[ CAS No. 656-46-2 ] {[proInfo.proName]}

Name: 656-46-2|2,2-Difluorobenzo[d][1,3]dioxole-5-carboxylic acid|98%
Brand: Ambeed
SKU: A163768
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2D 3D

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Quality Control of [ 656-46-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 656-46-2 ]

SDS Specification

Alternatived Products of [ 656-46-2 ]

Product Details of [ 656-46-2 ]

CAS No. :	656-46-2	MDL No. :	MFCD00792417
Formula :	C₈H₄F₂O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VJLDRFCNFNQTTH-UHFFFAOYSA-N
M.W :	202.11	Pubchem ID :	608772
Synonyms :

Calculated chemistry of [ 656-46-2 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	1
Num. H-bond acceptors :	6.0
Num. H-bond donors :	1.0
Molar Refractivity :	39.6
TPSA :	55.76 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) :	-6.7 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.56
Log Po/w (XLOGP3) :	1.18
Log Po/w (WLOGP) :	2.55
Log Po/w (MLOGP) :	1.07
Log Po/w (SILICOS-IT) :	1.66
Consensus Log Po/w :	1.6

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.09
Solubility :	1.65 mg/ml ; 0.00817 mol/l
Class :	Soluble
Log S (Ali) :	-1.95
Solubility :	2.29 mg/ml ; 0.0113 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.08
Solubility :	1.69 mg/ml ; 0.00838 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.13

Safety of [ 656-46-2 ]

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

Application In Synthesis of [ 656-46-2 ]

* 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 [ 656-46-2 ]
Downstream synthetic route of [ 656-46-2 ]

[ 656-46-2 ] Synthesis Path-Upstream 1~9

1
[ 773873-95-3 ]
[ 656-46-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: With sodium hydroxide In methanol at 20℃; Stage #2: With hydrogenchloride In water	Step 2. 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid A solution of methyl 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylate (1.4 g, 6.48 mmol) and sodium hydroxide (830 mg, 20.75 mmol) in methanol (30 ml) was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (20 ml), adjusted pH to 3 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid as a white solid (1.2 g, 92percent). ¹H-NMR (300 MHz, DMSO) δ 13.23 (s, 1H), 7.85 (s, 1H), 7.53 (d, J=1.5 Hz, 1H), 7.53 (d, J=9.0 Hz, 1H)

Reference： [1] Patent: US2012/277224, 2012, A1, . Location in patent: Page/Page column 26

2
[ 1583-59-1 ]
[ 656-46-2 ]

Yield	Reaction Conditions	Operation in experiment
40.7%	Stage #1: at 0 - 15℃; for 18.5 h; Stage #2: at 50℃; for 6 h; Stage #3: With sulfuric acid In water	Example 2; 2,2-Difluorobenzo-1,3-dioxole-5-carboxylic acid; 1012 g of HF were initially charged at 0° C. and 257 g of BF₃were injected within 60 min. Subsequently, 1000 g of difluorobenzodioxole were added within 60 minutes and the temperature was raised to 15° C. within 30 min. Subsequently, the mixture was stirred at 15° C. for a further 16 hours. Subsequently, 773 g of HF were distilled off at standard pressure up to internal temperature 55° C. 5 l of 10percent KOH solution were initially charged and the residue of the distillation was added dropwise with cooling. On completion of addition, the mixture was stirred at 50° C. for a further 6 h, in the course of which the pH was kept between 10 and 11 by adding KOH. Subsequently, the mixture was cooled, the precipitate was filtered off with suction and the mother liquor was adjusted to pH 5 using sulphuric acid. After filtration with suction and drying, 529 g of beige solid were obtained. Yield: 40.7percent {circumflex over (=)}81.4percent based on difluorobenzodioxole. ¹H NMR (400 MHz, DMSO-D₆): 13.52 (b, 1 H), 7.87 (m, 2 H), 7.53 (d, 1H)

Reference： [1] Patent: EP1595876, 2005, A1, . Location in patent: Page/Page column 5
[2] Patent: US2005/277692, 2005, A1, . Location in patent: Page/Page column 3

3
[ 33070-32-5 ]
[ 124-38-9 ]
[ 656-46-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: With magnesium In tetrahydrofuran at 40℃; Inert atmosphere; Reflux Stage #2: at 0℃; for 2 h;	Magnesium turnings (11.12g, 0.464mol) and anhydrous tetrahydrofuran (600 ml) were placed in a round-bottomed flask fitted with a mechanical stirrer, reflux condenser, pressure equalizing addition funnel and drying tube. 5-Bromo-2,2- difluoro-l,3-benzodioxole (lOOg) was added to the flask under nitrogen atmosphere. The temperature of the reaction mass was raised to 40°C during initiation. Upon initiation, remaining 5-Bromo-2,2-difluoro-l,3-benzodioxole (lOOg) was added drop- wise to the reaction mass. The temperature of the reaction mass was maintained below 40°C. The progress of the reaction was monitored by gas chromatography. The reaction mass was then cooled to 0°C and carbon-dioxide gas was passed for 2 hours at 0°C. The raction was monitored by liquid chromatography for completion. The reaction mass was quenched with 10percent HC1 (230g). The organic layer was separated, concentrated to obtain solid. The solid was washed with water (50g) and dichloromethane (50g), filtered and dried at 60°C under 50mmHg for 2 hours to obtain the title compound. Yield (percent): 70 Purity (percent): 99 (by liquid chromatography)

Reference： [1] Patent: WO2017/46816, 2017, A2, . Location in patent: Page/Page column 10

4
[ 135132-34-2 ]
[ 656-46-2 ]

Reference： [1] Patent: CN105153106, 2017, B, . Location in patent: Paragraph 0026; 0028; 0032; 0036

5
[ 33070-32-5 ]
[ 656-46-2 ]

Reference： [1] Patent: US2012/277224, 2012, A1,
[2] Patent: CN105153106, 2017, B,

6
[ 656-46-2 ]
[ 68119-31-3 ]

Reference： [1] Patent: WO2011/119984, 2011, A1,
[2] Patent: US2012/15999, 2012, A1,
[3] Patent: US2012/46330, 2012, A1,
[4] Patent: US2011/98311, 2011, A1,
[5] Patent: US2011/98311, 2011, A1,
[6] Patent: US2011/98311, 2011, A1,
[7] Patent: US2011/98311, 2011, A1,
[8] Patent: US2013/143918, 2013, A1,
[9] Patent: US2013/186801, 2013, A1,
[10] Patent: US2016/324788, 2016, A1,
[11] Patent: WO2013/185112, 2013, A1,
[12] Patent: WO2014/14841, 2014, A1,
[13] Patent: WO2014/71122, 2014, A1,
[14] Patent: WO2015/73231, 2015, A1,
[15] Patent: US2015/231142, 2015, A1,
[16] Patent: US9241934, 2016, B2,
[17] Patent: US2011/98311, 2011, A1,
[18] Patent: US2011/98311, 2011, A1,
[19] Patent: US2011/98311, 2011, A1,
[20] Patent: US2011/98311, 2011, A1,
[21] Patent: US2013/116238, 2013, A1,

