[ CAS No. 187543-87-9 ] {[proInfo.proName]}

Name: 187543-87-9|2,3-Difluoro-6-methoxybenzaldehyde|97%
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SKU: A323435
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Quality Control of [ 187543-87-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 187543-87-9 ]

SDS Specification

Alternatived Products of [ 187543-87-9 ]

Product Details of [ 187543-87-9 ]

CAS No. :	187543-87-9	MDL No. :	MFCD02093968
Formula :	C₈H₆F₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AKOJAYHBKACKNJ-UHFFFAOYSA-N
M.W :	172.13	Pubchem ID :	2774112
Synonyms :

Calculated chemistry of [ 187543-87-9 ] Expand+

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	38.24
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.24 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.59
Log Po/w (XLOGP3) :	1.56
Log Po/w (WLOGP) :	2.63
Log Po/w (MLOGP) :	1.97
Log Po/w (SILICOS-IT) :	2.82
Consensus Log Po/w :	2.11

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.13
Solubility :	1.28 mg/ml ; 0.00745 mol/l
Class :	Soluble
Log S (Ali) :	-1.72
Solubility :	3.26 mg/ml ; 0.019 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.03
Solubility :	0.162 mg/ml ; 0.00094 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.52

Safety of [ 187543-87-9 ]

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 [ 187543-87-9 ]

* 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 [ 187543-87-9 ]
Downstream synthetic route of [ 187543-87-9 ]

[ 187543-87-9 ] Synthesis Path-Upstream 1~5

1
[ 68-12-2 ]
[ 115144-40-6 ]
[ 187543-87-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: With magnesium chloride In 2-methyltetrahydrofuran for 20 h; Stage #2: With n-butyllithium In 2-methyltetrahydrofuran; hexanes at -78 - -75℃; for 1 h;	The thermal characteristics of this reaction were studied using an HEL Simular reaction calorimeter. The calorimeter was equipped with a double-jacketed, 0.8-liter, glass reactor (6 bar). The inner jacket contained a heat-transfer fluid and the outer jacket was evacuated to insulate the system. A quantity of 20.0 g (0.139 moles, 1 equivalent) of 3,4-difluoroanisole (5), 100 ml of 2-methyltetrahydrofuran (Me-THF) and 15.0 g (0.158 moles, 1.1 equivalents) of anhydrous magnesium chloride was charged to this reactor. The slurry was stirred for 20 hrs and then cooled to -78° C. A quantity of n-BuLi (2.5M in hexanes) 71.7 ml (0.179 moles, 1.3 equivalents) was charged into the batch, keeping the temp <--75° C. The batch was held for an hour and then 15.0 ml (0.194 moles, 1.4 equivalents) of N,N-dimethylformamide was added at -78° C., keeping the temperature <--75° C. The mixture was stirred for an hour and gradually warmed to 0° C. At 0° C., the reaction was quenched with 150 ml of 0.5M citric acid solution. The layers were separated and the organic layer was collected and concentrated to dryness to obtain the desired product (2) in >95percent yield and 98percent purity.
95%	Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane at -75℃; for 1 h; Stage #2: at -70℃; for 0.166667 h;	a) 2,3-Difluoro-6-methoxybenzaldehyde A solution of lithium diisopropylamide, 2M in THF/n-heptane (171 mL, 341 mmol) was further diluted with dry THE (250 mL) and cooled under nitrogen TO-75C. 3,4- Difluoroanisole (46.8 g, 325 mmol) in dry THF (100 mL) was added dropwise and the mixture stirred at-75C for LH. Dry N, N-DIMETHYLFORMAMIDE (27.6 mL, 358 mmol) was added dropwise and the mixture stirred for 10 mins AT-70C. Acetic acid (30 mL) and water (400 mL) were added, warming the temperature to 10C. Extracted into diethyl ether (2 x 300 mL). Combined extracts were washed with water (250 mL), aqueous hydrochloric acid (0.2 N, 400 ML) and brine (2 x 250 mL), dried (MGS04) and the solvent evaporated in vacuo to give a red/orange oil which crystallised. Purification was by recrystallisation from diethyl ETHER/PETROLEUM ether 40-60 to give (53. 0g, 95percent) of solid; 8H (300 MHz, CDC13) 10.40 (1H, s, CHO), 7.37 (1H, q, ArH), 6.71 (1H, m, ArH), and 3.93 (3H, s OCH3).
59%	Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78 - -55℃; Inert atmosphere Stage #2: at -78 - -10℃; Inert atmosphere Stage #3: With ammonium chloride In tetrahydrofuran; n-heptane; ethylbenzene; waterCooling with ice	Step 1: 2,3-Difluoro-6-methoxy-benzaldehyde A solution of 1,2-difluoro-4-methoxy-benzene (Aldrich; 10.0 g, 69.4 mmol) in dry tetrahydrofuran (500 mL) was cooled to -78° C. under a nitrogen atmosphere. A solution of lithium diisopropylamide (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 1.8 M in tetrahydrofuran/heptane/ethylbenzene, 40 mL, 72.9 mmol) was added dropwise by syringe. The reaction mixture was warmed to -55° C. and held at this temperature for 1 h. The mixture was then cooled again to -78° C., and dry N,N-dimethylformamide (10.7 mL, 139 mmol) was added by syringe. The cooling bath was removed and the reaction was allowed to warm to -10° C. and quenched by the addition of ice flakes (~200 mL) and a solution of saturated ammonium chloride (200 mL). Ethyl acetate (200 mL) was added, the layers were separated and the aqueous later was extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, evaporated, and purified by silica gel chromatography, eluting with 0-30percent ethyl acetate/hexanes to give 2,3-difluoro-6-methoxy-benzaldehyde (7.0 g, 59percent yield) as an oil that solidified upon standing.

