[ CAS No. 2646-91-5 ] {[proInfo.proName]}

Name: 2646-91-5|2,3-Difluorobenzaldehyde|97%
Brand: Ambeed
SKU: A112534
Price: 5.0 USD
Availability: InStock
Rating: 91 (25 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

HazMat Fee +

There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

DV 2D 3D

3d Animation Molecule Structure of 2646-91-5

Structure of 2646-91-5 * Storage: {[proInfo.prStorage]}

Please Login or Create an Account to: See VIP prices and availability

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

* Shipping: {[proInfo.prShipping]}

For Research Only 120K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 2646-91-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 2646-91-5 ]

SDS Specification

Alternatived Products of [ 2646-91-5 ]

Product Details of [ 2646-91-5 ]

CAS No. :	2646-91-5	MDL No. :	MFCD00010292
Formula :	C₇H₄F₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WDBAXYQUOZDFOJ-UHFFFAOYSA-N
M.W :	142.10	Pubchem ID :	137664
Synonyms :

Calculated chemistry of [ 2646-91-5 ] Expand+

Physicochemical Properties

Num. heavy atoms :	10
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 :	31.75
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) :	-6.05 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.52
Log Po/w (XLOGP3) :	1.58
Log Po/w (WLOGP) :	2.62
Log Po/w (MLOGP) :	2.32
Log Po/w (SILICOS-IT) :	2.82
Consensus Log Po/w :	2.17

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.09
Solubility :	1.14 mg/ml ; 0.00805 mol/l
Class :	Soluble
Log S (Ali) :	-1.55
Solubility :	4.01 mg/ml ; 0.0282 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.88
Solubility :	0.188 mg/ml ; 0.00132 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.04

Safety of [ 2646-91-5 ]

Signal Word:	Danger	Class:	3
Precautionary Statements:	P261-P305+P351+P338	UN#:	1989
Hazard Statements:	H226-H315-H319-H335	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 2646-91-5 ]

* 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 [ 2646-91-5 ]
Downstream synthetic route of [ 2646-91-5 ]

[ 2646-91-5 ] Synthesis Path-Upstream 1~9

1
[ 2646-91-5 ]
[ 341-24-2 ]

Yield	Reaction Conditions	Operation in experiment
45%	at 180℃; for 10 h;	Hydrazine monohydrate (3 ml) was added to 2,3-difluorobenzaldehyde (1.85 g), and the mixture was heated at 180°C with stirring for 10 hr. The reaction mixture was cooled to room temperature, ethyl acetate and water were added thereto, and the organic layer was separated. The organic layer was washed with saturated brine, was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under the reduced pressure. The residue was purified by chromatography on silica gel developed with chloroform/acetone to give the title compound (790 mg, yield 45percent). ¹H-NMR (CD₃OD, 400 MHz): δ 7.08 - 7.12 (m, 2H), 7.56 - 7.59 (m, 1H), 8.10 (d, J = 3.4 Hz, 1H)
41%	at 150℃; for 3 h;	Reference Example 29 [0626] Step 1 [0627] Hydrazine monohydrate (10mL) was slowly added to Compound xii-1 (5g, 35.2mmol), and the mixture was stirred for 3 hours at 150 °C. The reaction mixture was concentrated in vacuo, and water was added to the mixture. The precipitated solids were collected by filtration to give Compound xii-2 (1.98g, Yield 41percent). [0628] ¹H-NMR (CDCl₃) δ: 10.40 (1H, br s), 7.32-7.28 (1H, m), 7.18-7.12 (2H, m).

Reference： [1] Patent: EP1870414, 2007, A1, . Location in patent: Page/Page column 23
[2] Patent: EP2752410, 2014, A1, . Location in patent: Paragraph 0626

2
[ 2646-91-5 ]
[ 6418-38-8 ]
[ 4519-39-5 ]

Reference： [1] Advanced Synthesis and Catalysis, 2005, vol. 347, # 7-8, p. 1027 - 1034

3
[ 2646-91-5 ]
[ 6418-38-8 ]
[ 4519-39-5 ]

Reference： [1] Advanced Synthesis and Catalysis, 2005, vol. 347, # 7-8, p. 1027 - 1034

4
[ 3828-49-7 ]
[ 2646-91-5 ]

Yield	Reaction Conditions	Operation in experiment
48.2%	at 120℃;	(1) Apparatus: The connection type of the tubular reactor is determined according to Fig. 2, and the pipe type is: (3a + 3c) DC type channel + inclined square cake type variable diameter flat pipe,Pipeline diameter and volume according to the flow rate and reaction time to determine,Heat transfer medium for the heat transfer oil.(2) 6.06 g of cobalt acetate and 6.06 g of sodium molybdate were respectively dissolved200 mg of 2,3-difluorotoluene and 200 ml of acetic acid to form a mixed solution at which time n (cobalt acetate): n (2,3-difluorotoluene) = 0.015: 1, 6.06 g of sodium bromide was dissolved in35percent H2O2 to form H2O2-acetic acid solution, then n (sodium bromide):N (2,3-difluorotoluene) = 0.015: 1,2,3-difluorotoluene-acetic acid solution with andH2O2-acetic acid solution at 5.56 ml / min and 11.11 ml / min, respectivelyOf the flow rate through the constant current pump into the continuous heat exchanger tube reactor,At this time n (H2O2): n (2,3-difluorotoluene) = 2: 1, using Figure 2 microchannel reactor,Control reaction temperature 120 , residence time 1500s. Export material 0 cooling,The reaction was quenched with difluoromethane. After GC analysis,The conversion of 2,3-difluorotoluene was 65.1percent and the yield of 2,3-difluorobenzaldehyde was 48.2percent.

