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[ CAS No. 123973-25-1 ] {[proInfo.proName]}

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Chemical Structure| 123973-25-1

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Quality Control of [ 123973-25-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 123973-25-1 ]

CAS No. :	123973-25-1	MDL No. :	MFCD00061241
Formula :	C₇H₅F₄N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YKPDYPPZLUZONK-UHFFFAOYSA-N
M.W :	179.11	Pubchem ID :	145569
Synonyms :

Calculated chemistry of [ 123973-25-1 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	35.81
TPSA :	26.02 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) :	-5.81 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.55
Log Po/w (XLOGP3) :	2.23
Log Po/w (WLOGP) :	4.01
Log Po/w (MLOGP) :	2.99
Log Po/w (SILICOS-IT) :	2.55
Consensus Log Po/w :	2.67

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.66
Solubility :	0.392 mg/ml ; 0.00219 mol/l
Class :	Soluble
Log S (Ali) :	-2.41
Solubility :	0.694 mg/ml ; 0.00388 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.2
Solubility :	0.112 mg/ml ; 0.000628 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.28

Safety of [ 123973-25-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302+H312+H332-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 123973-25-1 ]

* 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 [ 123973-25-1 ]

[ 123973-25-1 ] Synthesis Path-Downstream 1~50

1
[ 1004991-82-5 ]
[ 123973-25-1 ]
[ 1004991-83-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl 3-formyl-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ylcarbamate; 2-fluoro-3-(trifluoromethyl)aniline With acetic acid In methanol at 25℃; Molecular sieve; Stage #2: With polymer-bound trimethyl ammonium cyanoborohydride In methanol for 5h;	3.3 Step 3: A mixture of 2-fluoro-3-(trifluoromethyl)aniline (228 ul; 1.77 mmol) and 3A molecular sieves (0.5 g) was added to a solution of C16 (0.5 g; 1.45 mmol), acetic acid (1 mL; 10 % in V) in MeOH (9 mL). The resulting reaction mixture was stirred at 250C overnight, treated with MP-Cyanoborohydride (1.45 g, 2.5 mmol/g, 3.65 mmol), and stirred for an additional 5 hr. The mixture was filtered and the solids rinsed with MeOH. The combined organic phases were concentrated to provide tert-butyl 3-((2-fluoro-3- (trifluoromethyl)phenylamino)methyl)-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3- ylcarbamate (C17). LRMS (M+): 509.3; tR (LCMS standard): 2.3 min.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2008/12635, 2008, A2 Location in patent: Page/Page column 81

2
[ 79-04-9 ]
[ 123973-25-1 ]
[ 630116-35-7 ]

Yield	Reaction Conditions	Operation in experiment
72%	In toluene at 100℃; for 24h;	26A EXAMPLE 26 ; 2-[4-(3-cyano-2-pyridinyl)-1-piperazinyl]-N-[2-fluoro-3-(trifluoromethyl)phenyl]acetamide ; EXAMPLE 26A ; 2-chloro-N-(2-fluoro-3-trifluoromethyl)phenyl]acetamide The procedure described in Example 22A was followed, substituting 2-fluoro-3-(trifluoromethyl)aniline (Acros) for 3,4,5-trimethoxyaniline, to provide the title compound (72% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) ? 4.39 (m, 2H), 7.41 (dd, 1H, J=8.2, 8.2 Hz), 7.57 (dd, 1H, J=6.5 Hz), 8.18 (dd, 1H, J=7.1 Hz), 10.37 (br s, 1H).

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC - US2003/232836, 2003, A1 Location in patent: Page 46

3
[ 87-13-8 ]
[ 123973-25-1 ]
[ 693818-09-6 ]

Yield	Reaction Conditions	Operation in experiment
98%	In 1,4-dioxane at 100℃; for 18h; Heating / reflux;	2.a EXAMPLE 2; 2'-Fluoro-5'-(8-fluoro-7-trifluoromethylquinolin-4-yl)biphenyl-2-carbonitrile; a) 2-[(2-Fluoro-3-trifluoromethylphenylamino)methylene]malonic acid diethyl ester A mixture of 3-amino-2-fluorobenzotrifluoride (2 g, 15.5 mmol) and ethoxymethylenemalonic acid diethyl ester (2.4 g, 11.1 mmol) in 1, 4- dioxane (20 ml) was heated at 100°C for 18 h. The reaction was cooled to ambient temperature and then concentrated in vacuo to give the title compound as a crude residue (3.75g, 98%) : M/Z (ES+) 350 (M++H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2004/43930, 2004, A1 Location in patent: Page 21

4
[ 666262-52-8 ]
[ 123973-25-1 ]
[ 666263-13-4 ]

Yield	Reaction Conditions	Operation in experiment
	at 180℃; for 0.5h; Irradiation;	252 2-Chloro-4-trifluoromethyl-pyrimidin-5-carboxylic acid cyclobutylmethyl-amide (200mg) in 2- fluoro-3- (trifluoromethyl) aniline (0. 5ml) was heated at 180°C under microwave irradiation for 30 minutes. The residue was dissolved in dichloromethane and purified over silica gel (Merck 9385) using the Biotage Horizon system eluting with 10% ethylacetate/isohexane to 100% ethyl acetate gradient to afford the title compound. NMR (CDC13) 81. 70-1.81 (2H, m), 1.86-2. 00 (2H, m), 2.07-2. 17 (2H, m), 2.51-2. 65 (1H, m), 3.48 (2H, dd), 5.78-5. 86 (1H, m), 7.25-7. 36 (2H, m), 7.70-7. 76 (1H, bs), 8.64-8. 72 (1H, m), 8.75-8. 79 (1H, s) LC/MS, t = 3.64min, Molecular ion observed 437 consistent with the molecular formula C18H15F7N4O
	at 180℃; for 0.5h; Microwave irradiation;	252 Example 252: 2-(2-Fluoro-3-trifluoromethyl-phenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclobutylmethyl-amide 2-Chloro-4-trifluoromethyl-pyrimidin-5-carboxylic acid cyclobutylmethyl-amide (200mg) in 2- fluoro-3- (trifluoromethyl) aniline [(0.] [5ML)] was heated at [180C] under microwave irradiation for 30 minutes. The residue was dissolved in dichloromethane and purified over silica gel [(MERCK] 9385) using the Biotage Horizon system eluting with [10%] ethylacetate/isohexane to 100% ethyl acetate gradient to afford the title compound. NMR [(CDC13)] [51.] 70-1.81 (2H, m), 1.86-2. 00 (2H, m), 2.07-2. 17 (2H, m), 2.51-2. 65 [(1H,] m), 3.48 (2H, dd), 5.78-5. 86 [(1H,] m), 7.25-7. 36 (2H, m), 7.70-7. 76 [(1H,] bs), 8.64-8. 72 [(1H,] m), 8.75- 8.79 [(1H,] s) LC/MS, t = 3. [64MIN,] Molecular ion observed [(MH+)] = 437 consistent with the molecular formula [C18 H15 F7] N4 [0]

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2005/74939, 2005, A1 Location in patent: Page/Page column 99
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2004/18433, 2004, A1 Location in patent: Page 115

5
[ 123973-25-1 ]
[ 159329-03-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	With 1-bromopyrrolidine-2,5-dione In N,N-dimethyl-formamide at 15 - 20℃; for 1h; Inert atmosphere;	19.1 Step 1: 4-bromo-2-fluoro-3-(trifluoromethyl)analine To a solution of 2-fluoro-3-(trifluoromethyl)benzenamine (10 g, 55.8 mmol) in DMF (100 mL) was added NBS (9.93g, 55.8 mmol) in portions at 15 °C under nitrogen atmosphere. Then, the reaction mixture was stirred at rt for 1 h. The mixture was diluted with water (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (2 x 150 mL) and Na2C03 (10% aq. 150 mL) and dried over anhydrous Na2S04. After the removal of solvent, the crude product was purified with column chromatography to afford 4-bromo-2-fluoro-3-(trifluoromethyl)analine (14 g, 97% yield) as a red liquid.
97%	With 1-bromopyrrolidine-2,5-dione In N,N-dimethyl-formamide at 15℃; for 1h;	19.1 1. Synthesis of 4-bromo-2-fluoro-3-(trifluoromethyl)aniline To a mixture of 2-fluoro-3-(trifluoromethyl)aniline (21.0 g, 117 mmol) in DMF (150 mL) was added NBS (20.9 g, 117 mmol) in portions. The mixture was stirred at 15 °C for 1 h. The reaction mixture was diluted with EtOAc (500 mL) and was washed sequentially with H20 (500 mL) and brine (500 mL). The organic layer was dried (Na2S04), filtered, and concentrated in vacuo to give the crude product. The crude material was purified by silica-gel column chromatography (petroleum ether/EtOAc, grading from 10:1 to 4:1) to give 4-bromo-2-fluoro-3- (trifluoromethyl)aniline as a yellow oil (29.0 g, yield: 97%). 1H NMR: (400 MHz, DMSO-r/e) d: 7.32 (d, / = 8.8 Hz, 1H), 6.93 (t, / = 8.8 Hz, 1H), 5.81 (br s, 2H).
91%	With 1-bromopyrrolidine-2,5-dione In N,N-dimethyl-formamide at 20℃; for 2h;	13.a a) 4-Bromo-2-fluoro-3-(trifluoromethyl)aniline To a solution of 2-fluoro-3-(trifluoromethyl)aniline (1.79 g, 10.0 mmol) in N,N-dimethylformamide (7 mL), N-bromosuccinimide (1.78 g, 10.0 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. A 10% solution of sodium thiosulfate was added to the reaction mixture, the resulting mixture was extracted with diethyl ether, the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain the title compound as oil (2.36 g, yield 91%). 1H-NMR (CDCl3) δ: 3.92 (2H, br), 6.77 (1H, t, J=8.9 Hz), 7.24-7.28 (1H, m)