51.8%	Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -70℃; for 1 h; Inert atmosphere Stage #2: at -70℃; for 1 h;	To a solution of LDA (23.4 mL) in 25 mL of THF was added A2.1 (4.68 g,32.5 mmol) in 10 mL THF dropwise at -70 ^oC under N₂. The mixture was stirred for 1 h at -70 ^oC, then DMF (3.74 mL) was added dropwise, the reaction mixture was stirred for another 1 h at -70 ^oC, and then warmed to rt. The reaction was quenched by 3 mL CH₃COOH and 40 mL H₂O, extracted with ethyl acetate (100 mL × 3), the combined organic layers were washed with H₂O (100 mL), 1N HCl (100 mL), and brine (100 mL), dried over Na₂SO₄, concentrated. The residue was purified by column chromatography on silica gel (PE/EtOAc = 5:1) to give the title compound (2.9 g, 51.8percent) as a yellow solid. LC-MS: [MH]⁺ = 173.2.
10 g	Stage #1: With magnesium chloride In 2-methyltetrahydrofuran at 20℃; Stage #2: With n-butyllithium In 2-methyltetrahydrofuran at -65℃; for 1 h; Stage #3: at -65 - 0℃; for 2 h;	Compound 10g to 3,4-difluoro anisole was added 50ml of tetrahydrofuran freshly distilled methyl Weigh 7.5g of anhydrous magnesium chloride, stirred at room temperature overnight.The next day the reaction solution cooled to -65 deg.] C, was slowly added n-butyllithium 60ml1.6M, the reaction 1 hour at -65 deg.] C, was added dropwise 7.5mlDMF, -65 incubated for 1 hour, then warmed to 0 1 hour, gussets raw reaction was complete.0 75ml0.5M citric acid was slowly added, the mixture was poured into a separatory funnel carve liquid, organic phase was collected, and the aqueous phase was extracted twice with EA, dried, rotary dried to give 2,3-difluoro compound 10g - 6- methoxybenzaldehyde.

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 21, p. 5395 - 5399
[2] Patent: US2009/118546, 2009, A1, . Location in patent: Page/Page column 5-6
[3] Patent: WO2004/43904, 2004, A1, . Location in patent: Page 39 - 40
[4] Patent: US2011/124686, 2011, A1, . Location in patent: Page/Page column 45
[5] Patent: WO2017/221092, 2017, A1, . Location in patent: Paragraph 00142
[6] Journal of Medicinal Chemistry, 1996, vol. 39, # 21, p. 4261 - 4274
[7] Patent: CN105523908, 2016, A, . Location in patent: Paragraph 0011; 0012; 0013; 0014
[8] Patent: WO2008/107455, 2008, A1, . Location in patent: Page/Page column 27-28

