[ CAS No. 261762-39-4 ] {[proInfo.proName]}

Name: 261762-39-4|2-Chloro-3,6-difluorobenzaldehyde|98%
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SKU: A116961
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Quality Control of [ 261762-39-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 261762-39-4 ]

SDS Specification

Alternatived Products of [ 261762-39-4 ]

Product Details of [ 261762-39-4 ]

CAS No. :	261762-39-4	MDL No. :	MFCD01631443
Formula :	C₇H₃ClF₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KPYBGKSDBNMHTO-UHFFFAOYSA-N
M.W :	176.55	Pubchem ID :	2773509
Synonyms :

Calculated chemistry of [ 261762-39-4 ] Expand+

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	36.76
TPSA :	17.07 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) :	1.47
Log Po/w (XLOGP3) :	2.21
Log Po/w (WLOGP) :	3.27
Log Po/w (MLOGP) :	2.9
Log Po/w (SILICOS-IT) :	3.47
Consensus Log Po/w :	2.66

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 :	0.382 mg/ml ; 0.00217 mol/l
Class :	Soluble
Log S (Ali) :	-2.2
Solubility :	1.11 mg/ml ; 0.00627 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.52
Solubility :	0.0536 mg/ml ; 0.000303 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.56

Safety of [ 261762-39-4 ]

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

Application In Synthesis of [ 261762-39-4 ]

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

Upstream synthesis route of [ 261762-39-4 ]
Downstream synthetic route of [ 261762-39-4 ]

[ 261762-39-4 ] Synthesis Path-Upstream 1~1

1
[ 2367-91-1 ]
[ 68-12-2 ]
[ 261762-39-4 ]

Yield	Reaction Conditions	Operation in experiment
71%	Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: at -78℃; for 0.25 h;	2-Chloro-l,4-difluorobenzene (1.78 g, 12.0 mmol) was dissolved in tetrahydroiuran (50 mL) and cooled to -78 °C. Lithium diisopropyl amide (1.8 M in tetrahydroiuran, 7.3 mL, 13.2 mmol) was added. After stirring at -78 °C for 30 min, N,N-dimethylformamide (1.05 g, 14.4 mmol) was added. After stirring at - 78 °C for an additional 15 min, acetic acid (3 mL) and water (100 mL) was added and the mixture was warmed to RT. After extraction with ethyl acetate, the organic phase was washed with 1 M hydrochloride acid solution and brine, and dried over magnesium sulfate. Concentration in vacuo afforded the title compound (1.51 g, 71percent of theory). GC-MS (Method 1G): R_t = 3.25 min, MS (ESIPos): m/z = 177 [M+H]⁺
1.51 g	Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: at -78℃; for 0.25 h;	Example 152A 2-Chloro-3,6-difluorobenzaldehyde 2-Chloro-1,4-difluorobenzene (1.78 g, 12.0 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to -78° C. Lithium diisopropyl amide (1.8 M in tetrahydrofuran, 7.3 mL, 13.2 mmol) was added. After stirring at -78° C. for 30 min, N,N-dimethylformamide (1.05 g, 14.4 mmol) was added. After stirring at -78° C. for an additional 15 min, acetic acid (3 mL) and water (100 mL) was added and the mixture was warmed to RT. After extraction with ethyl acetate, the organic phase was washed with 1 M hydrochloride acid solution and brine, and dried over magnesium sulfate. Concentration in vacuo afforded the title compound (1.51 g, 71percent of theory). GC-MS (Method 1G): R_t=3.25 min, MS (ESIPos): m/z=177 [M+H]⁺

Reference： [1] Patent: WO2015/67549, 2015, A1, . Location in patent: Page/Page column 143
[2] Patent: US2015/126449, 2015, A1, . Location in patent: Paragraph 0803 - 0806