7
[ 67-56-1 ]
[ 656-46-2 ]
[ 773873-95-3 ]

Yield	Reaction Conditions	Operation in experiment
94.2%	for 4 h; Reflux	1197 g of methanol was put into a dry reaction tank,2,2-difluoro-piperonic acid 171 g,Stir so 2,2-difluoro-pepper acid dissolved, then add thionyl chloride 215g,Reflux reaction 4h, after the reaction was cooled to 20 ,Add 3.8kg of water, separate the lower organic layer,Vacuum distillation product 172g, which 2,2-difluoro-methyl benzoate content of 99.9percentYield 94.2percent.

Reference： [1] Patent: CN105153106, 2017, B, . Location in patent: Paragraph 0029; 0033; 0034; 0037

8
[ 656-46-2 ]
[ 862574-87-6 ]

Reference： [1] Patent: WO2011/119984, 2011, A1,
[2] Patent: US2013/143918, 2013, A1,
[3] Patent: US2013/186801, 2013, A1,
[4] Patent: WO2013/185112, 2013, A1,
[5] Patent: WO2014/14841, 2014, A1,
[6] Patent: WO2014/71122, 2014, A1,
[7] Patent: WO2015/73231, 2015, A1,
[8] Patent: US2015/231142, 2015, A1,
[9] Patent: US9241934, 2016, B2,
[10] Patent: US2016/324788, 2016, A1,
[11] Patent: US2011/98311, 2011, A1,
[12] Patent: US2011/98311, 2011, A1,
[13] Patent: US2011/98311, 2011, A1,
[14] Patent: US2011/98311, 2011, A1,
[15] Patent: US2011/98311, 2011, A1,
[16] Patent: US2011/98311, 2011, A1,
[17] Patent: US2011/98311, 2011, A1,
[18] Patent: US2011/98311, 2011, A1,
[19] Patent: US2013/116238, 2013, A1,

9
[ 656-46-2 ]
[ 1152311-62-0 ]

Reference： [1] Patent: WO2011/119984, 2011, A1,
[2] Patent: US2013/143918, 2013, A1,
[3] Patent: WO2013/185112, 2013, A1,
[4] Patent: WO2014/14841, 2014, A1,
[5] Patent: US2015/231142, 2015, A1,
[6] Patent: US2013/116238, 2013, A1,

[ 656-46-2 ] Synthesis Path-Downstream 1~60

2
[ 1583-59-1 ]
[ 656-46-2 ]

Yield	Reaction Conditions	Operation in experiment
40.7%		Example 2; 2,2-Difluorobenzo-1,3-dioxole-5-carboxylic acid; 1012 g of HF were initially charged at 0 C. and 257 g of BF3 were injected within 60 min. Subsequently, 1000 g of difluorobenzodioxole were added within 60 minutes and the temperature was raised to 15 C. within 30 min. Subsequently, the mixture was stirred at 15 C. for a further 16 hours. Subsequently, 773 g of HF were distilled off at standard pressure up to internal temperature 55 C. 5 l of 10% KOH solution were initially charged and the residue of the distillation was added dropwise with cooling. On completion of addition, the mixture was stirred at 50 C. for a further 6 h, in the course of which the pH was kept between 10 and 11 by adding KOH. Subsequently, the mixture was cooled, the precipitate was filtered off with suction and the mother liquor was adjusted to pH 5 using sulphuric acid. After filtration with suction and drying, 529 g of beige solid were obtained. Yield: 40.7% {circumflex(=)}81.4% based on difluorobenzodioxole. 1H NMR (400 MHz, DMSO-D6): 13.52 (b, 1 H), 7.87 (m, 2 H), 7.53 (d, 1H)

Reference： [1]Patent: EP1595876,2005,A1 .Location in patent: Page/Page column 5
[2]Patent: US2005/277692,2005,A1 .Location in patent: Page/Page column 3

3
[ 109-72-8 ]
[ 656-46-2 ]
[ 624-92-0 ]
2,2-difluoro-4-methylsulphenyl-1,3-benzodioxole-5-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In tetrahydrofuran;	Reference Example 19 n-Butyllithium (11.6ml of a 2.5M solution in hexanes) was added dropwise to a stirred solution of <strong>[656-46-2]2,2-difluoro-1,3-benzodioxole-5-carboxylic acid</strong> (2.8 g) in dry, tetrahydrofuran maintained at -78 C. under an inert atmosphere. After 6 hours at -78 C., a solution of dimethyl disulphide (3.75 ml) was added dropwise and the mixture left to reach room temperature overnight. Sodium hydroxide solution (2M) was added, the mixture washed 10 with ether, acidified (hydrochloric acid) and the precipitated solid filtered. This was washed (hexane) and dried to give 2,2-difluoro-4-methylsulphenyl-1,3-benzodioxole-5-carboxylic acid (2.59 g) as a cream solid. A pure sample was obtained as colourless crystals m.p. 190-192 C. by recrystallisation from toluene/cyclohexane. Similarly prepared were the following: 4-(methylsulphenyl)-1,3-benzodioxole-5-carboxylic acid as a cream solid, m.p. 196-198 C. 5-(methylsulphenyl)-1,4-benzodioxan-6-carboxylic acid as a cream solid, m.p. 122-124 C. 1,4-benzodioxan-6-carboxylic acid is described in G. Coudert et al, Tetrahedron Letters, 1978, 1059.

