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Chemical Structure| 881674-56-2
Chemical Structure| 881674-56-2
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Product Details of [ 881674-56-2 ]

CAS No. :881674-56-2 MDL No. :MFCD11875867
Formula : C11H8FNO Boiling Point : -
Linear Structure Formula :- InChI Key :MQULPEUCGKEHEG-UHFFFAOYSA-N
M.W : 189.19 Pubchem ID :46908593
Synonyms :

Calculated chemistry of [ 881674-56-2 ]

Physicochemical Properties

Num. heavy atoms : 14
Num. arom. heavy atoms : 11
Fraction Csp3 : 0.0
Num. rotatable bonds : 2
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 51.57
TPSA : 32.86 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.08 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.92
Log Po/w (XLOGP3) : 1.94
Log Po/w (WLOGP) : 3.05
Log Po/w (MLOGP) : 1.57
Log Po/w (SILICOS-IT) : 3.63
Consensus Log Po/w : 2.42

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.68
Solubility : 0.391 mg/ml ; 0.00207 mol/l
Class : Soluble
Log S (Ali) : -2.25
Solubility : 1.05 mg/ml ; 0.00557 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.35
Solubility : 0.00837 mg/ml ; 0.0000443 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.95

Safety of [ 881674-56-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 881674-56-2 ]

* 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 [ 881674-56-2 ]
  • Downstream synthetic route of [ 881674-56-2 ]

[ 881674-56-2 ] Synthesis Path-Upstream   1~22

  • 1
  • [ 1240948-77-9 ]
  • [ 881674-56-2 ]
YieldReaction ConditionsOperation in experiment
84.4% With hydrogen; acetic acid In tetrahydrofuran; water at 15 - 25℃; for 4 h; In a four-necked flask, 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (10.0 g, 53.71 mmol) and THF (30 mL) were added and dissolved, and acetic acid (50 mL) and water (10 mL) were added.
After substitution with nitrogen gas, Raney-nickel (Kawaken Fine Chemicals Co., Ltd., NDHT-90, 5 mL) was added.
Then, the mixture was vigorously stirred under a hydrogen atmosphere at inside temperature 15-25° C. for about 4 hr.
After substitution with nitrogen gas, Raney-nickel was filtered off and the residue was washed with ethyl acetate (64 mL).
Ethyl acetate (36 mL) was added, 8N aqueous sodium hydroxide solution (87 mL) was added to the filtrate at an inside temperature 10-40° C. to adjust the pH to 6.5-7.5, and the mixture was partitioned.
The organic layer was washed with 5percent aqueous sodium hydrogen carbonate solution (50 mL) and 5percent brine (50 mL).
To the organic layer was added 5percent brine (50 mL), and the mixture was adjusted to pH 3.0-3.5 by adding 6N hydrochloric acid at room temperature, stirred at room temperature for 10 hr, and partitioned.
The organic layer was washed with 5percent brine (50 mL), and the reaction mixture was concentrated to about 35 g under reduced pressure at not more than 45° C. Furthermore, ethyl acetate (50 mL) was added to the concentrated solution, and the reaction mixture was concentrated to about 35 g under reduced pressure at not more than 45° C.
After stirring at room temperature for 1 hr, n-heptane (50 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hr.
Successively, the mixture was stirred at an inside temperature of 0-10° C. for 1 hr.
The precipitated crystals were collected by filtration, and washed with n-heptane (20 mL)/ethyl acetate (10 mL) cooled to 5° C.
The crystals were dried under reduced pressure at 50° C. until a constant weight was reached to give the title compound (8.6 g, yield 84.4percent).
1H-NMR (DMSO-d6, TMS, 500 MHz) δ (ppm): 6.91 (d, J=1.6 Hz, 1H), 7.21-7.31 (m, 3H), 7.75-7.80 (m, 2H), 9.76 (s, 1H), 12.17 (brs, 1H).
78%
Stage #1: With hydrogen; acetic acid In tetrahydrofuran; water at 15 - 25℃; for 3 h;
Stage #2: With water; sodium hydroxide In tetrahydrofuran; ethyl acetate at 10 - 35℃;
Stage #3: With hydrogenchloride; water In tetrahydrofuran; ethyl acetate at 15 - 25℃;
Example 3
5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde
5-(2-Fluorophenyl)-1H-pyrrole-3-carbonitrile (5.0 g, 26.9 mmol) and THF (33 ml) were added in a four neck flask, and the mixture was dissolved at the internal temperature of 15-25° C. Acetic acid (55 ml) and water (11 ml) were added.
After purging with nitrogen gas, Raney-nickel (Kawaken Fine Chemicals Co., Ltd., NDHT-90, 2.5 ml, wet weight 4 g) was added.
Under a hydrogen atmosphere, the mixture was vigorously stirred at the internal temperature of 15-25° C. for about 3 hr.
