1186194-98-8|2,4-Dichloro-3-(trifluoromethyl)pyridine| Ambeed

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Quality Control of [ 1186194-98-8 ] Purity: 95% SDS Specification

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Product Details of [ 1186194-98-8 ]

CAS No. :	1186194-98-8
Formula :	C₆H₂Cl₂F₃N
M.W :	215.99
SMILES Code :	FC(F)(F)C1=C(Cl)C=CN=C1Cl
MDL No. :	MFCD12547046
InChI Key :	NXLBDZNYRDNGIN-UHFFFAOYSA-N
Pubchem ID :	45588361

Safety of [ 1186194-98-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P301+P312-P302+P352-P304+P340-P305+P351+P338

Application In Synthesis of [ 1186194-98-8 ]

* 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 [ 1186194-98-8 ]

[ 1186194-98-8 ] Synthesis Path-Downstream 1~35

1
[ 1186194-98-8 ]
[ 100-51-6 ]
[ 1254981-27-5 ]

Yield	Reaction Conditions	Operation in experiment
50%		A solution of benzyl alcohol (commercially available, 1.201 mL, 11.55 mmol) was added to a mixture of 60% sodium hydride dispersion in mineral oil (0.484 g, 12.10 mmol) and DMF (30 mL) in an ice bath at 0 C. The mixture was allowed to stir at 0 C for 30 min, then a solution of <strong>[1186194-98-8]2,4-dichloro-3-(trifluoromethyl)pyridine</strong>30 (2.376 g, 11 mmol) in DMF (3 mL) was quickly added. The resulting mixture was stirred at 0 C for 1 h, then quenched by the addition of water. The aqueous mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (5:1 hexanes/ethyl acetate) to afford 4-(benzyloxy)-2-chloro-3-(trifluoromethyl)pyridine (1.59 g, 50% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 5.9 Hz, 1H), 7.47-7.37 (m, 6H), 6.95 (d, J = 5.6 Hz, 1H), 5.28 (s, 2H); LC-MS (M+H)+ 288.1.
38%		To a solution of NaH (60% in oil, 24 g, 600 mmol) in DMF (2 L) at 0 C was added benzyl alcohol (35 g, 325 mmol), then the reaction was stirred for 2 mm. Intermediate(160 mg, 741 mmol) was added in one portion, and stirred at 0 C for 1 h. The reaction was diluted by the addition of H20 and extracted with Et20. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/EtOAc = 20/1). The pure fractions were collected and the solvent was evaporated to yield intermediate 3(lOOg,38%).
38%		To a solution of NaH (60% in oil, 24 g, 600 mmol) in DMF (2 L) at 0 C was added benzyl alcohol (35 g, 325 mmol), then the reaction was stirred for 2 mm. Intermediate 2(160 mg, 741 mmol) was added in one portion, and stirred at 0 C for 1 h. The reaction was diluted by the addition of H20 and extracted with Et20. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/EtOAc = 20/1). The pure fractions were collected and the solvent was evaporated to yield intermediate 3(100 g, 38%).