86%	With 1-bromopyrrolidine-2,5-dione In N,N-dimethyl-formamide
76.6%	With 1-bromopyrrolidine-2,5-dione In N,N-dimethyl-formamide at 25℃; for 16h;	1.1 Step 1: To a solution of 2-fluoro-3-(trifluoromethyl)aniline (25 g, 139.6 mmol) in DMF (200 mL) was added NBS (27.3 g, 153.5 mmol) in portions, the resulting mixture was stirred at 25°C for 16 h. The reaction mixture was poured into water (800 mL) and extracted with EA (200 mLx3), the combined organic layers were washed with water (800 mL) and brine (800 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to afford 4-bromo-2-fluoro-3-(trifluoromethyl)aniline (27.5 g, 76.6% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.32 (dd, 1H), 6.94 (t, 1H), 5.81 (br s, 2H).
76.6%	With 1-bromopyrrolidine-2,5-dione In N,N-dimethyl-formamide at 25℃; for 16h;	1.1 Step 1: To a solution of 2-fluoro-3-(trifluoromethyl)aniline (25 g, 139.6 mmol) in DMF (200 mL) was added NBS (27.3 g, 153.5 mmol) in portions, the resulting mixture was stirred at 25°C for 16 h. The reaction mixture was poured into water (800 mL) and extracted with EA (200 mLx3), the combined organic layers were washed with water (800 mL) and brine (800 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to afford 4-bromo-2-fluoro-3-(trifluoromethyl)aniline (27.5 g, 76.6% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.32 (dd, 1H), 6.94 (t, 1H), 5.81 (br s, 2H).
75%	With 1-bromopyrrolidine-2,5-dione In N,N-dimethyl-formamide at 20℃; for 3h;	Preparation of compound 14[00182] To a compound 13 (2.88g, 16.1mmol) solution in DMF (30mL) was added a DMF solution (30mL) of NBS (2.86g, 16.1mmol) drop-wise at room temperature. After 3h, the reaction mixture is diluted with Et20 (lOOmL) and washed with brine (2xl00mL). The separated organic phase was dried (Na2S04) and concentrated to give the title compound (14) as an oil (3.1g, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.32 (d, 1H), 6.96 (t, 1H), 5.847(s, 2H); ESI-MS (M+H)+: 259.8.
75%	With 1-bromopyrrolidine-2,5-dione In N,N-dimethyl-formamide at 20℃; for 3h;	[00167] Synthesis of isothiocyanate 3b [00168] Preparation of compound 14[00169] To a compound 13 (2.88g, 16.1mmol) solution in DMF (30mL) was added aDMF solution (30mL) of NBS (2.86g, 16.1mmol) drop-wise at room temperature. After 3h, the reaction mixture is diluted with Et20 (lOOmL) and washed with brine (2xl00mL). The separated organic phase was dried (Na2S04) and concentrated to give the title compound 14 as an oil (3.1g, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.32 (d, 1H), 6.96 (t, 1H), 5.847(s, 2H); ESI-MS (M+H)+: 259.8.
	With 1-bromopyrrolidine-2,5-dione In DMF (N,N-dimethyl-formamide) at 20℃; for 3h;	1.K K. 4-CYCLOPROPYL-2-FLUORO-3-TRIFLUOROMETHYLANILINE K. 4-CYCLOPROPYL-2-FLUORO-3-TRIFLUOROMETHYLANILINE 4-Bromo-2-fluoro-3-trifluoromethylaniline is prepared from 2-fluoro-3- trifluoromethylaniline by treatment with NBS in DMF according to the procedure described in International Application WO 94/18179. 2-FLUORO-3-TRIFLUOROMETHYLANILINE (28.8 g, 161 MMOL) is dissolved in DMF (100 mL). A solution of NBS (28.6 g, 161 MMOL) in DMF (100 mL) is added dropwise at room temperature. After 3 hours, the reaction is diluted with ET20 and washed with brine. The separated organic phase is dried (NA2SO4) and concentrated to give 4-bromo-2-fluoro-3- trifluoromethylaniline as an oil. 4-CYCLOPROPYL-2-FLUORO-3-TRIFLUOROMETHYLANILINE is prepared from 4-bromo-2-fluoro-3- trifluoromethylaniline by palladium-catalyzed coupling to cyclopropylboronic acid, similarly to the method outlined in Tetrahedron Letters, Vol. 43, p. 6987 (2002). 4-Bromo-2-fluoro-3-trifluoromethylaniline (5.0 g, 19.4 MMOL), cyclopropylboronic acid (2.16 g, 25.2 MMOL), K3PO4 (14.4 g, 67.8 MMOL) and tricyclohexyl phosphine (0.54 g, 1.9 MMOL) are dissolved in toluene (80 mL) and water (4 mL). The solution is degassed with N2, heated to 90°C, and Pd (OAC) 2 (0.22 g, 1.0 MMOL) is added. The reaction is heated at 90°C for 5 hours, cooled, diluted with Et2O, filtered, washed with brine, dried (NA2SO4) and concentrated in vacuo. The residue is purified by column chromatography (ETOAC/HEXANES) to give 4-cyclopropyl-2-fluoro-3-trifluoromethylaniline. Similarly prepared are 4-cyclopropyl-2-fluoro-5-trifluoromethylaniline and 4-CYCLOPROPYL-2, 6-DIFLUOROANILINE.
	With 1-bromopyrrolidine-2,5-dione In N,N-dimethyl-formamide	R.11 REFERENCE EXAMPLE 11 REFERENCE EXAMPLE 11 A solution of N-bromosuccinimide (24.9 g) in N,N-dimethyl formamide was added to a solution of 2-fluoro-3-trifluoromethylaniline (25 g) in dimethyl formamide. The mixture was stirred for four and a half hours. It was poured into water and the oil was separated. The aqueous layers was extracted with ether and the combined organic layers were washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was distilled to give 4-bromo-2-fluoro-3-trifluoromethylaniline (27.44 g) as an orange oil, b.p. 88°-94° C./4 mbar.
	With 1-bromopyrrolidine-2,5-dione In N,N-dimethyl-formamide	R.15 REFERENCE EXAMPLE 15 REFERENCE EXAMPLE 15 A solution of N-bromosuccinimide (24.9g) in N,N-dimethyl formamide was added to a solution of 2-fluoro-3-trifluoromethylaniline (25g) in dimethyl formamide. The mixture was stirred for four and a half hours. It was poured into water and the oil was separated. The aqueous layers were extracted with ether and the combined organic layers were washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was distilled to give 4-bromo-2-fluoro-3-trifluoromethylaniline (27.44g) as an orange oil, b.p. 88-94oC/4mbar
	With 1-bromopyrrolidine-2,5-dione In N,N-dimethyl-formamide for 2.5h;	1.C To a solution of 2-fluoro-3-trifluoromethylaniline (5.0 g, 28 mmol) in DMF (25 mL) is added a solution of NBS (5.0 g, 28 mmol) in DMF (25 mL). After 2.5 h, the reaction is partitioned between ether and saturated aqueous NaCI. The separated organic phase is washed twice with fresh saturated aqueous NaCI, dried over Na2SO4, and concentrated under reduced pressure to give 4-bromo-2-fluoro-3-trifluoromethylaniline as an oil.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/67664, 2012, A1 Location in patent: Page/Page column 57-58
[2]Current Patent Assignee: BIOGEN IDEC INC. - WO2019/222101, 2019, A1 Location in patent: Page/Page column 79
[3]Current Patent Assignee: KASUMA PARTNERS - US2017/298081, 2017, A1 Location in patent: Paragraph 0233-0235
[4]Current Patent Assignee: UNIVERSITY OF SOUTHERN CALIFORNIA - WO2021/189051, 2021, A1 Location in patent: Page/Page column 34-35
[5]Current Patent Assignee: ILDONG PHARMACEUTICAL CO.,LTD. - WO2022/123310, 2022, A1 Location in patent: Paragraph 00335; 00355
[6]Current Patent Assignee: ILDONG PHARMACEUTICAL CO.,LTD. - WO2022/123310, 2022, A1 Location in patent: Paragraph 00335; 00355
[7]Current Patent Assignee: SUZHOU KINTOR PHARMACEUTICALS INC - WO2011/29392, 2011, A1 Location in patent: Page/Page column 59
[8]Current Patent Assignee: SUZHOU KINTOR PHARMACEUTICALS INC - WO2012/119559, 2012, A1 Location in patent: Page/Page column 81
[9]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2004/48314, 2004, A1 Location in patent: Page 31
[10]Current Patent Assignee: BAYER AG - US5856274, 1999, A
[11]Current Patent Assignee: BAYER AG; SANOFI - EP625508, 1994, A2
[12]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz); ANGIOTECH PHARMACEUTICALS, INC. - WO2008/2853, 2008, A2 Location in patent: Page/Page column 22-23