After purging with nitrogen gas, Raney-nickel was filtered off, and washed with ethyl acetate (50 ml).
5 N Aqueous sodium hydroxide solution (about 180 ml) was added to the filtrate at the internal temperature of 10-35° C. to adjust the mixture to pH 7-8 and the mixture was partitioned.
The organic layer was washed with 5percent aqueous sodium hydrogen carbonate solution (25 ml) and 5percent brine (25 ml).
Water (25 ml) was added to the organic layer, and the mixture was adjusted with 6 N hydrochloric acid to pH 3.0-3.5 at the internal temperature of 15-25° C.
After stirring overnight, the mixture was partitioned.
The organic layer was washed with 5percent brine (25 ml), concentrated under reduced pressure to about 18 g.
After increasing the internal temperature to 65-70° C., the mixture was cooled to the internal temperature of 45-55° C., and further stirred for 1 hr.
After cooling to the internal temperature of 15-25° C., n-heptane (25 ml) was added dropwise, and the mixture was stirred at the same temperature for 1 hr.
Furthermore, the mixture was stirred at the internal temperature of 0-10° C. for 1 hr.
The precipitated crystals were collected by filtration, washed with ethyl acetate:n-heptane (1:2, 15 ml), and dried under reduced pressure at 50° C. until a constant weight was reached to give the title compound (23.9 g, yield 78percent).
1H-NMR (300 MHz, DMSO-d6) δ (ppm): 6.91 (d, J=1.6 Hz, 1H), 7.21-7.31 (m, 3H), 7.75-7.80 (m, 2H), 9.76 (s, 1H), 12.17 (brs, 1H).
elemental analysis (C11H8NOF). Calculated: C, 69.83; H, 4.26; N, 7.40; O, 8.46; F, 10.04.Found: C, 69.91; H, 4.27; N, 7.33.melting point 123.0-126.0° C. dec.
51.5% With formic acid; water; hydrogen In tetrahydrofuran for 2.5 h; Compound (4) (6.62g, 35.6mmol), tetrahydrofuran (45ml), formic acid (36.5 ml), water (15ml), and Raney nickel (397.2um, wet weight 5.3g) was added to the reaction flask. In a hydrogen atmosphere (0.1 MPa) and room humidity, the reaction was stirred for 2.5 hours. After the reaction was complete, the system was purged with nitrogen, the solution was filtered and washed with ethyl acetate (25 ml x 2). The filtrate was adjusted to pH 6 to 7 with 5N aqueous sodium hydroxide under ice-cooling. After phase separation, the ethyl acetate layer was collected and the aqueous layer was extracted again with ethyl acetate (25 ml). The ethyl acetate layers were combined, washed sequentially with saturated aqueous sodium bicarbonate and saturated brine, dissolved in ethyl acetate (20 ml), stirred on 100 to 200 mesh silica gel and spin dried. The resulting solution was purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 5: 1 to 3: 1) and dried under reduced pressure to give a pale yellow solid (3.47 g, yield 51.5percent).
42% With hydrogen; acetic acid In tetrahydrofuran; water at 20℃; for 2 h; 1 g of the intermediate V-1 was dissolved in a mixed solution of 20 ml of tetrahydrofuran, 6 ml of acetic acid and 1 ml of water, then 1 ml of Raney nickel was added, hydrogen gas was introduced, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, to give a compound of Formula VI-1, 427 mg of a white solid, yield 42percent

Reference: [1] Patent: US2018/186736, 2018, A1, . Location in patent: Paragraph 0139; 0140; 0141
[2] Patent: US2011/306769, 2011, A1, . Location in patent: Page/Page column 28
[3] Patent: CN106432191, 2017, A, . Location in patent: Paragraph 0019; 0022; 0023
[4] Patent: CN108558831, 2018, A, . Location in patent: Paragraph 0161-0164
  • 2
  • [ 881674-58-4 ]
  • [ 881674-56-2 ]
YieldReaction ConditionsOperation in experiment
95.1% With sodium bromate; sulfuric acid; bromine; sodium bromide In dichloromethane; water; butan-1-ol at 0 - 5℃; for 3.5 h; Sodium bromate was added 52g (0.34mol) in a beaker, 400ml of water and dissolved with stirring, as a backup solution, the other solution of (5- (2-fluorophenyl) lH-pyrrol-3-yl) in a 3000 ml three-necked flask - methanol (6) 191g (1.0mol), dichloromethane 400ml, n-butanol 400ml, 35percent sulfuric acid 20g (0.07mol), sodium bromide 1.2g, ice-salt bath to 0 ~ 5 , bromine was added dropwise sodium stock solution, an ice-salt bath after the addition stirring was continued for 3.5h, TLC detection starting material the reaction is completed, the reaction solution was transferred to a single neck flask, under reduced pressure to remove most of the organic solvent was concentrated under rotation, the precipitated yellow solid was cooled in a water bath with stirring 0.5h, yellow solid was collected by filtration, dried under reduced pressure to give 5- (2-fluorophenyl) lH-pyrrole-3-carbaldehyde 180g, (HPLC content: 98.4percent), yield 95.1percent.