Reference： [1]Patent: US5489570,1996,A

4
[ 656-46-2 ]
[ 127163-51-3 ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 8h;	To a stirred solution of oxalyl chloride (2M solution in dichloromethane, 10 mL) was added <strong>[656-46-2]2,2-difluorobenzo[1,3]dioxole-5-carboxylic acid</strong> (1.01 g) in one lot followed by a drop of DMF. The reaction was stirred continuously at room temperature for 8 h and concentrated in vacuo. The residue was dissolved in toluene (20 mL), and the solvent removed to afford 2,2-difluorobenzo[1,3]dioxole-5-carbonyl chloride, which was used in the subsequent step without purification. To a stirred mixture of TMSCH2N2 (10 mL of 2M solution in hexanes) and triethylamine (2.5 mL) in THF (20 mL) and acetonitrile (20 mL) at 0 C. was added 2,2-difluorobenzo[1,3]dioxole-5-carbonyl chloride, and continued stirring at 0 C. for 30 h. The reaction mixture was concentrated in vacuo. Benzyl alcohol (4 mL) and 2,4,6-trimethylpyridine (4 mL) were added to the evaporated residue and the mixture was stirred at 180-185 C. for 10 minutes. The reaction mixture was cooled to room temperature, diluted with ether and washed successively with 10% aqueous citric acid, water and saturated aqueous sodium chloride. The organic layer was dried over MgSO4, and concentrated in vacuo. The residue was disolved in 15 mL of 2M solution sodium hydroxide in methanol, stirred at room temperature for 18 h and concentrated in vacuo. The residue was suspended in water, and the aqueous layer was extracted with ether, and the organic layer was discarded. The aqueous layer was acidified to pH 3-4 with 6N hydrochloric acid then extracted with ether to yield (2,2-difluorobenzo[1,3]dioxole-5-yl)acetic acid. (2,2-difluorobenzo[1,3]dioxole-5-yl)acetic acid pentafluorophenyl ester was prepared from (2,2-difluorobenzo[1,3]dioxole-5-yl)acetic acid following Method A (0.1 g, 5% yield for 5 steps).

Reference： [1]Patent: US2006/211603,2006,A1 .Location in patent: Page/Page column 66
[2]Organic Letters,2019,vol. 21,p. 9852 - 9855

5
[ 656-46-2 ]
[ 72768-97-9 ]

Yield	Reaction Conditions	Operation in experiment
92%		Commercially available 2,2-difluoro-l,3-benzodioxole-5-carboxylic acid (1.0 eq) is slurried in toluene (10 vol). Vitride (2 eq) is added via addition funnel at a rate to maintain the temperature at 15-25 0C. At the end of addition the temperature is increased to 40 0C for 2 h then 10% (w/w) aq. NaOH (4.0 eq) is carefully added via addition funnel maintaining the temperature at 40-50 0C. After stirring for an additional 30 minutes, the layers are allowed to separate at 40 0C. The organic phase is cooled to 20 0C then washed with water (2 x 1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-l,3-benzodioxol-5-yl)- methanol that is used directly in the next step.
86 - 92%		Synthesis of 3-(6-q-(2,2-difluorobenzo[dl [l,31dioxol-5-vn cvclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid * HCl.[00236] Acid Chloride Moiety[00237] Synthesis of (2,2-difluoro-l,3-benzodioxol-5-yl)-methanol (Compound 18).1. Vitride (2 equiv) PhCH3 (IO vOl)2. 10% aq (w/w) NaOH (4 equiv) 86-92% yield [00238] Commercially available 2,2-difluoro-l,3-benzodioxole-5-carboxylic acid (1.0 eq) is slurried in toluene (10 vol). Vitride (2 eq) is added via addition funnel at a rate to maintain the temperature at 15-25 0C. At the end of addition the temperature is increased to 40 0C for 2 h then 10% (w/w) aq. NaOH (4.0 eq) is carefully added via addition funnel maintaining the temperature at 40-50 0C. After stirring for an additional 30 minutes, the layers are allowed to separate at 40 0C. The organic phase is cooled to 20 0C then washed with water (2 x 1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude Compound 18 that is used directly in <n="51"/>the next step.
84%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 4h;Inert atmosphere;	Under nitrogen atmosphere, at 0 C, to a stirred suspension of LiA1H4 (2.0 M THF solution, 6.94 mL, 13.88 mmol) in dry THF (29 mL), 2,2-difluoro-1,3-benzodioxole-5- carboxylic acid (0.70 g, 3.46 mmol) in dry THF (8.0 mL) was added dropwise. The resulting reaction mixture was stirred at r.t. for 4 h, and then cooled to 0 C. H20 (1.5 mL) was slowly andcautiously added, followed by 3.0 M KOH solution (1.0 mL) and additional H20 (1.0 mL). The mixture was stirred at 0 C for 30 mm and then filtered off. The organic layer was dried over Na2SO4, filtered and concentrated to dryness, affording the title compound (0.57 g, 84%), which was used in the next step without any further purification. R= 1.99 mm. ?H NMR (DMSO-d6): oe 7.35-7.29 (m, 2H), 7.14 (d, 1H, J= 8.2 Hz), 5.33 (t, 1H, J= 5.7 Hz), 4.49 (d, 2H, J= 5.7 Hz).

