211] The reaction was cooled to room temperature and Celite (50 wtpercent) was added, followed by ethyl acetate (10 vol). The resulting mixture was filtered to remove Celite and sieves and washed with ethyl acetate (2 vol). The filtrate was washed with ammonium chloride solution (4 vol, 20percent w/v). The organic layer was washed with sodium bicarbonate solution (4 vol x 2.5percent w/v). The organic layer was concentrated in vacuo on a rotovap. The resulting slurry was dissolved in isopropyl acetate (10 vol) and this solution was transferred to a Buchi hydrogenator.[00212] The hydrogenator was charged with 5wtpercent Pt(S)/C (1.5 molpercent>) and the mixture was stirred under N2 at 30 °C (internal temperature). The reaction was flushed with N2 followed by hydrogen. The hydrogenator pressure was adjusted to 1 Bar of hydrogen and the mixture was stirred rapidly (>1200 rpm). At the end of the reaction, the catalyst was filtered through a pad of Celite and washed with dichloromethane (10 vol). The filtrate wasconcentrated in vacuo. Any remaining isopropyl acetate was chased with dichloromethane (2 vol) and concentrated on a rotavap to dryness. [00213] The resulting residue was dissolved in dichloromethane (10 vol), p- Toluenesulfonic acid mono hydrate (1.2 equiv) was added and stirred overnight. The product was filtered and washed with dichloromethane (2 vol) and suction dried. The wetcake was transferred to drying trays and into a vacuum oven and dried at 45 °C with N2 bleed until constant weight was achieved. Benzylglycolated-4-ammonium-2-bromo-5-fluoroaniline tosylate salt was isolated as an off-white solid.
		Synthesis of benzylglycolated-4-ammonium-2-bromo-5-fluoroaniline tosylate salt A thoroughly dried flask under N2 was charged with the following: Activated powdered 4A molecular sieves (50 wt percent based on <strong>[952664-69-6]2-bromo-5-fluoro-4-nitroaniline</strong>), 2-Bromo-5-fluoro-4-nitroaniline (1.0 equiv), zinc perchlorate dihydrate (20 mol percent), and toluene (8 vol). The mixture was stirred at room temperature for NMT 30 min. Lastly, (R)-benzyl glycidyl ether (2.0 equiv) in toluene (2 vol) was added in a steady stream. The reaction was heated to 80° C. (internal temperature) and stirred for approximately 7 hours or until 2-Bromo-5-fluoro-4-nitroaniline was <5percent AUC. The reaction was cooled to room temperature and Celite (50 wt percent) was added, followed by ethyl acetate (10 vol). The resulting mixture was filtered to remove Celite and sieves and washed with ethyl acetate (2 vol). The filtrate was washed with ammonium chloride solution (4 vol, 20percent w/v). The organic layer was washed with sodium bicarbonate solution (4 vol*2.5percent w/v). The organic layer was concentrated in vacuo on a rotovap. The resulting slurry was dissolved in isopropyl acetate (10 vol) and this solution was transferred to a Buchi hydrogenator. The hydrogenator was charged with 5 wt percent Pt(S)/C (1.5 mol percent) and the mixture was stirred under N2 at 30° C. (internal temperature). The reaction was flushed with N2 followed by hydrogen. The hydrogenator pressure was adjusted to 1 Bar of hydrogen and the mixture was stirred rapidly (>1200 rpm). At the end of the reaction, the catalyst was filtered through a pad of Celite and washed with dichloromethane (10 vol). The filtrate was concentrated in vacuo. Any remaining isopropyl acetate was chased with dichloromethane (2 vol) and concentrated on a rotavap to dryness. The resulting residue was dissolved in dichloromethane (10 vol). p-Toluenesulfonicacid monohydrate (1.2 equiv) was added and stirred overnight. The product was filtered and washed with dichloromethane (2 vol) and suction dried. The wetcake was transferred to drying trays and into a vacuum oven and dried at 45° C. with N2 bleed until constant weight was achieved. Benzylglycolated-4-ammonium-2-bromo-5-fluoroaniline tosylate salt was isolated as an off-white solid. Chiral purity was determined to be >97percent ee.
		Synthesis of benzylglycolated-4-ammonium-2-bromo-5-fluoroaniline tosylate salt A thoroughly dried flask under N2 was charged with the following: Activated powdered 4A molecular sieves (50 wt percent based on <strong>[952664-69-6]2-bromo-5-fluoro-4-nitroaniline</strong>), 2-Bromo-5-fluoro-4-nitroaniline (1.0 equiv), zinc perchlorate dihydrate (20 mol percent), and toluene (8 vol). The mixture was stirred at room temperature for NMT 30 min. Lastly, (R)-benzyl glycidyl ether (2.0 equiv) in toluene (2 vol) was added in a steady stream. The reaction was heated to 80° C. (internal temperature) and stirred for approximately 7 hours or until 2-Bromo-5-fluoro-4-nitroaniline was <5percent AUC. The reaction was cooled to room temperature and Celite (50 wt percent) was added, followed by ethyl acetate (10 vol). The resulting mixture was filtered to remove Celite and sieves and washed with ethyl acetate (2 vol). The filtrate was washed with ammonium chloride solution (4 vol, 20percent w/v). The organic layer was washed with sodium bicarbonate solution (4 vol*2.5percent w/v). The organic layer was concentrated in vacuo on a rotovap. The resulting slurry was dissolved in isopropyl acetate (10 vol) and this solution was transferred to a Buchi hydrogenator. The hydrogenator was charged with 5 wt percent Pt(S)/C (1.5 mol percent) and the mixture was stirred under N2 at 30° C. (internal temperature). The reaction was flushed with N2 followed by hydrogen. The hydrogenator pressure was adjusted to 1 Bar of hydrogen and the mixture was stirred rapidly (>1200 rpm). At the end of the reaction, the catalyst was filtered through a pad of Celite and washed with dichloromethane (10 vol). The filtrate was concentrated in vacuo. Any remaining isopropyl acetate was chased with dichloromethane (2 vol) and concentrated on a rotavap to dryness. The resulting residue was dissolved in dichloromethane (10 vol). p-Toluenesulfonic acid monohydrate (1.2 equiv) was added and stirred overnight. The product was filtered and washed with dichloromethane (2 vol) and suction dried. The wetcake was transferred to drying trays and into a vacuum oven and dried at 45° C. with N2 bleed until constant weight was achieved. Benzylglycolated-4-ammonium-2-bromo-5-fluoroaniline tosylate salt was isolated as an off-white solid. Chiral purity was determined to be >97percent ee.