Reference： [1] Patent: CN106748682, 2017, A, . Location in patent: Paragraph 0052-0054
[2] Kogyo Kagaku Zasshi, 1956, vol. 59, p. 1160[3] Chem.Abstr., 1958, p. 13265

5
[ 79-46-9 ]
[ 113211-94-2 ]
[ 2646-91-5 ]

Reference： [1] Tetrahedron Letters, 2005, vol. 46, # 27, p. 4535 - 4538

6
[ 2646-91-5 ]
[ 75853-18-8 ]

Yield	Reaction Conditions	Operation in experiment
20 g	at 0 - 50℃; for 1 h;	Step 1 (MW-Si):Sodium borohydride (5.3 g, 140.84 mmol) was slowly added in 3 equal portions (over 25 mm)to a solution of 2,3-difluorobenzaldehyde (20 g, 140.84 mmol) in methanol (200 mL) at 0°C.Due to the exothermic reaction the temperature raised up to ‘50°C. The reaction mixturewas stirred for 1 h and the solvent was evaporated under reduced pressure. Ethyl acetateand thereafter saturated ammonium chloride solution was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to afford 20 g of MW-Si as a colorless liquid, further used withoutany purification.

Reference： [1] Patent: WO2014/140279, 2014, A1, . Location in patent: Page/Page column 88; 169
[2] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1345 - 1360

7
[ 2646-91-5 ]
[ 113211-94-2 ]

Reference： [1] Patent: WO2014/140279, 2014, A1,

8
[ 2646-91-5 ]
[ 346592-74-3 ]

Reference： [1] Bioorganic and medicinal chemistry, 2004, vol. 12, # 9, p. 2251 - 2273
[2] Patent: WO2014/31784, 2014, A1,

9
[ 2646-91-5 ]
[ 633327-22-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	at 60℃; for 12 h;	j0617j To a stirred solution of 2,3-difluorobenzaldehyde (XVIII) (75.0 g, 528 mmol, 1.0 eq) in H2S04 (565 mL) was added NBS (113 g, 633 mmol, 1.2 eq) in portions at 60 °C. The resulting mixture was stirred at 60 °C for 12 hr. LC/MS showed the reaction was completed. The reaction mixture was poured into ice water and petroleum ether (500 mL) and stirred for 10 mm, the organic layer was separated and concentrated under vacuum to give cmde product. The residue was purified column chromatography silica gel (100percent petroleum ether) to give 5-bromo-2,3- difluorobenzaldehyde (XIX) (120 g, 543.0 mmol, quantitative yield). ESIMS found C7H3BrF2O mlz 221.1 (M+1).
100%	at 60℃; for 12 h;	[0617] To a stirred solution of 2,3-difluorobenzaldehyde (XVIII) (75.0 g, 528 mmol, 1.0 eq) in H₂SC>4 (565 mL) was added NBS (1 13 g, 633 mmol, 1.2 eq) in portions at 60 °C. The resulting mixture was stirred at 60 °C for 12 hr. LC/MS showed the reaction was completed. The reaction mixture was poured into ice water and petroleum ether (500 mL) and stirred for 10 min, the organic layer was separated and concentrated under vacuum to give crude product. The residue was purified column chromatography silica gel (100percent petroleum ether) to give 5-bromo-2,3- difluorobenzaldehyde (XIX) (120 g, 543.0 mmol, quantitative yield). ESIMS found C₇H₃BrF₂0 mlz 221.1 (M+l).
100%	at 60℃; for 12 h;	To a stirred solution of 2,3-difluorobenzaldehyde (XVIII) (75.0 g, 528 mmol, 1.0 eq) in H2SO4 (565 mL) was added NBS (113 g, 633 mmol, 1.2 eq) in portions at 60 °C. The resulting mixture was stirred at 60 °C for 12 hr. LC/MS showed the reaction was completed. The reaction mixture was poured into ice water and petroleum ether (500 mL) and stirred for 10 min, the organic layer was separated and concentrated under vacuum to give crude product. The residue was purified column chromatography silica gel (100percent petroleum ether) to give 5-bromo-2,3- difluorobenzaldehyde (XIX) (120 g, 543.0 mmol, quantitative yield). ESIMS found C₇H₃BrF₂0 mlz 221 A (M+l).