2
[ 758-16-7 ]
[ 115144-40-6 ]
[ 187543-87-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -75℃; for 1 h; Stage #2: at -70 - 10℃; for 0.166667 h;	2, 3-DIFLUORO-6-METHOXYBENZALDEHYDE A solution of lithium diisopropylamide, 2M in THF/N-HEPTANE (171 mL, 341 mmol) was further diluted with dry THF (250 ML) and cooled under nitrogen TO-75C. 3,4- Difluoroanisole (46.8 g, 325 mmol) in dry THF (100 ML) was added dropwise and the mixture stirred at-75C for LH. Dry N, N dimethylformamide (27.6 ML, 358 mmol) was added dropwise and the mixture stirred for 10 mins AT-70C. Acetic acid (30 ML) and water (400 ML) were added, warming the temperature to 10C. Extracted into diethyl ether (2 x 300 mL). Combined extracts were washed with water (250 mL), aqueous hydrochloric acid (0.2 N, 400 mL) and brine (2 x 250 mL), dried (MgSO4) and the solvent evaporated in vacuo to give a RED/ORANGE oil which crystallised. Purification was by recrystallisation from diethyl ETHER/PETROLEUM ether 40-60 to give (53. 0g, 95percent) of solid; ON (300 MHz, CDC13) 10.40 (1H, s, CHO), 7.37 (1H, q, ArH), 6.71 (1H, m, ArH), and 3.93 (3H, s OCH3).

Reference： [1] Patent: WO2004/43903, 2004, A1, . Location in patent: Page 40 - 41

3
[ 115144-40-6 ]
[ 187543-87-9 ]

Reference： [1] Organic Process Research and Development, 2008, vol. 12, # 6, p. 1293 - 1298
[2] Patent: US5935973, 1999, A,

4
[ 2713-33-9 ]
[ 187543-87-9 ]

Reference： [1] Journal of Medicinal Chemistry, 1996, vol. 39, # 21, p. 4261 - 4274

5
[ 187543-87-9 ]
[ 773873-26-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: With potassium hydroxide; dihydrogen peroxide In water at 70℃; for 2 h; Stage #2: With hydrogenchloride In water	Preparation XIV; Synthesis of 2,3-difluoro-6-methoxy-benzoic acidTo a suspension of 2,3-difluoro-6-methoxybenzaldehyde (0.5 g, 2.91 mmoles) in potassium hydroxide solution (3 g of KOH in 20 ml of water) was added hydrogen peroxide solution (27.5percent w/w, 4 ml) and then heated at 70 ⁰C for 2 hours. The reaction mixture was acidified to pH 2 with concentrated HCl, and then washed with ethyl acetate. The organic portion was dried (MgSO₄), filtered, evaporated in vacuo and then azeotoped with toluene to give 2,3-difluoro-6-methoxy-benzoic acid as a white solid (500 mg, 91percent). (LC/MS: R₁2.08, no molecular ion observed).
2.6 g	With dihydrogen peroxide; potassium hydroxide In water at 70℃; for 2 h;	To a solution of 5 g of the compound 2,3-difluoro-6-methoxybenzaldehyde in 200 ml of an aqueous solution in which 30 g of potassium hydroxide was dissolved,Slowly add 40ml 29.5percent hydrogen peroxide, rose to 70 ° C reaction for two hours, TLC detection of raw materials completely.Cooled to room temperature, extracted with DCM until no organic compound was present, cooled to 0 ° C in aqueous phase,Concentrated hydrochloric acid was slowly added dropwise to pH 2, and EA was extracted three times to the aqueous phase without addition of compound, dried and dried.The resulting tan solid was dissolved with a small amount of DCM and EA and PE was added to the solid to precipitate several times,To give 2.6 g of the compound 2,3-difluoro-6-methoxybenzoic acid.

Reference： [1] Patent: WO2006/77414, 2006, A1, . Location in patent: Page/Page column 148
[2] Patent: CN105523921, 2016, A, . Location in patent: Paragraph 0014; 0015; 0016

[ 187543-87-9 ] Synthesis Path-Downstream 1~59

1
[ 75-52-5 ]
[ 187543-87-9 ]
1,2-Difluoro-4-methoxy-3-((E)-2-nitro-vinyl)-benzene [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 4261 - 4274

2
[ 68-12-2 ]
[ 115144-40-6 ]
[ 187543-87-9 ]