Reference： [1]Patent: WO2011/119984,2011,A1 .Location in patent: Page/Page column 51-52
[2]Patent: US2013/143918,2013,A1 .Location in patent: Paragraph 0202; 0203; 0204; 0205; 0206; 0207
[3]Patent: US2013/116238,2013,A1 .Location in patent: Paragraph 0290; 0291; 0292; 0293; 0294; 0295

11
[ 952664-69-6 ]
[ 1152311-62-0 ]

Reference： [1]Patent: WO2011/119984,2011,A1
[2]Patent: US2013/143918,2013,A1
[3]Patent: WO2013/185112,2013,A1
[4]Patent: WO2014/14841,2014,A1
[5]Patent: US2015/231142,2015,A1
[6]Patent: US2013/116238,2013,A1

12
[ 952664-69-6 ]
[ 1294504-66-7 ]

13
[ 952664-69-6 ]
[ 1294504-67-8 ]

14
[ 952664-69-6 ]
[ 1294504-68-9 ]

15
[ 128-08-5 ]
[ 2369-13-3 ]
[ 952664-69-6 ]

Yield	Reaction Conditions	Operation in experiment
97.5%	In N2; water; ethyl acetate; isopropyl alcohol;	Synthesis of 2-bromo-5-fluoro-4-nitroanilineA flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22° C.At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap.The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight.The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50° C. overnight with N2 bleed until constant weight was achieved.A yellowish tan solid was isolated (50percent yield, 97.5percent AUC).