6
[ 61822-02-4 ]
[ 123973-25-1 ]
[ 815600-92-1 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 20℃;	10 Example 10 (Cmpd No.24); 2-(4-CHLORO-PHENVL)-4§5-DIHVDRO-THIAZOLE-4-CARBOXYLIC acid (2-fluoro-3- TRIFLUOROMETHYL-PHENVL)-AMIDE To a solution of 2- (4-CHLORO-PHENYL)-4, 5-DIHYDRO-THIAZOLE-4-CARBOXYLIC acid (112 mg, 0.463 MMOL) and 3-amino-2-fluorobenzotrifluoride (91 mg, 0.509 MMOL) in DMF (10 mL) were added DMAP (56.5 mg, . 463 MMOL), IPR2NET (0.25 mL), and PyBroP (863 mg, 1. 86 MMOL) sequentially. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic extracts were washed with 1 N HCI and brine, then dried over anhydrous NA2SO4. The dessicant was filtered off and the filtrate was concentrated under vacuum to yield crude product. The crude product was purified by column chromatography (silica gel, 20% EtOAc/hexane) to YIELD 2- (4-CHLORO-PHENYL)-4, 5-DIHYDRO-THIAZOLE-4-CARBOXYLIC acid (2-fluoro-3-trifluoromethyl-phenyl)-amide. 1H NMR (300 MHz, CECI3) : 8 9.15 (br s, 1H), 8.64 (dt, 1H, J = 1.3, 7.0 Hz), 7. 84 (d, 2H, J = 8.6 Hz), 7.79-7. 89 (m, 1 H), 7.45 (d, 2H, J = 8.6 Hz), 7.28 - 7. 45 (m, 2H), 5.38 (t, 1 H, 9.7 Hz), 3.73-3. 89 (m, 2H) MS m/z (M+H) = 403.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2004/113309, 2004, A1 Location in patent: Page 27-28

7
[ 815600-95-4 ]
[ 123973-25-1 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 20℃;	12.D Step D: 2-(4-FLUORO-PHENVL)-4V5-DIHYDRO-THIAZOLE-4-CARBOXYLIC acid (2-fluoro-3- TRIFLUOROMETHVL-PHENVL)-AMIDE To a solution OF 2- (4-FLUORO-PHENYL)-4, 5-DIHYDRO-THIAZOLE-4-CARBOXYLIC acid (151 mg, 0.671 MMOL) and 3-amino-2-fluorobenzotrifluoride (132 mg, 0.738 MMOL) in DMF (10 mL) were added DMAP (82 mg, . 671 MMOL)), IPR2NET (0.25 mL), and PyBroP (940 mg 2.01 MMOL) sequentially. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and EtOAc. The organic layer was washed with 1 N HCI and brine, / then dried over anhydrous NA2SO4. The dessicant was filtered off and the filtrate was concentrated under vacuum to yield crude product. The crude product was purified by column chromatography (silica gel, 20% EtOAc/hexane) to yield 2- (4-fluoro-phenyl)-4, 5-dihydro-thiazole-4-carboxylic acid (2-fluoro-3-trifluoromethyl-phenyl)-amide. 1H NMR (300 MHZ, CDCI3) : No. 9. 17 (br s, 1 H), 8.64 (dt, 1 H, J = 1. 4,6. 9 Hz), 7. 87-7. 94 (m, 3H), 7.07-7. 36 (m, 4H), 5.37 (t, 1 H, J = 9.6 Hz), 3.74- 3.88 (m, 2H) MS m/z (M-H) = 385.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2004/113309, 2004, A1 Location in patent: Page 30

8
[ 815601-02-6 ]
[ 123973-25-1 ]
[ 815601-08-2 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 20℃;	24 Example 24 (Cmpd No.32); 2- (3-CHLORO-PHENVI)-4, 5-DIHVDRO-THIAZOLE-4-CARBOXVLIC acid (2-fluoro-3- TRIFLUOROMETHVL-PHENVL)-AMIDE To a SOLUTION OF 2- (3-CHLORO-PHENYL)-4, 5-DIHYDRO-THIAZOLE-4-CARBOXYLIC acid (167 mg, 0.691 MMOL) and 3-amino-2-fluorobenzotrifluoride (136 mg, 0.760 MMOL) in DMF (10 mL) were added DMAP (84 mg, 0.691 MMOL)), IPR2NET (0.25 mL), and PyBroP (966 mg 2.073 MMOL) sequentially. The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added water and EtOAc. The organic layer was washed with 1 N HCI and brine. The organic extracts were dried over anhydrous NA2SO4, filtered, and the filtrate was concentrated under vacuum to yieldcrude product. The crude product was purified by column chromatography (silica gel, 20% EtOAc/hexane) to yield 2- (3-CHLORO-PHENYL)-4, 5-DIHYDRO-THIAZOLE-4-CARBOXYLIC acid (2-fluoro-3-trifluoromethyl-phenyl)-amide. H NMR (300 MHZ) 089. 13 (br s, 1H), 8.61 (dt, 1 H, J = 1.3, 6.9), 7.77- 7. 88 (m, 2H), 7.27-7. 53 (m, 4H), 5.39 (t, 1 H, J = 9.7 Hz), 3.75-3. 89 (m, 2H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2004/113309, 2004, A1 Location in patent: Page 41

9
[ 672-75-3 ]
[ 123973-25-1 ]
[ 882670-70-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-bromo-4-fluorobenzoyl chloride; 2-fluoro-3-(trifluoromethyl)aniline In dichloromethane at 20℃; for 0.5h; Stage #2: With triethylamine In dichloromethane at 20℃; for 1h;	183.2 2-Fluoro-3- (trifluromethyl)aniline (0.515 g, 0.37 mL, 2.88 mmol) was added to a solution of 3-bromo-4- fluorobenzoyl chloride (0.650 g, 2.74 mmol) in dichloromethane (5 ml) , and the mixture stirred 'at room temperature for 30 min. Triethylamine (0.360 g, 0.50 ml, 3.56 mmol) was added and the solution stirred at room temperature for 1 h. The reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a light yellow solid. Trituration with dichloromethane and filtering afforded 3-bromo-4-fluoro-N- (2-fluoro-3-(trifluoromethyl)phenyl)benzamide as a white solid. MS (M- H+) 377.9; Calculated for C14H7BrF5NO: 379. EPO

Reference： [1]Current Patent Assignee: AMGEN INC - WO2006/44823, 2006, A2 Location in patent: Page/Page column 184

10
[ 321-14-2 ]
[ 123973-25-1 ]
[ 439144-72-6 ]

Yield	Reaction Conditions	Operation in experiment
71.7%		107 Example 107 Example 107 5-Chloro-N-[2-fluoro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide (Comopund No. 107). Using 5-chlorosalicylic acid and 2-fluoro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. Yield: 71.7%, white solid. 1H-NMR(DMSO-d6):δ 7.07(1H, d, J=9.0Hz), 7.46(1H, t, J=7.8Hz), 7.52(1H, dd, J=9.0, 2.7Hz), 7.58(1H, t, J=7.2Hz), 7.96(1H, d, J=2.7Hz), 8.49(1H, t, J=7.2Hz), 10.82(1H, s), 12.13(1H, brs).
	With pyridine; phosphorus trichloride In toluene for 12h; Inert atmosphere; Reflux;	54 4.1.1 Procedure A General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley’s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]Current Patent Assignee: INSTITUTE OF MEDICINAL MOLECULAR DESIGN INC - EP1352650, 2003, A1
[2]Lee, Ill-Young; Gruber, Todd D.; Samuels, Amanda; Yun, Minhan; Nam, Bora; Kang, Minseo; Crowley, Kathryn; Winterroth, Benjamin; Boshoff, Helena I.; Barry III, Clifton E. [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 1, p. 114 - 126]