33%		Description 74-benzyloxy-3-trifluoromethyl-2-chloro-pyridine (D7)To a suspension of NaH (0.487 g, 12.732 mmol, 60% mineral oil) in DMF (50 ml) cooled at 0 0C, was added benzyl alcohol (1.262 ml, 12.2 mmol). The resulting mixture was stirred for 2 min. Then, intermediate compound D6 (2.5 g, 11.575 mmol) was added. The resulting reaction mixture was gradually warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water and extracted with Et2O.The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM gradient as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D7 (1.1 g, 33%).
33%		To a suspension of NaH (0.487 g, 12.732 mmol, 60% mineral oil) in DMF (50 ml) cooled at 0 0C, was added benzyl alcohol (1.262 ml, 12.2 mmol). The resulting mixture was stirred for 2 min. Intermediate compound D13 (2.5 g, 11.575 mmol) was then added. The resulting reaction mixture was stirred for 1 h while gradually allowing it to warm to r.t., quenched with water and extracted with Et2O. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM gradient as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D14 (l.l g, 33%).
33%		To a suspension of NaH (0.487 g, 12.732 mmol, 60% mineral oil) in DMF (50 ml) cooled at 0 0C, was added benzyl alcohol (1.262 ml, 12.2 mmol). The resulting mixture was stirred for 2 min., then, intermediate compound D25 (2.5 g, 11.575 mmol) was added. The resulting reaction mixture was gradually warmed to r.t. and stirred for 1 h. The reaction mixture was quenched with water and extracted with Et2O. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM gradient as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D26 (1.1 g, 33%).
33%		4-Benzyloxy-2-chloro-3 -trifluoromethyl-pyridine (1-7)To a suspension of NaH (0.49 g, 12.73 mmol, 60% mineral oil) in DMF (50 mL) cooled at 0 C, was added benzyl alcohol (1.26 mL, 12.2 mmol). The resulting mixture was stirred for 2 min then; intermediate 1-6 (2.5 g, 11.57 mmol) was added. The resulting r.m. was gradually warmed to r.t. and stirred for 1 h. The r.m. was quenched with water and extracted with Et20. The organic layer was separated, dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography (silica; DCM in Heptane 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield intermediate 1-7 (1.1 g, 33%).
33%		Intermediate 3 (1-3)4-Benzyloxy-2-chloro-3-trifluoromethyl-pyridine (1-3)To a suspension of NaH (0.49 g, 12.73 mmol, 60% mineral oil) in DMF (50 mL) cooled at 0 C, was added benzyl alcohol (1.26 mL, 12.2 mmol). The resulting mixture was stirred for 2 min. then; intermediate compound 1-2 (2.5 g, 11.57 mmol) was added. The resulting reaction mixture was gradually warmed to r.t. and stirred for 1 h. The reaction mixture was quenched with water and extracted with diethyl ether. The organic layer was separated, dried (Na2SC>4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM in Heptane 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield intermediate compound 1-3 (1.1 g, 33%).
33%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 1h;	Intermediate 9(1-9)-3-trifluoromethyl-pyridine (1-9)To a suspension of NaH (0.49 g, 12.73 mmol, 60% mineral oil) in DMF (50 mL) cooled at 0 C, was added benzyl alcohol (1.26 mL, 12.2 mmol). The resulting mixture was stirred for 2 min. then; intermediate compound 1-8 (2.5 g, 11.57 mmol) was added. The resulting reaction mixture was gradually warmed to r.t. and stirred for 1 h. The reaction mixture was quenched with water and extracted with Et20. The organic layer was separated, dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM in Heptane 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield intermediate compound 1-9 (1.1 g, 33%).
33%		Intermediate 3 (1-3)-3-trifluoromethyl-pyridine (1-3)To a suspension of NaH (0.49 g, 12.73 mmol, 60% mineral oil) in DMF (50 mL) cooled at 0 C, was added benzyl alcohol (1.26 mL, 12.2 mmol). The resulting mixture was stirred for 2 min. then; intermediate compound 1-2 (2.5 g, 11.57 mmol) was added. The resulting reaction mixture was gradually warmed to r.t. and stirred for 1 h. The reaction mixture was quenched with water and extracted with diethyl ether. The organic layer was separated, dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM in Heptane 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield intermediate compound 1-3 (1.1 g, 33%).
33%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 1h;	4-Benzyloxy-2-chloro-3-trifluoromethyl-pyridine (I-3) To a suspension of NaH (0.49 g, 12.73 mmol, 60% mineral oil) in DMF (50 mL) cooled at 0 C., was added benzyl alcohol (1.26 mL, 12.2 mmol). The resulting mixture was stirred for 2 min. then; intermediate compound I-2 (2.5 g, 11.57 mmol) was added. The resulting reaction mixture was gradually warmed to r.t. and stirred for 1 h. The reaction mixture was quenched with water and extracted with diethyl ether. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM in Heptane 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield intermediate compound I-3 (1.1 g, 33%).
33%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃;	4-Benzyloxy-2-chloro-3-trifluoromethyl-pyridine (I-7) To a suspension of NaH (0.49 g, 12.73 mmol, 60% mineral oil) in DMF (50 mL) cooled at 0 C., was added benzyl alcohol (1.26 mL, 12.2 mmol). The resulting mixture was stirred for 2 min then; intermediate I-6 (2.5 g, 11.57 mmol) was added. The resulting r.m. was gradually warmed to r.t. and stirred for 1 h. The r.m. was quenched with water and extracted with Et2O. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica; DCM in Heptane 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield intermediate I-7 (1.1 g, 33%).
33%		To a suspension of NaH (0.487 g, 12.732 mmol, 60% mineral oil) in DMF (50 mL) cooled at 0 C, was added benzyl alcohol (1.262 mL, 12.2 mmol). The resulting mixture was stirred for 2 min, then, 1-2 (2.5 g, 11.575 mmol) was added. The resulting reaction mixture was gradually warmed to rt and stirred for 1 h. The reaction mixture was quenched with water and extracted with Et20. The organic layer was separated, dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM gradient as eluent). The desired fractions were collected and concentrated in vacuo to yield 1-3 (1.1 g, 33%).
30%		Asolutionofbenzylalcohol(2.4g,22mM)wasaddedtoamixtureof60%sodiumhydride dispersioninmineraloil(0.97mg,24mM)anddimethylformamide(80mL)inanicebathat0C. Themixturewasallowedtostirat0Cfor30min,andthenasolutionof2,4-dichloro-3- (trifluoromethyl)pyridine(C1,5.0g,23mM)indimethylformamide(10mL)wasquicklyadded. Theresultingmixturewasstirredat0Cfor1h,thenquenchedbytheadditionofwater.The aqueousmixturewasextractedwithethylacetate.Thecombinedorganiclayerswerewashed withbrine,driedovermagnesiumsulfate,filtered,andconcentratedinvacuo.Theresiduewas purifiedbysilica-gelcolumnchromatography(5:1hexanes/ethylacetate)toafford4-(benzyloxy)- 2-chloro-3-(trifluoromethyl)pyridine(C3,1.9g,6.9mM)in30%yield.ToasuspensionofC3(1.09 g,3.79mM)in1,4-dioxane(9mL),wasaddedhydrazinemonohydrate(3.68mL,75.8mM).The reactionmixturewasheatedat160Cfor30minundermicrowaveirradiation.Afterthemixture wascooledtoroomtemperature,thevolatileswereevaporatedinvacuo.Theresiduethus obtainedwasdissolvedindichloromethaneandwashedwithsaturatedsodiumbicarbonate aqueoussolution.Theorganiclayerwasseparated,driedoversodiumsulfate,concentratedin vacuoandpurifiedbysilica-gelcolumnchromatographytogive4-(benzyloxy)-2-hydrazineyl-3- (trifluoromethyl)pyridine(C4,0.86g,3.03mM)in80%yield.