Reference： [1]Patent: US2012/15999,2012,A1

16
[ 952664-69-6 ]
[ 1432656-97-7 ]

Reference： [1]Patent: US2013/116238,2013,A1

17
[ 952664-69-6 ]
[ 1432656-98-8 ]

Reference： [1]Patent: US2013/116238,2013,A1
[2]Patent: US2013/116238,2013,A1
[3]Patent: US2013/116238,2013,A1

18
[ 952664-69-6 ]
[ 1432656-99-9 ]

Reference： [1]Patent: US2013/116238,2013,A1

19
[ 952664-69-6 ]
[ 1432657-00-5 ]

Reference： [1]Patent: US2013/116238,2013,A1

20
[ 952664-69-6 ]
C₂₇H₂₂F₃N₂O₈^(1-)*Na⁽¹⁺⁾ [ No CAS ]

Reference： [1]Patent: US2013/116238,2013,A1

21
[ 952664-69-6 ]
[ 1432657-01-6 ]

Reference： [1]Patent: US2013/116238,2013,A1

22
[ 952664-69-6 ]
[ 1294504-63-4 ]

Reference： [1]Patent: WO2016/109362,2016,A1
[2]Patent: US2013/116238,2013,A1

23
[ 952664-69-6 ]
[ 104-15-4 ]
[ 14618-80-5 ]
(R)-1-((4-amino-2-bromo-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol p-toluenesulfonic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A thoroughly dried t1ask under N2 was charged with the :following: Activatedpowdered 4 A molecular sieves (50 wtpercent based on <strong>[952664-69-6]2-bromo-5-fluoro-4-nitroaniline</strong>), 2-Bromo-5-fluoro-4-nitroaniline (1.0 equiv), zinc perchlorate dihydrate (20 moWo), and toluene (8 vol). Themixture was stirred at room temperature for no more than 30 min. Lastly, (R)-benzyl glycidylether (2.0 equiv) in toluene (2 vol) was added in a steady stream. The reaction was heated to 80oc (internal temperature) and stirred for approximately 7 hours or until2-bromo-5-t1uoro-4-nitroaniline was <5percentAUC.The reaction was cooled to room temperature and Celite® (50 wtpercent) was added,followed by ethyl acetate (l 0 vol). The resulting mixture was filtered to remove Celite® andsieves and washed with ethyl acetate (2 vol). The filtrate was washed with amrno:nium chloridesolution (4 vol, 20percent w/v). The organic layer was washed with sodium bicarbonate solution (4vol x 2.5percent w/v). The organic layer was concentrated in vacuo on a rotovap. The resultingslurry was dissolved in isopropyl acetate (10 vol) and this solution was transferred to a BuchihydrogenatorThe hydroge:nator was charged with 5wtpercent Pt(S)/C (1.5 moWo) and the mixture wasstirred under Nz at 30 cc (internal temperature). The reaction was flushed with N2 followed byhydrogen. The hydrogenator pressure was adjusted to 1 Bar of hydrogen and the mixture wasstirred rapidly(> 1200 rpm). At tl1e end of the reaction, the catalyst was filtered through a pad ofCelite® and washed with dichloromethane (10 vol), The t11trate was concentrated in vacuo. Any remaining isopropyl acetate was chased with dichloromethane (2 vol) and concentrated on arotavap to dryness.The resulting residue was dissolved in dichloromethane (10 'lOl). p-Toluenesulfonicacid monohydrate (1.2 equiv) was added and stilTed overnight. The product was filtered andwashed with dichloromethane (2 vol) and suction driext The wetcake was transferred to dryingtrays and into a vacuum oven and dried at 45 oc with N2 bleed until constant weight wasachieved. The p-toluenesulfonic acid salt of (R)-1-(( 4-amino-2-bromo-5-fluorophenyl)amino )-3-(benzyloxy)propan-2-ol was isolated as an off-white solid.