84%		Under nitrogen atmosphere, at 0 C, to a stirred suspension of LiAlH4 (2.0 M THF solution, 6.94 mL,13.88 mmol) in dry THF (29 mL), <strong>[656-46-2]2,2-difluoro-1,3-benzodioxole-5-carboxylic acid</strong> (0.70 g, 3.46mmol) in dry THF (8.0 mL) was added dropwise. The resulting reaction mixture was stirred at roomtemperature for 4 h, and then cooled to 0 C. H2O (1.5 mL) was slowly and cautiously added, followedby 3.0 M KOH solution (1.0 mL) and additional H2O (1.0 mL). The mixture was stirred at 0 C for 30min and then filtered off. The organic layer was dried over Na2SO4, filtered and concentrated todryness, affording the title compound (0.57 g, 84%), which was used in the next step without anyfurther purification. Rt = 1.99 min. 1H NMR (DMSO-d6): delta 7.35-7.29 (m, 2H), 7.14 (d, 1H, J = 8.2Hz), 5.33 (t, 1H, J = 5.7 Hz), 4.49 (d, 2H, J = 5.7 Hz).
		Commercially available 2,2-difluoro-l,3-benzodioxole-5-carboxylic acid (1.0 eq) is slurried in toluene (10 vol). Vitride (2 eq) is added via addition funnel at a rate to maintain the temperature at 15-25 0C. At the end of addition the temperature is increased to 40 0C for 2 h then 10% (w/w) aq. NaOH (4.0 eq) is carefully added via addition funnel maintaining the temperature at 40-50 0C. After stirring for an additional 30 minutes, the layers are allowed to separate at 40 0C. The organic phase is cooled to 20 0C then washed with water (2 x 1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2- difluoro-l,3-benzodioxol-5-yl)-methanol that is used directly in the next step.
		[00193] Synthesis of (2,2-difluoro-l,3-benzodioxol-5-yl)-methanol.1. Vitride (2 equiv)PhCH3 (10 vol)2. 10% aq (w/w) NaOH (4 equiv) 86-92% yield[00194] Commercially available 2,2-difluoro-l,3-benzodioxole-5-carboxylic acid (1.0 eq) is slurried in toluene (10 vol). Vitride (2 eq) is added via addition funnel at a rate to maintain the temperature at 15-25 C. At the end of addition the temperature is increased to 40 C for 2 h then 10% (w/w) aq. NaOH (4.0 eq) is carefully added via addition funnel maintaining the temperature at 40-50 C. After stirring for an additional 30 minutes, the layers are allowed to separate at 40 C. The organic phase is cooled to 20 C then washed with water (2 x 1.5 vol), dried (Na2S04), filtered, and concentrated to afford crude (2,2-difluoro-l,3- benzodioxol-5-yl)-methanol that is used directly in the next step.
	With aq. NaOH; In toluene;	Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol Commercially available <strong>[656-46-2]2,2-difluoro-1,3-benzodioxole-5-carboxylic acid</strong> (1.0 eq) is slurried in toluene (10 vol). Vitride (2 eq) is added via addition funnel at a rate to maintain the temperature at 15-25 C. At the end of addition the temperature is increased to 40 C. for 2 h then 10% (w/w) aq. NaOH (4.0 eq) is carefully added via addition funnel maintaining the temperature at 40-50 C. After stirring for an additional 30 minutes, the layers are allowed to separate at 40 C. The organic phase is cooled to 20 C. then washed with water (2*1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol that is used directly in the next step.
	In toluene;	(2,2-Difluoro-1,3-benzodioxol-5-yl)-methanol Commercially available <strong>[656-46-2]2,2-difluoro-1,3-benzodioxole-5-carboxylic acid</strong> (1.0 eq) was slurried in toluene (10 vol). Vitride (2 eq) was added via addition funnel at a rate to maintain the temperature at 15-25 C. At the end of addition the temperature was increased to 40 C. for 2 hours (h) then 10% (w/w) aq. NaOH (4.0 eq) was carefully added via addition funnel maintaining the temperature at 40-50 C. After stirring for an additional 30 minutes (min), the layers were allowed to separate at 40 C. The organic phase was cooled to 20 C. then washed with water (2*1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol that was used directly in the next step.
		Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol Commercially available <strong>[656-46-2]2,2-difluoro-1,3-benzodioxole-5-carboxylic acid</strong> (1.0 eq) is slurried in toluene (10 vol). Vitride (2 eq) is added via addition funnel at a rate to maintain the temperature at 15-25 C. At the end of addition the temperature is increased to 40 C. for 2 h then 10% (w/w) aq. NaOH (4.0 eq) is carefully via addition funnel maintaining the temperature at 40-50 C. After stirring for an additional 30 minutes, the layers are allowed to separate at 40 C. The organic phase is cooled to 20 C. then washed with water (2*1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol that is used directly in the next step.
		Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol Commercially available <strong>[656-46-2]2,2-difluoro-1,3-benzodioxole-5-carboxylic acid</strong> (1.0 eq) is slurried in toluene (10 vol). Vitride (2 eq) is added via addition funnel at a rate to maintain the temperature at 15-25 C. At the end of addition the temperature is increased to 40 C. for 2 h then 10% (w/w) aq. NaOH (4.0 eq) is carefully added via addition funnel maintaining the temperature at 40-50 C. After stirring for an additional 30 minutes, the layers are allowed to separate at 40 C. The organic phase is cooled to 20 C. then washed with water (2*1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol that is used directly in the next step.
	With sodium bis(2-methoxyethoxy)aluminium dihydride; In toluene; at 15 - 40℃; for 2h;	Preparation of (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol Commercially available <strong>[656-46-2]2,2-difluoro-1,3-benzodioxole-5-carboxylic acid</strong> (1.0 eq) was slurried in toluene (10 vol). Vitride (2 eq) was added via addition funnel at a rate to maintain the temperature at 15-25 C. At the end of the addition, the temperature was increased to 40 C. for 2 hours (h), then 10% (w/w) aqueous (aq) NaOH (4.0 eq) was carefully added via addition funnel, maintaining the temperature at 40-50 C. After stirring for an additional 30 minutes (min), the layers were allowed to separate at 40 C. The organic phase was cooled to 20 C., then washed with water (2*1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol that was used directly in the next step.
	With sodium bis(2-methoxyethoxy)aluminium dihydride; In toluene; at 15 - 40℃; for 2h;	Commercially available <strong>[656-46-2]2,2-difluoro-1,3-benzodioxole-5-carboxylic acid</strong> (1.0 eq)was slurried in toluene (l 0 vol). Vitride (2 eq) was added via addition funnel at a rate tomaintain the temperature at I 5-25 cc. At the end of the addition, the temperature was increasedto 40 oc for 2 hours (h), then 10% (w/w) aqueous (aq) NaOH (4.0 eq) was carefully added viaaddition funnel, maintaining the temperature at 40-50 oc. After stirring for an additional 30minutes (min), the layers were allowed to separate at 40 C. The organic phase was cooled to 20C, then washed with water (2 x 1.5 vol), dried (Na2S04), filtered, and concentrated to affordcrude (2,2-dit1uoro-1,3-benzodioxol-5-yl)-methanol that was used directly in the next step.
		Commercially available <strong>[656-46-2]2,2-difluoro-1,3-benzodioxole-5-carboxylic acid</strong> (1.0 eq) is slurried in toluene (10 vol). Vitride (2 eq) is added via addition funnel at a rate to maintain the temperature at 15-25 C. At the end of addition the temperature is increased to 40 C for 2 h then 10% (w/w) aq. NaOH (4.0 eq) is carefully added via addition funnel maintaining the temperature at 40-50 C. After stirring for an additional 30 minutes, the layers are allowed to separate at 40 C. The organic phase is cooled to 20 C then washed with water (2 x 1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol that is used directly in the next step.
		[00283] Commercially available <strong>[656-46-2]2,2-difluoro-1,3-benzodioxole-5-carboxylic acid</strong> (1.0 eq) wasslurried in toluene (10 vol). Vitride (2 eq) was added via addition funnel at a rate to maintainthe temperature at 15-25 C. At the end of the addition, the temperature was increased to 40 ocfor 2 hours (h), then 10% (w/w) aqueous (aq) NaOH (4.0 eq) was carefully added via additionfunnel, maintaining the temperature at 40-50 C. After stirring for an additional30 minutes(min), the layers were allowed to separate at 40 C. The organic phase was cooled to 20 C, thenwashed with water (2 x 1.5 vol), dried (Na2S04), filtered, and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol that was used directly in the next step.
		Commercially available 2,2-difluoro-l,3-benzodioxole-5-carboxylic acid (1.0 eq) was slurried in toluene (10 vol). Vitride (2 eq) was added via addition funnel at a rate to maintain the temperature at 15-25 C. At the end of the addition, the temperature was increased to 40 C for 2 hours (h), then 10% (w/w) aqueous (aq) NaOH (4.0 eq) was carefully added via addition funnel, maintaining the temperature at 40-50 C. After stirring for an additional 30 minutes (min), the layers were allowed to separate at 40 C. The organic phase was cooled to 20 C, then washed with water (2 x 1.5 vol), dried (Na2S04), filtered, and concentrated to afford crude (2,2- difluoro-l ,3-benzodioxol-5-yl)-methanol that was used directly in the next step.
	With sodium bis(2-methoxyethoxy)aluminum hydride; In toluene; at 15 - 40℃; for 2h;	Commercially available <strong>[656-46-2]2,2-difluoro-1,3-benzodioxole-5-carboxylic acid</strong> (1.0 eq) was slurried in toluene (10 vol). Vitride (2 eq) was added via addition funnel at a rate to maintain the temperature at 15-25 C. At the end of the addition, the temperature was increased to 40 C. for 2 hours (h), then 10% (w/w) aqueous (aq) NaOH (4.0 eq) was carefully added via addition funnel, maintaining the temperature at 40-50 C. After stirring for an additional 30 minutes (min), the layers were allowed to separate at 40 C. The organic phase was cooled to 20 C., then washed with water (2*1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol that was used directly in the next step. 5-Chloromethyl-2,2-difluoro-1,3-benzodioxole
	In toluene;	Preparation of (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol Commercially available <strong>[656-46-2]2,2-difluoro-1,3-benzodioxole-5-carboxylic acid</strong> (1.0 eq) was slurried in toluene (10 vol). Vitride (2 eq) was added via addition funnel at a rate to maintain the temperature at 15-25 C. At the end of the addition, the temperature was increased to 40 C. for 2 hours (h), then 10% (w/w) aqueous (aq) NaOH (4.0 eq) was carefully added via addition funnel, maintaining the temperature at 40-50 C. After stirring for an additional 30 minutes (min), the layers were allowed to separate at 40 C. The organic phase was cooled to 20 C., then washed with water (2*1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol that was used directly in the next step.
	With sodium bis(2-methoxyethoxy)aluminium dihydride; In toluene; at 15 - 40℃; for 2h;	Preparation of (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol Commercially available <strong>[656-46-2]2,2-difluoro-1,3-benzodioxole-5-carboxylic acid</strong> (1.0 eq) was slurried in toluene (10 vol). Vitride (2 eq) was added via addition funnel at a rate to maintain the temperature at 15-25 C. At the end of the addition, the temperature was increased to 40 C. for 2 hours (h), then 10% (w/w) aqueous (aq) NaOH (4.0 eq) was carefully added via addition funnel, maintaining the temperature at 40-50 C. After stirring for an additional 30 minutes (min), the layers were allowed to separate at 40 C. The organic phase was cooled to 20 C., then washed with water (2*1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol that was used directly in the next step.
		Commercially available <strong>[656-46-2]2,2-difluoro-1,3-benzodioxole-5-carboxylic acid</strong> (1.0 eq.) was slurried in toluene (10 vol). Vitride (2 equivalents) was added via an addition funnel at a rate that maintained the temperature at 15-25 C. At the end of the addition, the temperature was raised to 40 C for 2 h, then 10% (w/w) aqueous NaOH (4.0 eq.) was carefully added via the addition funnel and the temperature was maintained at 40-50 C. After stirring for an additional 30 minutes (min), the layers were separated at 40 C. The organic phase was cooled to 20 C then washed with water (2 x 1.5 vol), dried (Na 2SO 4), filtered and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5 -Base)-Methanol, which was used directly in the next step.