100%	at 60℃; for 12 h;	To a stirred solution of 2,3-difluorobenzaldehyde (XVIII) (75.0 g, 528 mmol, 1.0 eq) in H₂SC>4 (565 mL) was added NBS (1 13 g, 633 mmol, 1.2 eq) in portions at 60 °C. The resulting mixture was stirred at 60 °C for 12 hr. LC/MS showed the reaction was completed. The reaction mixture was poured into ice water and petroleum ether (500 mL) and stirred for 10 min, the organic layer was separated and concentrated under vacuum to give crude product. The residue was purified column chromatography silica gel (100percent petroleum ether) to give 5-bromo-2,3- difluorobenzaldehyde (XIX) (120 g, 543.0 mmol, quantitative yield). ESIMS found C₇H₃BrF₂0 mlz 221.1 (M+l).
100%	at 60℃; for 12 h;	To a stirred solution of 2,3-difluorobenzaldehyde (XXIII) (75.0 g, 528 mmol, 1.0 eq) in H₂SO₄(565 mL) was added NBS (113 g, 633 mmol, 1.2 eq) in portions at 60° C. The resulting mixture was stirred at 60° C. for 12 hr. LC/MS showed the reaction was completed. The reaction mixture was poured into ice water and petroleum ether (500 mL) and stirred for 10 min, the organic layer was separated and concentrated under vacuum to give crude product. The residue was purified column chromatography silica gel (100percent petroleum ether) to give 5-bromo-2,3-difluorobenzaldehyde (XXIV) (120 g, 543.0 mmol, quantitative yield). ESIMS found C₇H₃BrF₂O m/z 221.1 (M+1).
100%	at 60℃; for 12 h;	Step 1 (0813) To a stirred solution of 2,3-difluorobenzaldehyde (XXIII) (75.0 g, 528 mmol, 1.0 eq) in H₂SO₄(565 mL) was added NBS (113 g, 633 mmol, 1.2 eq) in portions at 60° C. The resulting mixture was stirred at 60° C. for 12 hr. LC/MS showed the reaction was completed. The reaction mixture was poured into ice water and petroleum ether (500 mL) and stirred for 10 min, the organic layer was separated and concentrated under vacuum to give crude product. The residue was purified column chromatography silica gel (100percent petroleum ether) to give 5-bromo-2,3-difluorobenzaldehyde (XXIV) (120 g, 543.0 mmol, quantitative yield). ESIMS found C₇H₃BrF₂O m/z 221.1 (M+1).
50%	at 60℃; for 3.33 h; Inert atmosphere	Step 1 followed the general procedure from Example 3 step 1. 2,3-difluorobenzaldehyde (200 mg, 1.408 mmol) was dissolved in concentrated H2S04 (0.64 mL) and heated to 60 00. To this was added N-bromosuccinimide (301 mg, 1.690 mmol) in three portions over a period of 20 mm. After being heated for 3 h under argon, the reaction mixture was poured into ice water. The product was extracted with hexanes, washed with water and brine, and then dried over anhydrous Na2SO4. Purification by flash chromatography yielded an orange liquid as 2,3- difluoro-5-bromobenzaldehyde (155 mg, 50percent yield), which was dissolved in 6 mL of methanol. To this stirring solution was added NaBH4 (32 mg, 0.84 mmol). The reaction was stirred for I h at room temperature. Then the reaction was diluted with ethyl acetate, washed with saturated aqueous NH4CI, followed by brine. The organic layer was dried over anhydrous Na2SO4, and evaporated under reduced pressure yielded 2,3-difluoro-5-bromobenzyl alcohol as a white solid (163 mg, 87percent yield). The boronate product was then obtained from 2,3-difluoro-5-bromobenzyl alcohol according to the general procedure of Example 1. The crude material was used for Suzuki coupling reaction without purification.
45%	at 60℃; for 4 h; Inert atmosphere	Compound 1 (5.0 g, 3.5 mmol) was dissolved in concentrated H2SO4 (16 mL) and heated to 60 °C. N-bromosuccinimide (7.5, 4.2 mmol) was added in three portions over a period of 30 min. After being heated for 3 h under N₂, the reaction mixture was poured into ice water. The product was extracted with EtOAc, washed with water and brine, and dried over Na₂S0₄. Purification by silica gel column chromatography (0-10percent EtOAc in PE) yielded an orange liquid as product 2 in 45percent yield. 1H NMR (400 MHz, CDCI3) δ 10.31 (d, 1H, / = 1.2 Hz), 7.80 - 7.99 (m, 1H), 7.64 - 7.60 (m, 1H).
45%	at 60℃; for 4 h; Inert atmosphere	Step I : 5-bromo-2,3-difluorobenzaldehyde 2,3-difluorobenzaldehyde (3.00 g, 21.22 mmol, 1.00 equivalent) was dissolved in sulfuric acid (18.4 mol/L, 10.20 mL, 8.89 equivalents) and was heated to 60° C within 40 minutes. At this time, 1-bromopyrrolidine-2,5-dione (4.51 g, 25.33 mmol, 1.20 equivalents) was added in three portions within 20 minutes. The mixture was heated for 3 hours in a nitrogen atmosphere. TLC and HPLC showed completion of the reaction. The reaction mixture was poured into ice water, subjected to extraction twice using petroleum ether (30 mL2, washed with water (30 mL2) and saturated brine (30 mL*2), and then concentrated under reduced pressure. The concentrated residue was purified by column chromatography (petroleum ether) to give the title compound (2.10 g, 9.50 mmol, 45.00percent yield) as a yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ 10.29 (s, 1H), 7.77 (br s, 1H), 7.65-7.54 (m, 1H).
23.5%	at 0 - 60℃; for 16 h;	To a stirred solution of 2,3-difluorobenzaldehyde (30 g, 211 mmol) in H₂SO₄ (120 mL) was added N-bromo succinamide (45 g, 253 mmol) at 0° C. The reaction mixture was stirred for 16 h at 60° C., after completion of reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. Organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography by using 0.8percent EtOAc in n-hexane to afford 5-bromo-2,3-difluorobenzaldehyde (11.7 g, 23.5percent) as a white solid
280 mg	Stage #1: at 20℃; Stage #2: at 45 - 50℃;	Add in 100mL three-necked bottles2,3-difluorobenzaldehyde (1 g, 7.04 mmol) and concentrated sulfuric acid (50 mL),Stir at room temperature to obtain a brownish yellow reaction solution.Slowly add NBS (1.05g, 5.90mmol) in batches, add,The temperature was raised to 45-50 ° C for 2-3 h.The reaction solution was slowly added dropwise to 200 mL of ice water, and extracted twice with ethyl acetate (50 mL×2).The organic phases were combined and washed twice with saturated brine.Dry over anhydrous sodium sulfate for 30 min, filter, and concentrate the filtrate under reduced pressure.Got 280mg. Raw material recovery.

Reference： [1] Patent: WO2017/24021, 2017, A1, . Location in patent: Paragraph 0616; 0617
[2] Patent: WO2017/24013, 2017, A1, . Location in patent: Paragraph 0616; 0617
[3] Patent: WO2017/24010, 2017, A1, . Location in patent: Paragraph 0616; 001
[4] Patent: WO2017/23986, 2017, A1, . Location in patent: Paragraph 0620; 0621
[5] Patent: US2016/75701, 2016, A1, . Location in patent: Paragraph 0812; 0813
[6] Patent: US2016/90380, 2016, A1, . Location in patent: Paragraph 0813
[7] Patent: WO2017/133670, 2017, A1, . Location in patent: Page/Page column 63; 64
[8] Patent: WO2017/133667, 2017, A1, . Location in patent: Page/Page column 183; 184
[9] Patent: WO2016/118825, 2016, A1, . Location in patent: Page/Page column 32
[10] Journal of the American Chemical Society, [11] Journal of the American Chemical Society, 2009, vol. 131, p. 5488 - 5494
[12] Patent: WO2013/96744, 2013, A1, . Location in patent: Page/Page column 229
[13] Patent: EP3269715, 2018, A1, . Location in patent: Paragraph 0272; 0273; 0274
[14] Patent: US2016/347717, 2016, A1, . Location in patent: Paragraph 0690; 0691
[15] Patent: US2012/71535, 2012, A1, . Location in patent: Page/Page column 57
[16] Patent: CN108707139, 2018, A, . Location in patent: Paragraph 0615; 0618; 0619; 0620

[ 2646-91-5 ] Synthesis Path-Downstream 1~50

1
[ 3828-49-7 ]
[ 2646-91-5 ]