References: [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 496 - 513.
[2]Patent: WO2015/32790,2015,A1 .Location in patent: Page/Page column 33.
[3]Patent: WO2015/110435,2015,A1 .Location in patent: Page/Page column 56.
[4]Patent: WO2010/130422,2010,A1 .Location in patent: Page/Page column 54.
[5]Patent: WO2010/130423,2010,A1 .Location in patent: Page/Page column 54.
[6]Patent: WO2010/130424,2010,A1 .Location in patent: Page/Page column 105-106.
[7]Patent: WO2012/62752,2012,A1 .Location in patent: Page/Page column 26-27.
[8]Patent: WO2012/62751,2012,A1 .Location in patent: Page/Page column 35.
[9]Patent: WO2012/62750,2012,A1 .Location in patent: Page/Page column 39-40.
[10]Patent: WO2012/62759,2012,A1 .Location in patent: Page/Page column 38.
[11]Journal of Medicinal Chemistry,2012,vol. 55,p. 8770 - 8789.
[12]Patent: US2013/252952,2013,A1 .Location in patent: Paragraph 0136; 0137.
[13]Patent: US2013/230459,2013,A1 .Location in patent: Paragraph 0166.
[14]Patent: WO2016/92002,2016,A1 .Location in patent: Page/Page column 31.
[15]Patent: WO2021/155196,2021,A1 .Location in patent: Page/Page column 76.