Yield	Reaction Conditions	Operation in experiment
> 95%		The thermal characteristics of this reaction were studied using an HEL Simular reaction calorimeter. The calorimeter was equipped with a double-jacketed, 0.8-liter, glass reactor (6 bar). The inner jacket contained a heat-transfer fluid and the outer jacket was evacuated to insulate the system. A quantity of 20.0 g (0.139 moles, 1 equivalent) of <strong>[115144-40-6]<strong>[115144-40-6]3,4-difluoroanisol</strong>e</strong> (5), 100 ml of 2-methyltetrahydrofuran (Me-THF) and 15.0 g (0.158 moles, 1.1 equivalents) of anhydrous magnesium chloride was charged to this reactor. The slurry was stirred for 20 hrs and then cooled to -78 C. A quantity of n-BuLi (2.5M in hexanes) 71.7 ml (0.179 moles, 1.3 equivalents) was charged into the batch, keeping the temp ?75 C. The batch was held for an hour and then 15.0 ml (0.194 moles, 1.4 equivalents) of N,N-dimethylformamide was added at -78 C., keeping the temperature ?75 C. The mixture was stirred for an hour and gradually warmed to 0 C. At 0 C., the reaction was quenched with 150 ml of 0.5M citric acid solution. The layers were separated and the organic layer was collected and concentrated to dryness to obtain the desired product (2) in >95% yield and 98% purity.
95%		a) 2,3-Difluoro-6-methoxybenzaldehyde A solution of lithium diisopropylamide, 2M in THF/n-heptane (171 mL, 341 mmol) was further diluted with dry THE (250 mL) and cooled under nitrogen TO-75C. 3,4- Difluoroanisole (46.8 g, 325 mmol) in dry THF (100 mL) was added dropwise and the mixture stirred at-75C for LH. Dry N, N-DIMETHYLFORMAMIDE (27.6 mL, 358 mmol) was added dropwise and the mixture stirred for 10 mins AT-70C. Acetic acid (30 mL) and water (400 mL) were added, warming the temperature to 10C. Extracted into diethyl ether (2 x 300 mL). Combined extracts were washed with water (250 mL), aqueous hydrochloric acid (0.2 N, 400 ML) and brine (2 x 250 mL), dried (MGS04) and the solvent evaporated in vacuo to give a red/orange oil which crystallised. Purification was by recrystallisation from diethyl ETHER/PETROLEUM ether 40-60 to give (53. 0g, 95%) of solid; 8H (300 MHz, CDC13) 10.40 (1H, s, CHO), 7.37 (1H, q, ArH), 6.71 (1H, m, ArH), and 3.93 (3H, s OCH3).
59%		Step 1: 2,3-Difluoro-6-methoxy-benzaldehyde A solution of <strong>[115144-40-6]1,2-difluoro-4-methoxy-benzene</strong> (Aldrich; 10.0 g, 69.4 mmol) in dry tetrahydrofuran (500 mL) was cooled to -78 C. under a nitrogen atmosphere. A solution of lithium diisopropylamide (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 1.8 M in tetrahydrofuran/heptane/ethylbenzene, 40 mL, 72.9 mmol) was added dropwise by syringe. The reaction mixture was warmed to -55 C. and held at this temperature for 1 h. The mixture was then cooled again to -78 C., and dry N,N-dimethylformamide (10.7 mL, 139 mmol) was added by syringe. The cooling bath was removed and the reaction was allowed to warm to -10 C. and quenched by the addition of ice flakes (~200 mL) and a solution of saturated ammonium chloride (200 mL). Ethyl acetate (200 mL) was added, the layers were separated and the aqueous later was extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, evaporated, and purified by silica gel chromatography, eluting with 0-30% ethyl acetate/hexanes to give 2,3-difluoro-6-methoxy-benzaldehyde (7.0 g, 59% yield) as an oil that solidified upon standing.

51.8%		To a solution of LDA (23.4 mL) in 25 mL of THF was added A2.1 (4.68 g,32.5 mmol) in 10 mL THF dropwise at -70 oC under N2. The mixture was stirred for 1 h at -70 oC, then DMF (3.74 mL) was added dropwise, the reaction mixture was stirred for another 1 h at -70 oC, and then warmed to rt. The reaction was quenched by 3 mL CH3COOH and 40 mL H2O, extracted with ethyl acetate (100 mL × 3), the combined organic layers were washed with H2O (100 mL), 1N HCl (100 mL), and brine (100 mL), dried over Na2SO4, concentrated. The residue was purified by column chromatography on silica gel (PE/EtOAc = 5:1) to give the title compound (2.9 g, 51.8%) as a yellow solid. LC-MS: [MH]+ = 173.2.
10 g		Compound 10g to 3,4-difluoro anisole was added 50ml of tetrahydrofuran freshly distilled methyl Weigh 7.5g of anhydrous magnesium chloride, stirred at room temperature overnight.The next day the reaction solution cooled to -65 deg.] C, was slowly added n-butyllithium 60ml1.6M, the reaction 1 hour at -65 deg.] C, was added dropwise 7.5mlDMF, -65 incubated for 1 hour, then warmed to 0 1 hour, gussets raw reaction was complete.0 75ml0.5M citric acid was slowly added, the mixture was poured into a separatory funnel carve liquid, organic phase was collected, and the aqueous phase was extracted twice with EA, dried, rotary dried to give 2,3-difluoro compound 10g - 6- methoxybenzaldehyde.
		Description 25: 2,3-Difluoro-6-(methyloxy)benzaldehyde (D25) <n="29"/>To a solution of diisopropylamine (14.6 ml_, 103.5 mmol) in dry THF (50 mL) cooled to -78 0C was added a solution of BuLi (1.6 M in hexane, 47 mL, 75.9 mmol) dropwise under argon, keeping the temperature below -60 0C. It was stirred at this temperature for 15 minutes after which a solution of 1 ,2-difluoro-4-(methyloxy)benzene (10 g, 69 mmol)in dry THF (50 mL) was added slowly. The mixture was left stirring at -78 0C for 45 minutes followed by slow addition of DMF (6.37 mL, 82.8 mmol) maintaining the temperature below -60 0C. The resulting mixture was stirred at -78 0C for circa 3.5 hours after which water (100 mL) was added and the cooling removed to allow it to warm up to room temperature. It was diluted with EtOAc and the organic separated. The aqueous was re-extracted with EtOAc (3x) and the combined organics washed with brine and dried over MgSO4. The crude material (10.26 g) was purified by flash chromatography to afford the title compound (D25) (9 g).LC-MS: MH+ = 173 (C8H6F2O2 = 172)