[ 261762-39-4 ] Synthesis Path-Downstream 1~101

1
[ 261762-39-4 ]
[ 890133-16-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	With hydroxylamine hydrochloride; tetrabutyl-ammonium chloride; sodium hydrogencarbonate; In water; acetonitrile; at 20℃; for 1.25h;	2-Chloro-3,6-difluoro-benzaldehyde (25.0 g, 142 mmol) was dissolved in CH3CN (175 mL). To this sol. was added NaHCO3 (35.7 g, 424 mmol), and the mixture was stirred vigorously for 5 min. Water (350 mL) was added, and the mixture was stirred for 10 min. NH2OH.HCl (19.7 g, 283 mmol) and TBAC (1.97 g, 7.08 mmol) were added, and the reaction mixture was stirred at rt for 1 h. AcOH (20 mL) was added dropwise to pH 6-7. The mixture was extracted with Et2O (3×). The combined org. extracts were washed with brine, dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Drying under high vacuum yielded the title compound (25.0 g, 92%). LC-MS: tR=0.93 min.
92%	With hydroxylamine hydrochloride; sodium hydrogencarbonate;tetrabutyl-ammonium chloride; In acetonitrile; at 20℃; for 1h;	2-Chloro-3,6-difluoro-benzaldehyde Oxime 2-Chloro-3,6-difluoro-benzaldehyde (25.0 g, 142 mmol) was dissolved in CH3CN (175 mL). To this sol. was added NaHCO3 (35.7 g, 424 mmol), and the mixture was stirred vigorously for 5 min. Water (350 mL) was added, and the mixture was stirred for 10 min. NH2OH.HCl (19.7 g, 283 mmol) and TBAC (1.97 g, 7.08 mmol) were added, and the reaction mixture was stirred at rt for 1 h. AcOH (20 mL) was added dropwise to pH 6-7. The mixture was extracted with Et2O (3*). The combined org. extracts were washed with brine, dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Drying under high vacuum yielded the title compound (25.0 g, 92%). LC-MS: tR=0.93 min.
92%		2-Chloro-3,6-difluoro-benzaldehyde oxime. 2-Chloro-3,6-difluoro-benzaldehyde (25.0 g, 142 mmol) was dissolved in CH3CN (175 mL). To this sol. was added NaHCO3 (35.7 g, 424 mmol), and the mixture was stirred vigorously for 5 min. Water (350 mL) was added, and the mixture was stirred for 10 min.NH2OH-HCl (19.7 g, 283 mmol) and TBAC (1.97 g, 7.08 mmol) were added, and the reaction mixture was stirred at rt for 1 h. AcOH (20 mL) was added dropwise to pH 6-7. The mixture was extracted with Et2O (3x). The combined org. extracts were washed with brine, dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Drying under high vacuum yielded the title compound (25.0 g, 92%). LC-MS: tR = 0.93 min.