11
[ 123973-25-1 ]
[ 61324-97-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium perborate In acetic acid at 55℃; for 0.5h;	1 A solution of 2-Fluoro-3-trif.uoromethyl-phenylamine (645 mg, 3.6 mmol) in acetic acid (7 mL) was added drop-wise to a solution of sodium perborate tetrahydrate in acetic acid (7 mL) heated to about 55 0C. After about 30 minutes following the addition the reaction mixture was cooled to room temperature diluted with diethyl ether and ethyl acetate (10:1) and water. The organic layer was separated and washed repeatedly with saturated sodium bicarbonate until neutral pH was achieved. The organic layer was dried, filtered and concentrated to provide 560 mg of the crude product that was used in subsequent reactions without further purification. RP- HPLC R, 6.46 min. (table 1, method a).
	With sodium perborate tetrahydrate In acetic acid at 55℃; for 15h;	7.1 Step 1 : Synthesis of 2-fluoro-l-nitro-3-(trifluoromethyl)benzene 7-b To a solution of 2-fluoro-3-(trifluoromethyl)aniline 7-a (11.6 g, 64.8 mmol, 1 eq.) in acetic acid (120 mL) sodium perborate monohydrate (12.3 g, 64.8 mmol, 1 eq.) in acetic acid (240 mL) was added dropwise at 55°C over 6 h. After being stirred at 55°C for an additional 9 h, the solution was allowed to cool to room temperature and filtered. The filtrate was concentrated to 60 ml under vacuum below 50°C. The residue was dissolved in ethyl acetate (500 mL), washed with water (150 ml x 3), aqueous NaHC03 solution (150 mL x 2) and brine, and then dried over MgS04, and concentrated in vacuum. 11.2 g of intermediate 7-b was obtained (yield 50%).

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC - WO2007/84728, 2007, A2 Location in patent: Page/Page column 50
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2013/186332, 2013, A1 Location in patent: Page/Page column 48

12
[ 945667-88-9 ]
[ 945667-92-5 ]
[ 123973-25-1 ]
[ 945667-71-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-chloro-6-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)pyrrolo[1,2-a]pyrazine-4-carboxamide; 1-(1H-1,2,3-benzotriazol-1-yloxy)-6-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)pyrrolo[1,2-a]pyrazine-4-carboxamide; 2-fluoro-3-(trifluoromethyl)aniline With methanesulfonic acid In 1,4-dioxane at 180℃; for 0.25h; Microwave irradiation; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate Stage #3: With hydrogenchloride In methanol; diethyl ether	27 Example 27: 1 -[2-Fluoro-3-(trifluoromethyl)phenyl]amino}-6-methyl-λ/-(tetrahydro- 2/-/-pyran-4-ylmethyl)pyrrolo[1 ,2-a]pyrazine-4-carboxamide hydrochloride; To Intermediate 8(b) (150mg) in 1 ,4-dioxane (1.5ml) was added 2-fluoro-3- (trifluoromethyl)aniline (103ul) and methanesulfonic acid (52ul) and the reaction mixture heated under microwave conditions at 18O0C for fifteen minutes. The reaction mixture was dissolved in methanol, transferred to a round bottomed flask and evaporated. The residue was dissolved in ethyl acetate / water, transferred to a separating funnel and saturated aqueous sodium hydrogen carbonate added and washed. The organic layer was dried (MgSO4) and evaporated to a brown oil. The oil was purified by MDAP and the pale yellow solid obtained was suspended in methanol and treated with 1 M hydrochloric acid in diethyl ether to give a solution. The solution was evaporated and co-evaporated from diethyl ether to afford the title compound (42mg) as a pale yellow solid. LC/MS [MH+] 451 consistent with molecular formula C22H22F4N4O2

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/88168, 2007, A1 Location in patent: Page/Page column 57

13
[ 123973-25-1 ]
[ 630116-35-7 ]

Yield	Reaction Conditions	Operation in experiment
72%		26.A 2-chloro-N-(2-fluoro-3-trifluoromethylphenyl)acetamide EXAMPLE 26A 2-chloro-N-(2-fluoro-3-trifluoromethylphenyl)acetamide The procedure described in Example 22A was followed, substituting 2-fluoro-3-(trifluoromethyl)aniline (Acros) for 3,4,5-trimethoxyaniline, to provide the title compound (72% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ4.39 (m, 2H), 7.41(dd, 1H, J=8.2, 8.2 Hz), 7.57 (dd, 1H, J=6.5 Hz), 8.18 (dd, 1H, J=7.1 Hz), 10.37 (br s, 1H).

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC - US2004/29887, 2004, A1

14
[ 123973-25-1 ]
[ 10397-30-5 ]
[ 1012861-15-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃;

Reference： [1]Deak, Holly L.; Newcomb, John R.; Nunes, Joseph J.; Boucher, Christina; Cheng, Alan C.; DiMauro, Erin F.; Epstein, Linda F.; Gallant, Paul; Hodous, Brian L.; Huang, Xin; Lee, Josie H.; Patel, Vinod F.; Schneider, Stephen; Turci, Susan M.; Zhu, Xiaotian [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 3, p. 1172 - 1176]

15
[ 37517-81-0 ]
[ 1762-95-4 ]
[ 123973-25-1 ]
[ 1187853-30-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-chloro-3-oxopropanoic acid methyl ester; ammonium thiocyanate In acetonitrile at 20℃; Stage #2: 2-fluoro-3-(trifluoromethyl)aniline In acetonitrile at 0 - 20℃;	19 3-Chloro-3-oxo-propanoic acid methyl ester (7.5 g) in MeCN (50 ml) was slowly added to a stirred solution of ammonium thiocyanate (4.6 g) in MeCN (400 ml) at r.t. After 1.5 h, the reaction mixture was cooled to 0 0C and a solution of 2-fluoro-3- (trifluoromethyl)aniline (9.8 g) in MeCN (50 ml) was slowly added. After 5-10 min, the ensuing reaction mixture was allowed to warm to r.t. and after 1 h. the solvent was removed under reduced pressure and the resulting residue partitioned between H2O/DCM and the phases separated. The aqueous phase was extracted with DCM (x 2) and the combined organic extracts washed with brine, then dried (Na2SO4). Filtration and concentration gave the crude material as an amber oil. Yield : 17.1 g of intermediate D19 (60 %).

Reference： [1]Current Patent Assignee: THURING JOHANNES WILHELMUS JOH; JOHNSON & JOHNSON INC; VAN ROOSBROECK YVES EMIEL MARI - WO2009/115547, 2009, A1 Location in patent: Page/Page column 33-34

16
[ 19398-47-1 ]
[ 123973-25-1 ]
[ 1198181-22-4 ]

Yield	Reaction Conditions	Operation in experiment
27%	Stage #1: 1,4-dibromo-2-butanol; 2-fluoro-3-(trifluoromethyl)aniline at 100℃; for 3h; Stage #2: With sodium carbonate In water at 20℃;	56 Reference Example 56 1-[2-fluoro-3-(trifluoromethyl)phenyl]pyrrolidin-3-ol; 2-Fluoro-3-(trifluoromethyl)aniline (5.0 g) and 1,4-dibromobutan-2-ol (6.7 g) were stirred at 100°C for 3 hr. After cooling to room temperature, to the reaction mixture was added saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 - 50:50) to give the title compound (1.9 g, yield 27%) as a pale-yellow solid. 1H-NMR (300 MHz, CDCl3)δ:1.70 (d, J = 3.8 Hz, 1 H), 1.94 - 2.24 (m, 2 H), 3.34 - 3.52 (m, 2 H), 3.60 - 3.77 (m, 2 H), 4.58 (br. s, 1 H), 6.83 (m, J=8.3, 8.3 Hz, 1 H), 6.90 (m, J = 7.6, 6.1 Hz, 1 H), 7.04 (t, J = 8.0 Hz, 1 H).
27%	at 100℃; for 3h;	56 2-Fluoro-3-(trifluoromethyl)aniline (5.0 g) and 1,4-dibromobutan-2-ol (6.7 g) were stirred at 100° C. for 3 hr. After cooling to room temperature, to the reaction mixture was added saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10-50:50) to give the title compound (1.9 g, yield 27%) as a pale-yellow solid.1H-NMR (300 MHz, CDCl3) δ: 1.70 (d, J=3.8 Hz, 1H), 1.94-2.24 (m, 2H), 3.34-3.52 (m, 2H), 3.60-3.77 (m, 2H), 4.58 (br. s, 1H), 6.83 (m, J=8.3, 8.3 Hz, 1H), 6.90 (m, J=7.6, 6.1 Hz, 1H), 7.04 (t, J=8.0 Hz, 1H).
1.927%	at 100℃; for 3h;	52.1-[2-Fluoro-3-(trifluoromethyl)phenyl]pyrrolidin-3-ol (47e). 2-Fluoro-3-(trifluoromethyl)aniline (19c) (5.0 g, 27.9 mmol) and 1,4-dibromobutan-2-ol (6.7 g, 28.9 mmol) were stirred at 100 °C for 3 hours. After cooling to room temperature, to the reaction mixture was added saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 90 : 10 - 50 : 50) to give the title compound (1.9 g, 7.62 mmol, 27%) as a pale-yellow solid.1H-NMR (CDCl3): δ 1.70 (d,J =3.8 Hz, 1H), 1.942.24 (m, 2H), 3.343.52 (m, 2H), 3.603.77 (m, 2H), 4.58 (br. s, 1H), 6.707.00 (m, 2H), 7.04 (t,J =8.0 Hz, 1H).