92% With [bis(acetoxy)iodo]benzene In dichloromethane at 20℃; for 12 h; In 2000ml reaction flask was added Compound VII 100g, was added methylene chloride 800ml, iodine 177g, stirred at room temperature for 12h, the reaction was completed, filtered through celite, diatomaceous earth leached with 60ml of dichloromethane, The dichloromethane was concentrated to dryness, 400ml isopropanol was added, stirred overnight, a solid precipitated, cooled to 0 ~ 10 °C, incubated for 1h, suction filtered to give a brown solid 91 g, namely 5- (2-fluorophenyl ) -1H-pyrrole-3-carbaldehyde in 92percent yield and 99.2percent purity.
60% With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide In acetonitrile at 20℃; for 1.5 h; Reference Example 17 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde; A solution (220 mL) of ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate (11.6 g) in tetrahydrofuran was cooled to -78° C., and a 1.5 mol/L solution (100 mL) of diisobutylaluminum hydride in toluene was added dropwise over 10 min. The mixture was stirred at -78° C. for 1 hr and water (10 mL) was added dropwise over 2 min. The mixture was allowed to warm to room temperature and the mixture was stirred for 2 hr. The reaction mixture was filtered by adding celite and anhydrous magnesium sulfate and concentrated under reduced pressure to give a pale-yellow oil (yield 8.3 g). To a solution (220 mL) of the obtained pale-yellow oil (8.30 g) in acetonitrile were added tetra-n-propylammonium perruthenate (1.75 g), N-methylmorpholine N-oxide (13.5 g) and molecular sieves 4A powder (5 g), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3-->1:1) to give the title compound as yellow crystals (yield 5.6 g, 60percent). 1H-NMR (CDCl3) δ: 7.07-7.28 (4H, m), 7.52-7.54 (1H, m), 7.61-7.67 (1H, m), 9.49 (1H, brs), 9.86 (1H, s).
Reference: [1] Patent: CN104356043, 2016, B, . Location in patent: Paragraph 0020-0021
[2] Patent: CN106243008, 2016, A, . Location in patent: Paragraph 0049; 0050; 0051; 0052
[3] Patent: US2007/60623, 2007, A1, . Location in patent: Page/Page column 22
[4] Patent: WO2006/36024, 2006, A1, . Location in patent: Page/Page column 151-152; 288
[5] Journal of Medicinal Chemistry, 2012, vol. 55, # 9, p. 4446 - 4456
  • 3
  • [ 881674-06-2 ]
  • [ 881674-56-2 ]
YieldReaction ConditionsOperation in experiment
60%
Stage #1: With diisobutylaluminium hydride In tetrahydrofuran; toluene at -78℃; for 1.16667 h;
Stage #2: With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide In acetonitrile at 10 - 35℃; for 1.5 h; Molecular sieve
Reference Example 111
5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde
A solution (220 mL) of ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate (11.6 g) in tetrahydrofuran was cooled to -78°C, and a 1.5 mol/L solution (100 mL) of diisobutylaluminum hydride in toluene was added dropwise over 10 min.
The mixture was stirred at -78°C for 1 hr and water (10 mL) was added dropwise over 2 min.
The mixture was allowed to warm to room temperature and stirred for 2 hr.
To the reaction mixture were added celite and anhydrous magnesium sulfate and the mixture was filtered.
The filtrate was concentrated under reduced pressure to give a pale-yellow oil (yield 8.30 g).
To a solution (220 mL) of the obtained pale-yellow oil (8.30 g) in acetonitrile were added tetra-n-propylammonium perruthenate (1.75 g), N-methylmorpholine N-oxide (13.5 g) and molecular sieves 4A powder (5 g), and the mixture was stirred at room temperature for 1.5 hr.
The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate= 7:3→1:1) to give the title compound as yellow crystals (yield 5.6 g, 60percent).
1H-NMR (CDCl3)δ: 7.07-7.28 (4H, m), 7.52-7.54 (1H, m), 7.61-7.67 (1H, m), 9.49 (1H, brs), 9.86 (1H, s).
60%
Stage #1: With diisobutylaluminium hydride In tetrahydrofuran; water; toluene at -78 - 20℃; for 2 h;
Stage #2: With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide In acetonitrile at 20℃; for 1.5 h; Molecular sieve
Diisobutyl aluminum hydride 2.4ml dissolved in toluene, placed at -78 , take 2.3g dissolved in 100ml of tetrahydrofuranWas added dropwise to the reactor. After stirring for 1 hour, 2 ml of water was added slowly, and the mixture was stirred at room temperature for 1 hour.Adding anhydrous magnesium sulfate, filtering and concentrating the filtrate to dryness, dissolving in 45ml of acetonitrile, adding 2.36g of NMO,0.46g TPAP, molecular sieves, reaction at room temperature for 1.5 hours, the filtrate filtered diatomite, vacuum concentration, eluentWith hexane: ethyl acetate = 4: 1-1: 1 over the column that 1.1g, 60percent yield.