2
[ 680-15-9 ]
[ 343781-36-2 ]
[ 1186194-98-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed tube;	Description 6 2,4-dichloro-3-trifluoromethyl-pyridine(D6)To a mixture of compound D5 (2g, 7.302 mmol) in DMF (50 ml) were added fluorosulfonyl-difluoro-acetic acid methyl ester (1.858 ml, 14.605 mmol) [C.A.S. 680- 15-9] and copper (I) iodide (2.796. g, 14.605 mmol). The reaction mixture was heated in a sealed tube at 100 0C for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D6 (1.5 g, 95%).
95%	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed tube;	To a mixture of intermediate compound D12 (2g, 7.302 mmol) in DMF (50 ml) were added fluorosulfonyl-difluoro-acetic acid methyl ester (1.858 ml, 14.605 mmol)[C.A.S. 680-15-9] and copper (I) iodide (2.796. g, 14.605 mmol). The reaction mixture was heated in a sealed tube at 100 0C for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D 13 ( 1.5 g, 95%).
95%	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed tube;	To a mixture of compound D24 (2g, 7.302 mmol) in DMF (50 ml) were added fiuorosulfonyl-difluoro-acetic acid methyl ester [C.A.S. 680-15-9] (1.858 ml, 14.605 mmol) and copper (I) iodine (2.796. g, 14.605 mmol). The reaction mixture was heated in a sealed tube at 100 0C for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D25 (1.5 g, 95%).