Yield	Reaction Conditions	Operation in experiment
48.2%	With sodium molybdate; dihydrogen peroxide; cobalt(II) acetate; acetic acid; sodium bromide; at 120℃;	(1) Apparatus: The connection type of the tubular reactor is determined according to Fig. 2, and the pipe type is: (3a + 3c) DC type channel + inclined square cake type variable diameter flat pipe,Pipeline diameter and volume according to the flow rate and reaction time to determine,Heat transfer medium for the heat transfer oil.(2) 6.06 g of cobalt acetate and 6.06 g of sodium molybdate were respectively dissolved200 mg of <strong>[3828-49-7]2,3-difluorotoluene</strong> and 200 ml of acetic acid to form a mixed solution at which time n (cobalt acetate): n (<strong>[3828-49-7]2,3-difluorotoluene</strong>) = 0.015: 1, 6.06 g of sodium bromide was dissolved in35% H2O2 to form H2O2-acetic acid solution, then n (sodium bromide):N (<strong>[3828-49-7]2,3-difluorotoluene</strong>) = 0.015: 1,<strong>[3828-49-7]2,3-difluorotoluene</strong>-acetic acid solution with andH2O2-acetic acid solution at 5.56 ml / min and 11.11 ml / min, respectivelyOf the flow rate through the constant current pump into the continuous heat exchanger tube reactor,At this time n (H2O2): n (<strong>[3828-49-7]2,3-difluorotoluene</strong>) = 2: 1, using Figure 2 microchannel reactor,Control reaction temperature 120 , residence time 1500s. Export material 0 cooling,The reaction was quenched with difluoromethane. After GC analysis,The conversion of <strong>[3828-49-7]2,3-difluorotoluene</strong> was 65.1% and the yield of 2,3-difluorobenzaldehyde was 48.2%.

Reference： [1]Patent: CN106748682,2017,A .Location in patent: Paragraph 0052-0054
[2]Kogyo Kagaku zasshi / Journal of the Society of Chemical Industry,1956,vol. 59,p. 1160
Chem.Abstr.,1958,p. 13265

2
[ 2646-91-5 ]
[ 22259-53-6 ]
[1-(2,3-Difluoro-phenyl)-meth-(E)-ylidene]-(1H-indol-3-ylmethyl)-amine [ No CAS ]

Reference： [1]Archiv der Pharmazie,1994,vol. 327,p. 105 - 114

3
[ 2646-91-5 ]
[ 623-51-8 ]
ethyl 7-fluorobenzo[b]thiophene-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80.5%	With potassium carbonate In N,N-dimethyl-formamide at 0 - 70℃; for 17h;	4-1 [0504j To a solution of 4-1 (48 g, 0.34 mmol) and K2C03 (60 g, 0.5 mmol) at 0°C in DMF (200 mL) was added 4-2 (44 g, 0.37 mmol). The mixture was stirred at rt for 12 h, and then heated at 70°C for 5 h. After cooling to rt, the mixture was poured into water, and extracted with EA. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 4-4 (75 g, 80.5 %).
	With potassium carbonate In N,N-dimethyl-formamide at 20 - 60℃;

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2014/31784, 2014, A1 Location in patent: Paragraph 0504
[2]Matsunaga, Nobuyuki; Kaku, Tomohiro; Itoh, Fumio; Tanaka, Toshimasa; Hara, Takahito; Miki, Hiroshi; Iwasaki, Masahiko; Aono, Tetsuya; Yamaoka, Masuo; Kusaka, Masami; Tasaka, Akihiro [Bioorganic and medicinal chemistry, 2004, vol. 12, # 9, p. 2251 - 2273]

4
[ 2646-91-5 ]
[ 54016-70-5 ]
[ 762-42-5 ]
5-(2,3-difluoro-phenyl)-4-ethylamino-furan-2,3-dicarboxylic acid dimethyl ester [ No CAS ]

Reference： [1]Organic Letters,2005,vol. 7,p. 1343 - 1345

5
[ 79-46-9 ]
[ 113211-94-2 ]
1-(2,3-difluoro-phenyl)-2-methyl-2-nitro-propan-1-ol [ No CAS ]
[ 2646-91-5 ]

Reference： [1]Tetrahedron Letters,2005,vol. 46,p. 4535 - 4538

6
[ 2646-91-5 ]
[ 6418-38-8 ]
[ 4519-39-5 ]

Reference： [1]Advanced Synthesis and Catalysis,2005,vol. 347,p. 1027 - 1034

7
[ 2646-91-5 ]
[ 57260-71-6 ]
[ 851753-43-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate In 1,4-dioxane at 101℃; for 48h;
8.1%	With potassium carbonate In dimethyl sulfoxide at 95℃; for 12h; Inert atmosphere;	14.A Step A: Synthesis of tert-butyl 4-(2-fluoro-6-formylphenyl)piperazine-1-carboxylate To 2,3-difluorobenzaldehyde (2.00 g, 14.07 mmol) in dimethyl sulfoxide (12.0 mL) was added N-tert-butoxycarbonylpiperazine (2.62 g, 14.07 mmol) at room temperatureand potassium carbonate (2.33 g, 16.89 mmol),Under the protection of N2, the reaction was carried out at 95 degrees Celsius for 12 hours.After the reaction was completed, 50 mL of water and 50 mL of ethyl acetate were added to dilute, the layers were separated, and the organic phase was collected. The organic phase was washed with saturated brine (3 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10).350.0 mg of tert-butyl 4-(2-fluoro-6-formylphenyl)piperazine-1-carboxylate was obtained as a beige solid (yield: 8.1%).
	With potassium carbonate In DMF (N,N-dimethyl-formamide) at 110℃;	2.2A EXAMPLE 2.; 1-{4-[3-(2,4-DICHLOROPHENYL)-2R-(2-OXO-1-PYRROLIDINYL)PROPIONYL]-1- PIPERAZINYL}-2- {1 S- [3-AMINOPROPIONYLAMIDO]-3-METHYLBUTYL}-6-FLUOROBENZENE; Step 2A. 2-L4- (tert-Butoxycarbonyl)-1-piperazinvll-3-fluorobenzaldehyde 2a; To a solution of 2, 3-difluoro-benzaldehyde (10.0 g, 70.4 mmol) and 1-BOC- piperazine (19.7 g, 106 mmol) in 140 mL of DMF was added K2CO3 (97.1 g, 704 mmol). The reaction mixture was heated and stirred at 110 °C. After stirring overnight, the reaction mixture was cooled to room temperature and diluted with 200 mL of EtOAc. The mixture was filtered, and the filter was washed well with EtOAc (3 x 100 mL). The filtrate was washed with 5% aqueous HC1 (100 mL) and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with H20 (2 x 100 mL), brine (50 mL), dried (MgS04), and concentrated in vacuo. The residue was triturated with 3% EtOAc/Hexanes to give 2a as a yellow solid (21 g).