78%		2-Chloro-3,6-difluoro-benzaldehyde oximeA mixture of <strong>[261762-39-4]2-chloro-3,6-difluorobenzaldehyde</strong> (1.13 mmol, 200 mg) and NaHCO3 (3.4 mmol, 286 mg) in water (1.9 mL) was treated at it with H2NOH-HCl (2.3 mmol, 160 mg) and Bu4NCl (0.06 mmol, 16 mg). Acetonitrile (1.2 mL) was then added and the mixture was stirred at rt for 90 min. AcOH (0.2 mL) was then added and the mixture was stirred for 30 min at rt. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 3:7) yielded the title compound (170 mg, 78%). LC- MS: tR = 0.84 min; ES+ + CH3CN: 233.81.
78%		A mixture of <strong>[261762-39-4]2-chloro-3,6-difluorobenzaldehyde</strong> (1.13 mmol, 200 mg) and NaHCO3(3.4 mmol, 286 mg) in water (1.9 mL) was treated at rt with H2NOH-HCl (2.3 mmol, 160 mg) and Bu4NCl (0.06 mmol, 16 mg). Acetonitrile (1.2 mL) was then added and the mixture was stirred at rt for 90 min. AcOH (0.2 mL) was then added and the mixture was stirred for 30 min at rt. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced EPO <DP n="28"/>pressure. Purification of the residue by FC (EtO Ac/heptane 3:7) yielded the title compound (170 mg, 78%). LC-MS: tR = 0.84 min; ES+: CH3CN: 233.81.5
	With hydroxylamine hydrochloride; sodium acetate; In ethanol; for 16h;Heating / reflux;	EXAMPLE 54 4-Chloro-3-fluoro-10-methyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine hydrochloride (1:1); a) 2-Chloro-3-fluoro-6-(4-methyl-imidazol-1-yl)-benzonitrile; A solution of 2-chloro-3,6-difluoro-benzaldehyde (16.5 g, 93 mmol) in ethanol (80 ml) was treated with hydroxylamine HCl (7.80 g, 112 mmol) and sodium acetate (9.20 g, 112 mmol). The mixture was heated under reflux for 16 h, then the solvent was evaporated, and the residue stirred with water. The precipitate was filtered and dried to afford 2-chloro-3,6-difluoro-benzaldehyde oxime. It was dissolved in acetic anhydride (140 ml) and refluxed for 16 h, then the mixture was evaporated to afford 2-chloro-3,6-difluoro-benzonitrile as a light brown liquid (10.6 g, 65%). In analogy to example 5a, this compound was reacted with 4-methylimidazole and potassium carbonate for 20 h at 90 C. Aqueous workup, extraction with Ethyl acetate followed by chromatography (SiO2, dichloromethane:methanol=100:0 to 97:3) afforded the title compound as a white solid (yield: 6%). MS: m/e=336.1 [M+H]+.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 6291 - 6296
[2]Patent: US2009/62342,2009,A1 .Location in patent: Page/Page column 11
[3]Patent: US2009/176823,2009,A1 .Location in patent: Page/Page column 16
[4]Patent: WO2007/88514,2007,A1 .Location in patent: Page/Page column 44
[5]Patent: WO2006/63610,2006,A1 .Location in patent: Page/Page column 14
[6]Patent: WO2006/64484,2006,A1 .Location in patent: Page/Page column 26; 27
[7]Patent: US2006/128691,2006,A1 .Location in patent: Page/Page column 25

2
[ 261762-39-4 ]
2-furan-2-yl-N⁵-pyrrolidin-2-ylmethyl-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine [ No CAS ]
<i>N</i>⁵-[1-(2-chloro-3,6-difluoro-benzyl)-pyrrolidin-2-ylmethyl]-2-furan-2-yl-[1,2,4]triazolo[1,5-<i>a</i>][1,3,5]triazine-5,7-diamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 2009 - 2018

3
[ 261762-39-4 ]
[ 75-16-1 ]
[ 756520-68-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;	To a solution of <strong>[261762-39-4]2-chloro-3,6-difluorobenzaldehyde</strong> (5 g, 28 mmol) in dry THF (60 mL) at 0 C under nitrogen was added methyl magnesium bromide (3 M solution in THF, 40 mL, 1 13 mmol) dropwise and the mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution (200 mL) was added and the mixture was extracted with EtOAc (150 mL x 2). The combined organic extracts were washed with brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the title compound (5.35 g, 98%) as a white solid. LCMS-C: rt 1.98 min; m/z 192.9 [M+H]+.
		To a sol. of <strong>[261762-39-4]2-chloro-3,6-difluorobenzaldehyde</strong> (5.00 g, 28.32 mmol) in dry Et2O (60 mL) at 0 0C was added dropwise MeMgBr (3M in Et2O, 40 mL, 120 mmol). The mixture was stirred overnight at rt. Aq. sat. NH4Cl was added and the mixture was extracted with EtOAc (2x). The org. layer was washed with brine, dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. The residue was used in the next step without further purification.
17 g	In tetrahydrofuran; at 5 - 20℃;Inert atmosphere;	Under nitrogen protection,At 5C to <strong>[261762-39-4]2-chloro-3,6-difluorobenzaldehyde</strong> (15.0 g, 85.0 mmol)Tetrahydrofuran (300mL)Methyl magnesium bromide (3M, 31 mL) was added to the solution.The reaction was stirred overnight at room temperature.Quench with saturated aqueous ammonium chloride (2 mL) and concentrate under reduced pressure. The residue was dispersed in an aqueous solution of ethyl acetate (200 mL) and saturated ammonium chloride (30 mL).The separated organic phase was washed with water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.The title compound was obtained as a yellow oil (17.0 g, 104%).