Reference: [1] Patent: EP2336107, 2015, B1, . Location in patent: Paragraph 0285
[2] Patent: CN105440019, 2016, A, . Location in patent: Paragraph 0042; 0043
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 9, p. 4446 - 4456
  • 4
  • [ 881676-32-0 ]
  • [ 445-29-4 ]
  • [ 881674-56-2 ]
YieldReaction ConditionsOperation in experiment
96.5% With bis-triphenylphosphine-palladium(II) chloride; 1,10-Phenanthroline; copper (I) acetate; sodium hydroxide In dimethyl sulfoxide at 140℃; for 5 h; Inert atmosphere Dimethyl sulfoxide (200 mL) was added to a 500 mL three-neck flask, and 2-fluorobenzoic acid (II) (14.2 g, 0.1 mol) was added under nitrogen.5-bromopyrrole-3-carbaldehyde (III) (35.5 g, 0.2 mol), sodium hydroxide (40.1 g, 1 mol), Pd(PPh3)2Cl2 (14.1 g, 0.02 mol), CuOAc (4.9 g, 0.04 mol) ,1,10-Phenanthroline (7.3g, 0.04mol), stirring, heating to 140°C, reaction for 5h,The reaction was completed by HPLC (2-fluorobenzoic acid (II) content is less than 1percent), the temperature was lowered to 20°C, the pH was adjusted to 6 with 5percent aqueous hydrochloric acid solution, and the solid was slowly precipitated by adding water.The solid was extracted with ethyl acetate (50 mL X 3).The resulting organic phase was washed with saturated sodium bicarbonate solution (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to 80 g and re-crystallized by the dropwise addition of petroleum ether (150 mL).Filtration drying gave a reddish solid product (18.5 g, yield: 96.5percent based on 2-fluorobenzoic acid (II)).
Reference: [1] Patent: CN107935902, 2018, A, . Location in patent: Paragraph 0044-0055
  • 5
  • [ 881676-32-0 ]
  • [ 1993-03-9 ]
  • [ 881674-56-2 ]
YieldReaction ConditionsOperation in experiment
82.8% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; N,N-dimethyl-formamide at 105℃; for 20 h; Inert atmosphere Weigh 15.0 g (0.086 mol) of 5-bromopyrrole-3-carbaldehyde, 19.0 g (0.136 mol) of 2-fluorophenylboronic acid, 15.0 g of potassium carbonate in a four-necked flask, and add 100 g of DMF and 40 g of water in a nitrogen atmosphere. A catalytic amount of tetrakis(triphenylphosphine)palladium was added thereto, and the temperature was raised to 105 ° C, and the reaction was carried out for 20 hours. After the reaction was completed, the temperature was lowered to room temperature, diluted with water, and extracted with ethyl acetate. The extract was dried, suction filtered, concentrated and weighed. Crystallization gave 13.5 g of gray solid 1, yield 82.8percent, purity 99.94percent
Reference: [1] Patent: CN109006823, 2018, A, . Location in patent: Paragraph 0060; 0062; 0070; 0071
  • 6
  • [ 312307-38-3 ]
  • [ 881674-56-2 ]
  • [ 1240948-77-9 ]
YieldReaction ConditionsOperation in experiment
38.6% With water; hydrogen; acetic acid In tetrahydrofuran at 45 - 50℃; for 5 h; Example 52
[2-(2-Fluorophenyl)-2-oxoethyl]propanedinitrile (2.00 g, 9.89 mmol), acetic acid (22 ml) and THF (22 ml) were weighed and dissolved (under an argon atmosphere).
Then, Raney-nickel (1 ml) and water (2 ml) were weighed and added, and the mixture was purged with hydrogen.
This was reacted at 45-50° C. for about 5 hr.
Quantification of the filtrate by HPLC gave 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (718 mg, yield 38.6percent) and 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (277 mg, yield 14.8percent).
