[ CAS No. 1269232-93-0 ] {[proInfo.proName]}

Name: 1269232-93-0|3-Bromo-5-Chloro-2-fluorobenzoic acid|95%
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Product Details of [ 1269232-93-0 ]

CAS No. :	1269232-93-0	MDL No. :	MFCD21607478
Formula :	C₇H₃BrClFO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZSCAXCZFFCKFAE-UHFFFAOYSA-N
M.W :	253.45	Pubchem ID :	51034462
Synonyms :

Safety of [ 1269232-93-0 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 1269232-93-0 ]

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

Downstream synthetic route of [ 1269232-93-0 ]

[ 1269232-93-0 ] Synthesis Path-Downstream 1~31

1
diphenyl phosphorazide [ No CAS ]
[ 1269232-93-0 ]
[ 1269232-94-1 ]

Yield	Reaction Conditions	Operation in experiment
	With DIEA In n-heptane; ethyl acetate; toluene; <i>tert</i>-butyl alcohol	2 Step 2: Step 2: Preparation of tert-butyl 3-bromo-5-chloro-2-fluorophenyl-carbamate A mixture of 3-bromo-5-chloro-2-fluorobenzoic acid (3.34 g, 13.2 mmol), DIEA (2.04 g, 15.8 mmol) and diphenyl phosphorazide (DPPA, 4.53 g, 16.5 mmol) in 1:1 dry t-butanol and toluene (35 mL) was heated to and maintained at reflux for 23 hours. The reaction was allowed to cool to room temperature and was then partitioned between CHCl3 (75 mL) and water (75 mL). The organic layer was separated, washed with brine, dried (Na2SO4), and then concentrated under reduced pressure to yield an oily residue. Purification by flash chromatography (SiO2, 0-5% EtOAc in heptane) to yield tert-butyl 3-bromo-5-chloro-2-fluorophenylcarbamate (2.45 g, 7.5 mmol, 57%): LCMS(m/z) not ionized (MH+), tR=1.20 minutes; 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=5.1 Hz, 1H), 7.16 (m, 1H), 6.72 (br s, 1H), 1.53 (s, 9H).

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2011/52578, 2011, A1

2
[ 1996-30-1 ]
[ 1269232-93-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; n-butyllithium; carbon dioxide; diisopropylamine; In tetrahydrofuran; pentane;	Step 1: Preparation of 3-bromo-5-chloro-2-fluorobenzoic acid To a cooled solution of diisopropylamine (2.4 mL, 17.2 mmol) in dry THF (15 mL) under Argon at 0 C. was added n-butyllithium (7.5 mL, 2.0 M in pentane, 15.0 mmol). After 30 minutes the solution was cooled to -78 C. and a solution of <strong>[1996-30-1]2-bromo-4-chloro-1-fluorobenzene</strong> (3 g, 14.3 mmol) in dry THF (15 mL) was added over 15 minutes. After 1 hour, this solution was transferred via cannula over 10 minutes to a mixture of solid carbon dioxide and THF (30 mL) at -78 C. After 45 minutes the cold bath was removed and excess carbon dioxide was allowed to vent while the solution warmed to room temperature. The reaction mixture was then quenched with aqueous 0.5 M HCl solution (60 mL). After concentrating, the remaining aqueous phase was basified with aqueous 0.5 M NaOH solution and was washed with ethyl acetate (100 mL). The aqueous phase was then acidified with aqueous 1.0 M HCl solution and extracted with chloroform (2*75 mL). The combined organic portions were washed with brine, dried (Na2SO4) and concentrated to give 3.34 g of a semi-crystalline solid as a mixture of regioisomers with the desired isomer as the major: LCMS(m/z) not observed (MH+), tR=0.66 minute; 1H NMR (400 MHz, CDCl3) delta 7.80 (dd, J=5.5, 2.7 Hz, 1H), 7.95 (dd, J=5.5, 2.7 Hz, 1H).

Reference： [1]Patent: US2011/52578,2011,A1
[2]Patent: WO2011/161216,2011,A1
[3]Patent: WO2011/25927,2011,A1

3
[ 1269232-93-0 ]
[ 75-65-0 ]
[ 1269232-94-1 ]