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5395 - 5399
[2]Patent: US2009/118546,2009,A1 .Location in patent: Page/Page column 5-6
[3]Patent: WO2004/43904,2004,A1 .Location in patent: Page 39 - 40
[4]Patent: US2011/124686,2011,A1 .Location in patent: Page/Page column 45
[5]Patent: WO2017/221092,2017,A1 .Location in patent: Paragraph 00142
[6]Journal of Medicinal Chemistry,1996,vol. 39,p. 4261 - 4274
[7]Patent: CN105523908,2016,A .Location in patent: Paragraph 0011; 0012; 0013; 0014
[8]Patent: WO2008/107455,2008,A1 .Location in patent: Page/Page column 27-28

3
[ 2365-48-2 ]
[ 187543-87-9 ]
[ 476199-02-7 ]

Yield	Reaction Conditions	Operation in experiment
87%		Methyl 7-FLUORO-4-METHOXY-1-BENZOTHIOPHENE-2-CARBOXYLATE Methyl thioglycolate (28.8 ML, 320 mmol) was added under nitrogen to a solution of triethylamine (86.6 mL) in dry N, N dimethylformamide (220 ML) at 80C. Stirred at 100C for 15 mins. A solution of <strong>[187543-87-9]2,3-difluoro-6-methoxybenzaldehyde</strong> (55.1 g, 320 mmol) in N, N-DIMETHYLFORMAMIDE (80ML) was added and the mixture heated at 130C for 3h. Allowed to cool then poured onto ice-water (2L). The resulting yellow solid was filtered, washing with water (2 x 200 mL). Dried under vacuum over phosphorus pentoxide at room temperature overnight to give the title compound (67. 2G, 87%) ; ON (300 MHZ, CDC13) 8.20 (1H, d, ArH), 7.06 (1H, t, ArH), 6.68 (1H, m, ArH) and 3.99 (6H, s, OCH3 and C02CH3).
87%		b) Methyl 7-FLUORO-4-METHOXY-1-BENZOTHIOPHENE-2-CARBOXYLATE Methyl thioglycolate (28.8 ML, 320 mmol) was added under nitrogen to a solution of triethylamine (86.6 ML) in dry N, N-DIMETHYLFORMAMIDE (220 mL) at 80C. Stirred at 100C for 15 mins. A solution of <strong>[187543-87-9]2,3-difluoro-6-methoxybenzaldehyde</strong> (55.1 g, 320 mmol) in N, N-DIMETHYLFORMAMIDE (80ML) was added and the mixture heated at 130C for 3h. Allowed to cool then poured onto ice-water (2L). The resulting yellow solid was filtered, washing with water (2 x 200 mL). Dried under vacuum over phosphorus pentoxide at room temperature overnight to give the title compound (67.2g, 87%) ; 8H (300 MHz, CDC13) 8.20 (1H, d, ArH), 7.06 (1H, t, ArH), 6.68 (1H, m, ArH) and 3.99 (6H, s, OCH3 and C02CH3).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5395 - 5399
[2]Patent: WO2004/43903,2004,A1 .Location in patent: Page 41
[3]Patent: WO2004/43904,2004,A1 .Location in patent: Page 40