Reference： [1]Patent: WO2019/219820,2019,A1 .Location in patent: Page/Page column 107
[2]Patent: WO2006/64484,2006,A1 .Location in patent: Page/Page column 28
[3]Patent: CN104650049,2018,B .Location in patent: Paragraph 0398; 0399

4
[ 261762-39-4 ]
[ 100-46-9 ]
N-(2-chloro-3,6-difluorobenzylidene)benzylamine [ No CAS ]

Reference： [1]Organic Letters,2007,vol. 9,p. 5629 - 5631

5
[ 261762-39-4 ]
[ 617-35-6 ]
[ 934-22-5 ]
[ 1024611-21-9 ]

Yield	Reaction Conditions	Operation in experiment
26%		Compound 472: 1 -(1 H-benzo[d]imidazol-6-yl)-5-(2-chloro-3,6-difluorophenyl)-3- hydroxy-4-methyl-1 H-pyrrol-2(5H)-one; 1H-Benzoimidazol-5-ylamine (1 mmol) was dissolved in 5mL of dry EtOH and 2-chloro-3,6- difluoro-benzaldehyd (1 mmol) were added. The solution was stirred overnight and after that 2- oxal-propionsaure diethylester (1 mmol) was added and the solution was stirred for 2Oh at 500C. After that the solvent was evaporated and remaining oil was subjected to a flash chromatography device and purified by means of a CHCI3/MeOH gradient. The purified carboxylic acid ethyl ester derivative was suspended in 1OmL of a 10% aqueous solution of HCI and kept for 3h at reflux. The resulting precipitate was filtered off and dried. Yield: 0.092g (26 %);1H-NMR 400 MHz, CD3OD, ?:1.78 - 1.82 (2 s, 1 H + 2H, CH3), 6.35 (s, 0.4H, CH-N), 6.40 (s, 0.6 H, CH-N), 6.90 - 7.00 (m, 0.6 H, aro), 7.16 - 7.24 (m, 1.6 H, aro) 7.68 - 7.79 (2H, benzimid), 8.04 - 8.08 (2s, 0.6 + 0.4 H, benzimid), 9.28 (s, 1 H, benzimid); MS m/z 376.3 (M+H)+, HPLC (254 nm): purity 98 % molecular weight (g/mol): 375.75 1 Ki: hQC (nM): 55.79

Reference： [1]Patent: WO2008/55945,2008,A1 .Location in patent: Page/Page column 191

6
[ 261762-39-4 ]
[ 676-58-4 ]
[ 756520-68-0 ]

Yield	Reaction Conditions	Operation in experiment
		2-CHLORO-3, 6-DIFLUOROBENZALDEHYDE (1. 0 molar equivalent) was dissolved in THF (0. 2M) and stirred at 0 C for 5 min. The corresponding methylmagnesium chloride solution (1. 1 molar equivalent) was added. The reaction was warmed up gradually to ambient temperature and stirred for 2 hr. Methanol, and 1 N HCI was added to the mixture and diluted with ethyl acetate. The mixture was washed with water, brine, dried over MgS04, filtered, and concentrated to give 1- (2-CHLORO-3, 6-DIFLUORO-PHENYL)- ethanol as OIL. 1H NMR (400 MHz, DMSO-d6) 5 1. 42 (d, 3H), 5. 21 (m, 1H), 5. 42 (m, 1H), 7. 09 (m, 1H), 7. 18 (m, 1H).