Yield	Reaction Conditions	Operation in experiment
	With diphenylphosphoranyl azide; N-ethyl-N,N-diisopropylamine In toluene at 110℃; for 36h;	[00192] Intermediate. Tert-butyl 3-bromo-5-chloro-2-fluorophenylcarbamate [00193] A solution of crude Intermediate S-bromo-S-chloro-l-fluorobenzoic acid(2.03 g, 8 mmol), diphenylphosphoryl azide (2.07 rnL, 9.6 mmol, 1.2 eq), and DIPEA (1.67 rnL, 9.6 mmol, 1.2 eq) in 1:1 ^-butanol/toluene (25 ml) was heated at 110 0C for 36h. The mixture was concentrated, then partitioned between ethyl acetate and water. The organic layer was washed with brine, and was then dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (30:1 to 10:1 hexanes/ethyl acetate eluant) to provide the title compound. MS m/z: 267.8 (M+H)+. (M- 'Bu).
	Stage #1: 3-bromo-5-chloro-2-fluorobenzoic acid; <i>tert</i>-butyl alcohol With diphenylphosphoranyl azide; triethylamine In toluene at 75 - 84℃; for 2h; Stage #2: With water In toluene at 35℃; for 0.25h;	6.14 [00229] Step 14. Te/t-butyl 3-bromo-5-chloro-2-fluorophenylcarbamate. A mixture of 3-bromo-5-chloro-2-fluorobenzoic acid (243 g, 97.5%, 0.935 mol), triethylamine (105 g, 99.5%, 1.02 mol), and tert-butanol (1.4 L) was heated to 74 0C. A solution of diphenylphosphoryl azide (260 g, 97%, 0.916 mol) in toluene (960 mL) was added slowly into the mixture at 75-79 0C over 1 h (gentle refluxing). The mixture was heated slowly to 83 0C over 30 min and maintained at 83-84 0C (gentle refluxing) for 1 h. The contents were concentrated under vacuum (65-70 0C) to a viscous oil. Toluene (2 L) and water (1.5 L) were added sequentially into the batch and the mixture was then stirred at 35 0C for 15 min. The aqueous layer was discarded The organic layer was washed with saturated sodium bicarbonate solution (400 mL) and water (400 mL). The organic layer was concentrated under vacuum (60- 65 0C) to -350 mL residue (-94% purity). 10% ethyl acetate/hexane (-1.2 L, v/v) was added into the batch and the mixture was then heated at 50 0C for 15 min to give a light yellow homogenous solution. Ethyl acetate/hexane solution was transferred onto a premade silica gel (1.8 kg, 70-200 mesh)/hexane bed on a 4-L Pyrex Biichner funnel (with coarse fritted discs, 40- 60μm, 16 cm diameter, 18 cm height). t-Butyl carbamate product was eluted (by gravity) slowly with 3-5% ethyl acetate/ hexane (total volume -5 L, v/v) to collect the title compound as an off- white solid, mp 87-88 0C; HPLC purity (225 nm) : 97-98%; 1H NMR (d6-DMSO): δ 1.48 (s, 9H), 7.48-7.49 (m, IH), 7.80-7.82 (m, IH), 9.42 (s, IH); MS m/z 325 (M+H).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/25927, 2011, A1 Location in patent: Page/Page column 51
[2]Current Patent Assignee: PFIZER INC - WO2011/25927, 2011, A1 Location in patent: Page/Page column 65-66

4
[ 1996-30-1 ]
[ 124-38-9 ]
[ 1269232-93-0 ]

Yield	Reaction Conditions	Operation in experiment
		00189] Intermediate. S-Bromo-S-chloro^-fluorobenzoic acid[00190] A solution of 2-bromo-4-chloro-l-fluorobenzene (4.31 g, 20 mmol) was added dropwise to a -78 0C solution of LDA in THF (prepared from diisopropylamine (3.38 ml, 24 mmol) and n-BuLi (1.6 M, 13.1 ml, 21 mmol)). The mixture was stirred at -78 0C for 1 h, and then was transferred slowly (~ 30-60 min) via canula to a stirred -78 0C mixture of dry ice and THF (40 ml). The mixture was stirred at -78 0C for 1 h, and then was allowed to warm to rt (gas evolution). The mixture was concentrated, and was then treated with 50 ml of 1 N sodium hydroxide solution. The mixture was extracted with ethyl acetate (discarded). The aqueous layer was acidified with IN hydrochloric acid, and then was extracted with chloroform (3 x 400 ml). The chloroform extract was dried over sodium sulfate, filtered, and concentrated to provide the crude title compound. The product was contaminated with a small amount of the isomeric product 2-bromo-6-chloro-3-flurobenzoic acid. 1H NMR for title compound 3-Bromo-5-chloro-2-fluorobenzoic acid: (400 MHz, CDCl3) delta 7.93 (dd, IH, J = 2.8, 5.6 Hz), 7.79 (dd, IH, J = 2.8, 5.6 Hz) ppm.