4
[ 187543-87-9 ]
[ 476198-98-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5395 - 5399
[2]Patent: WO2004/43904,2004,A1

5
[ 187543-87-9 ]
[ 476199-23-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5395 - 5399

6
[ 187543-87-9 ]
[ 476199-03-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5395 - 5399
[2]Patent: WO2004/43904,2004,A1

7
[ 187543-87-9 ]
[ 476199-75-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5395 - 5399

8
[ 187543-87-9 ]
[ 476199-46-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5395 - 5399

9
[ 187543-87-9 ]
[3-(7-fluoro-benzo[<i>b</i>]thiophen-4-yloxy)-3-phenyl-propyl]-methyl-amine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5395 - 5399

10
[ 187543-87-9 ]
[3-(7-fluoro-benzo[<i>b</i>]thiophen-4-yloxy)-3-phenyl-propyl]-methyl-amine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5395 - 5399

11
[ 2713-33-9 ]
[ 187543-87-9 ]

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 4261 - 4274

12
[ 187543-87-9 ]
[ 910394-72-8 ]

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 4261 - 4274

13
[ 187543-87-9 ]
1-(5-Bromo-pyridin-2-yl)-3-[2-(2,3-difluoro-6-methoxy-phenyl)-ethyl]-thiourea [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 4261 - 4274

14
[ 187543-87-9 ]
[ 773873-26-0 ]

Yield	Reaction Conditions	Operation in experiment
91%		Preparation XIV; Synthesis of 2,3-difluoro-6-methoxy-benzoic acidTo a suspension of 2,3-difluoro-6-methoxybenzaldehyde (0.5 g, 2.91 mmoles) in potassium hydroxide solution (3 g of KOH in 20 ml of water) was added hydrogen peroxide solution (27.5% w/w, 4 ml) and then heated at 70 0C for 2 hours. The reaction mixture was acidified to pH 2 with concentrated HCl, and then washed with ethyl acetate. The organic portion was dried (MgSO4), filtered, evaporated in vacuo and then azeotoped with toluene to give 2,3-difluoro-6-methoxy-benzoic acid as a white solid (500 mg, 91%). (LC/MS: R12.08, no molecular ion observed).
2.6 g	With dihydrogen peroxide; potassium hydroxide; In water; at 70℃; for 2h;	To a solution of 5 g of the compound 2,3-difluoro-6-methoxybenzaldehyde in 200 ml of an aqueous solution in which 30 g of potassium hydroxide was dissolved,Slowly add 40ml 29.5% hydrogen peroxide, rose to 70 C reaction for two hours, TLC detection of raw materials completely.Cooled to room temperature, extracted with DCM until no organic compound was present, cooled to 0 C in aqueous phase,Concentrated hydrochloric acid was slowly added dropwise to pH 2, and EA was extracted three times to the aqueous phase without addition of compound, dried and dried.The resulting tan solid was dissolved with a small amount of DCM and EA and PE was added to the solid to precipitate several times,To give 2.6 g of the compound 2,3-difluoro-6-methoxybenzoic acid.

Reference： [1]Patent: WO2006/77414,2006,A1 .Location in patent: Page/Page column 148
[2]Patent: CN105523921,2016,A .Location in patent: Paragraph 0014; 0015; 0016

15
[ 115144-40-6 ]
[ 187543-87-9 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; potassium tert-butylate; In tetrahydrofuran; N-methyl-acetamide; water; Petroleum ether;	EXAMPLE 27 The solvent was evaporated in vacuo at ambient temperature from a solution of butyllithium in hexanes (2.5 M; 55.6 ml) giving a viscous oil, which was cooled to -78 C. under nitrogen and a pre-cooled solution of potassium tert-butoxide (15.6 g) in tetrahydrofuran (280 ml) was added slowly. <strong>[115144-40-6]3,4-Difluoroanisole</strong> (20.0 g) was then added dropwise, maintaining the reaction temperature below -60 C., giving a brown solution. After stirring for 2 hours at -78 C., dry dimethylformamide (10.8 ml) was added and the mixture allowed to warm to ambient temperature over 18 hours. Water (200ml) was added and the mixture extracted with ether (3*300 ml). The combined extracts were washed with aqueous lithium chloride solution (40%; 100 ml), water (200 ml) and dried over magnesium sulphate. The solvent was evaporated to give an orange oil (23.0 g) which was purified by flash chromatography over silica eluding with a 9:1 mixture of petroleum ether (b.p. 40-60 C.) and ethyl acetate. Appropriate fractions were combined and the solvent removed in vacuo to give 2,3-difluoro-6-methoxybenzaldehyde (10.1 g) as a yellow solid.