Reference： [1]Patent: WO2013/185112,2013,A1 .Location in patent: Paragraph 00581; 00582; 00583; 00584

24
[ 952664-69-6 ]
[ 14618-80-5 ]
[ 1342896-73-4 ]

Yield	Reaction Conditions	Operation in experiment
70%		Step 13[00169] (R)-l-(benzyloxy)-3-(2-bromo-5-fluoro-4-nitrophenylamino)propan-2-ol: 2- bromo-5-fluoro-4-nitroaniline (6.00 g, 25.56 mmol, 1.00 equiv.), Zn(C104)2 (1.90 g, 5.1 mmol, 0.20 equiv.), 4A Molecular Sieves (3 g), toluene (60 mL) was stirred at room temperature for 2 h and maintain with an inert atmosphere of N2 until (2R)-2- [(benzyloxy)methyl]oxirane (1.37 g, 8.34 mmol, 2.00 equiv.) was added. Then the resulting mixture was stirred for 15 h at 85 °C. The reaction progress was monitored by LCMS. The solids were filtered out and the resulting solution was diluted with 20 mL of ethyl acetate. The resulting mixture was washed with 2 x 20 mL of Sat. NH4CI and 1 x 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column, eluted with ethyl acetate/petroleum ether (1 :5) to afford 7.5 g (70percent) of N-[(2R)-3-(benzyloxy)-2-hydroxypropyl]-2-bromo-5-fluoro-4- nitroaniline as a yellow solid.
		[00329] A thoroughly dried flask under N2 was charged with the following: Activated powdered 4A molecular sieves (50 wtpercent based on <strong>[952664-69-6]2-bromo-5-fluoro-4-nitroaniline</strong>), 2-Bromo-5-fluoro-4-nitroaniline (1.0 equiv), zinc perchlorate dihydrate (20 molpercent), and toluene (8 vol). The mixture was stirred at room temperature for NMT 30 min. Lastly, (R)-benzyl glycidyl ether (2.0 equiv) in toluene (2 vol) was added in a steady stream. The reaction was heated to 80 °C (internal temperature) and stirred for approximately 7 hours or until 2-Bromo-5-fluoro-4-nitroaniline was [00330] The reaction was cooled to room temperature and Celite (50 wtpercent) was added, followed by ethyl acetate (10 vol). The resulting mixture was filtered to remove Celite and sieves and washed with ethyl acetate (2 vol). The filtrate was washed with ammonium chloride solution (4 vol, 20percent w/v). The organic layer was washed with sodium bicarbonate solution (4 vol x 2.5percent w/v). The organic layer was concentrated in vacuo on a rotovap. The resulting slurry was dissolved in isopropyl acetate (10 vol) and this solution was transferred to a Buchi hydrogenator.
		A thoroughly dried flask wider N2 was charged with the following: Activated powdered 4 molecular sieves (50 wt percent based on <strong>[952664-69-6]2-bromo-5-fluoro-4-nitroaniline</strong>), 2-Bromo-5-fluoro-4-nitroaniline (1.0 equiv), zinc perchlorate dihydrate (20 mol percent), and toluene (8 vol). The mixture was stirred at room temperature for no more than 30 min. Lastly, (R)-benzyl glycidyl ether (2.0 equiv) in toluene (2 vol) was added in a steady stream. The reaction was heated to 80° C. (internal temperature) and stirred for approximately 7 hours or until 2-Bromo-5-fluoro-4-nitroaniline was (1981) The reaction was cooled to room temperature and Celite® (50 wt percent) was added, followed by ethyl acetate (10 vol). The resulting mixture was filtered to remove Celite® and sieves and washed with ethyl acetate (2 vol). The filtrate was washed with ammonium chloride solution (4 vol, 20percent w/v). The organic layer was washed with sodium bicarbonate solution (4 vol×2.5percent w/v). The organic layer was concentrated in vacuo on a rotovap. The resulting slurry was dissolved in isopropyl acetate (10 vol) and this solution was transferred to a Buchi hydrogenator.

Reference： [1]Patent: WO2016/109362,2016,A1 .Location in patent: Paragraph 00169
[2]Patent: WO2014/14841,2014,A1 .Location in patent: Paragraph 00328; 00329; 00330
[3]Patent: US2015/231142,2015,A1 .Location in patent: Paragraph 1980; 1981

25
[ 952664-69-6 ]
[ 1294504-64-5 ]

Reference： [1]Patent: US2015/231142,2015,A1
[2]Patent: WO2016/109362,2016,A1

26
[ 952664-69-6 ]
1-[5-amino-2-[1-(benzyloxy)-2-methylpropan-2-yl]-6-fluoro-1H-indol-1-yl]-3-(benzyloxy) (3,3-²H₂)propan-2-ol [ No CAS ]