Reference: [1] Patent: US2011/306769, 2011, A1, . Location in patent: Page/Page column 39
  • 7
  • [ 114615-82-6 ]
  • [ 881674-06-2 ]
  • [ 881674-56-2 ]
Reference: [1] Patent: EP1803709, 2007, A1,
  • 8
  • [ 312307-38-3 ]
  • [ 881674-56-2 ]
Reference: [1] Patent: US2011/306769, 2011, A1,
[2] Patent: US2011/306769, 2011, A1,
[3] Patent: US2011/306769, 2011, A1,
[4] Patent: US2011/306769, 2011, A1,
[5] Patent: US2011/306769, 2011, A1,
[6] Patent: US2011/306769, 2011, A1,
[7] Patent: CN106432191, 2017, A,
[8] Patent: US2018/186736, 2018, A1,
[9] Patent: CN108558831, 2018, A,
  • 9
  • [ 1240948-72-4 ]
  • [ 881674-56-2 ]
Reference: [1] Patent: US2011/306769, 2011, A1,
[2] Patent: CN106432191, 2017, A,
[3] Patent: CN108558831, 2018, A,
  • 10
  • [ 655-15-2 ]
  • [ 881674-56-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 9, p. 4446 - 4456
[2] Patent: EP2336107, 2015, B1,
[3] Patent: CN105440019, 2016, A,
[4] Patent: CN108558831, 2018, A,
  • 11
  • [ 445-27-2 ]
  • [ 881674-56-2 ]
Reference: [1] Patent: EP2336107, 2015, B1,
[2] Patent: CN106432191, 2017, A,
[3] Patent: CN106243008, 2016, A,
[4] Patent: CN108558831, 2018, A,
  • 12
  • [ 1240948-81-5 ]
  • [ 881674-56-2 ]
Reference: [1] Patent: US2011/306769, 2011, A1,
  • 13
  • [ 1240948-83-7 ]
  • [ 881674-56-2 ]
Reference: [1] Patent: US2011/306769, 2011, A1,
  • 14
  • [ 1240949-27-2 ]
  • [ 881674-56-2 ]
Reference: [1] Patent: US2011/306769, 2011, A1,
  • 15
  • [ 881673-98-9 ]
  • [ 881674-56-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 9, p. 4446 - 4456
[2] Patent: EP2336107, 2015, B1,
[3] Patent: CN105440019, 2016, A,
  • 16
  • [ 881674-01-7 ]
  • [ 881674-56-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 9, p. 4446 - 4456
[2] Patent: EP2336107, 2015, B1,
  • 17
  • [ 1428932-17-5 ]
  • [ 881674-56-2 ]
Reference: [1] Patent: CN106243008, 2016, A,
  • 18
  • [ 7126-39-8 ]
  • [ 881674-56-2 ]
Reference: [1] Patent: CN109006823, 2018, A,
  • 19
  • [ 16133-25-8 ]
  • [ 881674-56-2 ]
  • [ 881677-11-8 ]
YieldReaction ConditionsOperation in experiment
90.6% With dmap; N-ethyl-N,N-diisopropylamine In acetonitrile at 20 - 50℃; for 2 h; Take 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde 300 g, 4-dimethylaminopyridine 37.5 g, N,N-diisopropylethylamine 300 g, 1L acetonitrile, and add to the reaction flask.300 g of pyridine-3-sulfonyl chloride was dissolved in 1L of acetonitrile, and added dropwise to the above reaction system at 20-30[deg.] C., and the addition was completed in about 1 hour.After the dripping, the system was heated to 40-50°C, and the reaction was continued for 1 hour until the raw material was consumed completely.The system was cooled down to 30° C., and 1.8 L of purified water was added to quench the reaction. The pH was adjusted to 4 to 5 with 0.5 mol/L HCl, and a yellow solid precipitated.To the system, 3.6 L of purified water was added and stirred at 0 to 10C for 1 hour.After suction filtration, the filter cake was washed with 900 ml of acetonitrile: purified water (1:2) and 900 ml of purified water, and dried under reduced pressure at 50° C. to obtain 475 g of a brown powdery solid with a yield of 90.6percent.