Reference： [1]Patent: WO2011/25927,2011,A1 .Location in patent: Page/Page column 50

5
[ 1269232-93-0 ]
[ 1269232-95-2 ]

Yield	Reaction Conditions	Operation in experiment
15%	With diphenyl phosphoryl azide; N-ethyl-N,N-diisopropylamine In toluene; <i>tert</i>-butyl alcohol at 10 - 100℃; for 16.4167h;
	Multi-step reaction with 2 steps 1.1: diphenylphosphoranyl azide; triethylamine / toluene / 2 h / 75 - 84 °C 1.2: 0.25 h / 35 °C 2.1: trifluoroacetic acid / tetrahydrofuran; dichloromethane / 1 h / 20 °C

Reference： [1]Tsang, Jonathan E.; Urner, Lorenz M.; Kim, Gyudong; Chow, Kingsley; Baufeld, Lynn; Faull, Kym; Cloughesy, Timothy F.; Clark, Peter M.; Jung, Michael E.; Nathanson, David A. [ACS Medicinal Chemistry Letters, 2020, vol. 11, # 10, p. 1799 - 1809]
[2]Current Patent Assignee: PFIZER INC - WO2011/25927, 2011, A1

6
[ 1269232-93-0 ]
[ 1269440-69-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: diphenylphosphoranyl azide; triethylamine / toluene / 2 h / 75 - 84 °C 1.2: 0.25 h / 35 °C 2.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate / 1,4-dioxane / 16 h / 100 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/25927, 2011, A1

7
[ 1269232-93-0 ]
[ 1269440-09-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: diphenylphosphoranyl azide; triethylamine / toluene / 2 h / 75 - 84 °C 1.2: 0.25 h / 35 °C 2.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate / 1,4-dioxane / 16 h / 100 °C 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / ethanol; water; toluene / 16 h / 80 °C 4.1: triethylamine / dichloromethane / 16 h / 20 °C 4.2: 16 h / 85 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/25927, 2011, A1

8
[ 1269232-93-0 ]
[ 1269440-77-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: diphenylphosphoranyl azide; triethylamine / toluene / 2 h / 75 - 84 °C 1.2: 0.25 h / 35 °C 2.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate / 1,4-dioxane / 16 h / 100 °C 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / ethanol; water; toluene / 16 h / 80 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/25927, 2011, A1

9
[ 1269232-93-0 ]
[ 1269440-78-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: diphenylphosphoranyl azide; triethylamine / toluene / 2 h / 75 - 84 °C 1.2: 0.25 h / 35 °C 2.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate / 1,4-dioxane / 16 h / 100 °C 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / ethanol; water; toluene / 16 h / 80 °C 4.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/25927, 2011, A1

10
[ 1269232-93-0 ]
[ 1269440-17-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: diphenylphosphoranyl azide; triethylamine / toluene / 2 h / 75 - 84 °C 1.2: 0.25 h / 35 °C 2.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate / 1,4-dioxane / 16 h / 100 °C 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / ethanol; water; toluene / 16 h / 80 °C 4.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 5.1: triethylamine / 2-methyltetrahydrofuran / -5 - 20 °C 5.2: pH 6 - 6.5 5.3: 0.17 h / 20 °C / pH 7 - 7.5 6.1: sodium hydroxide / 2-methyltetrahydrofuran; water / 0.5 h / 20 - 23 °C 6.2: pH 6 - 6.5 6.3: pH 8.5

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/25927, 2011, A1

11
[ 1269232-93-0 ]
[ 1269440-99-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: diphenylphosphoranyl azide; triethylamine / toluene / 2 h / 75 - 84 °C 1.2: 0.25 h / 35 °C 2.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate / 1,4-dioxane / 16 h / 100 °C 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / ethanol; water; toluene / 16 h / 80 °C 4.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 5.1: triethylamine / 2-methyltetrahydrofuran / -5 - 20 °C 5.2: pH 6 - 6.5 5.3: 0.17 h / 20 °C / pH 7 - 7.5

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/25927, 2011, A1

12
[ 1269440-82-5 ]
[ 1269232-93-0 ]