Reference： [1]Patent: WO2009/73757,2009,A1 .Location in patent: Page/Page column 20
[2]Patent: WO2009/76142,2009,A2 .Location in patent: Page/Page column 49-50
[3]Patent: WO2014/144836,2014,A2 .Location in patent: Paragraph 1037; 1038
[4]European Journal of Medicinal Chemistry,2016,vol. 111,p. 138 - 159
[5]Patent: WO2010/37066,2010,A2 .Location in patent: Page/Page column 12; 24-25
[6]Patent: WO2011/119984,2011,A1 .Location in patent: Page/Page column 45
[7]Patent: US2012/15999,2012,A1
[8]Patent: US2011/98311,2011,A1
[9]Patent: US2013/143918,2013,A1 .Location in patent: Paragraph 0187; 0188
[10]Patent: US2013/116238,2013,A1 .Location in patent: Paragraph 0271; 0272
[11]Patent: US2013/186801,2013,A1 .Location in patent: Paragraph 0351; 0352
[12]Patent: WO2013/185112,2013,A1 .Location in patent: Paragraph 00558; 00559
[13]Patent: WO2014/14841,2014,A1 .Location in patent: Paragraph 00319; 00320
[14]Patent: WO2014/71122,2014,A1 .Location in patent: Paragraph 00143; 00145; 00281; 00282
[15]Patent: WO2015/73231,2015,A1 .Location in patent: Paragraph 00297-00298
[16]Patent: US2015/231142,2015,A1 .Location in patent: Paragraph 1405; 1973
[17]Patent: US9241934,2016,B2
[18]Patent: US2016/324788,2016,A1 .Location in patent: Paragraph 0351; 0352
[19]Patent: TWI636051,2018,B .Location in patent: Sheet 71

6
[ 656-46-2 ]
[ 917-54-4 ]
[ 136593-45-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1432 - 1435

7
[ 656-46-2 ]
[ 74-88-4 ]
[ 162506-80-1 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of 2,2-difluorobenzo[d][1 ,3]dioxole-5-carboxylic acid (1g, 4.95 mmol) in dry THF (20 mL) was added n-Bu (6.8 ml_, 10.8 mmol of 1.6M) drop wise at - 78 0C. After being stirred for 6h, the resulting reaction mixture was then treated with MeI (0.61 mL, 9.90 mmol) at RT. The resultant reaction mixture was stirred at RT for 16h. The progress of the reaction was monitored by TLC.The reaction mixture was quenched with a saturated solution of NH4CI, extracted with EtOAc (3x 30 mL) and dried over Na2SO4. The resulting material was concentrated under reduced pressure to afford the title compound (1 g, as crude) as a brown solid. TLC system: 10% MeOH/dichloromethane, Rf = 0.5.