Reference： [1]Patent: WO2004/76412,2004,A2 .Location in patent: Page 93-94; 94

7
[ 261762-39-4 ]
(rac)-(1RS,5SR)-6-[cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyl]-7-(4-methylaminomethylphenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-butyl ester [ No CAS ]
(rac)-(1RS,5SR)-7-(4-[(2-chloro-3,6-difluoro-benzyl)-methyl-amino]-methyl}-phenyl)-6-[cyclopropyl-(3-methoxy-2-methyl-benzyl)-carbamoyl]-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-butyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 3689 - 3702

8
[ 261762-39-4 ]
[ 1002975-83-8 ]

Reference： [1]European Journal of Organic Chemistry,2011,p. 3985 - 3994

9
[ 261762-39-4 ]
C₁₆H₁₆FNO [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2011,p. 3985 - 3994

10
[ 261762-39-4 ]
[ 1323977-24-7 ]

Reference： [1]European Journal of Organic Chemistry,2011,p. 3985 - 3994

11
[ 261762-39-4 ]
[ 100-46-9 ]
[ 1002975-65-6 ]

Reference： [1]European Journal of Organic Chemistry,2011,p. 3985 - 3994

12
[ 261762-39-4 ]
[ 105761-77-1 ]
C₁₅H₁₃ClF₂O₃ [ No CAS ]

Reference： [1]Combinatorial Chemistry and High Throughput Screening,2012,vol. 15,p. 81 - 89

13
[ 261762-39-4 ]
{cis-3-piperazin-1-yl-1-[ 4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile [ No CAS ]
C₃₁H₃₇ClF₂N₈OSi [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; In dichloromethane;	Example 16a. {cis-3-[4-(2-chloro-3,6-difluorobenzyl)piperazin-l-yl]-l-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyraz -l-yl]cyclobutyl}acetonitrileTo a solution of {cis-3-piperazin-l-yl-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]cyclobutyl}acetonitrile (0.030 g, 0.061 mmol, prepared as in Example la, Step 9) and 2-chloro-3,6- difluorobenzaldehyde (0.016 g, 0.091 mmol) in methylene chloride (1 mL) was added sodium triacetoxyborohydride (0.052 g, 0.24 mmol) and the reaction was stirred overnight. The reaction mixture was partitioned between IN NaOH, brine and DCM. The aqueous portion was extracted with three portions of DCM. The combined extracts were dried over sodium sulfate, decanted and concentrated. The crude product was deprotected by stirring with 1 :1 TFA:DCM for 2 hours. Solvent was then removed in vacuo, and the residue was stirred with 0.3 mL ethylenediamine in methanol until the deprotection was complete. The product was purified via preparative HPLC-MS (CI 8, eluting with a gradient of H20/MeCN containing 0.15% NH4OH). The eluent containing the desired mass was frozen and lyophilized to afford product as the free base (0.015 g, 47%). 1HNMR (400 MHz, d6-dmso): δ 12.11 (br s, 1H), 8.68 (s, 2H), 8.38 (s, 1H), 7.60 (d, 1H), 7.44 (ddd, 1H), 7.30 (ddd, 1H), 7.05 (d, 1H), 3.61 (s, 2H), 3.45 (s, 2H), 2.87 (tt, 1H), 2.61-2.13 (m, 12H); 19F NMR (376 MHz, d6-dmso): δ -117.52 - -117.64 (m, IF), -118.99 (ddd, IF); LCMS (M+H)+: 523.2/525.2.