Yield	Reaction Conditions	Operation in experiment
97.5%	Stage #1: 3-bromo-5-chloro-2-fluorobenzaldehyde With potassium permanganate In water; <i>tert</i>-butyl alcohol at 40 - 60℃; for 2.5h; Stage #2: With sodium carbonate In water; <i>tert</i>-butyl alcohol at 50℃; for 1h; Stage #3: With hydrogenchloride In tert-Amyl alcohol; water	6.13 [00228] Step 13. 3-Bromo-5-chloro-2-fluorobenzoic acid. A stirred mixture of 3- bromo-5-chloro-2-fluorobenzaldehyde (415 g), tert-butanol (1.2 L) and water (1.2 L) was warmed to 30 0C and then potassium permanganate (335 g, 2.12 mol) was added (5 portions) into the batch at 40-45 0C over 1 h. The dark purple contents were heated in a step-wise fashion at 45-50 0C for 30 min, 50-55 0C for 30 min and 55-60 0C for 30 min to afford a purple-brown suspension. The reaction mixture was allowed to cool to 20 0C, then saturated sodium sulfite solution was added at 22-27 0C, until a negative peroxide test was obtained. Warm water (2.5 L, -50 0C) and saturated sodium carbonate solution (100 mL) were added sequentially into the mixture over 15 min. The dark suspension was filtered through a 1 cm celite bed, and the filter cake was washed with warm water (4 x 1 L, -50 C ). The combined filtrate was acidified with 6 N hydrochloric acid solution to pH 1 to obtain a yellow oily suspension. Ethyl acetate (3 L) was added into the mixture and the mixture was stirred for 10 min. The (upper) organic layer was washed with water (1.2 L), dried over magnesium sulfate, filtered, and concentrated under vacuum (60-65 0C) to give a thick yellow suspension. Hexane (700 mL) was added into the residue and the suspension was cooled to 5-10 0C. The solid was collected by filtration, and the filter cake was dried under vacuum (65 0C) overnight to give the title compound as a yellow solid, mp 150-152 0C; HPLC purity (225 nm): 97.5%; 1H NMR (d6-DMSO): δ 7.82 (s, IH), 8.10 (s, IH), 13.82 (br s, IH); MS m/z 254 (M+H).
79%	Stage #1: 3-bromo-5-chloro-2-fluorobenzaldehyde With potassium permanganate In water; <i>tert</i>-butyl alcohol at 30 - 65℃; for 2.91667h; Stage #2: With sodium sulfite In water; <i>tert</i>-butyl alcohol at 20℃; for 0.166667h; Stage #3: With hydrogenchloride In water; <i>tert</i>-butyl alcohol at 15 - 25℃;	II.2 A suspension of 3-bromo-5-chloro-2-fluorobenzaldehyde (13.0 g, 54.7 mmol) in mixture of t-butanol (50 mL) and water (50 mL) was heated to 30 °C, followed by portionwise addition of KMn04 over 25 min with an internal temperature between 30-45 °C. The resulting mixture was then sequentially stirred at 45 °C for an additional 30 min, at 50- 55 °C for 30 min and at 55-65 °C for 1.5 h. The reaction was then allowed to cool to rt, quenched with saturated aqueous Na2S03 solution to a negative peroxide test, diluted with water (70 mL) and basified with saturated aqueous Na2C03 solution (9 mL) and stirred for 10 min. The resulting mixture was filtered through a pad of Celite under reduced pressure and the filter cake was washed with water (2 x 50 mL). The combined filtrates were acidified with concentrated HC1 to pH 1 at 15-25 °C, and then extracted with EtOAc (2 X 100 mL). The combined organic extracts were sequentially washed with water (100 mL), brine (100 mL), dried (Na2S04), and concentrated to give 3-bromo-5-chloro-2-fluorobenzoic acid (11.0 g, 79% yield) as a light yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 7.76 - 7.92 (m, 1 H) 8.07 - 8.28 (m, 1 H) 13.37 - 14.02 (m, 1 H).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/25927, 2011, A1 Location in patent: Page/Page column 65
[2]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2011/161216, 2011, A1 Location in patent: Page/Page column 28

13
[ 67-56-1 ]
[ 1269232-93-0 ]
[ 1353575-32-2 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sulfuric acid Reflux;	II.3 A solution of 3-bromo-5-chloro-2-fluorobenzoic acid (7.5 g, 29.6 mmol) in methanol (100 mL, 2470 mmol) was treated with cone. H2S04 (8 mL, 29.6 mmol) and the resulting mixture was heated to reflux overnight. The reaction mixture was allowed to cool to rt, diluted with ice water (200 mL), and extracted with EtOAc (2 X 200 mL). The combined organic extracts were washed with saturated aqueous Na2C03 solution (2 X 100 mL), brine (100 mL), dried (Na2S04), and concentrated to furnish methyl 3-bromo-5-chloro- 2-fiuorobenzoate (7.2 g, 26.9 mmol, 91 % yield) as a pale yellow solid: 1H NMR (400 MHz, CDC13) δ ppm 3.95 (s, 3 H) 7.69 - 7.77 (m, 1 H) 7.86 (dd, J=5.5, 2.4 Hz, 1H).

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2011/161216, 2011, A1 Location in patent: Page/Page column 28

14
[ 1269232-93-0 ]
[ 1353575-28-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / bis(dibenzylideneacetone)-palladium⁽⁰⁾ / 1,4-dioxane / 3 h / 110 °C / Inert atmosphere