95%	copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed tube;	Intermediate 2 (1-2)2,4-Dichloro-3 -trifluoromethyl-pyridine (1-2)To a mixture of compound 1-1 (2g, 7.30 mmol) in DMF (50 mL) were added fluorosulfonyl-difluoro-acetic acid methyl ester [C.A.S. 680-15-9] (1.86 ml,14.60 mmol) and copper (I) iodide (2.79 g, 14.60 mmol). The reaction mixture was heated in a sealed tube at 100 C for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel, DCM). The desired fractions were collected and concentrated in vacuo to yield intermediate compound 1-2 (1.5 g, 95%).
95%	copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed tube;	Intermediate 8 (1-8)o-3 -trifluoromethyl-pyridine (1-2)To a mixture of compound 1-7 (2g, 7.30 mmol) in DMF (50 mL) were added fluorosulfonyl-difluoro-acetic acid methyl ester [C.A.S. 680-15-9] (1.86 ml,14.60 mmol) and copper (I) iodide (2.79 g, 14.60 mmol). The reaction mixture was heated in a sealed tube at 100 C for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel, DCM). The desired fractions were collected and concentrated in vacuo to yield intermediate compound 1-8 (1.5 g, 95%).
95%	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed vessel;	Intermediate 2 (1-2)o-3-trifluoromethyl-pyridine (1-2)To a mixture of compound 1-1 (2g, 7.30 mmol) in DMF (50 mL) were added fluorosulfonyl-difluoro-acetic acid methyl ester [C.A.S. 680-15-9] (1.86 ml, 14.60 mmol) and copper (I) iodine (2.79 g, 14.60 mmol). The reaction mixture was heated in a sealed tube at 100 C for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel, DCM). The desired fractions were collected and concentrated in vacuo to yield intermediate compound 1-2 (1.5 g, 95%).
95%	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed tube;	2,4-Dichloro-3-trifluoromethyl-pyridine (I-2) To a mixture of compound I-1 (2 g, 7.30 mmol) in DMF (50 mL) were added fluorosulfonyl-difluoro-acetic acid methyl ester [C.A.S. 680-15-9] (1.86 ml, 14.60 mmol) and copper (I) iodide (2.79 g, 14.60 mmol). The reaction mixture was heated in a sealed tube at 100 C. for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel, DCM). The desired fractions were collected and concentrated in vacuo to yield intermediate compound I-2 (1.5 g, 95%).
95%	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed tube;	4-Dichloro-3-trifluoromethyl-pyridine (I-6) To a mixture of intermediate I-5 (2 g, 7.30 mmol) in DMF (50 mL) were added fluorosulfonyl-difluoro-acetic acid methyl ester [C.A.S. 680-15-9] (1.86 ml, 14.60 mmol) and copper (I) iodide (2.79 g, 14.60 mmol). The r.m. was heated in a sealed tube at 100 C. for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel, DCM). The desired fractions were collected and concentrated in vacuo to yield intermediate I-6 (1.5 g, 95%).
95%	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed tube;	To a mixture of 1-1 (2 g, 7.302 mmol) in DMF (50 mL) were added fluorosulfonyl- difluoro-acetic acid methyl ester ([CAS 680-15-9], 1.858 mL, 14.605 mmol) and copper (I) iodide (2.796. g, 14.605 mmol). The reaction mixture was heated in a sealed tube at 100 C for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and concentrated in vacuo to yield 1-2 (1.5 g, 95%).
160 g	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;	To a solution of <strong>[343781-36-2]2,4-dichloro-3-iodopyridine</strong> ([CAS 34378 1-36-2], 290 g, 1058 mmol)in DMF (1.7 L) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate ([CAS 680-15-9], 403 g, 2098 mmol) and Cul (403 g, 2.13 mol), the reaction was then heated at100Cfor5h.The reation was cooled and filtered. The filtrate was diluted with H20 and extracted with Et20 and washed with a NH3 solution. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to yield intermediate 2 (160 g), which was used without further purification.
160 g	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 5h;	To a solution of <strong>[343781-36-2]2,4-dichloro-3-iodopyridine</strong> ([CAS 34378 1-36-2], 290 g, 1058 mmol)in DMF (1.7 L) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate ([CAS 680-15-9], 403 g, 2098 mmol) and Cul (403 g, 2.13 mol), the reaction was then heated at i00Cfor5h.The reation was cooled and filtered. The filtrate was diluted with H20 and extracted with Et20 and washed with a NH3 solution. The organic layer was dried (Na2SO4),filtered and concentrated in vacuo to yield intermediate 2 (160 g), which was used without further purification.

References: [1]Patent: WO2010/130422,2010,A1 .Location in patent: Page/Page column 53-54.
[2]Patent: WO2010/130423,2010,A1 .Location in patent: Page/Page column 54.
[3]Patent: WO2010/130424,2010,A1 .Location in patent: Page/Page column 105.
[4]Patent: WO2012/62751,2012,A1 .Location in patent: Page/Page column 34.
[5]Patent: WO2012/62750,2012,A1 .Location in patent: Page/Page column 39.
[6]Patent: WO2012/62759,2012,A1 .Location in patent: Page/Page column 38.
[7]Patent: US2013/252952,2013,A1 .Location in patent: Paragraph 0134; 0135.
[8]Patent: US2013/230459,2013,A1 .Location in patent: Paragraph 0164.
[9]Patent: WO2016/92002,2016,A1 .Location in patent: Page/Page column 30.
[10]Patent: WO2015/32790,2015,A1 .Location in patent: Page/Page column 32.
[11]Patent: WO2015/110435,2015,A1 .Location in patent: Page/Page column 55.