Reference： [1]Patent: WO2012/68450,2012,A1 .Location in patent: Page/Page column 105-106

14
[ 261762-39-4 ]
[ 1350322-49-4 ]

Reference： [1]Patent: WO2012/158658,2012,A1

15
[ 261762-39-4 ]
[ 1263378-40-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium methylate; In tetrahydrofuran; methanol; at 60℃;	Alternative preparation: 2-Chloro-3,6-difluorobenzaldehyde (10.0 g, 56.6 mmol) was dissolved in 50 mL of tetrahydrofuran and 120 mL of methanol. The reaction mixture was heated at 60 C. To the hot solution, a solution of sodium methoxide in methanol (25 weight%, 16 mL, 69 mmol) was added through an additional funnel over a period of 30 min. The reaction was heated at 60 C for 16 hours. The reaction mixture was evaporated to remove the solvent on rotary evaporator, and water was added to the residue and stirred for 30 minutes. A solid separated out, which was filtered off and triturated with 10% ethyl acetate in hexanes to obtain the pure title compound (9.0 g, 85% yield).

Reference： [1]Patent: WO2012/158658,2012,A1 .Location in patent: Page/Page column 28

16
[ 261762-39-4 ]
[ 1350322-56-3 ]

Reference： [1]Patent: WO2012/158658,2012,A1

17
[ 261762-39-4 ]
[ 1350322-55-2 ]

Reference： [1]Patent: WO2012/158658,2012,A1

18
[ 261762-39-4 ]
[ 1350322-57-4 ]

Reference： [1]Patent: WO2012/158658,2012,A1

19
[ 261762-39-4 ]
[ 1263378-00-2 ]

Reference： [1]Patent: WO2012/158658,2012,A1

20
[ 261762-39-4 ]
[ 1413875-80-5 ]

Reference： [1]Patent: WO2012/158658,2012,A1

21
[ 261762-39-4 ]
[ 1413875-84-9 ]

Reference： [1]Patent: WO2012/158658,2012,A1

22
[ 261762-39-4 ]
[ 1413876-13-7 ]

Reference： [1]Patent: WO2012/158658,2012,A1

23
[ 261762-39-4 ]
[ 1413875-90-7 ]

Reference： [1]Patent: WO2012/158658,2012,A1

24
[ 261762-39-4 ]
[ 1413868-51-5 ]
[ 1413868-46-8 ]

Reference： [1]Patent: WO2012/158658,2012,A1

25
[ 261762-39-4 ]
[ 1420068-88-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine hydrate; In 1,2-dimethoxyethane; at 120℃; for 6h;Microwave irradiation;	4-Chloro-5-fluoro-1H-indazole <strong>[261762-39-4]2-chloro-3,6-difluorobenzaldehyde</strong> (500 mg, 2.83 mmol) in 8 ml 1,2-dimethoxyethane. The reaction was heated in the microwave for 2 h at 120 ºC. Further hydrazine hydrate (3 ml, 34 mmol) was added and the mixture was heated in the microwave at 120 ºC for 2 h. Further hydrazine hydrate (4 ml, 45 mmol) was added and the mixture was heated in the microwave for 4 h at 120 ºC. The mixture was evaporated to dryness, water was added and the aqueous was extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The resulting residue was purified using the Isolera Purification System ( ethyl acetate-hexane gradient, 0:100 rising to 100:0) to give 82 mg (0.48 mmol, 17%) of the title compound. Purity 90%.1H NMR (300 MHz, CHLOROFORM-d) δ ppm 10.26 (s, 1 H), 8.18 (s, 1 H), 7.33 - 7.50 (m, 1 H), 7.19 - 7.33 (m, J=2.47 Hz, 1 H).UPLC/MS (3 min) retention time 1.49 min.LRMS: m/z 171 (M+1).
	With hydrazine hydrate; In 1,2-dimethoxyethane; at 120℃; for 8h;Microwave irradiation;	Hydrazine hydrate (3 ml, 34 mmol) was added to a solution of 2-chloro-3,6- difluorobenzaldehyde (500 mg, 2.83 mmol) in 8 ml 1 ,2-dimethoxyethane. The reaction was heated in the microwave for 2 h at 120 C. Further hydrazine hydrate (3 ml, 34 mmol) was added and the mixture was heated in the microwave at 120 C for 2 h. Further hydrazine hydrate (4 ml, 45 mmol) was added and the mixture was heated in the microwave for 4 h at 120 C. The mixture was evaporated to dryness, water was added and the aqueous was extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The resulting residue was purified using the Isolera Purification System (ethyl acetate-hexane gradient, 0:100 rising to 100:0) to give 82 mg (0.48 mmol, 17%) of the title compound. Purity 90%. 1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 10.26 (s, 1 H), 8.18 (s, 1 H), 7.33 - 7.50 (m, 1 H), 7.19 - 7.33 (m, J=2.47 Hz, 1 H). UPLC/MS (3 min) retention time 1 .49 min. LRMS: m/z 171 (M+1 ).