Reference： [1]Patent: WO2010/117425,2010,A1 .Location in patent: Page/Page column 161

8
[ 656-46-2 ]
[ 476473-97-9 ]

Reference： [1]Patent: WO2011/119984,2011,A1
[2]Patent: US2012/15999,2012,A1
[3]Patent: US2012/46330,2012,A1
[4]Patent: US2011/98311,2011,A1
[5]Patent: US2011/98311,2011,A1
[6]Patent: US2013/143918,2013,A1
[7]Patent: US2013/186801,2013,A1
[8]Patent: WO2013/185112,2013,A1
[9]Patent: WO2014/14841,2014,A1
[10]Patent: WO2014/71122,2014,A1
[11]Patent: WO2015/73231,2015,A1
[12]Patent: US2015/231142,2015,A1
[13]Patent: US9241934,2016,B2
[14]Patent: US2011/98311,2011,A1
[15]Patent: US2011/98311,2011,A1
[16]Patent: US2013/116238,2013,A1
[17]Patent: TWI636051,2018,B

9
[ 656-46-2 ]
[ 68119-31-3 ]

Reference： [1]Patent: WO2011/119984,2011,A1
[2]Patent: US2012/15999,2012,A1
[3]Patent: US2012/46330,2012,A1
[4]Patent: US2011/98311,2011,A1
[5]Patent: US2011/98311,2011,A1
[6]Patent: US2011/98311,2011,A1
[7]Patent: US2011/98311,2011,A1
[8]Patent: US2013/143918,2013,A1
[9]Patent: US2013/186801,2013,A1
[10]Patent: WO2013/185112,2013,A1
[11]Patent: WO2014/14841,2014,A1
[12]Patent: WO2014/71122,2014,A1
[13]Patent: WO2015/73231,2015,A1
[14]Patent: US2015/231142,2015,A1
[15]Patent: US9241934,2016,B2
[16]Patent: US2011/98311,2011,A1
[17]Patent: US2011/98311,2011,A1
[18]Patent: US2011/98311,2011,A1
[19]Patent: US2011/98311,2011,A1
[20]Patent: US2013/116238,2013,A1
[21]Patent: TWI636051,2018,B

10
[ 656-46-2 ]
aqueous (aq) NaOH [ No CAS ]
[ 72768-97-9 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene;	(2,2-Difluoro-1,3-benzodioxol-5-yl)-methanol Commercially available <strong>[656-46-2]2,2-difluoro-1,3-benzodioxole-5-carboxylic acid</strong> (1.0 eq) was slurried in toluene (10 vol). Vitride (2 eq) was added via addition funnel at a rate to maintain the temperature at 15-25 C. At the end of the addition, the temperature was increased to 40 C. for 2 hours (h), then 10% (w/w) aqueous (aq) NaOH (4.0 eq) was carefully added via addition funnel, maintaining the temperature at 40-50 C. After stirring for an additional 30 minutes (min), the layers were allowed to separate at 40 C. The organic phase was cooled to 20 C., then washed with water (2*1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol that was used directly in the next step.

Reference： [1]Patent: US2011/98311,2011,A1

11
[ 656-46-2 ]
[ 862574-87-6 ]

Reference： [1]Patent: WO2011/119984,2011,A1
[2]Patent: US2013/143918,2013,A1
[3]Patent: US2013/186801,2013,A1
[4]Patent: WO2013/185112,2013,A1
[5]Patent: WO2014/14841,2014,A1
[6]Patent: WO2014/71122,2014,A1
[7]Patent: WO2015/73231,2015,A1
[8]Patent: US2015/231142,2015,A1
[9]Patent: US9241934,2016,B2
[10]Patent: US2016/324788,2016,A1
[11]Patent: US2011/98311,2011,A1
[12]Patent: US2011/98311,2011,A1
[13]Patent: US2011/98311,2011,A1
[14]Patent: US2011/98311,2011,A1
[15]Patent: US2011/98311,2011,A1
[16]Patent: US2011/98311,2011,A1
[17]Patent: US2011/98311,2011,A1
[18]Patent: US2011/98311,2011,A1
[19]Patent: US2013/116238,2013,A1
[20]Patent: TWI636051,2018,B

12
[ 656-46-2 ]
[ 862574-88-7 ]

Reference： [1]Patent: WO2011/119984,2011,A1
[2]Patent: US2012/15999,2012,A1
[3]Patent: US2012/46330,2012,A1
[4]Patent: US2013/143918,2013,A1
[5]Patent: US2013/186801,2013,A1
[6]Patent: WO2013/185112,2013,A1
[7]Patent: WO2014/14841,2014,A1
[8]Patent: WO2014/71122,2014,A1
[9]Patent: WO2015/73231,2015,A1
[10]Patent: US2015/231142,2015,A1
[11]Patent: US2016/324788,2016,A1
[12]Patent: US2011/98311,2011,A1
[13]Patent: US2011/98311,2011,A1
[14]Patent: US2011/98311,2011,A1
[15]Patent: US2011/98311,2011,A1
[16]Patent: US2011/98311,2011,A1
[17]Patent: US2011/98311,2011,A1
[18]Patent: US2011/98311,2011,A1
[19]Patent: US2011/98311,2011,A1
[20]Patent: US2013/116238,2013,A1
[21]Patent: TWI636051,2018,B

13
[ 656-46-2 ]
[ 1004294-65-8 ]

Reference： [1]Patent: WO2011/119984,2011,A1
[2]Patent: US2013/143918,2013,A1
[3]Patent: US2013/186801,2013,A1
[4]Patent: WO2013/185112,2013,A1
[5]Patent: WO2014/14841,2014,A1
[6]Patent: WO2014/71122,2014,A1
[7]Patent: WO2015/73231,2015,A1
[8]Patent: US2015/231142,2015,A1
[9]Patent: US2016/324788,2016,A1
[10]Patent: US2011/98311,2011,A1
[11]Patent: US2011/98311,2011,A1
[12]Patent: US2011/98311,2011,A1
[13]Patent: US2011/98311,2011,A1
[14]Patent: US2011/98311,2011,A1
[15]Patent: US2011/98311,2011,A1
[16]Patent: US2011/98311,2011,A1
[17]Patent: US2011/98311,2011,A1
[18]Patent: US2013/116238,2013,A1
[19]Patent: TWI636051,2018,B

14
[ 656-46-2 ]
[ 1152311-62-0 ]

Reference： [1]Patent: WO2011/119984,2011,A1
[2]Patent: US2013/143918,2013,A1
[3]Patent: WO2013/185112,2013,A1
[4]Patent: WO2014/14841,2014,A1
[5]Patent: US2015/231142,2015,A1
[6]Patent: US2013/116238,2013,A1

15
[ 656-46-2 ]
[ 1294504-68-9 ]

16
[ 656-46-2 ]
[ 1383542-03-7 ]
[ 1383542-04-8 ]

Yield	Reaction Conditions	Operation in experiment
51%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;	A mixture of intermediate 13 (0.95 g, 4.2 mmol), 2,2-difluoro-l,3-benzodioxole-5- carboxylic acid (1.0 g, 5.0 mmol), Et3N (5.0 ml, 36 mmol), HOBT (0.62 g) and EDCI (0.95 g) in DCM (50 ml) was stirred overnight at r.t. The mixture was washed with H20 (3 x 100 ml), dried (MgS04), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (eluent: PE/EtOAc from 20/1 to 10/1). The desired fractions were collected and the solvent was evaporated in vacuo. Yield: 0.8 g of intermediate 14 (51 % yield).