Reference： [1]Jiang, Wanlong; Chen, Chen; Marinkovic, Dragan; Tran, Joe A.; Chen, Caroline W.; Arellano, L. Melissa; White, Nicole S.; Tucci, Fabio C. [Journal of Organic Chemistry, 2005, vol. 70, # 22, p. 8924 - 8931]
[2]Current Patent Assignee: SHENZHEN SALUBRIS PHARMACEUTICALS CO., LTD. - WO2022/7866, 2022, A1 Location in patent: Page/Page column 36
[3]Current Patent Assignee: NEUROCRINE BIOSCIENCES INC - WO2005/42516, 2005, A2 Location in patent: Page/Page column 31

8
[ 2646-91-5 ]
[ 341-24-2 ]

Yield	Reaction Conditions	Operation in experiment
45%	With hydrazine; at 180℃; for 10h;	Hydrazine monohydrate (3 ml) was added to 2,3-difluorobenzaldehyde (1.85 g), and the mixture was heated at 180C with stirring for 10 hr. The reaction mixture was cooled to room temperature, ethyl acetate and water were added thereto, and the organic layer was separated. The organic layer was washed with saturated brine, was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under the reduced pressure. The residue was purified by chromatography on silica gel developed with chloroform/acetone to give the title compound (790 mg, yield 45%). 1H-NMR (CD3OD, 400 MHz): delta 7.08 - 7.12 (m, 2H), 7.56 - 7.59 (m, 1H), 8.10 (d, J = 3.4 Hz, 1H)
41%	With hydrazine hydrate; at 150℃; for 3h;	Reference Example 29 [0626] Step 1 [0627] Hydrazine monohydrate (10mL) was slowly added to Compound xii-1 (5g, 35.2mmol), and the mixture was stirred for 3 hours at 150 C. The reaction mixture was concentrated in vacuo, and water was added to the mixture. The precipitated solids were collected by filtration to give Compound xii-2 (1.98g, Yield 41%). [0628] 1H-NMR (CDCl3) delta: 10.40 (1H, br s), 7.32-7.28 (1H, m), 7.18-7.12 (2H, m).

Reference： [1]Patent: EP1870414,2007,A1 .Location in patent: Page/Page column 23
[2]Patent: EP2752410,2014,A1 .Location in patent: Paragraph 0626

9
[ 2646-91-5 ]
[ 346592-74-3 ]

Reference： [1]Bioorganic and medicinal chemistry,2004,vol. 12,p. 2251 - 2273
[2]Patent: WO2014/31784,2014,A1

10
[ 2646-91-5 ]
[ 550998-67-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / dimethylformamide / 20 - 60 °C 2: KOH / ethanol; H₂O / Heating
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 17 h / 0 - 70 °C 2: potassium hydroxide; water / ethanol / 2 h / Reflux

Reference： [1]Matsunaga, Nobuyuki; Kaku, Tomohiro; Itoh, Fumio; Tanaka, Toshimasa; Hara, Takahito; Miki, Hiroshi; Iwasaki, Masahiko; Aono, Tetsuya; Yamaoka, Masuo; Kusaka, Masami; Tasaka, Akihiro [Bioorganic and medicinal chemistry, 2004, vol. 12, # 9, p. 2251 - 2273]
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2014/31784, 2014, A1

11
[ 2646-91-5 ]
[ 112-02-7 ]
[ 342808-36-0 ]

Yield	Reaction Conditions	Operation in experiment
110 mg (4%)	With sodium hydroxide; In acetone;	Example 26 1,5-Bis-(2,3-difluorophenyl)-penta-1,4-dien-3-one To a solution of 0.5 g (8.61 mmol) of acetone and 2.51 g (17.65 mmol) of 2,3-difluoro benzaldehyde in 86 mL of a 0.25M solution of aqueous NaOH (21.52 mmol) was added 1.13 mL (0.86 mmol) of a 25% w/w aqueous solution of <strong>[112-02-7]cetyltrimethylammonium chloride</strong>. The mixture was allowed to stir vigorously at room temperature for 48 hours, at which point it was diluted with 100 ml of brine and extracted with two 75 mL portions of methylene chloride. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was recrystallized from ethyl acetate to provide 110 mg (4%) of a yellow powder.

Reference： [1]Patent: US2002/19382,2002,A1

12
[ 2646-91-5 ]
[ 120-35-4 ]
3-(2,3-Difluoro-benzylamino)-4-methoxy-N-phenyl-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 219 3-(2,3-Difluoro-benzylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 2,3-difluorobenzaldehyde as starting materials, which are commercially available from Aldrich; m.p. 134-135 C.

Reference： [1]Patent: US6268387,2001,B1

13
[ 617-35-6 ]
[ 2646-91-5 ]
[ 934-22-5 ]
[ 1024609-09-3 ]

Yield	Reaction Conditions	Operation in experiment
46%		Compound 467: 1 -(1 H-benzo[d]imidazol-6-yl)-5-(2,3-difluorophenyl)-3-hydroxy-4- methyl-1 H-pyrrol-2(5H)-one; 1 H-Benzoimidazol-5-ylamine (1 mmol) was dissolved in 5ml_ of dry EtOH and 2,3- difluorobenzaldehyd (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 CHC^/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: 0.15Og (46 %);1H-NMR (400 MHz, CD3OD), 1.78 (s, 3H, CH3), 6.06 (s, 1 H, CH-N), 6.94 - 7.17 (m, 3H, aro), 7.74 (s, 2H, benzimid), 8.08 (s, 1 H, benzimid), 9.27 (s, 1 H, benzimid), MS m/z 342.1 (M+H)+, HPLC (254 nm): purity 100 %molecular weight (g/mol): 341.3 Ki hQC (nM): 1 1.6

Reference： [1]Patent: WO2008/55945,2008,A1 .Location in patent: Page/Page column 188