Reference： [1]Patent: EP2548863,2013,A1 .Location in patent: Paragraph 0219
[2]Patent: WO2013/10881,2013,A1 .Location in patent: Page/Page column 83

26
[ 261762-39-4 ]
[ 1564287-32-6 ]
C₃₃H₄₃ClF₂N₃O₁₀P [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 3176 - 3183

27
[ 261762-39-4 ]
[ 118-93-4 ]
2-(2-chloro-3,6-difluorophenyl)-3-hydroxy-4H-chromen-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%		General procedure: A mixture of 2-hydroxyacetophenone (1 equiv) and the corresponding aldehyde (1 equiv) in ethanol (40 mL) and 1,4-dioxane (20 mL) was cooled to 0-10 C, 40% w/v KOH (5 equiv) solution was added dropwise. Then the reaction mixture was stirred at room temperature and monitored by TLC until the reaction completion. HCl (10%) was added to neutralize the reaction mixture. Ethyl acetate (50 mL) was then added, organic layer was separated and washed with H2O (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was dissolved in 1,4-dioxane (50 mL) and ethanol (30 mL), cooled in an ice-water bath, NaOH (5.4% w/v) solution (5 equiv), 35% H2O2(8 equiv) was added dropwise. The reaction mixture was stirred in an ice bath for 2 h and subsequently at room temperature overnight, resulting in a yellow suspension. After acidification with 2 M HCl to neutrality, ethyl acetate (3*50 mL) was used to extract the product, and the organic layer was washed with H2O (50 mL) and brine (50 mL), then dried over anhydrous sodium sulfate and concentrated in vacuum. The product was purified by column chromatography.The total yields for the two steps were varied from 40%to 65%.

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 6117 - 6123

28
[ 261762-39-4 ]
4-chloro-5-fluoro-1H-indazol-3-amine [ No CAS ]

Reference： [1]Patent: US2015/126449,2015,A1
[2]Patent: WO2015/67549,2015,A1

29
[ 261762-39-4 ]
tert-butyl 4-(10-chloro-9-fluoro-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2015/126449,2015,A1
[2]Patent: WO2015/67549,2015,A1

30
[ 2367-91-1 ]
[ 33513-42-7 ]
[ 261762-39-4 ]

Yield	Reaction Conditions	Operation in experiment
71%		2-Chloro-l,4-difluorobenzene (1.78 g, 12.0 mmol) was dissolved in tetrahydroiuran (50 mL) and cooled to -78 C. Lithium diisopropyl amide (1.8 M in tetrahydroiuran, 7.3 mL, 13.2 mmol) was added. After stirring at -78 C for 30 min, N,N-dimethylformamide (1.05 g, 14.4 mmol) was added. After stirring at - 78 C for an additional 15 min, acetic acid (3 mL) and water (100 mL) was added and the mixture was warmed to RT. After extraction with ethyl acetate, the organic phase was washed with 1 M hydrochloride acid solution and brine, and dried over magnesium sulfate. Concentration in vacuo afforded the title compound (1.51 g, 71% of theory). GC-MS (Method 1G): Rt = 3.25 min, MS (ESIPos): m/z = 177 [M+H]+
1.51 g		Example 152A 2-Chloro-3,6-difluorobenzaldehyde 2-Chloro-1,4-difluorobenzene (1.78 g, 12.0 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to -78 C. Lithium diisopropyl amide (1.8 M in tetrahydrofuran, 7.3 mL, 13.2 mmol) was added. After stirring at -78 C. for 30 min, N,N-dimethylformamide (1.05 g, 14.4 mmol) was added. After stirring at -78 C. for an additional 15 min, acetic acid (3 mL) and water (100 mL) was added and the mixture was warmed to RT. After extraction with ethyl acetate, the organic phase was washed with 1 M hydrochloride acid solution and brine, and dried over magnesium sulfate. Concentration in vacuo afforded the title compound (1.51 g, 71% of theory). GC-MS (Method 1G): Rt=3.25 min, MS (ESIPos): m/z=177 [M+H]+