Reference： [1]Organic Process Research and Development,2008,vol. 12,p. 1293 - 1298
[2]Patent: US5935973,1999,A

16
[ 187543-87-9 ]
2,3-difluoro-6-hydroxybenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With boron tribromide; In methanol; dichloromethane; water;	A solution of boron tribromide in dichloromethane (1.0 M; 197.4 ml) was added to a solution of <strong>[187543-87-9]2,3-difluoro-6-methoxybenzaldehyde</strong> (10.4 g; prepared in a similar manner to that described above) in dichloromethane (100 ml) under nitrogen stirring below -20 C. The resulting solution was allowed to warm to ambient temperature overnight, then methanol (200 ml) followed by water (100 ml) were added, and the mixture heated at 40 C. for 2 hours. The aqueous layer was separated and extracted with dichloromethane (2300 ml). The combined organic solutions were extracted with aqueous sodium hydroxide solution (1 M; 3400 ml) and the combined extracts acidified with concentrated hydrochloric acid, then extracted with ethyl acetate (3*300 ml). These combined extracts were dried over magnesium sulphate and the solvent removed in vacuo to give 2,3-difluoro-6-hydroxybenzaldehyde (8.12 g) as a solid.

Reference： [1]Patent: US5935973,1999,A

17
[ 187543-87-9 ]
[ 934180-41-3 ]

Yield	Reaction Conditions	Operation in experiment
94%	With ammonia; sulfur; In 2-methoxy-ethanol; water;	A method similar to that described for the synthesis of 7-methoxybenzo[d]isothiazole in WO 04/043904 was used from <strong>[187543-87-9]2,3-difluoro-6-methoxybenzaldehyde</strong> (prepared as described in WO 04/043904) (2.0 g, 11.62 mmol), sulphur (372 mg, 11.62 mmol), 2-methoxyethanol (10 mL) and aqueous ammonia (30%, 10 mL). The product was isolated as a pale yellow oil (2.0 g, 94%).

Reference： [1]Patent: US2007/112019,2007,A1 .Location in patent: Page/Page column 10/1

18
[ 187543-87-9 ]
[ 1056265-05-4 ]

Yield	Reaction Conditions	Operation in experiment
		Description 26 : 7-Fluoro-4-(methyloxy)-1H-indazole (D26)The <strong>[187543-87-9]2,3-difluoro-6-(methyloxy)benzaldehyde</strong> (D25) (5g, 29.05 mmol) was dissolved in DME (30 mL) and degassed by sonication under argon for 5 minutes. To this was added O- methylhydroxylamine hydrochloride (2.43 g, 29.05 mmol) and K2CO3 (4.42 g, 31.95 mmol) and the solution stirred for 3 hours. The mixture was filtered through celite and the volume reduced to approximately 20 mL under vacuo. To this was added hydrazine monohydrate (20 mL) and it was refluxed under argon for 2.5 days. The reaction was then cooled to room temperature, diluted with EtOAc (150 mL) and water (150 mL) and the phases separated. The aqueous layer was re-extracted with EtOAc (3x) and the combined organics were washed with brine and dried over MgSO4. The crude material (4.8 g) was purified by flash chromatography (ISCO Companion XL, 120 g silica column) with a gradient of EtOAc (0 to 50%) in hexane to afford 3.33 g of title compound (D26). LC-MS: MH+ = 167 (C8H7FN2O = 166)

Reference： [1]Patent: WO2008/107455,2008,A1 .Location in patent: Page/Page column 28

19
[ 758-16-7 ]
[ 115144-40-6 ]
[ 187543-87-9 ]

Yield	Reaction Conditions	Operation in experiment
95%		2, 3-DIFLUORO-6-METHOXYBENZALDEHYDE A solution of lithium diisopropylamide, 2M in THF/N-HEPTANE (171 mL, 341 mmol) was further diluted with dry THF (250 ML) and cooled under nitrogen TO-75C. 3,4- Difluoroanisole (46.8 g, 325 mmol) in dry THF (100 ML) was added dropwise and the mixture stirred at-75C for LH. Dry N, N dimethylformamide (27.6 ML, 358 mmol) was added dropwise and the mixture stirred for 10 mins AT-70C. Acetic acid (30 ML) and water (400 ML) were added, warming the temperature to 10C. Extracted into diethyl ether (2 x 300 mL). Combined extracts were washed with water (250 mL), aqueous hydrochloric acid (0.2 N, 400 mL) and brine (2 x 250 mL), dried (MgSO4) and the solvent evaporated in vacuo to give a RED/ORANGE oil which crystallised. Purification was by recrystallisation from diethyl ETHER/PETROLEUM ether 40-60 to give (53. 0g, 95%) of solid; ON (300 MHz, CDC13) 10.40 (1H, s, CHO), 7.37 (1H, q, ArH), 6.71 (1H, m, ArH), and 3.93 (3H, s OCH3).