88.7% With dmap; triethylamine In acetonitrile at 45℃; for 1.5 h; Example 1 (chlorobenzene solvent) 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0141) Pyridine-3-sulfonic acid (10.7 g, 68.5 mmol) and phosphorus pentachloride (15.7 g, 75.4 mmol) were suspended in chlorobenzene (15 mL) at room temperature. After heating and stirring at an inside temperature of 105±5°C for about 3 hr, the mixture was cooled to room temperature. Toluene (50 mL) and water (30 mL) were added into another kolben, and the mixture was cooled to an inside temperature of 5±5°C. The reaction solution was added dropwise at not more than an inside temperature of 15°C, and the dropping funnel was washed well with a mixed solution of toluene and water (1:1, 20 mL). After cooling to an inside temperature of 5±5°C, 50percent aqueous potassium carbonate solution (39 mL) was added dropwise at not more than an inside temperature of 20°C, and the mixture was adjusted to pH 7.5±0.5. After partitioning at room temperature, the organic layer was washed with 5percent brine (40 mL), and concentrated to about 20 mL under reduced pressure. Toluene (40 mL) was added and the mixture was concentrated again to about 20 mL. An operation of adding acetonitrile (40 mL) and concentrating the mixture to about 20 mL was repeated three times to give an acetonitrile solution of pyridine-3-sulfonylchloride (quantified yield 10.7 g, 87.9percent, total amount 20.3 g, 52.7 w/wpercent acetonitrile solution). (0142) To the acetonitrile solution (total amount) of pyridine-3-sulfonylchloride obtained above were added acetonitrile (45 mL), 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (10.0 g, 52.9 mmol), N,N-dimethylpyridin-4-amine (0.646 g, 5.29 mmol) and triethylamine (10.4 mL, 74.1 mmol), and the mixture was heated to an inside temperature of 45±5°C. After stirring at an inside temperature of 45±5°C for 1.5 hr, the mixture was cooled to room temperature, and water (30 mL) was added dropwise. The mixture was adjusted to pH 4 - 5 with 0.5M hydrochloric acid (about 20 mL). The seed crystal of the title compound was added and, after confirmation of crystal precipitation, water (60 mL) was added dropwise. After stirring at room temperature for 30 min and at 5±5°C for 1 hr, the precipitated crystals were collected by filtration. The crystals were washed twice with a mixed solution of acetonitrile and water (1:2, 30 mL) cooled to 5±5°C in advance, and dried at an outer temperature of 50°C under reduced pressure to give the title compound (15.5 g, isolation yield 88.7percent). 1H NMR (500 MHz, CDCl3) δ 6.68 (d, J = 1.6 Hz, 1H), 7.02 (dd, J = 8.2, 8.2 Hz, 1H), 7.14-7.19 (m, 2H), 7.38 (dd, J = 8.2, 4.9 Hz, 1H), 7.44-7.48 (m, 1H), 7.72 (ddd, J = 8.2, 2.5, 1.6 Hz, 1H), 8.17 (d, J = 1.9 Hz, 1H), 8.59 (d, J = 1.9 Hz, 1H), 8.82 (dd, J = 4.7, 1.6 Hz, 1H), 9.90 (s, 1H).
87.9% With dmap; N,N-diethyl-N-isopropylamine In acetonitrile at 15 - 50℃; for 3 h; Large scale Volonadezan Intermediate II 2.0Kg, N,N-dimethyl-4-aminopyridine 109g, Diethylisopropylamine 1.9Kg Acetonitrile 16L, pyridine-3-sulfonyl chloride 1.9Kg Acetonitrile 6L And then added dropwise at a temperature of 15°C to 25°C,After dripping, heat to 40°C to 50°C and stir for 3 hours.After cooling to 0 ~ 10 °C, add 12 L of water dropwise, cool to 0 ~ 10 °C, and stir for 1 hour.Filtration, drying at 40° C. to 50° C. (-0.08 to −1.0 MPa) for 8 to 12 hours gives Warnarazan Intermediate III 3.07 Kg with a yield of 87.9percent, which is directly input to the next step.
87% With dmap; N-ethyl-N,N-diisopropylamine In acetonitrile at 40 - 50℃; for 1 h; 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (7.0 g, 37.00 mmol), N,N-dimethylpyridine-4-amine (0.902 g, 7.38 mmol), diisopropylethylamine (6.69 g, 51.80 mmol) and acetonitrile (28 mL) were added to a four-necked flask, then pyridine-3-sulfonyl chloride (7.89 g, 44.42 mmol) was added dropwise, and the mixture was washed well with acetonitrile (3.5 mL).
The mixture was stirred at an inside temperature of 40-50° C. for about 1 hr, and cooled to an inside temperature of 25-35° C., and water (21 mL) was added dropwise at the same temperature.
Then the mixture was adjusted to pH 4-5 at room temperature with 0.5N hydrochloric acid (8 mL), and water (41 mL) was added dropwise at room temperature.
After stirring at room temperature for 30 min, the inside temperature was cooled to 0-10° C., and the mixture was stirred for 1 hr.
The precipitated crystals were collected by filtration, washed with acetonitrile (14 mL)/water (28 mL) cooled to 5° C., and dried under reduced pressure at 50° C. until a constant weight was reached to give the title compound (10.6 g, yield 87.0percent).
1H-NMR (CDCl3, TMS, 500 MHz) δ (ppm): 6.68 (d, J=1.6 Hz, 1H), 7.02 (dd, J=8.2, 8.2 Hz, 1H), 7.14-7.19 (m, 2H), 7.38 (dd, J=8.2, 4.9 Hz, 1H), 7.44-7.48 (m, 1H), 7.72 (ddd, J=8.2, 2.5, 1.6 Hz, 1H), 8.17 (d, J=1.9 Hz, 1H), 8.59 (d, J=1.9 Hz, 1H), 8.82 (dd, J=4.7, 1.6 Hz, 1H), 9.90 (s, 1H).