Reference： [1]Patent: WO2015/67549,2015,A1 .Location in patent: Page/Page column 143
[2]Patent: US2015/126449,2015,A1 .Location in patent: Paragraph 0803 - 0806

31
[ 261762-39-4 ]
[ 886501-33-3 ]

Yield	Reaction Conditions	Operation in experiment
0.42 g	With [bis(acetoxy)iodo]benzene; ammonium acetate; sodium dodecyl-sulfate; In water; at 70℃; for 0.5h;	Example 153A 2-Chloro-3,6-difluorobenzonitrile A mixture of <strong>[261762-39-4]2-chloro-3,6-difluorobenzaldehyde</strong> (1.51 g, 8.5 mmol), sodium lauryl sulfate (0.49 g, 1.71 mmol), (Diacetoxyiodo)benzene (4.12 g, 12.8 mmol) and ammonium acetate (3.29 g, 42.7 mmol) in water (9 mL) was stirred at 70 C. for 30 min After extraction with dichloromethane, the organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification via preparative HPLC (Method 1A) afforded the title compound (0.42 g, 28% of theory) in a purity of 60%. GC-MS (Method 1G): Rt=2.80 min, MS (ESIPos): m/z=175 [M+H]+
	With [bis(acetoxy)iodo]benzene; ammonium acetate; sodium dodecyl-sulfate; In water; at 70℃; for 0.5h;	A mixture of <strong>[261762-39-4]2-chloro-3,6-difluorobenzaldehyde</strong> (1.51 g, 8.5 mmol), sodium lauryl sulfate (0.49 g, 1.71 mmol), (Diacetoxyiodo)benzene (4.12 g, 12.8 mmol) and ammonium acetate (3.29 g, 42.7 mmol) in water (9 mL) was stirred at 70 C for 30 min. After extraction with dichloromethane, the organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification via preparative HPLC (Method 1A) afforded the title compound (0.42 g, 28% of theory) in a purity of 60%. GC-MS (Method 1G): Rt = 2.80 min, MS (ESIPos): m/z = 175 [M+H]+

Reference： [1]Patent: US2015/126449,2015,A1 .Location in patent: Paragraph 0806 - 0808
[2]Patent: WO2015/67549,2015,A1 .Location in patent: Page/Page column 144

32
[ 261762-39-4 ]
10-chloro-9-fluoro-4-(piperidin-4-yl)pyrimido[1,2-b]indazol-2(1H)-one hydrochloride [ No CAS ]

Reference： [1]Patent: WO2015/67549,2015,A1

33
[ 261762-39-4 ]
[ 60100-09-6 ]
N-(2-chloro-3,6-difluorobenzyl)formamide [ No CAS ]

Reference： [1]ACS Combinatorial Science,2015,vol. 17,p. 493 - 499

34
[ 261762-39-4 ]
2-chloro-1,4-difluoro-3-(isocyanomethyl)benzene [ No CAS ]

Reference： [1]ACS Combinatorial Science,2015,vol. 17,p. 493 - 499

35
[ 261762-39-4 ]
tert-butyl [[2-[6-(allyloxy)-2-chloro-3-fluorophenyl]cyclopropyl]methyl]carbamate [ No CAS ]