14
[ 2646-91-5 ]
[ 633327-22-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-Bromosuccinimide; sulfuric acid; at 60℃; for 12h;	j0617j To a stirred solution of 2,3-difluorobenzaldehyde (XVIII) (75.0 g, 528 mmol, 1.0 eq) in H2S04 (565 mL) was added NBS (113 g, 633 mmol, 1.2 eq) in portions at 60 C. The resulting mixture was stirred at 60 C for 12 hr. LC/MS showed the reaction was completed. The reaction mixture was poured into ice water and petroleum ether (500 mL) and stirred for 10 mm, the organic layer was separated and concentrated under vacuum to give cmde product. The residue was purified column chromatography silica gel (100% petroleum ether) to give 5-bromo-2,3- difluorobenzaldehyde (XIX) (120 g, 543.0 mmol, quantitative yield). ESIMS found C7H3BrF2O mlz 221.1 (M+1).
100%	With N-Bromosuccinimide; sulfuric acid; at 60℃; for 12h;	[0617] To a stirred solution of 2,3-difluorobenzaldehyde (XVIII) (75.0 g, 528 mmol, 1.0 eq) in H2SC>4 (565 mL) was added NBS (1 13 g, 633 mmol, 1.2 eq) in portions at 60 C. The resulting mixture was stirred at 60 C for 12 hr. LC/MS showed the reaction was completed. The reaction mixture was poured into ice water and petroleum ether (500 mL) and stirred for 10 min, the organic layer was separated and concentrated under vacuum to give crude product. The residue was purified column chromatography silica gel (100% petroleum ether) to give 5-bromo-2,3- difluorobenzaldehyde (XIX) (120 g, 543.0 mmol, quantitative yield). ESIMS found C7H3BrF20 mlz 221.1 (M+l).
100%	With N-Bromosuccinimide; sulfuric acid; at 60℃; for 12h;	To a stirred solution of 2,3-difluorobenzaldehyde (XVIII) (75.0 g, 528 mmol, 1.0 eq) in H2SO4 (565 mL) was added NBS (113 g, 633 mmol, 1.2 eq) in portions at 60 C. The resulting mixture was stirred at 60 C for 12 hr. LC/MS showed the reaction was completed. The reaction mixture was poured into ice water and petroleum ether (500 mL) and stirred for 10 min, the organic layer was separated and concentrated under vacuum to give crude product. The residue was purified column chromatography silica gel (100% petroleum ether) to give 5-bromo-2,3- difluorobenzaldehyde (XIX) (120 g, 543.0 mmol, quantitative yield). ESIMS found C7H3BrF20 mlz 221 A (M+l).