Reference： [1]Patent: WO2012/84804,2012,A1 .Location in patent: Page/Page column 55

17
[ 33070-32-5 ]
[ 656-46-2 ]

Reference： [1]Patent: US2012/277224,2012,A1
[2]Patent: CN105153106,2017,B

18
[ 656-46-2 ]
[ 1404448-98-1 ]

Reference： [1]Patent: US2012/277224,2012,A1

19
[ 773873-95-3 ]
[ 656-46-2 ]

Yield	Reaction Conditions	Operation in experiment
92%		Step 2. 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid A solution of methyl 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylate (1.4 g, 6.48 mmol) and sodium hydroxide (830 mg, 20.75 mmol) in methanol (30 ml) was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (20 ml), adjusted pH to 3 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid as a white solid (1.2 g, 92%). 1H-NMR (300 MHz, DMSO) delta 13.23 (s, 1H), 7.85 (s, 1H), 7.53 (d, J=1.5 Hz, 1H), 7.53 (d, J=9.0 Hz, 1H)

Reference： [1]Patent: US2012/277224,2012,A1 .Location in patent: Page/Page column 26

20
[ 2033-24-1 ]
[ 656-46-2 ]
[ 1404448-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	Step 3. 5-(2,2-Difluorobenzo[d][1,3]dioxole-5-carbonyl)-2,2-dimethyl-1,3-dioxane-4,6-dione To a solution of <strong>[656-46-2]2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid</strong> (1.2 g, 5.94 mmol) in dichloromethane (30 ml) was added 2,2-dimethyl-1,3-dioxane-4,6-dione (1.03 g, 7.15 mmol), 4-dimethylaminopyridine (1.09 g, 8.92 mmol) and 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC HCl) (1.71 g, 8.92 mmol). After stirring overnight at room temperature, the resulting solution was quenched by the addition of HCl (1N, 50 ml), washed with brine (2*50 ml), dried over anhydrous magnesium sulfate and concentrated under vacuum to afford 5-(2,2-difluorobenzo[d][1,3]dioxole-5-carbonyl)-2,2-dimethyl-1,3-dioxane-4,6-dione as an orange solid (1.74 g, crude).

Reference： [1]Patent: US2012/277224,2012,A1 .Location in patent: Page/Page column 26

21
[ 656-46-2 ]
Acetic acid (3S,4S,4aR,6S,6aS,12R,12aS,12bS)-4-acetoxymethyl-6,12-dihydroxy-4,6a,12b-trimethyl-11-oxo-9-pyridin-3-yl-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-2H,11H-7,10-dioxa-benzo[a]anthracen-3-yl ester [ No CAS ]
C₃₇H₃₇F₂NO₁₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1285 - 1287

22
[ 656-46-2 ]
[ 1432656-97-7 ]

Reference： [1]Patent: US2013/116238,2013,A1

23
[ 656-46-2 ]
[ 1432656-98-8 ]

Reference： [1]Patent: US2013/116238,2013,A1
[2]Patent: US2013/116238,2013,A1
[3]Patent: US2013/116238,2013,A1

24
[ 656-46-2 ]
[ 1432656-99-9 ]

Reference： [1]Patent: US2013/116238,2013,A1

25
[ 656-46-2 ]
[ 1432657-00-5 ]

Reference： [1]Patent: US2013/116238,2013,A1

26
[ 656-46-2 ]
C₂₇H₂₂F₃N₂O₈^(1-)*Na⁽¹⁺⁾ [ No CAS ]

Reference： [1]Patent: US2013/116238,2013,A1

27
[ 656-46-2 ]
[ 1432657-01-6 ]

Reference： [1]Patent: US2013/116238,2013,A1

28
[ 656-46-2 ]
[ 1160221-25-9 ]

Reference： [1]Patent: US2013/186801,2013,A1
[2]Patent: WO2013/185112,2013,A1
[3]Patent: WO2014/71122,2014,A1
[4]Patent: WO2015/73231,2015,A1
[5]Patent: US2015/231142,2015,A1
[6]Patent: US2016/324788,2016,A1
[7]Patent: TWI636051,2018,B

29
[ 656-46-2 ]
3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.HCL salt [ No CAS ]

Reference： [1]Patent: US2013/186801,2013,A1
[2]Patent: WO2013/185112,2013,A1

30
[ 656-46-2 ]
Lumacaftor [ No CAS ]

Reference： [1]Patent: US2013/186801,2013,A1
[2]Patent: US2013/186801,2013,A1
[3]Patent: WO2014/71122,2014,A1
[4]Patent: WO2014/71122,2014,A1
[5]Patent: WO2015/73231,2015,A1
[6]Patent: WO2015/73231,2015,A1
[7]Patent: US2016/324788,2016,A1
[8]Patent: US2016/324788,2016,A1
[9]Patent: TWI636051,2018,B

31
[ 656-46-2 ]
[ 1160221-26-0 ]

Reference： [1]Patent: WO2014/71122,2014,A1
[2]Patent: WO2015/73231,2015,A1
[3]Patent: US2015/231142,2015,A1
[4]Patent: US2016/324788,2016,A1
[5]Patent: TWI636051,2018,B

32
[ 656-46-2 ]
(2,2-difluoro-1,3-benzodioxol-5-yl)methyl N-[(3S)-2-oxoazetidin-3-yl]carbamate [ No CAS ]

Reference： [1]Patent: WO2014/144836,2014,A2
[2]European Journal of Medicinal Chemistry,2016,vol. 111,p. 138 - 159

33
[ 656-46-2 ]
(2,2-difluoro-1,3-benzodioxol-5-yl)methyl pyridin-2-yl carbonate [ No CAS ]