1.927%

at 100℃; for 3h;

52.1-[2-Fluoro-3-(trifluoromethyl)phenyl]pyrrolidin-3-ol (47e). 2-Fluoro-3-(trifluoromethyl)aniline (19c) (5.0 g, 27.9 mmol) and 1,4-dibromobutan-2-ol (6.7 g, 28.9 mmol) were stirred at 100 °C for 3 hours. After cooling to room temperature, to the reaction mixture was added saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 90 : 10 - 50 : 50) to give the title compound (1.9 g, 7.62 mmol, 27%) as a pale-yellow solid.1H-NMR (CDCl3): δ 1.70 (d,J =3.8 Hz, 1H), 1.942.24 (m, 2H), 3.343.52 (m, 2H), 3.603.77 (m, 2H), 4.58 (br. s, 1H), 6.707.00 (m, 2H), 7.04 (t,J =8.0 Hz, 1H).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2295406, 2011, A1 Location in patent: Page/Page column 68
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2011/251187, 2011, A1 Location in patent: Page/Page column 48-49
[3]Nakamura, Shinji; Kamaura, Masahiro; Akao, Yuichiro; Nakamura, Natsuko; Mizukami, Atsushi; Goto, Akihiko; Furuyama, Naoki; Cho, Nobuo; Kasai, Shizuo [Bioorganic and Medicinal Chemistry, 2022, vol. 54]
[4]Nakamura, Shinji; Kamaura, Masahiro; Akao, Yuichiro; Nakamura, Natsuko; Mizukami, Atsushi; Goto, Akihiko; Furuyama, Naoki; Cho, Nobuo; Kasai, Shizuo [Bioorganic and Medicinal Chemistry, 2022, vol. 54]

17
[ 24424-99-5 ]
[ 123973-25-1 ]
[ 1217303-70-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	With dmap In tetrahydrofuran Reflux;	236.1 A I L round bottom flask was charged with 2-fluoro-3- (trifluoromethyl)aniline (25 g, 0.14 mol), di-tert-butyl dicarbonate (91 g, 0.42 mol), 4-(dimethylamino)pyridine (1.7 g, 14 mmol) and THF (500 mL). The resulting mixture was stirred overnight at reflux. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 : 10). Work-up: the reaction mixture was concentrated in vacuo. The residue was re-dissolved in EtO Ac (500 mL) and washed with brine (100 mL). The organic layer was dried over anhydrous Na2S04 and then concentrated in vacuo, to afford 43 g (81 ) of the product as white oil

Reference： [1]Current Patent Assignee: KALYPSYS, INC. - WO2011/112731, 2011, A2 Location in patent: Page/Page column 263-264

18
[ 123973-25-1 ]
[ 1378869-30-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 1 h / 15 - 20 °C / Inert atmosphere 2.1: triethylamine / palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene / dimethyl sulfoxide / 16 h / 80 °C / 37503.8 Torr 3.1: hydrogen bromide / acetonitrile; water / 0.17 h / 0 °C 3.2: 1.08 h / 0 °C 3.3: 1.5 h / 0 - 70 °C 4.1: diisobutylaluminium hydride / toluene / 1 h / -78 - 0 °C 4.2: -78 °C 5.1: triphenylphosphine; N-Bromosuccinimide / dichloromethane / 0.5 h / -10 - 20 °C / Inert atmosphere 6.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/67664, 2012, A1

19
[ 123973-25-1 ]
[ 1378868-47-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 1 h / 15 - 20 °C / Inert atmosphere 2.1: triethylamine / palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene / dimethyl sulfoxide / 16 h / 80 °C / 37503.8 Torr 3.1: hydrogen bromide / acetonitrile; water / 0.17 h / 0 °C 3.2: 1.08 h / 0 °C 3.3: 1.5 h / 0 - 70 °C 4.1: diisobutylaluminium hydride / toluene / 1 h / -78 - 0 °C 4.2: -78 °C 5.1: triphenylphosphine; N-Bromosuccinimide / dichloromethane / 0.5 h / -10 - 20 °C / Inert atmosphere 6.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 7.1: potassium acetate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / 1,4-dioxane / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/67664, 2012, A1

20
[ 123973-25-1 ]
[ 1331943-81-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 1 h / 15 - 20 °C / Inert atmosphere 2: triethylamine / palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene / dimethyl sulfoxide / 16 h / 80 °C / 37503.8 Torr
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide / N,N-dimethyl-formamide / 1 h / 15 °C 2: triethylamine; palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene / dimethyl sulfoxide / 16 h / 80 °C / 2585.81 Torr

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/67664, 2012, A1
[2]Current Patent Assignee: BIOGEN IDEC INC. - WO2019/222101, 2019, A1

21
[ 123973-25-1 ]
[ 1331943-82-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 1 h / 15 - 20 °C / Inert atmosphere 2.1: triethylamine / palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene / dimethyl sulfoxide / 16 h / 80 °C / 37503.8 Torr 3.1: hydrogen bromide / acetonitrile; water / 0.17 h / 0 °C 3.2: 1.08 h / 0 °C 3.3: 1.5 h / 0 - 70 °C
	Multi-step reaction with 3 steps 1.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 1 h / 15 °C 2.1: triethylamine; palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene / dimethyl sulfoxide / 16 h / 80 °C / 2585.81 Torr 3.1: hydrogen bromide; sodium nitrite / water; acetonitrile / 0.33 h / 0 °C 3.2: 16 h / 70 °C

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/67664, 2012, A1
[2]Current Patent Assignee: BIOGEN IDEC INC. - WO2019/222101, 2019, A1

22
[ 123973-25-1 ]
[ 1331943-83-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 1 h / 15 - 20 °C / Inert atmosphere 2.1: triethylamine / palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene / dimethyl sulfoxide / 16 h / 80 °C / 37503.8 Torr 3.1: hydrogen bromide / acetonitrile; water / 0.17 h / 0 °C 3.2: 1.08 h / 0 °C 3.3: 1.5 h / 0 - 70 °C 4.1: diisobutylaluminium hydride / toluene / 1 h / -78 - 0 °C 4.2: -78 °C
	Multi-step reaction with 4 steps 1.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 1 h / 15 °C 2.1: triethylamine; palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene / dimethyl sulfoxide / 16 h / 80 °C / 2585.81 Torr 3.1: hydrogen bromide; sodium nitrite / water; acetonitrile / 0.33 h / 0 °C 3.2: 16 h / 70 °C 4.1: diisobutylaluminium hydride / toluene / 2 h / -78 - 0 °C

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/67664, 2012, A1
[2]Current Patent Assignee: BIOGEN IDEC INC. - WO2019/222101, 2019, A1

23
[ 123973-25-1 ]
[ 1378869-31-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 1 h / 15 - 20 °C / Inert atmosphere 2.1: triethylamine / palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene / dimethyl sulfoxide / 16 h / 80 °C / 37503.8 Torr 3.1: hydrogen bromide / acetonitrile; water / 0.17 h / 0 °C 3.2: 1.08 h / 0 °C 3.3: 1.5 h / 0 - 70 °C 4.1: diisobutylaluminium hydride / toluene / 1 h / -78 - 0 °C 4.2: -78 °C 5.1: triphenylphosphine; N-Bromosuccinimide / dichloromethane / 0.5 h / -10 - 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/67664, 2012, A1

24
[ 123973-25-1 ]
[ 1378869-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 1 h / 15 - 20 °C / Inert atmosphere 2.1: triethylamine / palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene / dimethyl sulfoxide / 16 h / 80 °C / 37503.8 Torr 3.1: hydrogen bromide / acetonitrile; water / 0.17 h / 0 °C 3.2: 1.08 h / 0 °C 3.3: 1.5 h / 0 - 70 °C 4.1: diisobutylaluminium hydride / toluene / 1 h / -78 - 0 °C 4.2: -78 °C 5.1: triphenylphosphine; N-Bromosuccinimide / dichloromethane / 0.5 h / -10 - 20 °C / Inert atmosphere 6.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/67664, 2012, A1