100%	With N-Bromosuccinimide; sulfuric acid; at 60℃; for 12h;	To a stirred solution of 2,3-difluorobenzaldehyde (XVIII) (75.0 g, 528 mmol, 1.0 eq) in H2SC>4 (565 mL) was added NBS (1 13 g, 633 mmol, 1.2 eq) in portions at 60 C. The resulting mixture was stirred at 60 C for 12 hr. LC/MS showed the reaction was completed. The reaction mixture was poured into ice water and petroleum ether (500 mL) and stirred for 10 min, the organic layer was separated and concentrated under vacuum to give crude product. The residue was purified column chromatography silica gel (100% petroleum ether) to give 5-bromo-2,3- difluorobenzaldehyde (XIX) (120 g, 543.0 mmol, quantitative yield). ESIMS found C7H3BrF20 mlz 221.1 (M+l).
100%	With N-Bromosuccinimide; sulfuric acid; at 60℃; for 12h;	To a stirred solution of 2,3-difluorobenzaldehyde (XXIII) (75.0 g, 528 mmol, 1.0 eq) in H2SO4 (565 mL) was added NBS (113 g, 633 mmol, 1.2 eq) in portions at 60 C. The resulting mixture was stirred at 60 C. for 12 hr. LC/MS showed the reaction was completed. The reaction mixture was poured into ice water and petroleum ether (500 mL) and stirred for 10 min, the organic layer was separated and concentrated under vacuum to give crude product. The residue was purified column chromatography silica gel (100% petroleum ether) to give 5-bromo-2,3-difluorobenzaldehyde (XXIV) (120 g, 543.0 mmol, quantitative yield). ESIMS found C7H3BrF2O m/z 221.1 (M+1).
100%	With N-Bromosuccinimide; sulfuric acid; at 60℃; for 12h;	Step 1 (0813) To a stirred solution of 2,3-difluorobenzaldehyde (XXIII) (75.0 g, 528 mmol, 1.0 eq) in H2SO4 (565 mL) was added NBS (113 g, 633 mmol, 1.2 eq) in portions at 60 C. The resulting mixture was stirred at 60 C. for 12 hr. LC/MS showed the reaction was completed. The reaction mixture was poured into ice water and petroleum ether (500 mL) and stirred for 10 min, the organic layer was separated and concentrated under vacuum to give crude product. The residue was purified column chromatography silica gel (100% petroleum ether) to give 5-bromo-2,3-difluorobenzaldehyde (XXIV) (120 g, 543.0 mmol, quantitative yield). ESIMS found C7H3BrF2O m/z 221.1 (M+1).
50%	With N-Bromosuccinimide; sulfuric acid; at 60℃; for 3.33h;Inert atmosphere;	Step 1 followed the general procedure from Example 3 step 1. 2,3-difluorobenzaldehyde (200 mg, 1.408 mmol) was dissolved in concentrated H2S04 (0.64 mL) and heated to 60 00. To this was added N-bromosuccinimide (301 mg, 1.690 mmol) in three portions over a period of 20 mm. After being heated for 3 h under argon, the reaction mixture was poured into ice water. The product was extracted with hexanes, washed with water and brine, and then dried over anhydrous Na2SO4. Purification by flash chromatography yielded an orange liquid as 2,3- difluoro-5-bromobenzaldehyde (155 mg, 50% yield), which was dissolved in 6 mL of methanol. To this stirring solution was added NaBH4 (32 mg, 0.84 mmol). The reaction was stirred for I h at room temperature. Then the reaction was diluted with ethyl acetate, washed with saturated aqueous NH4CI, followed by brine. The organic layer was dried over anhydrous Na2SO4, and evaporated under reduced pressure yielded 2,3-difluoro-5-bromobenzyl alcohol as a white solid (163 mg, 87% yield). The boronate product was then obtained from 2,3-difluoro-5-bromobenzyl alcohol according to the general procedure of Example 1. The crude material was used for Suzuki coupling reaction without purification.
45%	With N-Bromosuccinimide; sulfuric acid; at 60℃; for 4h;Inert atmosphere;	Compound 1 (5.0 g, 3.5 mmol) was dissolved in concentrated H2SO4 (16 mL) and heated to 60 C. N-bromosuccinimide (7.5, 4.2 mmol) was added in three portions over a period of 30 min. After being heated for 3 h under N2, the reaction mixture was poured into ice water. The product was extracted with EtOAc, washed with water and brine, and dried over Na2S04. Purification by silica gel column chromatography (0-10% EtOAc in PE) yielded an orange liquid as product 2 in 45% yield. 1H NMR (400 MHz, CDCI3) delta 10.31 (d, 1H, / = 1.2 Hz), 7.80 - 7.99 (m, 1H), 7.64 - 7.60 (m, 1H).
45.00%	With N-Bromosuccinimide; sulfuric acid; at 60℃; for 4h;Inert atmosphere;	Step I : 5-bromo-2,3-difluorobenzaldehyde 2,3-difluorobenzaldehyde (3.00 g, 21.22 mmol, 1.00 equivalent) was dissolved in sulfuric acid (18.4 mol/L, 10.20 mL, 8.89 equivalents) and was heated to 60 C within 40 minutes. At this time, 1-bromopyrrolidine-2,5-dione (4.51 g, 25.33 mmol, 1.20 equivalents) was added in three portions within 20 minutes. The mixture was heated for 3 hours in a nitrogen atmosphere. TLC and HPLC showed completion of the reaction. The reaction mixture was poured into ice water, subjected to extraction twice using petroleum ether (30 mL2, washed with water (30 mL2) and saturated brine (30 mL*2), and then concentrated under reduced pressure. The concentrated residue was purified by column chromatography (petroleum ether) to give the title compound (2.10 g, 9.50 mmol, 45.00% yield) as a yellow liquid. 1H NMR (400 MHz, CDCl3) delta 10.29 (s, 1H), 7.77 (br s, 1H), 7.65-7.54 (m, 1H).
25%	With N-Bromosuccinimide; sulfuric acid; at 60℃;	NBS (7.50 g, 42.00 mmol) was added into 250 2,3-difluorobenzaldehyde (5.00 g, 35.20 mmol) in 251 concentrated sulfuric acid (37.7 mL), and the reaction was heated to 60 C. and the mixture was stirred overnight. After cooling to room temperature, it was added to 252 ice-water, stirred for 10 min, extracted with petroleum ether, washed with brine, and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the filtrate was separated on column chromatography (100% petroleum ether) to afford 2.3 g of an oil, yield was 25.0%. LC-MS(APCI): m/z=221.1 (M+1)
23.5%	With N-Bromosuccinimide; sulfuric acid; at 0 - 60℃; for 16h;	To a stirred solution of 2,3-difluorobenzaldehyde (30 g, 211 mmol) in H2SO4 (120 mL) was added N-bromo succinamide (45 g, 253 mmol) at 0 C. The reaction mixture was stirred for 16 h at 60 C., after completion of reaction (monitored by TLC), the reaction mixture was diluted with EtOAc. Organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography by using 0.8% EtOAc in n-hexane to afford 5-bromo-2,3-difluorobenzaldehyde (11.7 g, 23.5%) as a white solid
	With N-Bromosuccinimide; sulfuric acid; at 60℃; for 6.5h;Inert atmosphere;	Example 22; Preparation of 5-(But-1-yn-1-yl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Intermediate 38)Step 1: 5-Bromo-2,3-difluorobenzaldehyde To a solution of 2,3-difluorobenzaldehyde (42 g, 0.296 mol) in H2SO4 (150 mL), was added NBS (63 g, 0.354 mol) in three portions over a period of 30 minutes at 60 C. The resulting mixture was heated for 6 hours at this temperature under N2. Work-up: the reaction mixture was poured into ice water. Petroleum ether (300 mL) was added, and the mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with more petroleum ether (300 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-0.5% EtOAc in petroleum ether) to give 5-bromo-2,3-difluorobenzaldehyde (17.4 g). 1H NMR (300 MHz, CDCl3): delta 10.32 (s, 1H), 7.81-7.79 (m, 1H), 7.65-7.60 (m, 1H).
280 mg		Add in 100mL three-necked bottles2,3-difluorobenzaldehyde (1 g, 7.04 mmol) and concentrated sulfuric acid (50 mL),Stir at room temperature to obtain a brownish yellow reaction solution.Slowly add NBS (1.05g, 5.90mmol) in batches, add,The temperature was raised to 45-50 C for 2-3 h.The reaction solution was slowly added dropwise to 200 mL of ice water, and extracted twice with ethyl acetate (50 mL×2).The organic phases were combined and washed twice with saturated brine.Dry over anhydrous sodium sulfate for 30 min, filter, and concentrate the filtrate under reduced pressure.Got 280mg. Raw material recovery.

Reference： [1]Patent: WO2017/24021,2017,A1 .Location in patent: Paragraph 0616; 0617
[2]Patent: WO2017/24013,2017,A1 .Location in patent: Paragraph 0616; 0617
[3]Patent: WO2017/24010,2017,A1 .Location in patent: Paragraph 0616; 001
[4]Patent: WO2017/23986,2017,A1 .Location in patent: Paragraph 0620; 0621
[5]Patent: US2016/75701,2016,A1 .Location in patent: Paragraph 0812; 0813
[6]Patent: US2016/90380,2016,A1 .Location in patent: Paragraph 0813
[7]Patent: WO2017/133670,2017,A1 .Location in patent: Page/Page column 63; 64
[8]Patent: WO2017/133667,2017,A1 .Location in patent: Page/Page column 183; 184
[9]Patent: WO2016/118825,2016,A1 .Location in patent: Page/Page column 32
[10]Journal of the American Chemical Society,2009,vol. 131,p. 5488 - 5494
[11]Patent: WO2013/96744,2013,A1 .Location in patent: Page/Page column 229
[12]Patent: EP3269715,2018,A1 .Location in patent: Paragraph 0272; 0273; 0274
[13]Journal of Medicinal Chemistry,2019,vol. 62,p. 2690 - 2707
[14]Patent: US2019/152954,2019,A1 .Location in patent: Paragraph 0397; 0398
[15]Patent: US2016/347717,2016,A1 .Location in patent: Paragraph 0690; 0691
[16]Patent: US2012/71535,2012,A1 .Location in patent: Page/Page column 57
[17]Patent: CN108707139,2018,A .Location in patent: Paragraph 0615; 0618; 0619; 0620