86.7% With N-ethyl-N,N-diisopropylamine In acetonitrile at 40 - 50℃; for 1.5 h; Example 4
5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde
5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (5.00 g, 26.43 mmol), N,N-dimethylpyridin-4-amine (0.65 g, 5.29 mmol), diisopropylethylamine (4.78 g, 37.00 mmol) and acetonitrile (18.5 ml) were added in a four neck flask, and a solution of pyridine-3-sulfonyl chloride (5.63 g, 31.71 mmol) in acetonitrile (5 ml) was added.
Acetonitrile (1.5 ml) was further added, and the mixture was stirred at the internal temperature of 40-50° C. for 1.5 hr.
The internal temperature was cooled to 30° C., and water (15 ml) was added dropwise.
The mixture was adjusted to pH 4-5 with 0.5 N hydrochloric acid.
Seed crystals (2.5 mg) of the title compound were added, and then water (about 30 ml) was added dropwise.
After stirring at the internal temperature of 20-30° C. for 0.5 hr, the internal temperature was cooled to 0-10° C., and the mixture was stirred for 1 hr.
The precipitated crystals were collected by filtration, washed with a cold mixed solution of acetonitrile and water (1:2, 7.5 ml), and water (7.5 ml*2), and dried under reduced pressure at 50° C. until a constant weight was reached to give the title compound (7.57 g, yield 86.7percent).
1H-NMR (300 MHz, CDCl3) δ (ppm): 6.68 (d, J=1.7 Hz, 1H), 7.01-7.05 (m, 1H), 7.16-7.18 (m, 2H), 7.37-7.40 (m, 1H), 7.45-7.51 (m, 1H), 7.69-7.72 (m, 1H), 8.15 (d, J=1.8 Hz, 1H), 8.58 (d, J=1.7 Hz, 1H), 8.82 (dd, J=4.8, 1.5 Hz, 1H), 9.90 (s, 1H).
elemental analysis (C16H11N2O3SF). Calculated: C, 58.17; H, 3.36; N, 8.48; O, 14.53; S, 9.71; F, 5.75.Found: C, 58.32; H, 3.46; N, 8.54; S, 9.76; F, 5.62.melting point 106-108° C.
86.6% With dmap; triethylamine In dichloromethane for 2 h; 10.00 g of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde, 1.29 g of 4-dimethylaminopyridine (DMAP), 7.49 g of triethylamine, and 1 L of dichloromethane were put into the reactor, and the temperature was reduced by stirring. 11.26 g of pyridine-3-sulfonyl chloride was added dropwise, and the reaction was stirred for 2 hours after the dropwise addition.Add water 20ml quench reaction, followed by 20ml of water, the mass percentage concentration of 20percent sodium chloride solution 20ml washing, distillation, add 70ml 75percent ethanol solution to heat the solution, cooling crystallization, filtration, washing, drying to obtain 1-(3- Pyridinesulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde 15.12 g.Yield 86.60percent.
68% With lithium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 1.08 h; 200 mg of intermediate VI-1 was dissolved in 15 ml of anhydrous tetrahydrofuran, and the temperature was lowered to 0 ° C, then 1.3 ml of 1 M bistrimethylsilylamide lithium was added dropwise, and the reaction was continued at 0 ° C after the addition was completed. After a minute, 213 mg of pyridine-3-sulfonyl chloride was further added, followed by incubation at 0 ° C for 5 minutes, and then the reaction was continued to room temperature for 1 hour. After completion of the reaction, the reaction was quenched by the addition of sodium hydrogen carbonate solution, and the mixture was evaporated to dryness. column chromatography to give the compound of formula VII-1, 237 mg of a white solid, yield 68percent
15.5 g With dmap; N-ethyl-N,N-diisopropylamine In acetonitrile at 40 - 50℃; for 2 h; Acetonitrile (50 ml) was added to the reaction flask at room temperature,5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde (10 g)4-dimethylaminopyridine (1.3 g)And N, N-diisopropylethylamine (13 g),40 ~ 50 stirring reaction 2 hours after the thin layer chromatography to complete the reaction.Adding 1mol / L hydrochloric acid solution to the reaction system to adjust pH = 4 ~ 5,Add water (60ml) and stir.filter,dry,To give 5- (2-fluorophenyl) -1 - [(pyridin-3-yl) sulfonyl] -1H-pyrrole-3-carbaldehyde(15.5 g, yellow solid).