25
[ 123973-25-1 ]
[ 1378868-48-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 1 h / 15 - 20 °C / Inert atmosphere 2.1: triethylamine / palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene / dimethyl sulfoxide / 16 h / 80 °C / 37503.8 Torr 3.1: hydrogen bromide / acetonitrile; water / 0.17 h / 0 °C 3.2: 1.08 h / 0 °C 3.3: 1.5 h / 0 - 70 °C 4.1: diisobutylaluminium hydride / toluene / 1 h / -78 - 0 °C 4.2: -78 °C 5.1: triphenylphosphine; N-Bromosuccinimide / dichloromethane / 0.5 h / -10 - 20 °C / Inert atmosphere 6.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 7.1: potassium acetate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / 1,4-dioxane / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/67664, 2012, A1

26
[ 188047-59-8 ]
[ 123973-25-1 ]
[ 1392131-66-6 ]

Yield	Reaction Conditions	Operation in experiment
76.2%	In tetrahydrofuran at 20℃; for 4h;

Reference： [1]Location in patent: experimental part Wu, Jian; Shi, Qing; Chen, Zhuo; He, Ming; Jin, Linhong; Hu, Deyu [Molecules, 2012, vol. 17, # 5, p. 5139 - 5150]

27
[ 357204-44-5 ]
[ 123973-25-1 ]
[ 1392131-58-6 ]

Yield	Reaction Conditions	Operation in experiment
74.9%	In tetrahydrofuran at 20℃; for 4h;

Reference： [1]Location in patent: experimental part Wu, Jian; Shi, Qing; Chen, Zhuo; He, Ming; Jin, Linhong; Hu, Deyu [Molecules, 2012, vol. 17, # 5, p. 5139 - 5150]

28
[ 1762-95-4 ]
[ 2251-65-2 ]
[ 123973-25-1 ]
[ 1428622-85-8 ]

Yield	Reaction Conditions	Operation in experiment
96%	Stage #1: ammonium thiocyanate; 3-(Trifluoromethyl)benzoyl chloride In acetone for 0.333333h; Reflux; Stage #2: 2-fluoro-3-(trifluoromethyl)aniline In acetone for 1h; Reflux;	266.1 [1563] Step 1: N-((2-fluoro-3-(trifluoromethyl)phenyl)carbamothionyl)-3-(trifluoromethyl)benzamide [1563] Step 1: N-((2-fluoro-3-(trifluoromethyl)phenyl)carbamothionyl)-3-(trifluoromethyl)benzamide[1564] To a solution of ammonium thiocyanate (512 mg, 6.7 mmol) in acetone (6.2 mL) was added dropwise 3-(trifluoromethyl)benzoyl chloride (911 uL, 6.2 mmol) over 5 minutes. The reaction mixture was refluxed under stirring for 15 minutes and then a solution of 2-fluoro-3-(trifluoromethyl)aniline (1.0 g, 5.6 mmol) in acetone (5.0 mL) was added thereto. The reaction mixture was refluxed under stirring for 1 hour, poured into ice water, and then filtered. The resulting solid was washed with water and then dried under reduced pressure to give 2.2 g of the titled compound as a yellow solid (Yield: 96%). [1565] 1H NMR (CDCl3, 400 MHz) δ 12.73(s, 1H), 9.15(s, 1H), 8.71(t, 1H), 8.19(s, 1H), 8.09(d, 1H), 7.94(d, 1H), 7.73(t, 1H), 7.53(t, 1H), 7.32(t, 1H)
96%	Stage #1: ammonium thiocyanate; 3-(Trifluoromethyl)benzoyl chloride In acetone for 0.333333h; Reflux; Stage #2: 2-fluoro-3-(trifluoromethyl)aniline In acetone for 1h; Reflux;	266.1 Step 1: N-((2-fluoro-3-(trifluoromethyl)phenyl)carbamothionyl)-3-(trifluoromethyl)benzamide Step 1: N-((2-fluoro-3-(trifluoromethyl)phenyl)carbamothionyl)-3-(trifluoromethyl)benzamide To a solution of ammonium thiocyanate (512 mg, 6.7 mmol) in acetone (6.2 mL) was added dropwise 3-(trifluoromethyl)benzoyl chloride (911 uL, 6.2 mmol) over 5 minutes. The reaction mixture was refluxed under stirring for 15 minutes and then a solution of 2-fluoro-3-(trifluoromethyl)aniline (1.0 g, 5.6 mmol) in acetone (5.0 mL) was added thereto. The reaction mixture was refluxed under stirring for 1 hour, poured into ice water, and then filtered. The resulting solid was washed with water and then dried under reduced pressure to give 2.2 g of the titled compound as a yellow solid (Yield: 96%). 1H NMR (CDCl3, 400 MHz) δ 12.73 (s, 1H), 9.15 (s, 1H), 8.71 (t, 1H), 8.19 (s, 1H), 8.09 (d, 1H), 7.94 (d, 1H), 7.73 (t, 1H), 7.53 (t, 1H), 7.32 (t, 1H)

Reference： [1]Current Patent Assignee: YUHAN CORPORATION - WO2013/43001, 2013, A1 Location in patent: Paragraph 1563; 1564; 1565
[2]Current Patent Assignee: YUHAN CORPORATION - US2015/11528, 2015, A1 Location in patent: Paragraph 0852-0853

29
[ 123973-25-1 ]
[ 55496-54-3 ]
[ 1449276-37-2 ]

Yield	Reaction Conditions	Operation in experiment
81.2%	In isopropyl alcohol at 80℃; for 0.5h; Microwave irradiation;	4.2.6. General procedure for the synthesis of 5,6,7-trimethoxy-Naryl-4-aminoquinazolines (6a-6z) General procedure: In the MW method, a mixture of 4-chloro-5,6,7-trimethoxyquinazoline (3.0 mmol) and aryl amine (3.0 mmol) in 2-propanol (10 mL) was stirred for 3 min and then reacted under MW at 100 W and 80 °C for 20 min. Upon reaction completion as monitored by thin-layer chromatography (TLC), the solvent was removed under reduced pressure. The residue was dissolved with methanol or chloroform and purified by TLC (petroleum ether/ethylacetate, 1:2, V:V). The target compound was eluted from the silica gel with ethyl acetate to give the title compounds.

Reference： [1]Zhang, Ying; Jin, Linhong; Xiang, Hongmei; Wu, Jian; Wang, Peiyi; Hu, Deyu; Xue, Wei; Yang, Song [European Journal of Medicinal Chemistry, 2013, vol. 66, p. 335 - 344]

30
[ 123973-25-1 ]
[ 1600526-86-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With hydrogenchloride; sodium nitrite In water at 0 - 20℃; for 20h;	Method A General procedure: Method A: A solution of sodium nitrite (34.5 mg, 0.5 mmol) in water (3 mL) was added dropwise to the suspension of the appropriate aniline (1 mmol) in 5% water solution of HCl (2.5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 18-23 h. Then, the solid material was filtered off and washed with water at 0 °C yielding the corresponding triazene.

Reference： [1]Cappoen, Davie; Vajs, Jure; Uythethofken, Cynthia; Virag, Andrej; Mathys, Vanessa; Kočevar, Marijan; Verschaeve, Luc; Gazvoda, Martin; Polanc, Slovenko; Huygen, Kris; Košmrlj, Janez [European Journal of Medicinal Chemistry, 2014, vol. 77, p. 193 - 203]

31
[ 1884223-58-8 ]
[ CAS Unavailable ]
[ 123973-25-1 ]
[ 1884221-12-8 ]

Yield	Reaction Conditions	Operation in experiment
6 mg	With zinc(II) chloride In diethyl ether at 120℃; for 0.166667h; Microwave irradiation;	172 Example 172: Preparation of 5-bromo-N-(2-fluoro-3-(trifluoromethyl)phenyl)-4-methoxy pyrimidin-2-amine Example 172: Preparation of 5-bromo-N-(2-fluoro-3-(trifluoromethyl)phenyl)-4-methoxy pyrimidin-2-amineA solution of 5-bromo-2,4-dichloropyrimidine (105 mg , 0.461 mmol, 1.0 equiv), 2- hydroxy-N-methylbenzamide (70 mg, 0.461 mmol, 1.0 equiv) and Ν,Ν-diisopropylethylamine (0.096 mL, 0.553 mmol, 1 .2 equiv) in 1 -butanol (3 mL) was stirred at 0 °C for 20 min, then at 21 °C for 16 h. The mixture was concentrated in vacuo, then 2-fluoro-3-(trifluoromethyl)aniline (82 mg, 0.461 mmol, 1.0 equiv), zinc chloride (1 M solution in ether, 0.461 mL, 0.461 mmol, 1 equiv) and acetic acid (2 mL) were added. This mixture was microwaved at 120 °C for 10 min, then concentrated in vacuo. The crude product was purified by reverse phase HPLC(water/MeOH eluent) to yield 6 mg of 5-bromo-N-(2-fluoro-3-(trifluoromethyl)phenyl)-4- methoxypyrimidin-2-amine. MS calcd for 365.99, found 365.25.