15
[ 2646-91-5 ]
[ 1779-49-3 ]
[ 1080636-91-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere;

Reference： [1]Location in patent: experimental part Sung, Jin Cho; Jensen, Niels H.; Kurome, Toru; Kadari, Sudhakar; Manzano, Michael L.; Malberg, Jessica E.; Caldarone, Barbara; Roth, Bryan L.; Kozikowski, Alan P. [Journal of Medicinal Chemistry, 2009, vol. 52, # 7, p. 1885 - 1902]

16
[ 2646-91-5 ]
[ 1260381-83-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-Bromosuccinimide; sulfuric acid / 6.5 h / 60 °C / Inert atmosphere 2: potassium carbonate / 1,2-dimethoxyethane / 14 h / 40 °C 3: hydrazine hydrate / tetrahydrofuran / 84 h / 90 °C
	Multi-step reaction with 3 steps 1: sulfuric acid; N-Bromosuccinimide / 12 h / 60 °C 2: potassium carbonate / 1,2-dimethoxyethane / 15 h / 40 °C 3: hydrazine hydrate / tetrahydrofuran / 84 h / 90 °C
	Multi-step reaction with 3 steps 1: N-Bromosuccinimide; sulfuric acid / 16 h / 0 - 60 °C 2: potassium carbonate / N,N-dimethyl-formamide / 16 h / 40 °C 3: hydrazine hydrate / tetrahydrofuran / 12 h / 90 °C

	Multi-step reaction with 3 steps 1: sulfuric acid; N-Bromosuccinimide / 12 h / 60 °C 2: potassium carbonate / 1,2-dimethoxyethane / 15 h / 40 °C 3: tetrahydrofuran / 90 °C
	Multi-step reaction with 3 steps 1: sulfuric acid; N-Bromosuccinimide / 12 h / 60 °C 2: potassium carbonate / 1,2-dimethoxyethane / 15 h / 40 °C 3: hydrazine / tetrahydrofuran / 90 °C
	Multi-step reaction with 3 steps 1: sulfuric acid; N-Bromosuccinimide / 12 h / 60 °C 2: potassium carbonate / 1,2-dimethoxyethane / 15 h / 40 °C 3: hydrazine hydrate / tetrahydrofuran / 84 h / 90 °C
	Multi-step reaction with 3 steps 1: sulfuric acid; N-Bromosuccinimide / 12 h / 50 - 60 °C 2: potassium carbonate / 1,2-dimethoxyethane / 12 h / 60 °C 3: hydrazine / tetrahydrofuran / 48 h / 90 °C
	Multi-step reaction with 3 steps 1: sulfuric acid; N-Bromosuccinimide / 12 h / 60 °C 2: potassium carbonate / 1,2-dimethoxyethane / 12 h / 60 °C 3: hydrazine / tetrahydrofuran / 48 h / 90 °C
	Multi-step reaction with 3 steps 1: sulfuric acid; N-Bromosuccinimide / 12 h / 60 °C 2: potassium carbonate / 1,2-dimethoxyethane / 15 h / 40 °C 3: hydrazine hydrate / tetrahydrofuran / 84 h / 90 °C
	Multi-step reaction with 2 steps 1.1: sulfuric acid / 20 °C 1.2: 45 - 50 °C 2.1: hydrazine hydrate / 100 - 110 °C
	Multi-step reaction with 3 steps 1: N-Bromosuccinimide; sulfuric acid / 60 °C 2: potassium carbonate / 1,2-dimethoxyethane / 45 °C 3: hydrazine hydrate / tetrahydrofuran / 96 h / 90 °C
	Multi-step reaction with 3 steps 1: N-Bromosuccinimide; sulfuric acid / 60 °C 2: potassium carbonate / 1,2-dimethoxyethane / 45 °C 3: hydrazine hydrate / tetrahydrofuran / 0.17 h / 150 °C / Microwave irradiation

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2012/71535, 2012, A1
[2]Current Patent Assignee: BIOSPLICE THERAPEUTICS INC - US2016/90380, 2016, A1 Current Patent Assignee: BIOSPLICE THERAPEUTICS INC - WO2017/23986, 2017, A1
[3]Current Patent Assignee: EISAI CO LTD - US2016/347717, 2016, A1
[4]Current Patent Assignee: BIOSPLICE THERAPEUTICS INC - WO2017/24021, 2017, A1
[5]Current Patent Assignee: BIOSPLICE THERAPEUTICS INC - WO2017/24013, 2017, A1
[6]Current Patent Assignee: BIOSPLICE THERAPEUTICS INC - WO2017/24010, 2017, A1
[7]Current Patent Assignee: EUROPEAN MOLECULAR BIOLOGY LABORATORY; SAVIRA PHARMACEUTICALS GMBH - WO2017/133670, 2017, A1
[8]Current Patent Assignee: SAVIRA PHARMACEUTICALS GMBH; EUROPEAN MOLECULAR BIOLOGY LABORATORY - WO2017/133667, 2017, A1
[9]Current Patent Assignee: BIOSPLICE THERAPEUTICS INC - US2016/75701, 2016, A1
[10]Current Patent Assignee: BEIJING ADAMADLE BIOTECHNOLOGY LIABILITY - CN108707139, 2018, A
[11]Current Patent Assignee: SHENZHEN TARGETRX INC - US2019/152954, 2019, A1
[12]Current Patent Assignee: TSINGHUA UNIVERSITY (CHINA) - CN111303118, 2020, A

17
[ 17115-51-4 ]
[ 1694-31-1 ]
[ 2646-91-5 ]
tert-butyl 5-methyl-7-(2,3-difluorophenyl)-2,3,4,7-tetrahydrothieno[3,2-b]pyridine-6-carboxylate-1,1-dioxide [ No CAS ]