Reference： [1]Patent: WO2014/144836,2014,A2

34
[ 656-46-2 ]
(2,2-difluoro-1,3-benzodioxol-5-yl)methyl 2-oxopyridine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2014/144836,2014,A2

35
[ 656-46-2 ]
N-((R)-2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide [ No CAS ]

Reference： [1]Patent: US2015/231142,2015,A1

36
[ 656-46-2 ]
N-((R)-2-tert-butyl-1-(2,3-dihydroxypropyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide [ No CAS ]

Reference： [1]Patent: US2015/231142,2015,A1

37
[ 656-46-2 ]
(R)-3-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-1-yl)-2-hydroxypropyl 4-methylbenzenesulfonate [ No CAS ]

Reference： [1]Patent: US2015/231142,2015,A1

38
[ 656-46-2 ]
(R)-N-(1-(3-azido-2-hydroxypropyl)-2-tert-butyl-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide [ No CAS ]

Reference： [1]Patent: US2015/231142,2015,A1

39
[ 656-46-2 ]
(S)-N-(1-(3-amino-2-hydroxypropyl)-2-tert-butyl-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide [ No CAS ]

Reference： [1]Patent: US2015/231142,2015,A1

40
[ 656-46-2 ]
(2,2-difluoro-1,3-benzodioxol-5-yl)methyl pyridin-2-yl carbonate [ No CAS ]
(2,2-difluoro-1,3-benzodioxol-5-yl)methyl 2-oxopyridine-1-carboxylate [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 111,p. 138 - 159

41
[ 33070-32-5 ]
[ 124-38-9 ]
[ 656-46-2 ]

Yield	Reaction Conditions	Operation in experiment
70%		Magnesium turnings (11.12g, 0.464mol) and anhydrous tetrahydrofuran (600 ml) were placed in a round-bottomed flask fitted with a mechanical stirrer, reflux condenser, pressure equalizing addition funnel and drying tube. 5-Bromo-2,2- difluoro-l,3-benzodioxole (lOOg) was added to the flask under nitrogen atmosphere. The temperature of the reaction mass was raised to 40C during initiation. Upon initiation, remaining 5-Bromo-2,2-difluoro-l,3-benzodioxole (lOOg) was added drop- wise to the reaction mass. The temperature of the reaction mass was maintained below 40C. The progress of the reaction was monitored by gas chromatography. The reaction mass was then cooled to 0C and carbon-dioxide gas was passed for 2 hours at 0C. The raction was monitored by liquid chromatography for completion. The reaction mass was quenched with 10% HC1 (230g). The organic layer was separated, concentrated to obtain solid. The solid was washed with water (50g) and dichloromethane (50g), filtered and dried at 60C under 50mmHg for 2 hours to obtain the title compound. Yield (%): 70 Purity (%): 99 (by liquid chromatography)

Reference： [1]Patent: WO2017/46816,2017,A2 .Location in patent: Page/Page column 10

42
[ 656-46-2 ]
N-((1R,3r,5S)-8-(4-aminocyclohexylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-2,2-difluorobenzo[d][1,3]dioxole-5-carboxamide trifluoroacetic acid salt [ No CAS ]

Reference： [1]Patent: KR2017/45749,2017,A

43
[ 656-46-2 ]
N-((1R,3r,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-2,2-difluorobenzo[d][1,3]dioxole-5-carboxamide [ No CAS ]

Reference： [1]Patent: KR2017/45749,2017,A

44
[ 656-46-2 ]
2,2-difluoro-N-((1R,3r,5S)-8-(4-oxocyclohexylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)benzo[d][1,3]dioxole-5-carboxamide [ No CAS ]

Reference： [1]Patent: KR2017/45749,2017,A

45
[ 656-46-2 ]
[ 207405-68-3 ]
tert-butyl (1R,3r,5S)-3-(2,2-difluoro-2H-1,3-benzo[d][1,3]dioxole-5-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 25℃; for 12h;	Into a 100-mL round-bottom flask was placed dichloromethane (50 mL), 2,2- difluoro-2H-1,3-benzo[d][1,3]dioxole-5-carboxylic acid (1.5 g, 7.42 mmol, 1.00 equiv), tert-butyl (1R,5S,7S)-7-amino-3-azabicyclo[3.3.2]decane-3-carboxylate (2.0 g, 7.86 mmol, 1.06 equiv), HATU (5.65 g), and TEA (2.25 g, 22.24 mmol, 3.00 equiv). The resulting solution was stirred for 12 h at 25oC. The resulting mixture was washed with 3x50 mL of H2O. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a silica gel column with PE: EA (1:1). This resulted in 3.0 g (92%) of tert-butyl(1R,5r,7S)-7-(2,2-difluoro-2H-1,3- benzo[d][1,3]dioxole-5-carboxamido)-3-azabicyclo[3.3.2]decane-3-carboxylate as a white solid

Reference： [1]Patent: KR2017/45749,2017,A .Location in patent: Paragraph 0826; 0829-0831

46
[ 135132-34-2 ]
[ 656-46-2 ]

Yield	Reaction Conditions	Operation in experiment
	With water; sodium hydroxide; for 5h;Reflux;	To the reaction tank was charged 820g of water,Sodium hydroxide 141g Stir the sodium hydroxide dissolved, add 5-cyano-2,2-difluoro pepper ring 162g,The reaction was refluxed 5h, cooled to 20 after the reaction, when the temperature dropped below 30 ,With a mass concentration of 30% hydrochloric acid system PH 2.The product was suction filtered, dried to 172g,2,2-difluoropentanoic acid content of 99.6%Yield 96.2%.

Reference： [1]Patent: CN105153106,2017,B .Location in patent: Paragraph 0026; 0028; 0032; 0036

47
[ 67-56-1 ]
[ 656-46-2 ]
[ 773873-95-3 ]

Yield	Reaction Conditions	Operation in experiment
94.2%	With thionyl chloride; for 4h;Reflux;	1197 g of methanol was put into a dry reaction tank,2,2-difluoro-piperonic acid 171 g,Stir so 2,2-difluoro-pepper acid dissolved, then add thionyl chloride 215g,Reflux reaction 4h, after the reaction was cooled to 20 ,Add 3.8kg of water, separate the lower organic layer,Vacuum distillation product 172g, which 2,2-difluoro-methyl benzoate content of 99.9%Yield 94.2%.

Reference： [1]Patent: CN105153106,2017,B .Location in patent: Paragraph 0029; 0033; 0034; 0037

48
[ 656-46-2 ]
C₁₈H₁₆N₂O₄*ClH [ No CAS ]
C₂₆H₁₈F₂N₂O₇ [ No CAS ]