Reference： [1]Current Patent Assignee: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE; YALE UNIVERSITY; SALK INSTITUTE FOR BIOLOGICAL STUDIES - WO2016/33100, 2016, A1 Location in patent: Page/Page column 176

32
[ 123973-25-1 ]
[ 870065-94-4 ]

Yield	Reaction Conditions	Operation in experiment
56%	With N-chloro-succinimide In N,N-dimethyl-formamide at 20℃; for 24h;	1.a a) 4-Chloro-2-fluoro-3-(trifluoromethyl)aniline To a solution of 2-fluoro-3-(trifluoromethyl)aniline (5.01 g, 27.97 mmol) in N,N-dimethylformamide (30 mL), N-chlorosuccinimide (4.11 g, 30.76 mmol) was added, and the resulting mixture was stirred at room temperature for one day. To the reaction solution, a 10% solution of sodium thiosulfate was added, the resulting mixture was extracted with diethyl ether, the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain the title compound (3.32 g, yield 56%). 1H-NMR (CDCl3) δ: 3.90 (2H, br), 6.84 (1H, t, J=8.6 Hz), 7.07 (1H, d, J=8.6 Hz)

Reference： [1]Current Patent Assignee: KASUMA PARTNERS - US2017/298081, 2017, A1 Location in patent: Paragraph 0164-0166

33
[ 463-71-8 ]
[ 123973-25-1 ]
[ 870063-31-3 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium hydrogencarbonate In dichloromethane; water at 0℃; for 2h;	116A To a two phase solution of 2-fluoro-3-trifluoromethyl-phenylamine (2 g, 11.17 mmole) in dichloromethane (40 ml) and sodium bicarbonate (6.57 g, 78.19 mmole) in water (30 ml) at 0 C was added dropwise a solution of thiophosgene (1.28 g, 11.17 mmole) in dichloromethane (10 ml). After 2 hrs, the organic layer was separated, washed sequentially with 1M NaHC03, brine and water. The organic layer was dried over Na2S04, filtered and concentrated to yield 2.2 g (91%) of product as a viscous liquid. MS (ESI+) m/z 221 (M+H)+.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2005/111003, 2005, A1 Location in patent: Page/Page column 147

34
[ 123973-25-1 ]
[ 56-81-5 ]
[ 2254409-44-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sulfuric acid; sodium 3-nitrobenzenesulfonate at 140℃;

Reference： [1]Buchler, Ingrid; Akuma, Daniel; Au, Vinh; Carr, Gregory; De León, Pablo; Depasquale, Michael; Ernst, Glen; Huang, Yifang; Kimos, Martha; Kolobova, Anna; Poslusney, Michael; Wei, Huijun; Swinnen, Dominique; Montel, Florian; Moureau, Florence; Jigorel, Emilie; Schulze, Monika-Sarah E. D.; Wood, Martyn; Barrow, James C. [Journal of Medicinal Chemistry, 2018, vol. 61, # 21, p. 9647 - 9665]

35
[ 88950-64-5 ]
[ 123973-25-1 ]
[ 2241010-81-9 ]

Yield	Reaction Conditions	Operation in experiment
13%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 2h;	11 Trans-(2-(1H-benzo[d]imidazol-2-yl) cyclopropane-1-carbonyl)-D-alanine benzyl General procedure: D-Alanine benzyl tosylate (1.75 g, 5.0 mmol), trans-2-(1H-benzo[d]imidazol-2-yl) cyclopropane-1-carboxylic acid (1.11 g, 5.5 mmol), and HATU (2.09 g, 5.5 mmol) were dissolved in DMF (30 mL), and then DIPEA (2.61 mL, 15 mmol) was added thereto, followed by stirring at room temperature for two hours. A saturated aqueous sodium hydrogen carbonate solution was added to a reaction liquid, the mixture was stirred for a while, and then extraction was performed with ethyl acetate. A separated organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, an insoluble substance was filtered, and then a solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain Diastereomer A (upper spot on TLC (ethyl acetate), white amorphous, 562 mg, 31%) and Diastereomer B (lower spot on TLC (ethyl acetate), white amorphous, 401 mg, 22%) of a title compound.

Reference： [1]Current Patent Assignee: KINDAI UNIVERSITY; NIPPON CHEMIPHAR CO LTD - EP3572403, 2019, A1 Location in patent: Paragraph 0114; 0115; 0150; 0151

36
[ CAS Unavailable ]
[ 123973-25-1 ]
[ 2550397-50-5 ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium <i>tert</i>-butylate In tetrahydrofuran at -20 - 20℃; for 3h;

Reference： [1]Mo, Cheng; Zhang, Zhang; Li, Yupeng; Huang, Minhao; Zou, Jian; Luo, Jinfeng; Tu, Zheng-Chao; Xu, Yong; Ren, Xiaomei; Ding, Ke; Lu, Xiaoyun [ACS Medicinal Chemistry Letters, 2020, vol. 11, # 3, p. 379 - 384]

37
[ 153493-48-2 ]
[ 123973-25-1 ]
[ 2379551-24-1 ]

Yield	Reaction Conditions	Operation in experiment
21%	Stage #1: 5,6-dichlorofurazano<3,4-b>pyrazine; 2-fluoro-3-(trifluoromethyl)aniline In tetrahydrofuran at 50℃; for 16h; Stage #2: With potassium hydroxide In tetrahydrofuran; water at 20℃; for 1h;

Reference： [1]Salamoun, Joseph M.; Garcia, Christopher J.; Hargett, Stefan R.; Murray, Jacob H.; Chen, Sing-Young; Beretta, Martina; Alexopoulos, Stephanie J.; Shah, Divya P.; Olzomer, Ellen M.; Tucker, Simon P.; Hoehn, Kyle L.; Santos, Webster L. [Journal of Medicinal Chemistry, 2020, vol. 63, # 11, p. 6203 - 6224]

38
[ 1929616-01-2 ]
[ 123973-25-1 ]
[ 298-12-4 ]
[ 2480135-80-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	With (R)-3,3'-bis(9-anthracenyl)-1,1'-binaphthyl-2,2'-diyl hydrogenphosphate; methyl[(1,1′-biphenyl-2-yl)di-tert-butyl phosphine]gold(I) In toluene at 25℃; Molecular sieve; enantioselective reaction;

Reference： [1]Álvarez, Rosana; Cala, Lara; De Lera, Ángel R.; Fañanás, Francisco J.; Rodríguez, Félix; Villar, Pedro [Chemical Science, 2020, vol. 11, # 34, p. 9181 - 9190]

39
[ 123973-25-1 ]
[ 52791-05-6 ]
[ 2305154-33-8 ]

Yield	Reaction Conditions	Operation in experiment
58%	In isopropyl alcohol at 80℃; Microwave irradiation;

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]

40
[ 115029-22-6 ]
2-fluoro-3-(trifluoromethyl)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: thionyl chloride / 3 h / 90 °C 2.1: ammonium hydroxide / tetrahydrofuran / 2 h / 2 °C 3.1: sodium hydroxide / ethanol / 0.5 h / 0 °C 3.2: 6 h / 0 - 80 °C

Reference： [1]Current Patent Assignee: ALI CHEMICAL CHANGZHOU CO LTD - CN112624911, 2021, A

41
[ 208173-19-7 ]
2-fluoro-3-(trifluoromethyl)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: ammonium hydroxide / tetrahydrofuran / 2 h / 2 °C 2.1: sodium hydroxide / ethanol / 0.5 h / 0 °C 2.2: 6 h / 0 - 80 °C

Reference： [1]Current Patent Assignee: ALI CHEMICAL CHANGZHOU CO LTD - CN112624911, 2021, A

42
[ 207853-60-9 ]
2-fluoro-3-(trifluoromethyl)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.4%		d. Add 1.2g of compound D and 12mL of ethanol to the reaction flask, stir to dissolve, then add 5.0g of 20% sodium hydroxide solution by mass fraction, stir for 40min, control the temperature at 0, add 20mL of aqueous solution containing 1.8g of sodium hypochlorite, and stir 1h, warm to 80C, keep for 5h, cool to room temperature, extract with ethyl acetate, wash with water, dry with anhydrous sodium sulfate, and concentrate to obtain 1g of compound E, which is 2-fluoro-3-trifluoromethylaniline. The rate is 96.4%, and the purity is 97.2%.