Reference： [1]Patent: WO2004/43903,2004,A1 .Location in patent: Page 40 - 41

20
[ 36082-50-5 ]
[ 187543-87-9 ]
[ 741714-88-5 ]

Yield	Reaction Conditions	Operation in experiment
80.5%		Example 1 (2,4-Dichloro-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanol To a stirred solution of 5-bromo-2,4-dichloropyrimidine (Aldrich, 3.02 g, 13.25 mmol) in 20 mL of THF at -30 C., isopropyl magnesium chloride (Aldrich, 2M solution in THF, 7.12 mL, 13.25 mmol) was added dropwise and the mixture was stirred for 20 minutes. Then <strong>[187543-87-9]2,3-difluoro-6-methoxy-benzaldehyde</strong> (Matrix, 2.28 g, 13.25 mmol) was added and the mixture was warmed to 0 C. and stirred for 40 minutes. The reaction was quenched with saturated ammonium chloride solution and the resulting mixture was extracted with EtOAc. The extract was dried with sodium sulfate. The solvent was removed on a rotary evaporator and the solid was treated with hexane (8 mL). The solid was filtered and dried to give an off-white solid. 3.42 g; Yield, 80.5%. MS (M+H)+, 322.

Reference： [1]Patent: US2005/277655,2005,A1 .Location in patent: Page/Page column 10

21
[ 1308662-10-3 ]
[ 187543-87-9 ]
[ 1308661-88-2 ]

Yield	Reaction Conditions	Operation in experiment
42%	With sodium cyanoborohydride; acetic acid; In methanol; at 20℃;Inert atmosphere;	Step 2: 2-(3-[(2,3-Difluoro-6-methoxy-benzyl)-((S)-1-dimethylaminomethyl-2-phenyl-ethyl)-amino]-methyl}-benzyl)-1,1-dioxo-1lambda6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide 2,3-Difluoro-6-methoxy-benzaldehyde (from Step 1; 29 mg, 0.17 mmol) was added to a solution of 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1lambda6-isothiazolidine-3-carboxylic acid ((1S,2S,3S,5R)-2,6,6-trimethyl-bicylo[3.1.1]hept-3-yl)amide (Intermediate 5; 90 mg, 0.16 mmol) in methanol (3 mL) at room temperature under argon. The mixture was stirred for a few minutes and then sodium cyanoborohydride (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 5 mg, 0.08 mmol) and glacial acetic acid (78 muL) were added. The mixture was stirred for 4 h at room temperature. 2,3-Difluoro-6-methoxy-benzaldehyde (from Step 1; 5 mg, 0.03 mmol) was added, followed by sodium cyanoborohydride (3 mg, 0.05 mmol) was added. The mixture was stirred for 4 h at room temperature. The mixture was stirred overnight at room temperature, and it was then concentrated under reduced pressure to remove methanol. Ethyl acetate (50 mL) was added and the mixture was washed with water (225 mL), and brine (25 mL). The aqueous layers were back-extracted with ethyl acetate (50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated to give crude product. Chromatography on a 12 gm silica column, eluting with 0-10% methanol/dichloromethane, followed by trituration with ether/pentane (1/1, 2 mL) to give partially purified material. Ethyl acetate (3 mL) and saturated sodium bicarbonate solution (2 mL) were added and the mixture was stirred for 30 min. The mixture was extracted with ethyl acetate (225 mL) and the organic layers were washed with brine, then dried, filtered and evaporated to give 2-(3-[(2,3-difluoro-6-methoxy-benzyl)-((S)-1-dimethylaminomethyl-2-phenyl-ethyl)-amino]-methyl}-benzyl)-1,1-dioxo-1lambda6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (48 mg, 42%) as a white solid. HRMS: calcd for C41H55F2N4O4S. Calc [M+H+] 737.3907, found 737.3906.

Reference： [1]Patent: US2011/124686,2011,A1 .Location in patent: Page/Page column 45

22
[ 187543-87-9 ]
tert-butyl [[2-[6-(allyloxy)-2,3-difluorophenyl]cyclopropyl]methyl]carbamate [ No CAS ]