3
[ 771-99-3 ]
[ 1186194-98-8 ]
[ 1254981-34-4 ]

Yield	Reaction Conditions	Operation in experiment
53%		To a solution of NaH (0.193 g, 4.834 mmol) in DMF (20 ml) cooled at 0 0C, was added 4-phenylpiperidine (0.844 g, 5.236 mmol) was added. The resulting reaction mixture was stirred at 0 0C for 10 min., before D25 (0.87 g, 4.028 mmol) was added. The resulting mixture was warmed to r.t. and stirred for 1 h.. The mixture was then quenched with water and extracted with Et2O. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 2% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D33 (0.73 g, 53%).

References: [1]Patent: WO2010/130424,2010,A1 .Location in patent: Page/Page column 108.
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 8770 - 8789.

4
[ 1056382-25-2 ]
[ 1186194-98-8 ]
[ 1254981-31-1 ]

Yield	Reaction Conditions	Operation in experiment
62%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 110℃; for 4h;Sealed tube;	D25 (0.4 g, 1.852 mmol), 4-fluoro-4-phenylpiperidine hydrochloride [C.A.S. 1056382- 25-2] (0.399 g, 1.852 mmol) and NN-DIPEA (0.645 ml, 3.704 mmol) in CH3CN (4 ml) were heated in a sealed tube at 110 0C for 4 h. The mixture was diluted with EtOAc and washed with NaHCO3 (aqueous sat. solution). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D30 (0.53 g, 62%).

References: [1]Patent: WO2010/130424,2010,A1 .Location in patent: Page/Page column 107.
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 8770 - 8789.

5
[ 26452-80-2 ]
[ 1186194-98-8 ]

6
[ 343781-36-2 ]
[ 1186194-98-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With copper(l) iodide; 2,2-difluoro-2-(fluorosulfonyl)acetate; In N,N-dimethyl-formamide; at 100℃; for 5h;Sealed tube;	Intermediate 62,4-Dichloro-3 -trifluoromethyl-pyridine (1-6)To a mixture of intermediate 1-5 (2g, 7.30 mmol) in DMF (50 mL) were added fluorosulfonyl-difluoro-acetic acid methyl ester [C.A.S. 680-15-9] (1.86 ml, 14.60 mmol) and copper (I) iodide (2.79 g, 14.60 mmol). The r.m. was heated in a sealed tube at 100 C for 5 h. After cooling, the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel, DCM). The desired fractions were collected and concentrated in vacuo to yield intermediate 1-6 (1.5 g, 95%).

References: [1]Patent: WO2012/62752,2012,A1 .Location in patent: Page/Page column 26.

7
[ 1186194-98-8 ]
[ 1254981-28-6 ]

References: [1]Patent: WO2012/62752,2012,A1 .
[2]Patent: WO2012/62751,2012,A1 .
[3]Patent: WO2012/62750,2012,A1 .
[4]Patent: WO2012/62759,2012,A1 .
[5]Patent: US2013/252952,2013,A1 .
[6]Patent: US2013/230459,2013,A1 .
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8
[ 1186194-98-8 ]
[ 1254981-29-7 ]

9
[ 1186194-98-8 ]
[ 1254981-30-0 ]

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10
[ 1186194-98-8 ]
[ 1376334-38-1 ]

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11
[ 1186194-98-8 ]
[ 1254982-02-9 ]

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[ 1186194-98-8 ]
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[ 1186194-98-8 ]
[ 1254982-04-1 ]

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[ 1186194-98-8 ]
[ 1254982-05-2 ]

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[ 1374765-94-2 ]

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3-(cyclopropylmethyl)-7-[3-(2-fluorophenyl)-3-methylmorpholin-4-yl]methyl}-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine [ No CAS ]

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17
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[ 1374582-87-2 ]