Reference： [1]Patent: CN112624911,2021,A .Location in patent: Paragraph 0018; 0020-0022; 0030; 0032-0034

43
[ 123973-25-1 ]
[ 1099597-93-9 ]

Yield	Reaction Conditions	Operation in experiment
91.2%	Stage #1: 2-fluoro-3-(trifluoromethyl)aniline With hydrogenchloride; sodium nitrite In water at 0℃; for 1h; Stage #2: With hydrogenchloride; copper(l) chloride In water at 95 - 98℃; for 2h;	1.3; 2.3 (3) Synthesis of compound F: Take 1.8g of compound E and dissolve it in 10mL of 10% by mass hydrochloric acid solution, add it to the reactor, control the temperature at 0, drop 12g of 10% by mass sodium nitrite solution, and stir. After 1h, the reaction solution was obtained. The reaction solution was added dropwise to a reaction flask containing 11g cuprous chloride hydrochloric acid solution at a temperature of 98°C. After the dropping, the temperature was maintained at 95°C, heated for 2h, cooled to room temperature, and extracted with ethyl acetate. After washing and concentrating, 1.82 g of compound F is obtained, which is 2-fluoro-3-trifluoromethylchlorobenzene, with a yield of 91.2% and a purity of 98.1%.

Reference： [1]Current Patent Assignee: ALI CHEMICAL CHANGZHOU CO LTD - CN112624911, 2021, A Location in patent: Paragraph 0018; 0023-0026; 0030; 0035-0038

44
[ 123973-25-1 ]
[ 91153-22-9 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
82%	In dichloromethane at 25℃; for 1h;	General Method for the Synthesis of Substituted Diamides General procedure: Synthetic method for the preparation of substituteddiamides is illustrated in Scheme 2 and carried out bythe following procedure: To a solution of primaryamine (52.0 mmol) in dichloromethane (20 mL) wasadded acyl chloride (25.0 mmol), and the resultingsolution was stirred at room temperature until startingmaterial was consumed. The solid product thatformed was filtered off and washed with cold methanoland dried under high vacuum to give (Va-m).

Reference： [1]Yılmaz, Özgür; Çevik, Pınar Küce; Yılmaz, Mustafa Kemal [Russian Journal of Bioorganic Chemistry, 2021, vol. 47, # 2, p. 543 - 551][Bioorg. Khim.]

45
[ CAS Unavailable ]
[ 123973-25-1 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
49%	With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 50℃; for 18h; Inert atmosphere;

Reference： [1]Bangalore, Pavan Kumar; Batchu, Uma Rajeswari; Estharala, Madhurekha; Kantevari, Srinivas; Misra, Sunil; Pedapati, Ravi Kumar; Pranathi, Abburi Naga; Sriram, Dharmarajan [Molecular Diversity, 2022]

46
[ 2754257-48-0 ]
[ 123973-25-1 ]

Yield	Reaction Conditions	Operation in experiment
100.9 g	With 5%-palladium/activated carbon; hydrazine hydrate monohydrate In methanol; lithium hydroxide monohydrate at 25℃; for 4h;	3-4 Example 4: Synthesis of 2-fluoro-3-(trifluoromethyl)aniline 125.7g of crude product of 2-fluoro-3-trifluoromethylphenyl azide (118.5g of pure product measured by actual external standard), 375g of methanol and 0.6g of 5% palladium on carbon were put into a 500mL reaction flask.72.3 g of a 40% aqueous hydrazine hydrate solution was added dropwise at room temperature of 25°C.After dripping, stirring was continued at room temperature for 4 hours.After filtration, the filtrate was distilled under reduced pressure to remove the solvent, and the residue was purified by steam distillation.100.9 g of the product was obtained with a purity of 99.7%, which was proved to be 2-fluoro-3-trifluoromethylaniline by NMR data.

Reference： [1]Current Patent Assignee: SHANGHAI WANSU PHARMACEUTICAL - CN113773204, 2021, A Location in patent: Paragraph 0077-0081

47
[ 32315-10-9 ]
[ 58971-11-2 ]
[ 123973-25-1 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: bis(trichloromethyl) carbonate; 2-fluoro-3-(trifluoromethyl)aniline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 1h; Stage #2: 2-(3-bromophenyl)ethan-1-amine In tetrahydrofuran at 0 - 25℃; for 2h;

Reference： [1]Zhang, Xing Xing; Xiao, Yun; Yan, Yao Yao; Wang, Yu Meng; Jiang, Han; Wu, Lei; Shi, Jing-Bo; Liu, Xin Hua [Journal of Medicinal Chemistry, 2022, vol. 65, # 18, p. 12095 - 12123]

48
[ 42287-90-1 ]
[ 123973-25-1 ]
[ 2852077-33-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-(3-bromophenyl)propionic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 25℃; for 0.666667h; Stage #2: 2-fluoro-3-(trifluoromethyl)aniline With N,N-dimethyl-4-aminopyridine In dichloromethane at 25℃; for 7h;

Reference： [1]Zhang, Xing Xing; Xiao, Yun; Yan, Yao Yao; Wang, Yu Meng; Jiang, Han; Wu, Lei; Shi, Jing-Bo; Liu, Xin Hua [Journal of Medicinal Chemistry, 2022, vol. 65, # 18, p. 12095 - 12123]

49
[ 105172-73-4 ]
[ 123973-25-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogen In tetrahydrofuran at 40℃; for 16h;	1.c; 2.c; 3.c c) Preparation of 2-fluoro-3-aminotrifluorotoluene 20.5g of 2-fluoro-3-nitro-5-chlorotrifluorotoluene was dissolved in 100mL of tetrahydrofuran,Add 4 g of freshly prepared Raney nickel, replace with nitrogen and introduce hydrogen, at 40°C,The reaction was stirred at 5 atm for 16 h. Suction filtration, and the filtrate was concentrated to obtain 15 g of pale yellow liquid,Yield 100%, GC purity >95%.The overall yield of the reaction was 74.9%.

Reference： [1]Current Patent Assignee: NANJING LYNSCI CHEMICAL - CN114920655, 2022, A Location in patent: Paragraph 0036-0038; 0046; 0047; 0052-0054; 0055; 0056; ...

50
[ 61324-97-8 ]
[ 123973-25-1 ]

Yield	Reaction Conditions	Operation in experiment
132.9 g	With ethanol; Pd/C; hydrogen at 50℃; Autoclave;	1.S4-4.S4 Example 2 A preparation method of 2-fluoro-3-trifluoromethylaniline, comprising the following steps, S1) nitration reaction: in a 1L three-necked flask, add 600mL of concentrated sulfuric acid, add 200g (1.0eq) 2-chloro-5-amino Trifluorotoluene, cool down to 0-10°C in an ice bath, slowly add 108.7g (1.05eq) of potassium nitrate in batches under temperature control, and keep warm for 1 hour, then slowly pour the reaction solution into ice water, and adjust the pH with sodium carbonate value of 9, DCM extraction, layering, washing, drying, evaporated to dryness to get 240.6g2-chloro-3-nitro-5-aminobenzotrifluoride; S2) Sandmeyer reaction: In a 2L three-necked flask, dissolve 240.6g of 2-chloro-3-nitro-5-aminobenzotrifluoride in 1.2L of 20% HCl, and slowly Add 72.5g (1.05eq) saturated aqueous solution of sodium nitrite dropwise and keep warm for half an hour to prepare a diazo solution. Slowly add 128g (2.0eq) of hypophosphorous acid aqueous solution into the diazo solution at 0-10°C, and the reaction will take 30 Minutes, heat up to 50°C and react overnight, pour the reaction solution into water, stir at 0-5°C for 2 hours to precipitate a solid, filter with suction to obtain the crude product, and then recrystallize with ethanol water to obtain 192.3g of 2-chloro-3-nitrobenzotrifluoride;S3) Substitution reaction: add 192.3g of 2-chloro -3-Nitrotrifluorotoluene, sulfolane 1L, 200-mesh powder-dried potassium fluoride 98g (2.0eq) and 14g TBAB, react overnight at 160°C, LC detects that the reaction is complete, the reaction solution is poured into water, extracted three times with EA, washed with water for 2 times, dried and concentrated to obtain 167.4g 2-fluoro-3-nitrobenzotrifluoride; S4) reduction reaction: add 167.4g 2-fluoro-3-nitrobenzotrifluoride, 1L ethanol, 8g palladium in a 2L autoclave Charcoal, pressurized with hydrogen to 2.0MPa, reacted at 50°C until no more hydrogen was absorbed, filtered the catalyst, concentrated to dry methanol to obtain the crude product (2-fluoro-3-trifluoromethylaniline), and obtained 132.9g of the finished product through oil pump rectification. 2-Fluoro-3-trifluoromethylaniline as a colorless oil.The total yield of this embodiment is 72.56%.

Reference： [1]Current Patent Assignee: SUZHOU UUGENE BIOPHARMA CO LTD - CN115141100, 2022, A Location in patent: Paragraph 0028-0039

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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
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