15 g With triethylamine In acetonitrile at 45℃; for 1.5 h; 5- (2-fluorophenyl) pyrrole-3-carbaldehyde 10g, 4- dimethylaminopyridine 1.3g, triethylamine 7.5g and acetonitrile (40ml) added to the reaction flask, stirred at room temperature; pyridine-3-sulfonyl chloride 11.3g and acetonitrile (10ml), the reaction flask was added dropwise; the reaction was heated to 45 1.5 hours; cooled to 25 , was added water (30ml); the system with concentrated hydrochloric acid adjusted to ph 4-5, stirred for half an hour at 25 deg.] C; was cooled to 0-5 deg.] C stirred for 1 hour; the filter cake with acetonitrile: water (1: 2) 30ml rinsed again with water (20ml) was rinsed 2 times, 50 deg.] C and dried in vacuo to give 5- (2-fluorophenyl yl) -1- (pyridin-3-sulfonyl) pyrrole-3-carbaldehyde 15g;

Reference: [1] Patent: CN106478601, 2017, A, . Location in patent: Paragraph 0036; 0037
[2] Patent: EP2963019, 2016, A1, . Location in patent: Paragraph 0142; 0146
[3] Patent: CN107586288, 2018, A, . Location in patent: Paragraph 0035-0037
[4] Patent: US2018/186736, 2018, A1, . Location in patent: Paragraph 0142; 0143
[5] Patent: US2011/306769, 2011, A1, . Location in patent: Page/Page column 28-29
[6] Patent: CN107778286, 2018, A, . Location in patent: Paragraph 0057-0058
[7] Journal of Medicinal Chemistry, 2012, vol. 55, # 9, p. 4446 - 4456
[8] Patent: CN108558831, 2018, A, . Location in patent: Paragraph 0166-0169
[9] Patent: CN106478597, 2017, A, . Location in patent: Paragraph 0029; 0030; 0031; 0032
[10] Patent: CN104860926, 2017, B, . Location in patent: Paragraph 0058-0061
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YieldReaction ConditionsOperation in experiment
82%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 10 - 35℃; for 0.5 h;
Stage #2: With 15-crown-5 In tetrahydrofuran; mineral oil for 0.5 h;
Stage #3: for 3 h;
Reference Example 245
5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde
To a solution (96 mL) of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (475 mg) in tetrahydrofuran was added sodium hydride (60percent in oil, 503 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (2.77 g) was added dropwise and the mixture was stirred for 30 min, pyridine-3-sulfonyl chloride hydrochloride (1.35 g) was added, and the mixture was further stirred for 3 hr.
Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→2:3), and crystallized from diisopropyl ether-ethyl acetate (4:1) to give the title compound as colorless crystals (yield 680 mg, 82percent).
1H-NMR (CDCl3)δ: 6.68 (1H, d, J=1.8 Hz), 6.99-7.05 (1H, m), 7.16-7.19 (2H, m), 7.35-7.39 (1H, m), 7.45-7.51 (1H, m), 7.69-7.73 (1H, m), 8.14 (1H, d, J=1.8 Hz), 8.58-8.59 (1H, m), 8.81-8.83 (1H, m), 9.91 (1H, s).
78%
Stage #1: With dmap; N-ethyl-N,N-diisopropylamine In acetonitrile at 45℃; for 5 h;
Stage #2: With hydrogenchloride In water; acetonitrile at 10 - 20℃; for 1.5 h;
A total of 0.5g, 4-dimethylaminopyridine 90mg, 5ml acetonitrile, take N, N-diisopropylethylamine1.5g with a small amount of acetonitrile dissolved in the above reaction bottle, take pyridine-3-sulfonyl chloride hydrochloride 1.1g, with 5mlAcetonitrile dissolved into the reaction flask, heated to 45 ° C stirring reaction 5h after cooling to room temperature, adding 5ml of water,The pH was adjusted to 5 with 0.5 N hydrochloric acid solution, and 20 ml of water was slowly added dropwise (at this time, a large amount of white solid precipitated)Stirring at room temperature for 0.5h, cooling to below 10 , stirring 1h, filtration, filter cake with a small amount of acetonitrile and water mixtureWashing, 50 ° C drying was V total of 0.69g, yield 78percent.
Reference: [1] Patent: WO2006/36024, 2006, A1, . Location in patent: Page/Page column 219-220; 295
[2] Patent: EP2336107, 2015, B1, . Location in patent: Paragraph 0419
[3] Patent: CN105440019, 2016, A, . Location in patent: Paragraph 0044; 0045
[4] Patent: EP1803709, 2007, A1,
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Reference: [1] Patent: CN106397404, 2017, A,
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YieldReaction ConditionsOperation in experiment
38.6% With water; hydrogen; acetic acid In tetrahydrofuran at 45 - 50℃; for 5 h; Example 52
[2-(2-Fluorophenyl)-2-oxoethyl]propanedinitrile (2.00 g, 9.89 mmol), acetic acid (22 ml) and THF (22 ml) were weighed and dissolved (under an argon atmosphere).
Then, Raney-nickel (1 ml) and water (2 ml) were weighed and added, and the mixture was purged with hydrogen.
This was reacted at 45-50° C. for about 5 hr.
Quantification of the filtrate by HPLC gave 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (718 mg, yield 38.6percent) and 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (277 mg, yield 14.8percent).
Reference: [1] Patent: US2011/306769, 2011, A1, . Location in patent: Page/Page column 39
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